CN105085429B - Aromatic heterocyclic derivative and application thereof in medicines - Google Patents

Abstract

The present invention provides a class of aromatic heterocyclic compounds or their stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs , and pharmaceutical compositions containing compounds of the invention. The invention also discloses the use of the compound of the invention or its pharmaceutical composition in the preparation of medicine for treating respiratory diseases, especially chronic obstructive pulmonary disease (COPD).

Description

Aromatic heterocyclic derivatives and their application in medicine

technical field

The invention belongs to the field of medicine, and in particular relates to a class of aromatic heterocyclic compounds, a composition containing the compound and its use and application method. In particular, the compounds described in the present invention are PDE 4 inhibitors for the treatment of chronic obstructive pulmonary disease (COPD).

Background technique

Cyclic nucleotide phosphodiesterases (PDEs) are an important super-enzyme family, which can effectively control the concentration of cAMP and cGMP in cells by hydrolyzing cAMP and cGMP, thereby regulating the transmission of second messengers in vivo biochemical effect. PDEs are widely distributed in mammalian tissues, and their diversity leads to specific distribution of different PDE enzymes at the cellular and subcellular levels, which can selectively regulate a variety of cellular functions, and are good drug design and therapeutic targets.

Phosphodiesterase 4 (PDE4) has been shown to be a master regulator of cyclic AMP in airway smooth muscle and inflammatory cells. Inhibitors of PDE4 are useful in the treatment of a variety of diseases, including allergic and inflammatory diseases, diabetes, central nervous system disorders, pain, and TNF-producing viruses.

Cyclic adenosine-3',5'-monophosphate (cAMP) is known to act as an important intracellular secondary messenger (Sutherland and Roll, Pharmacol. Rev, 1960, 12:265). Intracellular hydrolysis of cAMP to adenosine 5'-monophosphate (AMP) contributes to many inflammatory conditions including but not limited to psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, and ulcerative colitis. Cyclic nucleotide phosphodiesterases (PDEs), a biochemically and functionally highly variable superfamily of enzymes, are important factors controlling cAMP (and cGMP) levels. Eleven distinct families of phosphodiesterases with more than 25 gene products. Although PDE1, PDE2, PDE3, PDE4, and PDE7 all use cAMP as a substrate, only the PDE4 and PDE7 types are highly selective for cAMP hydrolysis. Therefore, PDE inhibitors, especially PDE4 inhibitors (eg rolipram or Ro-1724) are considered to be cAMP enhancers. Immune cells contain PDE3 and PDE4, with PDE4 ubiquitously present in human monocytes. Inhibition of type IV phosphodiesterases is therefore a target for modulation for therapeutic intervention in various disease processes. Studies have shown that administration of PDE4 inhibitors has the effect of restoring memory loss in animal models (including those of Alzheimer's disease) (Expert Opin Ther. Targets, 2005, 9(6): 1283-1305; Drug Discovery Today, 2005, 10(22):1503-19).

The initial observation that xanthine derivatives, theophylline and caffeine inhibit cAMP hydrolysis led to the discovery of the hydrolytic activity required for cyclic nucleotide phosphodiesterases (PDEs). Recently, various types of PDEs have been identified (Beavo and Reifsnyder, Trends Pharmacol. Sci., 1990, 11:150), whose selective inhibition improves drug therapy (Nicholus, Challiss and Shahid, Trends Pharmacol. Sci., 1991 , 12:19). Therefore, it has been recognized that inhibition of PDE4 can inhibit the release of inflammatory mediators (Verghese et al., J. Mol. Cell. Cardiol., 1989, 12(Suppl II): S 61).

WO 2004046095 discloses certain arylthiourea derivatives and related compounds having antiviral activity. WO 00/35891 discloses certain morpholinones and morpholinone derivatives useful as selective antagonists of the human alpha _la receptor. WO 200450024 discloses 3-aminopyrrolidine derivatives and their use as modulators of chemokine receptors. WO 2005/21515 relates to isoxazoline derivatives which act as selective inhibitors of type IV phosphodiesterase (PDE). WO2005/051931 discloses type IV phosphodiesterase inhibitors.

Summary of the invention

The present invention relates to novel aromatic heterocyclic derivatives and a method for treating chronic respiratory obstruction. The compound of the present invention or the pharmaceutical composition containing the compound has better affinity to PDE4, especially has better therapeutic effect on chronic respiratory obstruction.

In one aspect, the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrated Compounds, solvates, metabolites, pharmaceutically acceptable salts or prodrugs:

in:

m is 0, 1, 2, 3 or 4;

p is 0, 1 or 2;

each e is independently 0, 1 or 2;

each f is independently 0, 1 or 2;

X is -N(R ⁸ )-, -O- or -S-;

Y is O or S;

A is a bond or -N(R ⁷ )-;

B is -(CR ^a R ^b ) _p -;

R ¹ is D, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _2-10 heterocyclyl, halogenated C _1-6 alkyl , R ^9a R ⁹ NC _1-6 alkyl-, C _1-6 alkyl-C(=O)-, -C(=O)OR ^9c , -C(=O)-NR ⁹ R ^9a , R ⁹ R ^9a NS(=O) ₂ -, R ^9d -S(=O) ₂ -, R ^9d -S(=O)-C _1-6 alkyl-, R ⁹ R ^9a NC(=O)-C _{1 -6} alkyl-, C _6-10 aryl, C _1-9 heteroaryl, C _3-8 cycloalkyl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl, C _6-10 aryl C _1-6 alkyl or C _1-9 heteroaryl C _1-6 alkyl;

Each R ² is independently H, D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , -S(=O) ₂ Cl, R ^9a R ⁹ N-, -C(=O) -R ^9d , -C(=O)-NR ⁹ R ^9a , -OC(=O)-NR ⁹ R ^9a , -OC(=O)OR ^9c , -N(R ⁹ )-C(=O)- NR ⁹ R ^9a , -N(R ⁹ )-C(=O)OR ^9c , R ^9d -S(=O) ₂ -, R ^9d -S(=O) ₂ -N(R ^9a )-, HOC( =O)-C _1-6 alkoxy-, C _1-6 alkoxy-(CH ₂ ) _e -C(=O)-C _1-6 alkoxy-, C _2-10 heterocyclyl- NH-C _1-6 alkoxy-, C _2-10 heterocyclyl-(CH ₂ ) _e -OC(=O)-C _1-6 alkoxy-, C _2-10 heterocyclyl-(CH ₂ ) _e -NH-C(=O)-C _1-6 alkoxy-, C _3-8 cycloalkyl-(CH ₂ ) _e -NH-C(=O)-C _1-6 alkoxy -, C _6-10 aryl-(CR ^c R ^d ) _f -NH-C _1-6 alkoxy-, C _1-6 alkyl-NH-C(=O)-C _1-6 alkoxy -, R ^e R ^f NC(=O)-C _1-6 alkoxy-, C _1-9 heteroaryl-C _2-10 heterocyclyl-C(=O)-C _1-6 alkoxy -, C _3-8 cycloalkyl-C(=O)-C _2-10 heterocyclyl-C(=O)-C _1-6 alkoxy-, NH ₂ -C(=O)-C _{1 -6} alkoxy-, C _1-6 alkyl-OC(=O)-(CR ^c R ^d ) _f -NH-C(=O)-C _1-6 alkoxy-, NH ₂ -NH- C(=O)-C _1-6 alkoxy-, NH ₂ -C(=O)-(CR ^c R ^d ) _f -NH-C(=O)-C _1-6 alkoxy-, C _1-6 Alkyl-S(=O) ₂ -NH-C(=O)-C _1-6 Alkoxy-, C _1-6 Alkyl-OC(=O)-C _1-6 Alkoxy -, NH ₂ -S(=O) ₂ -NH-C(=O)-C _1-6 alkoxy-, C _2-10 heterocyclyl-C(=O)-C _1-6 alkoxy -, C _6-10 aryl, C _1-9 heteroaryl, C _1-6 alkoxy, amino-substituted C _1-6 alkoxy, halogenated C _1-6 alkoxy, C _1-6 Alkylamino, C _3-8 cycloalkyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _2-10 heterocyclyloxy, C _6-10 aryl C _1-6 alkoxy , C _3-8 cycloalkyloxy or C _3-8 cycloalkylC _1-6 alkoxy; each R ² is independently optionally replaced by one or more R ¹² replaced;

R ³ is D, F, Cl, Br, I, CN, NO ₂ , NH ₂ , OH, COOH, C _1-6 alkylamino, NH ₂ -C _1-6 alkyl-C _1-9 heteroaryl- , NH ₂ -C _1-6 alkyl-C _1-9 heteroaryl-C _1-6 alkyl-, NH ₂ -C _1-6 alkyl-C _6-10 aryl-, NH ₂ -C _{1 -6} alkyl-C _6-10 aryl-C _1-6 alkyl-, C _1-6 alkyl-C(=O)-NH-, R ¹³ OC(=O)-C _1-6 alkyl -C(=O)-NH-, C _3-8 cycloalkyl-C(=O)-NH- or -C(=O)-NR ⁹ R ^9a ;

Each R ⁵ and R ⁶ is independently H, D, F, Cl, Br, I, CN, NO ₂ , NH ₂ , OH, COOH, C _1-6 alkyl, halogenated C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkylamino, C _1-6 alkoxy, halogenated C _1-6 alkoxy, hydroxy substituted C _1-6 alkyl, mercapto substituted C _1-6 alkyl, carboxyl substituted C _1-6 alkyl, NH ₂ -C _1-6 alkyl-C _1-9 heteroaryl-, NH ₂ -C _1-6 alkyl-C _{1- 9} heteroaryl-C _1-6 alkyl-, NH ₂ -C _1-6 alkyl-C _6-10 aryl-, NH ₂ -C _1-6 alkyl-C _6-10 aryl-C _{1 -6} alkyl-, C _3-6 cycloalkyl, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _3-8 cycloalkyl-C (=O)-NH-, -C(=O)-NR ⁹ R ^9a , C _6-10 aryl or C _1-9 heteroaryl;

Or optionally any two of R ³ , R ⁵ and R ⁶ together with the C atoms they are connected to form C=O;

R ⁴ is C _6-10 aryl, C _6-10 aryl-S(=O) ₂ -, C _1-9 heteroaryl, C _1-9 heteroaryl-S(=O) ₂ -, C _6-10 aryl C _1-6 alkyl or C _1-9 heteroaryl C _1-6 alkyl; R ⁴ is optionally substituted by one or more R ¹⁴ ;

each R ⁷ and R ⁸ is independently H, D or C _1-6 alkyl;

Each of R ^a and R ^b is independently H, D, F, Cl, Br, I, CN, OH, NO ₂ , NH ₂ , -COOR ^9c , C _1-6 alkyl, -C(=O)-NR ⁹ R ^9a , -C _1-6 alkyl-C(=O)-NR ⁹ R ^9a , -C(=S)-NH ₂ , amino-substituted C _1-6 alkyl, -NH-C(=O )-R ^9b , -C _1-6 alkyl-NH-C(=O)-R ^9b ,-NH-S(=O) ₂ -C _1-6 alkyl,-C _1-6 alkyl-NH -S(=O) ₂ -C _1-6 alkyl, -NH-S(=O) ₂ -C _3-8 cycloalkyl, -C _1-6 alkyl-NH-S(=O) ₂ - C _3-8 cycloalkyl, -S(=O) ₂ -C _1-6 alkyl, -C _1-6 alkyl-S(=O) ₂ -C _1-6 alkyl, C _6-10 aromatic or C _1-9 heteroaryl; or R ^a , R ^b and the carbon atoms connected to it together form a ring consisting of 3-8 atoms;

each R and R ^is independently H, OH, CN, F, Cl, Br, I or ^C _1-6 alkyl;

Each R ^e and R ^f is independently H, OH or C _1-6 alkyl;

Each of R ⁹ , R ^9a , R ^9b and R ^9d is independently H, D, OH, NH ₂ , -S(=O) ₂ -NH ₂ , -C(=O)-NH ₂ , -C _1-6 Alkyl-C(=O)-NH ₂ ,-C _1-6Alkyl -C(=O)OC _1-6Alkyl ,-C _1-6Alkyl -OC(=O)-C _1-6 Alkyl, C _1-6 alkyl, -S(=O) ₂ -C _1-6 alkyl, -S(=O) ₂ -C _3-8 cycloalkyl, halogenated C _1-6 alkyl, Amino-substituted C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _6-10 aryl, C _2-10 heterocyclyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl C _1-6 alkylamino, C _3-8 cycloalkyl C _1-6 alkyl, C _6-10 aryl C _1-6 alkyl, C _6-10 aryloxy, C _2-10 heterocyclyloxy, C _3-8 cycloalkyloxy, C _6-10 arylamino, C _2-10 heterocyclylamino, C _3-8 cycloalkylamino, C _1-9 heteroaryl or C _3-8 carbocyclic group; or R ⁹ , R ^9a and the nitrogen atom connected to it together form a ring composed of 3-8 atoms; the ring composed of 3-8 atoms, R ⁹ , R ^9a , R ^9b and R ^9d are each independently optionally substituted by one or more R ¹⁵ ;

Each R ^9c is independently H, D, -C _1-6 alkyl-C(=O)-NH ₂ , -C _1-6 alkyl-C(=O)OC _1-6 alkyl, -C _{1 -6} alkyl-OC(=O)-C _1-6 alkyl, C _1-6 alkyl, halogenated C _1-6 alkyl, amino-substituted C _1-6 alkyl, C _6-10 aryl , C _1-9 heteroaryl, C _3-8 cycloalkyl, C _2-10 heterocyclyl, C _3-8 cycloalkyl C _1-6 alkyl, C _6-10 aryl C _1-6 alkane Base or C _3-8 carbocyclyl;

Each R ¹² is independently D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, Halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, halogenated C _1-6 alkylamino, hydroxy substituted C _1-6 alkyl, hydroxy substituted C _1-6 alkoxy or hydroxy Substituted C _1-6 alkylamino;

R ¹³ is H, D or C _1-6 alkyl;

Each R ¹⁴ is independently D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH, -C(=O)-NH ₂ , -C _1-6 alkyl-C(=O )-NH ₂ ,-C _1-6 alkyl-C(=O)OC _1-6 alkyl,-C _1-6 alkyl-OC(=O)-C _1-6 alkyl,C _1-6 Alkyl, C _1-6 alkoxy, C _1-6 alkylamino, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, halogenated C _1-6 alkylamino, hydroxy substituted C _1-6 alkyl, hydroxy substituted C _1-6 alkoxy, hydroxy substituted C _1-6 alkylamino or C _3-6 cycloalkyl;

Each R ¹⁵ is independently D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH, C _1-6 alkyl, C _6-10 aryl, C _1-9 heteroaryl, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl C _1-6 alkyl, C _2-10 heterocyclyl, C _2-10 heterocyclyl C _1-6 alkyl, C _3-8 cycloalkylcarbonyl, C _2-10 heterocyclylcarbonyl, C _6-10 arylcarbonyl or C _{1- 9} heteroarylcarbonyl; and

The R ¹ , R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ^9c , R ^a , R ^b , R ^c , R ^d , R ^e , R ^f , R ¹² , R ¹³ , R ¹⁴ and Each R ¹⁵ is independently optionally substituted by one or more R; wherein each R is independently H, D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH, C _1-6 alkane group or C _1-6 alkoxy group.

Some of these embodiments are, R ¹ is D, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, C _2-6 heterocyclyl, C _{2 -6} heterocyclyl C _1-4 alkyl, halogenated C _1-4 alkyl, -C(=O)-C _1-4 alkyl, -C(=O)OR ^9c , -C(=O) -NR ⁹ R ^9a , R ⁹ R ^9a NC(=O)-C _1-4 alkyl-, C _6-10 aryl, C _6-10 aryl C _1-4 alkyl, C _1-9 heteroaryl Group or C _3-6 cycloalkyl C _1-4 alkyl.

In some embodiments, each R ² is independently H, D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , HOC(=O)-C _1-6 alkoxy-, C _1-4 alkoxy-(CH ₂ ) _e -C(=O)-C _1-6 alkoxy-, C _2-6 heterocyclyl-NH-C _1-6 alkoxy-, C _{2- 6} Heterocyclyl-(CH ₂ ) _e -OC(=O)-C _1-6 Alkoxy-, C _2-6 Heterocyclyl-(CH ₂ ) _e -NH-C(=O)-C _{1 -6} alkoxy-, C _3-6 cycloalkyl-(CH ₂ ) _e -NH-C(=O)-C _1-6 alkoxy-, C _6-10 aryl-(CR ^c R ^d ) _f -NH-C _1-6 alkoxy-, C _1-4 alkyl-NH-C (=O)-C _1-6 alkoxy-, R ^e R ^f NC (= O)-C _{1 -6} alkoxy-, C _1-5 heteroaryl-C _2-6 heterocyclyl-C(=O)-C _1-6 alkoxy-, C _3-6 cycloalkyl-C(=O )-C _2-6 heterocyclyl-C(=O)-C _1-6 alkoxy-, NH ₂ -C(=O)-C _1-6 alkoxy-, C _1-6 alkyl- OC(=O)-(CR ^c R ^d ) _f -NH-C(=O)-C _1-6 alkoxy-, NH ₂ -NH-C(=O)-C _1-6 alkoxy- , NH ₂ -C(=O)-(CR ^c R ^d ) _f -NH-C(=O)-C _1-6 alkoxy-, C _1-4 alkyl-S(=O) ₂ -NH -C(=O)-C _1-6 alkoxy-, C _1-4 alkyl-OC(=O)-C _1-6 alkoxy-, NH ₂ -S(=O) ₂ -NH- C(=O)-C _1-6 alkoxy-, C _2-6 heterocyclyl-C(=O)-C _1-6 alkoxy-, C _6-10 aryl, C _1-5 heterocyclyl Aryl, C _1-6 alkoxy, C _{1-6 alkoxy substituted by amino, halogenated C 1-6 alkoxy} , C _1-4 alkylamino, C _3-6 cycloalkyl, C _{1- 4} alkyl, halogenated C _1-4 alkyl, C _2-6 heterocyclyloxy, C _6-10 aryl C _1-4 alkoxy, C _3-6 cycloalkyloxy or C _{3- 6} CycloalkylC _1-4 alkoxy; Each R ² is independently optionally substituted by one or more R ¹² ;

each R and R ^is independently H, OH, CN, F, Cl, Br, I or ^C _1-4 alkyl;

each R ^e and R ^f is independently H, OH or C _1-4 alkyl; and

Each R ¹² is independently D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, Halogenated C _1-4 alkyl, halogenated C _1-4 alkoxy, halogenated C _1-4 alkylamino, hydroxy substituted C _1-4 alkyl, hydroxy substituted C _1-4 alkoxy or hydroxy Substituted C _1-4 alkylamino.

In some embodiments, R ³ is D, F, Cl, Br, I, CN, NO ₂ , NH ₂ , OH, COOH, C _1-4 alkylamino, NH ₂ -C _1-4 alkyl-C _{1 -5} heteroaryl-, NH ₂ -C _1-4 alkyl-C _1-5 heteroaryl-C _1-4 alkyl-, NH ₂ -C _1-4 alkyl-C _6-10 aryl- , NH ₂ -C _1-4 alkyl-C _6-10 aryl-C _1-4 alkyl-, C _1-4 alkyl-C(=O)-NH-, R ¹³ OC(=O)- C _1-4 alkyl-C(=O)-NH-, C _3-6 cycloalkyl-C(=O)-NH- or -C(=O)-NR ⁹ R ^9a ;

Each R ⁵ and R ⁶ is independently H, D, F, Cl, Br, I, CN, NO ₂ , NH ₂ , OH, COOH, C _1-4 alkyl, halogenated C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkylamino, C _1-4 alkoxy, halogenated C _1-4 alkoxy, hydroxy substituted C _1-4 alkyl, mercapto substituted C _1-4 alkyl, carboxyl substituted C _1-4 alkyl, NH ₂ -C _1-4 alkyl-C _1-5 heteroaryl-, NH ₂ -C _1-4 alkyl-C _{1- 5} heteroaryl-C _1-4 alkyl-, NH ₂ -C _1-4 alkyl-C _6-10 aryl-, NH ₂ -C _1-4 alkyl-C _6-10 aryl-C _{1 -4} alkyl-, C _3-6 cycloalkyl, C _6-10 aryl C _1-4 alkyl, C _3-6 cycloalkyl-C(=O)-NH-,-C(=O) -NR ⁹ R ^9a , C _6-10 aryl or C _1-5 heteroaryl;

Or optionally any two of R ³ , R ⁵ and R ⁶ together with the C atoms they are connected to form C=O;

each R ⁷ and R ⁸ is independently H, D or C _1-4 alkyl; and

R ¹³ is H, D or C _1-4 alkyl.

Some of the embodiments are that the present invention relates to a compound, which is a compound represented by formula (I') or a stereoisomer, a geometric isomer, a tautomer of a compound represented by formula (I'), Nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs:

in:

X, R ₁ , R ₂ , R ₄ , R ₅ , R ₆ , R ₇ , R _a , R _b and p have the meanings described in the present invention;

R ¹¹ is H, C _1-4 alkyl, C _1-4 alkyl-C(=O)-, R ¹³ OC(=O)-C _1-4 alkyl-C(=O)- or C _{3 -6cycloalkyl} -C(=O)-.

Some of the embodiments are that the present invention relates to a compound, which is a compound represented by formula (II) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide Compounds, Hydrates, Solvates, Metabolites, Pharmaceutically Acceptable Salts or Prodrugs:

in:

X, R ₁ , R ₂ , R ₄ , R ₅ , R ₆ , R _a and R _b have the meanings described in the present invention;

m is 0, 1, 2 or 3;

R ¹⁰ is H, HOC(=O)-C _1-6 alkyl-, C _1-6 alkoxy-(CH ₂ ) _e -C(=O)-C _1-6 alkyl-, C _{2- 10} Heterocyclyl-NH-C _1-6 Alkyl-, C _2-10 Heterocyclyl-(CH ₂ ) _e -OC(=O)-C _1-6 Alkyl-, C _2-10 Heterocyclyl -(CH ₂ ) _e -NH-C(=O)-C _1-6 alkyl-, C _3-8 cycloalkyl-(CH ₂ ) _e -NH-C(=O)-C _1-6 alkane Base-, C _6-10 aryl-(CR ^c R ^d ) _f -NH-C _1-6 alkyl-, C _1-6 alkyl-NH-C(=O)-C _1-6 alkyl- , R ^e R ^f NC(=O)-C _1-6 alkyl-, C _1-9 heteroaryl-C _2-10 heterocyclyl-C(=O)-C _1-6 alkyl-, C _3-8 Cycloalkyl-C(=O)-C _2-10 Heterocyclyl-C(=O)-C _1-6 Alkyl-, NH ₂ -C(=O)-C _1-6 Alkyl -, C _1-6 alkyl-OC(=O)-(CR ^c R ^d ) _f -NH-C(=O)-C _1-6 alkyl-, NH ₂ -NH-C(=O)- C _1-6 alkyl-, NH ₂ -C(=O)-(CR ^c R ^d ) _f -NH-C(=O)-C _1-6 alkyl-, C _1-6 alkyl-S( =O) ₂ -NH-C(=O)-C _1-6 alkyl-, C _1-6 alkyl-OC(=O)-C _1-6 alkyl-, NH ₂ -S(=O) ₂ -NH-C(=O)-C _1-6 alkyl-, C _2-10 heterocyclyl-C(=O)-C _1-6 alkyl-, amino-substituted C _1-6 alkyl, Halogenated C _1-6 alkyl, C _1-6 alkyl, C _2-10 heterocyclyl, C _6-10 aryl C _1-6 alkyl, C _3-8 cycloalkyl or C _3-8 ring Alkyl C _1-6 alkyl; R ¹⁰ is optionally substituted by one or more R ¹² ; and

R ¹¹ is H, C _1-4 alkyl, C _1-4 alkyl-C(=O)-, R ¹³ OC(=O)-C _1-4 alkyl-C(=O)- or C _{3 -6cycloalkyl} -C(=O)-.

In some embodiments, the pharmaceutically acceptable salt is hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, maleate, succinate, mandelate, fumarate Malonate, Malonate, Malate, 2-Hydroxypropionate, Pyruvate, Oxalate, Glycolate, Salicylate, Glucuronate, Galacturonate, Citrate salt, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, triflate Sulfonates or combinations thereof.

^In some embodiments, R is methyl, ethyl, propyl, isopropyl, halomethyl, haloethyl, halopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclo Hexyl, oxetanyl, oxetanylmethyl, oxetanylethyl, tetrahydrofuryl, tetrahydrofurylmethyl, tetrahydrofurylethyl, phenyl, benzyl, phenethyl, cyclopropylmethyl , cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl or cyclohexylethyl.

_In some embodiments, each R2 is independently H, D, F, Cl, Br, I, CN, _NO2 , OH, ^NH2 , methoxy, ethoxy, propoxy, isopropoxy , butoxy, isobutyloxy, tert-butyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy, cyclopropyl Ethoxy, cyclobutylmethoxy, cyclobutylethoxy, cyclopentylmethoxy, cyclopentylethoxy, cyclohexylmethoxy, cyclohexylethoxy, oxetanyloxy, Tetrahydrofuryloxy, benzyloxy, phenylethoxy, HOC(=O)-C _1-6 alkoxy-, C _1-3 alkoxy-(CH ₂ ) _e -C(=O)- C _1-6 alkoxy-, C _1-4 alkyl-OC(=O)-C _1-6 alkoxy-, C _2-4 heterocyclyl-(CH ₂ ) _e -OC(=O) -C _1-6 alkoxy-, C _2-4 heterocyclyl-C (=O)-C _1-6 alkoxy-, C _1-4 heteroaryl-C _2-4 heterocyclyl-C (=O)-C _1-6 alkoxy-, C _3-6 cycloalkyl-C(=O)-C _2-4 heterocyclyl-C(=O)-C _1-6 alkoxy- , NH ₂ -C(=O)-C _1-6 alkoxy-, NH ₂ -NH-C(=O)-C _1-6 alkoxy-, NH ₂ -C(=O)-(CR ^c R ^d ) _f -NH-C(=O)-C _1-6 alkoxy-, R ^e R ^f NC(=O)-C _1-6 alkoxy-, C _1-4 alkyl-OC (=O)-(CR ^c R ^d ) _f -NH-C(=O)-C _1-6 alkoxy-, NH ₂ -S(=O) ₂ -NH-C(=O)-C _{1 -6} alkoxy-, C _1-3 alkyl-S(=O) ₂ -NH-C(=O)-C _1-6 alkoxy-, C _3-6 cycloalkyl-(CH ₂ ) _e -NH-C(=O)-C _1-6 alkoxy-, C _2-4 heterocyclyl-(CH ₂ ) _e -NH-C(=O)-C _1-6 alkoxy-, Amino-substituted C _1-6 alkoxy, C _2-4 heterocyclyl-NH-C _1-6 alkoxy- or phenyl-(CR ^c R ^d ) _f -NH-C _1-6 alkoxy -; each R ² is independently optionally substituted by one or more R ¹² ;

each R and R ^is independently H, OH, CN, F, Cl, Br, I or ^C _1-3 alkyl;

each R ^e and R ^f is independently H, OH or C _1-3 alkyl; and

Each R ¹² is independently D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, hydroxy Substituted methyl or halomethyl.

^In some embodiments, each ^R5 and R6 is independently H, D, F, Cl, Br, I, _NH2 , methyl, ethyl, propyl, isopropyl, hydroxy-substituted methyl, benzene base, benzyl or phenethyl.

In some embodiments, R ⁴ is C _6-10 aryl, C _6-10 aryl-S(=O) ₂ -, C _1-9 heteroaryl, C _1-9 heteroaryl-S(= O) _2- , C _6-10 aryl C _1-4 alkyl or C _1-9 heteroaryl C _1-4 alkyl; R ⁴ is optionally substituted by one or more R ¹⁴ ; and

Each R ¹⁴ is independently D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH, -C(=O)-NH ₂ , -C _1-4 alkyl-C(=O )-NH ₂ ,-C _1-4 alkyl-C(=O)OC _1-4 alkyl,-C _1-4 alkyl-OC(=O)-C _1-4 alkyl,C _1-4 Alkyl, C _1-4 alkoxy, C _1-4 alkylamino, halogenated C _1-4 alkyl, halogenated C _1-4 alkoxy, halogenated C _1-4 alkylamino, hydroxy substituted C _1-4 alkyl, C _1-4 alkoxy substituted by hydroxy, C _1-4 alkylamino substituted by hydroxy or C _3-6 cycloalkyl.

Other embodiments are that ^R is phenyl, naphthyl, thiazolyl, thienyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, oxadiazolyl, pyridyl , N-oxypyridin-2-yl, N-oxypyridin-4-yl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl, furo[3,2 -c]pyridyl, furo[3,2-b]pyridyl, furo[2,3-b]pyridyl, furo[2,3-c]pyridyl, benzoxadiazolyl, ind Indolyl, isoindolyl, indazolyl, benzimidazolyl, benzopyrazinyl, benzofuryl, pyridopyrazinyl, 3,4-dihydro-pyridine[3,2-b][ 1,4]oxazinyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuryl, thieno[3,2-b]pyridyl, thieno[2,3- c] pyridyl, thieno[2,3-b]pyridyl, 1,4-benzodioxanyl, 1,2,3,4-tetrahydroquinolin-2-yl or benzenesulfonyl; R ⁴ is optionally substituted with one or more R ¹⁴ ; and

Each R ¹⁴ is independently D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH, -C(=O)-NH ₂ , -C _1-3 alkyl-C(=O )-NH ₂ ,-C _1-3 alkyl-C(=O)OC _1-4 alkyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, methoxy, ethoxy, methylamino or ethylamino.

In some embodiments, each R ^a and R ^b is independently H, D, F, Cl, Br, I, CN, OH, NO ₂ , NH ₂ , -COOR ^9c , C _1-4 alkyl, -C (=O)-NR ⁹ R ^9a ,-C _1-4 alkyl-C(=O)-NR ⁹ R ^9a ,-C(=S)-NH ₂ , amino-substituted C _1-4 alkyl,- NH-C(=O)-R ^9b ,-C _1-4 alkyl-NH-C(=O)-R ^9b ,-NH-S(=O) ₂ -C _1-4 alkyl,-C _{1 -4} Alkyl-NH-S(=O) ₂ -C _1-4 Alkyl, -NH-S(=O) ₂ -C _3-6 Cycloalkyl, -C _1-4 Alkyl-NH-S (=O) ₂ -C _3-6 cycloalkyl, -S(=O) ₂ -C _1-4 alkyl, -C _1-4 alkyl-S(=O) ₂ -C _1-4 alkyl , C _6-10 aryl or C _1-5 heteroaryl; or R ^a , R ^b and the carbon atom connected to it together form a ring consisting of 3-6 atoms;

Each of R ⁹ , R ^9a and R ^9b is independently H, D, OH, NH ₂ , -S(=O) ₂ -NH ₂ , -C(=O)-NH ₂ , -C _1-4 alkyl- C(=O)-NH ₂ , -C _1-4 alkyl-C(=O)OC _1-6 alkyl, -C _1-4 alkyl-OC(=O)-C _1-6 alkyl, C _1-4 alkyl, -S(=O) ₂ -C _1-4 alkyl, -S(=O) ₂ -C _3-6 cycloalkyl, halogenated C _1-4 alkyl, amino substituted C _1-4 alkyl, C _1-4 alkoxy, C _1-6 alkylamino, C _6-10 aryl, C _2-6 heterocyclyl, C _3-6 cycloalkyl, C _3-6 Cycloalkyl C _1-4 alkylamino, C _3-6 cycloalkyl C _1-4 alkyl, C _6-10 aryl C _1-4 alkyl, C _6-10 aryloxy, C _2-6 Heterocyclyloxy, C _3-6 cycloalkyloxy, C _6-10 arylamino, C _2-6 heterocyclylamino, C _3-6 cycloalkylamino, C _1-5 heteroaryl or C _3-6 carbocyclyl; or R ⁹ , R ^9a and the nitrogen atom connected to it together form a ring composed of 3-6 atoms; the ring composed of 3-6 atoms, R ⁹ , R ^9a and R ^9b each independently optionally substituted by one or more R ¹⁵ ;

Each R ^9c is independently H, D, -C _1-4 alkyl-C(=O)-NH ₂ , -C _1-4 alkyl-C(=O)OC _1-4 alkyl, -C _{1 -4} alkyl-OC(=O)-C _1-6 alkyl, C _1-5 alkyl, halogenated C _1-4 alkyl, amino-substituted C _1-4 alkyl, C _6-10 aryl , C _1-5 heteroaryl, C _3-6 cycloalkyl, C _2-6 heterocyclyl, C _3-6 cycloalkylC _1-4 alkyl, C _6-10 aryl C _1-4 alkane base or C _3-6 carbocyclyl; and

Each R ¹⁵ is independently D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH, C _1-4 alkyl, C _6-10 aryl, C _1-5 heteroaryl, C _6-10 aryl C _1-4 alkyl, C _1-5 heteroaryl C _1-4 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl C _1-4 alkyl, C _2-6 heterocyclyl, C _2-6 heterocyclyl C _1-4 alkyl, C _3-6 cycloalkylcarbonyl, C _2-6 heterocyclylcarbonyl, C _6-10 arylcarbonyl or C _{1- 5} Heteroarylcarbonyl.

In other embodiments, each R ^a and R ^b is independently H, D, F, Cl, Br, I, CN, OH, NO ₂ , NH ₂ , -COOR ^9c , methyl, ethyl, propyl, Isopropyl, -C(=O)-NR ⁹ R ^9a , -C(=S)-NH ₂ , aminomethyl, aminoethyl, -C _1-3 alkyl-NH-C(=O)- R ^9b , -C _1-3 alkyl-NH-S(=O) ₂ -C _3-6 cycloalkyl, -C _1-3 alkyl-S(=O) ₂ -C _1-3 alkyl, Pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, phenyl, pyridyl or pyrimidinyl; or R ^a , R ^b together with the carbon atom to which it is attached Formation of oxetane or 1,3-dioxolane;

Each of R ⁹ , R ^9a and R ^9b is independently H, D, OH, NH ₂ , -S(=O) ₂ -NH ₂ , -C(=O)-NH ₂ , -C _1-3 alkyl- C(=O)-NH ₂ , -C _1-4 alkyl-C(=O)OC _1-4 alkyl, -C _1-3 alkyl-OC(=O)-C _1-3 alkyl, Methyl, ethyl, propyl, isopropyl, -S(=O) ₂ -C _1-3 alkyl, -S(=O) ₂ -cyclopropyl, -S(=O) ₂ -cyclobutyl radical, -S(=O) ₂ -cyclopentyl, -S(=O) ₂ -cyclohexyl, halogenated C _1-4 alkyl, amino substituted C _1-4 alkyl, methoxy, ethoxy radical, propoxy, isopropoxy, methylamino, dimethylamino, ethylamino, propylamino, isopropylamino, phenyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclo Propylmethylamino, Cyclobutylmethylamino, Cyclopentylmethylamino, Benzyl, Phenethyl, Phenoxy, Cyclopropyloxy, Cyclobutyloxy, Cyclopentyloxy, Anilino, Cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or R ⁹ , R ^9a and the nitrogen atom attached to it together form 3-6 atoms The ring composed of 3-6 atoms is azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, 1-oxo-thiomorpholine or 1, 1-dioxo-thiomorpholine; the ring consisting of 3-6 atoms, R ⁹ , R ^9a and R ^9b are each independently optionally substituted by one or more R ¹⁵ ;

Each R ^9c is independently H, D, -C _1-3 alkyl-C(=O)-NH ₂ , -C _1-3 alkyl-C(=O)OC _1-3 alkyl, -C _{1 -3} alkyl-OC(=O)-C _1-4 alkyl, methyl, ethyl, propyl, isopropyl, halogenated C _1-4 alkyl, amino-substituted C _1-4 alkyl, phenyl, benzyl, phenethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; and

Each R ¹⁵ is independently D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH, methyl, ethyl, propyl, phenyl, pyridyl, pyrimidinyl, thiazolyl, thiophene base, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, oxadiazolyl, benzyl, phenethyl, pyridylmethyl, pyrimidinylmethyl, pyridylethyl , pyrimidinylethyl, benzoyl, cyclopropylcarbonyl, cyclobutylcarbonyl or cyclopentylcarbonyl.

Some other embodiments are that R ¹⁰ is H, HOC(=O)-C _1-6 alkyl-, C _1-4 alkoxy-(CH ₂ ) _e -C(=O)-C _1-6 alkane Base-, C _2-6 heterocyclyl-NH-C _1-6 alkyl-, C _2-6 heterocyclyl-(CH ₂ ) _e -OC(=O)-C _1-6 alkyl-, C _2-6 heterocyclyl-(CH ₂ ) _e -NH-C(=O)-C _1-6 alkyl-, C _3-6 cycloalkyl-(CH ₂ ) _e -NH-C(=O) -C _1-6 alkyl-, C _6-10 aryl-(CR ^c R ^d ) _f -NH-C _1-6 alkyl-, C _1-4 alkyl-NH-C(=O)-C _1-6 alkyl-, R ^e R ^f NC(=O)-C _1-6 alkyl-, C _1-5 heteroaryl-C _2-6 heterocyclyl-C(=O)-C _{1- 6} Alkyl-, C _3-6 Cycloalkyl-C(=O)-C _2-6 Heterocyclyl-C(=O)-C _1-6 Alkyl-, NH ₂ -C(=O)- C _1-6 alkyl-, C _1-6 alkyl-OC(=O)-(CR ^c R ^d ) _f -NH-C(=O)-C _1-6 alkyl-, NH ₂ -NH- C(=O)-C _1-6 alkyl-, NH ₂ -C(=O)-(CR ^c R ^d ) _f -NH-C(=O)-C _1-6 alkyl-, C _{1- 4Alkyl} -S(=O) ₂ -NH-C(=O) _-C1-6Alkyl- , _C1-4Alkyl -OC(=O) _-C1-4Alkyl- , _NH2 -S(=O) ₂ -NH-C(=O)-C _1-6 alkyl-, C _2-6 heterocyclyl-C(=O)-C _1-6 alkyl-, amino-substituted C _1-6 alkyl, halogenated C _1-6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, C _2-6 heterocyclyl, C _6-10 aryl C _1-4 alkyl, C _3-6 cycloalkyl or C _3-6 cycloalkyl C _1-4 alkyl; R ¹⁰ is optionally substituted by one or more R ¹² ;

each R and R ^is independently H, OH, CN, F, Cl, Br, I or ^C _1-3 alkyl;

each R ^e and R ^f is independently H, OH or C _1-3 alkyl; and

Each R ¹² is independently D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylamino, Halo C _1-3 alkyl, halo C _1-3 alkoxy, halo C _1-3 alkylamino, hydroxy substituted C _1-3 alkyl, hydroxy substituted C _1-3 alkoxy or hydroxy Substituted C _1-3 alkylamino.

^In other embodiments, R is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclo Hexyl, Cyclopropylmethyl, Cyclopropylethyl, Cyclobutylmethyl, Cyclobutylethyl, Cyclopentylmethyl, Cyclopentylethyl, Cyclohexylmethyl, Cyclohexylethyl, Oxetane Base, tetrahydrofuryl, benzyl, phenethyl, HOC(=O)-C _1-6 alkyl-, C _1-3 alkoxy-(CH ₂ ) _e -C(=O)-C _1-6 Alkyl-, C _2-4 heterocyclyl-(CH ₂ ) _e -OC(=O)-C _1-6 alkyl-, C _1-4 alkyl-OC(=O)-C _1-4 alkane Base-, C _2-4 heterocyclyl-C(=O)-C _1-6 alkyl-, C _1-4 heteroaryl-C _2-4 heterocyclyl-C(=O)-C _{1- 6} Alkyl-, C _3-6 Cycloalkyl-C(=O)-C _2-4 Heterocyclyl-C(=O)-C _1-6 Alkyl-, NH ₂ -C(=O)- C _1-6 alkyl-, NH ₂ -NH-C(=O)-C _1-6 alkyl-, NH ₂ -C(=O)-(CR ^c R ^d ) _f -NH-C(=O )-C _1-6 alkyl-, R ^e R ^f NC(=O)-C _1-6 alkyl-, C _1-4 alkyl-OC(=O)-(CR ^c R ^d ) _f -NH -C(=O)-C _1-6 alkyl-, NH ₂ -S(=O) ₂ -NH-C(=O)-C _1-6 alkyl-, C _1-3 alkyl-S( =O) ₂ -NH-C(=O)-C _1-6 alkyl-, C _3-6 cycloalkyl-(CH ₂ ) _e -NH-C(=O)-C _1-6 alkyl- , C _2-4 heterocyclyl-(CH ₂ ) _e -NH-C(=O)-C _1-6 alkyl-, amino-substituted C _1-6 alkyl, C _2-4 heterocyclyl-NH -C _1-6 alkyl- or phenyl-(CR ^c R ^d ) _f -NH-C _1-6 alkyl-; R ¹⁰ is optionally substituted by one or more R ¹² ;

each ^R and R ^is independently H, OH, CN, F, Cl, Br, I, methyl, ethyl or propyl;

each ^R and R ^is independently H, OH, methyl, ethyl or propyl; and

Each R ¹² is independently D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, hydroxy Substituted methyl or halomethyl.

In one aspect, the present invention relates to a pharmaceutical composition comprising a compound according to the present invention.

In some embodiments, the pharmaceutical composition of the present invention further comprises at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant or vehicle.

In some embodiments, the pharmaceutical composition of the present invention further comprises additional therapeutic agents, and these additional therapeutic agents are drugs, active agents or combinations thereof for treating chronic respiratory obstruction.

Some other embodiments are, the pharmaceutical composition of the present invention, wherein the additional therapeutic agent is: sodium pyruvate, doxofylline (Doxofylline), roflumilast (Roflumilast), apremilast (Apremilast) ), Tetomilast, Tipelukast, Theophylline, Formoterol, Salmeterol, Fluticasone propionate, Salmeterol/fluticasone propionate combination (Salmeterol Xinafoate/Fluticasone Propionate), Rolipram, Piclamist, Cilomilast, CDP-840, Indacaterol, olodaterol ), QVA149, Midestine (Midesteine), Zileuton (Zileuton), albuterolamine, carmoxicol, budesonide and its epimers, beclomethasone dipropionate, triamcinolone acetonide, Flunisolide, mometasone furoate, rofluconide, ciclesonide, ipratropium bromide, ipratropium bromide and albuterol compound, oxitropium bromide, tiotropium bromide bromide), glycopyrronium bromide, Umeclidinium bromide, vilanterol, umeclidinium/vilanterol, aclidinium bromide, Aclidinium bromide/formoterol fumarate compound, LAS40464, LAS100977 (abediterol), AZD-8999, RPL-554, OCID-2987, CHF-6001, CR-3465, HPP-737, fluticasone furoate/vitamin Lanterol compound (fluticasone furoate/vilanterol, FF/VI), benralizumab, ravatropate or their combination.

In another aspect, the present invention relates to the use of the compound or pharmaceutical composition of the present invention in the preparation of medicaments for preventing, treating, treating or alleviating diseases related to phosphodiesterase type 4 (PDE 4).

In some embodiments, the disease associated with phosphodiesterase type 4 (PDE 4) is respiratory disease, allergy and inflammation, central nervous system (CNS) disease, pulmonary fibrosis or non-insulin dependent diabetes.

In other embodiments, the respiratory disease is: chronic obstructive respiratory disease (COPD), chronic bronchitis, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, allergic bronchitis, bronchiectasis, pulmonary tuberculosis Fibrotic lesions, cystic fibrosis of the lung, diffuse panbronchiolitis, bronchiolitis obliterans, acute respiratory distress syndrome (ARDS), or airway inflammation.

Some other embodiments are that the inflammation is: allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, allergic rhinitis, ulcerative colitis, ankylosing spondylitis, rheumatoid arthritis, or psoriatic arthritis.

Another aspect of the present invention relates to methods for the preparation, isolation and purification of compounds represented by formula (I), formula (I') or formula (II).

The preceding description merely outlines certain aspects of the invention, but is not intended to be limiting. These and other aspects will be described more specifically and fully below.

Detailed description of the invention

Definitions and General Terms

Certain embodiments of the invention are now described in detail, examples of which are illustrated by the accompanying Structural and Chemical Formulas. The present invention is intended to cover all alternatives, modifications and equivalent technical solutions, which are included within the scope of the present invention as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application (including, but not limited to, defined terms, term usage, described techniques, etc.), this Application shall prevail.

It is further appreciated that certain features of the invention, which, for clarity, have been described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications referred to herein are hereby incorporated by reference in their entirety.

As used herein, the following definitions shall apply unless otherwise stated. For the purposes of the present invention, the chemical elements correspond to the Periodic Table of the Elements, CAS Edition, and Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, the general principles of organic chemistry can refer to the descriptions in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and JerryMarch, John Wiley & Sons, New York: 2007, The entire contents of which are incorporated herein by reference.

As used herein, the articles "a", "an" and "the" are intended to include "at least one" or "one or more" unless otherwise stated or clearly contradicted by context. Therefore, as used herein, these articles refer to articles of one or more than one (ie, at least one) object. For example, "a component" refers to one or more components, ie there may be more than one component contemplated to be employed or used in the practice of the described embodiment.

The term "subject" as used in the present invention refers to an animal. Typically the animal is a mammal. Subjects, for example, also refer to primates (such as humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

The term "patient" as used herein refers to a human (including adults and children) or other animals. In some embodiments, a "patient" refers to a human.

The term "comprising" is an open expression, that is, it includes the content specified in the present invention, but does not exclude other content.

"Stereoisomers" refer to compounds that have the same chemical structure, but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. .

"Chiral" is a molecule that has the property of being nonsuperimposable to its mirror image; and "achiral" is a molecule that is superimposable to its mirror image.

"Enantiomer" refers to two non-superimposable isomers of a compound that are mirror images of each other.

"Diastereoisomer" refers to stereoisomers that have two or more chiral neutralities and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting points, boiling points, spectral properties and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, eg HPLC.

The stereochemical definitions and rules used in the present invention generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

Many organic compounds exist in optically active forms, ie they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to its chiral center or centers. The prefixes d and 1 or (+) and (-) are symbols used to designate rotation of plane polarized light by a compound, where (-) or 1 indicates that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. A specific stereoisomer is an enantiomer and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate and can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched form, such as (R)-, (S)- or (R,S)-configuration exist. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

Depending on the choice of starting materials and processes, the compounds of the invention can be obtained as one of the possible isomers or as mixtures thereof, such as racemates and diastereomer mixtures (depending on the number of asymmetric carbon atoms) form exists. Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may have the cis or trans configuration.

The resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereoisomers on the basis of differences in the physicochemical properties of the components, for example, by chromatography method and/or fractional crystallization.

The racemates of any resulting final products or intermediates can be resolved into the optical antipodes by known methods by methods familiar to those skilled in the art, e.g., by subjecting the obtained diastereomeric salts thereof to separate. Racemic products can also be separated by chiral chromatography, eg, high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers may be prepared by asymmetric synthesis, see for example Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 ^nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SHTables of Resolving Agents and Optical Resolutions p.268 (ELEliel, Ed., Univ.of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that are interconvertible through a low energy barrier. If tautomerism is possible (eg, in solution), then a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol isomerization and imine-enol isomerization Amine isomerization. Valence tautomers include interconversions by recombination of some of the bonding electrons. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

As described in the present invention, the compounds of the present invention can be optionally substituted by one or more substituents, such as the above general formula compounds, or as specific examples in the examples, subclasses, and included in the present invention A class of compounds. It should be understood that the term "optionally substituted" and the term "substituted or unsubstituted" are used interchangeably. In general, the term "substituted" means that one or more hydrogen atoms in a given structure have been replaced by a particular substituent. Unless otherwise indicated, an optional substituent may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted by one or more substituents selected from a particular group, then the substituents can be substituted at each position the same or differently. The substituents mentioned therein can be, but are not limited to, deuterium, hydroxyl, amino, fluorine, chlorine, bromine, iodine, cyano, azido, aryl, heteroaryl, alkoxy, alkylamino, alkyl Thio, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo, carboxyl, haloalkyl, hydroxy-substituted alkyl, hydroxy-substituted alkoxy , hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O) ₂ -, hydroxy-substituted alkyl -S(=O)-, hydroxy-substituted alkyl-S(=O) ₂ -, carboxyalkoxy and the like.

In addition, it should be noted that, unless otherwise clearly stated, the descriptions used in the present invention "each...independently are" can be interchanged with "...independently" and "...independently". It should be understood in a broad sense. It can mean that in different groups, the specific options expressed between the same symbols do not affect each other, and it can also mean that in the same group, the specific options expressed between the same symbols do not affect each other. Taking R ⁹ as an example, the specific options for R ⁹ between the structural formula "-N(R ⁹ )-C(=O)-NR ⁹ R ^9a " and the structural formula "R ^9a R ⁹ NC _1-6 alkyl-" They are not affected by each other, and at the same time, in the same chemical formula "-N(R ⁹ )-C(=O)-NR ⁹ R ^9a ", multiple specific options of R ⁹ are not affected by each other.

In each part of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the type or range of the group. It is specifically intended that the invention includes each individual subcombination of individual members of these radical classes and ranges. For example, the term "C ₁ -C ₆ alkyl" or "C _1-6 alkyl" specifically refers to independently disclosed methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl and C ₆ alkane base.

In various sections of the invention linking substituents are described. When the structure clearly requires a linking group, the Markush variables recited for that group are to be understood as linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable recites, for example, "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represent linking groups, respectively. An alkylene group or an arylene group.

The term "alkyl" or "alkyl group" used in the present invention means a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group can be optionally substituted by one or more of the substituents described in the present invention, wherein the substituents are deuterium, hydroxyl, amino, fluorine, chlorine, bromine, iodine, cyano, azido, heteroaryl, alkoxy radical, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo, carboxyl, haloalkyl, hydroxy-substituted alkyl, Hydroxyl substituted alkoxy, hydroxy substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O) ₂ - , hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O) ₂ -, carboxyalkoxy and the like. Unless otherwise specified, an alkyl group contains 1-20 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms; in another embodiment, the alkyl group contains 1-6 carbon atoms; in yet another embodiment, the alkyl group contains 1 - 4 carbon atoms; in yet another embodiment, the alkyl group contains 1-3 carbon atoms.

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), n-propyl (n-Pr, -CH ₂ CH ₂ CH ₃ ), isopropyl (i-Pr, -CH(CH ₃ ) ₂ ), n-butyl (n-Bu, -CH ₂ CH ₂ CH ₂ CH ₃ ), isobutyl (i-Bu, -CH ₂ CH (CH ₃ ) ₂ ), sec-butyl (s-Bu, -CH(CH ₃ )CH ₂ CH ₃ ), tert-butyl (t-Bu, -C(CH ₃ ) ₃ ), n-pentyl (-CH 2CH ₂ CH ₂ CH ₂ CH ₃ ), ₂ -pentyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 2-methyl -2-butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1- Butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), n-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ ) CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH (CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH(CH ₃ )C(CH ₃ ) ₃ ), n-heptyl, n-octyl, and the like.

The term "alkylene" denotes a saturated divalent hydrocarbyl group obtained by removing two hydrogen atoms from a saturated straight or branched chain hydrocarbon. Unless otherwise specified, an alkylene group contains 1-12 carbon atoms. In one embodiment, an alkylene group contains 1-6 carbon atoms; in another embodiment, an alkylene group contains 1-4 carbon atoms; in yet another embodiment, an alkylene group The group contains 1-3 carbon atoms; in yet another embodiment, the alkylene group contains 1-2 carbon atoms. Such examples include methylene (-CH ₂ -), ethylene (-CH ₂ CH ₂ -), propylene (-CH ₂ CH ₂ CH ₂ -), isopropylidene (-CH(CH ₃ ) CH ₂ -) and so on.

The term "alkenyl" means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one unsaturated site, that is, a carbon-carbon sp ² double bond, wherein the alkenyl group Groups may be optionally substituted with one or more substituents described herein, including the "cis" and "tans" orientation, or the "E" and "Z" orientation. In one embodiment, an alkenyl group contains 2-8 carbon atoms; in another embodiment, an alkenyl group contains 2-6 carbon atoms; in yet another embodiment, an alkenyl group contains 2 - 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl (-CH= _CH2 ), allyl (-CH2CH= _{CH2 )} , and the like.

The term "alkynyl" means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one unsaturated site, that is, a carbon-carbon sp triple bond, wherein the alkynyl group Can be optionally substituted with one or more substituents described herein. In one embodiment, the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 - 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), ₁ -propynyl (-C≡C- _CH3 ), and the like .

The term "carboxy", whether used alone or in combination with other terms, such as "carboxyalkyl", means -CO ₂ H or -COOH; the term "carbonyl", whether used alone or in combination with other terms, such as "aminocarbonyl " or "acyloxy" means -(C=O)-. The term "cycloalkylcarbonyl", "heterocyclylcarbonyl", "arylcarbonyl" or "heteroarylcarbonyl" means a cycloalkyl, heterocyclyl, aryl or heteroaryl group through a carbonyl group (i.e. (C=O )) is connected to the rest of the molecule.

The term "H" denotes a single hydrogen atom. Such atomic groups can be linked to other groups, such as oxygen atoms, to form hydroxyl groups.

^The term "D" or "2H" denotes a single deuterium atom. For example, one such atom replaces one hydrogen atom in a methyl group to form a mono-deuteromethyl group (-CDH ₂ ), and two deuterium atoms replace two hydrogen atoms in a methyl group to form a bis-deuteromethyl group (-CDH 2 ). -CD ₂ H), and three deuterium atoms replacing three hydrogen atoms in the methyl group to form tris-deuteromethyl (-CD ₃ ).

_The term "azido" or "N3" denotes an azide structure. This group can be linked to other groups, for example, a methyl group to form azidomethane (MeN ₃ ), or a phenyl group to form azidobenzene (PhN ₃ ).

The term "heteroalkyl" means that one or more heteroatoms may be inserted into the alkyl chain, wherein the alkyl group and the heteroatom have the meanings described in the present invention. Unless otherwise specified, heteroalkyl groups contain 1-12 carbon atoms, some embodiments have 1-10 carbon atoms, and other embodiments have heteroalkyl groups contain 1- 5 carbon atoms, and in other embodiments, the heteroalkyl group contains 1-4 carbon atoms. Such examples include, but are not _limited to, _{CH3OCH2- , CH3CH2OCH2- , CH3SCH2-} , _{( CH3 ) 2NCH2-} , _{( CH3 ) 2CH2OCH2-} , _CH3OCH2CH2- , _{CH3CH2OCH2CH2-} , _{CH3C ( =} O)CH2-, _{CH3C ( =} O _{) OCH2-} , _{CH3S (} =O _{) 2OCH2} -Wait.

As used herein, the term "unsaturated" means that a group contains one or more degrees of unsaturation.

The term "heteroatom" refers to O, S, N, P, and Si, including forms in any oxidation state of N, S, and P; forms of primary, secondary, and tertiary amines, and quaternary ammonium salts; or Hydrogen-substituted forms, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like N-substituted pyrrolidinyl NR).

The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term "hydroxy-substituted alkyl", "hydroxy-substituted alkoxy" or "hydroxy-substituted alkylamino" means an alkyl group, alkoxy group or alkylamino group replaced by one or more hydroxy groups Substitution, wherein the alkyl groups, alkoxy groups and alkylamino groups have the meanings as described in the present invention. Such examples include, but are not limited to, hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl, hydroxymethoxy, hydroxyethoxy, hydroxymethylamino, hydroxyethylamino, and the like.

The term "haloalkyl", "haloalkenyl" or "haloalkoxy" means an alkyl, alkenyl or alkoxy group substituted with one or more halogen atoms, examples of which include, but are not limited to, Fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, etc.

The term "alkoxy" denotes an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning described herein. Unless specified otherwise, the alkoxy groups contain 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in yet another embodiment, the alkoxy group Groups contain 1-3 carbon atoms. The alkoxy groups may be optionally substituted with one or more substituents described herein.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH ₃ ), ethoxy (EtO, -OCH ₂ CH ₃ ), 1-propoxy (n-PrO, n- Propoxy, -OCH ₂ CH ₂ CH ₃ ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH ₃ ) ₂ ), 1-butoxy (n-BuO, n- Butoxy, -OCH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH ₂ CH(CH ₃ ) ₂ ), 2-butane Oxygen (s-BuO, s-butoxy, -OCH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH ₃ ) ₃ ), 1-pentyloxy (n-pentyloxy, -OCH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyloxy (-OCH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyloxy (-OCH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butoxy (-OC(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butoxy (-OCH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-l-butoxy (-OCH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-l-butoxy ( _-OCH2CH ( _CH3 ) _{CH2CH3 )} , and so on.

The term "alkylthio" includes a C _1-6 straight or branched chain alkyl attached to a divalent sulfur atom. In some embodiments, the alkylthio group is a lower C _1-4 alkylthio group, examples of which include, but are not limited to, methylthio (CH ₃ S—).

The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino", wherein the amino groups are each independently substituted with one or two alkyl groups. In some embodiments, alkylamino is a lower alkylamino group with one or two C _1-6 alkyl groups attached to a nitrogen atom. In some other embodiments, the alkylamino is a C _1-3 lower alkylamino group. Suitable alkylamino groups may be mono- or di-alkylamino, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N- -Diethylamino and the like.

The term "aminoalkyl" or "amino-substituted alkyl" includes C _1-10 straight or branched chain alkyl groups substituted with one or more amino groups. In some embodiments, aminoalkyl is C _1-6 "lower aminoalkyl" substituted with one or more amino groups, examples of which include, but are not limited to, aminomethyl, amino Ethyl, aminopropyl, aminobutyl and aminohexyl.

The term "n atoms", where n is an integer, typically describes the number of ring atoms in a molecule, the number of ring atoms in said molecule being n. For example, piperidinyl is a heterocycloalkyl group of 6 atoms, and tetrahydronaphthalene is a carbocyclyl group of 10 atoms.

The term "ring" includes carbocycle, heterocycle, aromatic ring, heteroaromatic ring, spirocycle, spiroheterocycle, fused ring, fused heterocycle, etc., wherein said carbocycle, heterocycle, aromatic ring, heteroaromatic ring, spiro Ring, spiroheterocycle, fused ring, fused heterocyclic group have the meanings as described in the present invention.

The terms "fused bicyclic", "fused ring", "fused bicyclyl" and "fused cycloyl" are used interchangeably herein, and all refer to monovalent or multivalent saturated or partially unsaturated bridged ring systems, so The bridged ring system refers to a non-aromatic bicyclic system. Such systems may contain independent or conjugated unsaturated systems, but their core structure does not contain aromatic or heteroaromatic rings (although aromatic groups may act as substituents thereon).

The terms "spirocyclyl", "spirocycle", "spirobicyclyl" or "spirobicyclo" are used interchangeably herein to refer to monovalent or multivalent saturated or partially unsaturated ring systems in which one ring is derived from the other A specific ring carbon atom on a ring. For example, as described below, a saturated bridged ring system (rings B and B') is called a "fused bicyclic ring", while rings A and B share a carbon atom in two saturated ring systems, called Known as "spirocycle" or "spirobicycle". Each ring in the fused bicyclyl and spirobicyclyl can be carbocyclyl or heterocyclyl, and each ring is optionally substituted with one or more substituents described herein.

The term "heterocycloalkyl" refers to a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3-12 ring atoms, at least one of which is selected from nitrogen, sulfur or oxygen atoms.

The term "carbocyclyl" or "carbocycle" denotes a monovalent or polyvalent non-aromatic saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3-12 carbon atoms. Carbocyclyls include spirocarbobicyclyls and fused carbocyclyls, and suitable carbocyclyl groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl. Examples of carbocyclyl groups further include, cyclopropanyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl- 3-alkenyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl Cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc.

The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. In one embodiment, cycloalkyl contains 3-12 carbon atoms; In another embodiment, cycloalkyl contains 3-8 carbon atoms; In yet another embodiment, cycloalkyl contains 3-6 carbon atom. The cycloalkyl groups can be independently unsubstituted or substituted with one or more substituents described herein.

The term "cycloalkylalkyl" means that an alkyl group is substituted by one or more cycloalkyl groups, wherein the alkyl group and the cycloalkyl group have the meanings described herein, examples of which include , but not limited to cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclopentylmethyl, cyclopentylethyl , cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, etc.

The term "cycloalkyloxy" or "carbocyclyloxy" includes an optionally substituted cycloalkyl or carbocyclyl, as defined herein, attached to an oxygen atom and connected by the oxygen atom to the rest of the molecule , such examples include, but are not limited to, cyclopropanyloxy, cyclopentyloxy, cyclohexyloxy, hydroxy-substituted cyclopropanyloxy, and the like.

The term "cycloalkylamino" means that an amino group is substituted by one or two optionally substituted cycloalkyl groups, wherein cycloalkyl has a meaning as described herein, examples of which include, but are not limited to Cyclopropanylamino, cyclopentylamino, cyclohexylamino, hydroxy-substituted cyclopropanylamino, dicyclohexylamino, dicyclopropanylamino and the like.

The term "cycloalkylalkoxy" ("carbocyclylalkoxy") denotes an alkoxy group substituted by one or more cycloalkyl ("carbocyclyl") groups, wherein cycloalkyl ( "Carbocyclyl") groups and alkoxy groups have the meanings described herein, examples of which include, but are not limited to, cyclopropanylmethoxy, cyclopropanylethoxy, cyclopentylethyl Oxy, cyclohexylethoxy, cyclohexylmethoxy, cyclopropanylpropoxy, etc.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein, and both refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing 3-12 ring atoms, wherein the monocyclic, bicyclic or tricyclic The ring does not contain an aromatic ring, and at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. Unless otherwise stated, a heterocyclyl group can be carbonyl or nitrogenyl, and a _-CH2- group can optionally be replaced by -C(=O)-. Ring sulfur atoms can optionally be oxidized to S-oxides. Ring nitrogen atoms can optionally be oxidized to N-oxygen compounds. Examples of heterocyclic groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl , pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuryl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolyl, dithiocyclopentyl, tetrahydro Pyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, tetrahydropyridyl, morpholinyl, thiomorpholinyl, 1-oxo Subo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, homopiperazinyl, homopiperidinyl , oxepanyl, thiepanyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl. Examples of -CH ₂ - groups in heterocyclic groups substituted by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidine Keto and 3,5-dioxopiperidinyl. Examples of oxidized sulfur atoms in heterocyclic groups include, but are not limited to, sulfolane, 1,1-dioxothiomorpholinyl. Said heterocyclyl groups may be optionally substituted with one or more substituents described herein.

In one embodiment, the heterocyclic group is a heterocyclic group consisting of 4-7 atoms, which refers to a saturated or partially unsaturated monocyclic ring containing 4-7 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. Unless otherwise stated, a heterocyclyl group of 4-7 atoms may be carbonyl or nitrogenyl, and a _-CH2- group may optionally be replaced by -C(=O)-. Ring sulfur atoms can optionally be oxidized to S-oxides. Ring nitrogen atoms can optionally be oxidized to N-oxygen compounds. Examples of heterocyclic groups consisting of 4-7 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrroline base, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuryl, tetrahydrothiophenyl, dihydrothienyl, 1,3-dioxolyl, dithiocyclopentyl, tetrahydrofuryl Hydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, tetrahydropyridyl, morpholinyl, thiomorpholinyl, piperazine Dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl. Examples of -CH ₂ - groups in heterocyclic groups substituted by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidine Keto and 3,5-dioxopiperidinyl. Examples of oxidized sulfur atoms in heterocyclic groups include, but are not limited to, sulfolane, 1,1-dioxothiomorpholinyl. The heterocyclyl group consisting of 4-7 atoms can be optionally substituted by one or more substituents described in the present invention.

In another embodiment, heterocyclyl is a 4-atom heterocyclyl, which refers to a saturated or partially unsaturated monocyclic ring comprising 4 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms replaced. Unless otherwise stated, a 4-atom heterocyclic group may be carbonyl or nitrogenyl, and a _-CH2- group may optionally be replaced by -C(=O)-. Ring sulfur atoms can optionally be oxidized to S-oxides. Ring nitrogen atoms can optionally be oxidized to N-oxygen compounds. Examples of 4-atom heterocyclic groups include, but are not limited to: azetidinyl, oxetanyl, thietanyl. The 4-atom heterocyclyl group can be optionally substituted with one or more substituents described in the present invention.

In another embodiment, heterocyclyl is a 5-atom heterocyclyl, which refers to a saturated or partially unsaturated monocyclic ring comprising 5 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms . Unless otherwise stated, a 5-atom heterocyclic group may be carbon or nitrogen, and a _-CH2- group may optionally be replaced by -C(=O)-. Ring sulfur atoms can optionally be oxidized to S-oxides. Ring nitrogen atoms can optionally be oxidized to N-oxygen compounds. Examples of 5-atom heterocyclic groups include, but are not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydro Furyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolyl, dithiocyclopentyl. Examples of -CH ₂ - groups in heterocyclic groups substituted by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl. Examples of oxidized sulfur atoms in heterocyclic groups include, but are not limited to, sulfolane groups. The 5-atom heterocyclyl group may be optionally substituted with one or more substituents described herein.

In another embodiment, heterocyclyl is a 6-atom heterocyclyl, which refers to a saturated or partially unsaturated monocyclic ring comprising 6 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms . Unless otherwise stated, a 6-atom heterocyclic group may be carbonyl or nitrogenyl, and a _-CH2- group may optionally be replaced by -C(=O)-. Ring sulfur atoms can optionally be oxidized to S-oxides. Ring nitrogen atoms can optionally be oxidized to N-oxygen compounds. Examples of 6-atom heterocyclic groups include, but are not limited to: tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, Morpholinyl, Thiomorpholinyl, Piperazinyl, Dioxanyl, Dithianyl, Thioxanyl. Examples of -CH ₂ - groups in heterocyclic groups substituted by -C(=O)- include, but are not limited to, 2-piperidinonyl, 3,5-dioxopiperidinyl. Examples of oxidized sulfur atoms in heterocyclic groups include, but are not limited to, 1,1-dioxothiomorpholinyl. The 6-atom heterocyclyl group can be optionally substituted with one or more substituents described in the present invention.

In another embodiment, the heterocyclic group is a heterocyclic group consisting of 7-12 atoms, which refers to a saturated or partially unsaturated spirobicyclic or fused bicyclic ring containing 7-12 ring atoms, wherein at least one ring atom selected from nitrogen, sulfur and oxygen atoms. Unless otherwise stated, a heterocyclyl group of 7-12 atoms may be carbonyl or nitrogenyl, and a _-CH2- group may optionally be replaced by -C(=O)-. Ring sulfur atoms can optionally be oxidized to S-oxides. Ring nitrogen atoms can optionally be oxidized to N-oxygen compounds. Examples of heterocyclic groups consisting of 7-12 atoms include, but are not limited to: 2-oxa-5-azabicyclo[2.2.1]hept-5-yl. The heterocyclyl group consisting of 7-12 atoms can be optionally substituted with one or more substituents described in the present invention.

The term "heterocyclylalkyl" refers to a heterocyclyl-substituted alkyl group; wherein the heterocyclyl and alkyl groups have the meanings described herein. Such examples include, but are not limited to, thiomorpholin-4-ylmethyl, tetrahydrofuran-3-ylmethyl, oxetan-3-ylmethyl, pyrrolidin-2-ylmethyl, Lin-4-ylmethyl etc.

The term "heterocyclylalkoxy" includes heterocyclyl-substituted alkoxy groups wherein the oxygen atom is attached to the remainder of the molecule; the term "heterocyclylalkylamino" includes heterocyclyl-substituted alkylamino groups wherein the nitrogen atom is bonded to the rest of the molecule; The rest of the molecule is connected. Where heterocyclyl, alkoxy and alkylamino have the meanings described herein, such examples include, but are not limited to, pyrrolidin-2-ylmethoxy, morpholin-2-ylethoxy, morpholin-2-ylethoxy, Lin-3-ylethoxy, piperazin-2-ylethoxy, piperidin-4-ylethylamino and the like.

The term "heterocyclyloxy" includes optionally substituted heterocyclyl groups, as defined herein, attached to an oxygen atom which is attached to the rest of the molecule, examples of which include, but are not limited to, pyrrole Alkyl-2-yloxy, pyrrolidin-3-yloxy, piperidin-2-yloxy, piperidin-3-yloxy, piperazin-2-yloxy, piperidin-4-yl Oxygen etc.

The term "heterocyclylamino" means that the amino group is substituted by one or two heterocyclyl groups, wherein the nitrogen atom is attached to the rest of the molecule, and the heterocyclyl has the meaning as described in the present invention, such examples Including, but not limited to, pyrrolidin-2-ylamino, pyrrolidin-3-ylamino, piperidin-2-ylamino, piperidin-3-ylamino, piperidin-4-ylamino, piperazine- 2-ylamino, etc.

The term "aryl" denotes monocyclic, bicyclic and tricyclic carbocyclic ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic family in which each ring system contains rings of 3-7 atoms and has one or more points of attachment to the rest of the molecule. The term "aryl" is used interchangeably with the term "aromatic ring". Examples of aryl groups may include phenyl, naphthyl and anthracene. The aryl groups may be independently optionally substituted with one or more substituents described herein.

The term "aralkyl" or "arylalkyl" includes aryl-substituted alkyl groups. In some of these embodiments, an aralkyl group refers to a "lower aralkyl" group, ie, an aryl group attached to a C _1-6 alkyl group. In some other embodiments, the aralkyl group refers to a "phenylalkyl group" containing a C _1-4 alkyl group. Specific examples thereof include benzyl, diphenylmethyl, and phenethyl. The aryl group on the aralkyl group may be further substituted by halogen, alkyl, alkoxy, haloalkyl and haloalkoxy.

The term "aryloxy" includes an optionally substituted aryl group, as defined herein, attached to an oxygen atom, and through the oxygen atom, to the remainder of the molecule, wherein the aryl group has a meaning as defined herein , such examples include, but are not limited to, phenoxy, tolyloxy, ethylphenoxy, and the like.

The term "arylamino" means that an amino group is substituted by one or two aryl groups, examples of which include, but are not limited to, N-phenylamino. In some embodiments, the aromatic ring on the arylamino group can be further substituted.

The term "arylalkylamino" means that an alkylamino group is substituted by one or more optionally substituted aryl groups, wherein aryl and alkylamino have the meanings described herein, examples of which include, but are not Limited to phenylmethylamino, phenylethylamino, phenylpropylamino, p-tolylmethylamino, etc.

The term "arylalkoxy" means that an alkoxy group is substituted by one or more optionally substituted aryl groups, wherein aryl and alkoxy have the meanings described herein, examples of which include, but do not It is not limited to phenylmethoxy, phenylethoxy, p-tolylmethoxy, phenylpropoxy and the like.

The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic, And at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring composed of 5-7 atoms and has one or more points of attachment to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl", "heteroaromatic ring" or "heteroaromatic". The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, the heteroaryl group of 5-10 atoms contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, for example

Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3- Triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5- Triazinyl, pyrimidinonyl, pyridinonyl; also include, but are by no means limited to, the following bicyclic rings: benzimidazolyl, benzofuryl, benzotetrahydrofuranyl, benzothienyl, indolyl (such as 2-indolyl), purinyl, quinolinyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), tetrahydroquinolyl (such as 1,2,3,4-tetra Hydroquinolinyl), isoquinolinyl (such as 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), tetrahydroisoquinolinyl (such as 1,2,3,4- tetrahydroisoquinolinyl), imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1 ,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridyl, etc.

As described in the present invention, the substituents draw a bond to the central ring to form a ring system (as shown in the formula below) which means that any substitutable position of the substituent on the ring can be substituted. For example, formula e represents any position that may be substituted on ring A or B, as shown in formulas f ¹ -f ⁷ :

The term "heteroarylamino" means that an amino group is substituted by one or two optionally substituted heteroaryl groups, wherein heteroaryl has the meaning described herein, examples of which include, but are not limited to , N-thienylamino, pyridin-4-ylamino, m-fluoropyridylamino, dipyridylamino, etc.

The terms "heteroaryloxy" or "heteroaryloxy" include optionally substituted heteroaryl groups, as defined herein, attached to and through an oxygen atom to the remainder of the molecule, wherein the heteroaryl The radical group has the meaning as described in the present invention, such examples include, but are not limited to, pyridyloxy, pyrimidinyloxy and the like.

The term "heteroarylalkyl" means that an alkyl group is substituted by one or more heteroaryl groups, wherein heteroaryl and alkyl groups have the meanings described herein, examples of which include, but are not limited to imidazol-2-ylmethyl, furan-2-ylethyl, indol-3-ylmethyl, etc.

The term "heteroarylalkylamino" includes heteroarylalkyl groups containing a nitrogen atom attached to other groups through the nitrogen atom, wherein heteroarylalkyl has the meaning described herein, examples of which include, But not limited to pyridin-2-ylmethylamino, thiazol-2-ylethylamino, imidazol-2-ylethylamino, pyrimidin-2-ylpropylamino, pyrimidin-2-ylmethylamino and the like.

The term "heteroarylalkoxy" includes heteroarylalkyl groups containing an oxygen atom attached to other groups through an oxygen atom, wherein heteroarylalkyl has the meaning described herein, examples of which include , but not limited to pyridin-2-ylmethoxy, thiazol-2-ylethoxy, imidazol-2-ylethoxy, pyrimidin-2-ylpropoxy, pyrimidin-2-ylmethoxy, etc. .

The term "prodrug" used in the present invention means that a compound is transformed into a compound represented by formula (I), formula (I') or formula (II) in vivo. Such conversion is effected by prodrug hydrolysis in blood or enzymatic conversion in blood or tissue to the parent structure. The prodrug compound of the present invention can be an ester. In the existing invention, the ester can be used as a prodrug with phenyl esters, aliphatic (C _1-24 ) esters, acyloxymethyl esters, and carbonates. , carbamates and amino acid esters. For example, a compound of the present invention that contains a hydroxyl group can be acylated to give a prodrug form of the compound. Other prodrug forms include phosphate esters, eg, phosphorylated parent hydroxyl groups. A complete discussion of prodrugs can be found in the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328 -2345.

"Metabolite" refers to a product obtained through metabolism of a specific compound or its salt in vivo. Metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized using assays as described herein. Such products can be obtained by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, degreasing, enzymatic cleavage and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds, including metabolites produced by contacting a compound of the invention with a mammal for a substantial period of time.

The "pharmaceutically acceptable salt" used in the present invention refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., J. Pharmaceutical Sciences, 66:1-19, 1977. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods such as ion exchange methods recorded in books and literature these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphorate Salt, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, Gluconate, Hemisulfate, Heptanoate, Hexanoate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lactobionate, Lactate, Laurate, Lauryl Sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3 - Phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates the quaternary ammonium salts of any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed as counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C _{1 -8} sulfonates and aromatic sulfonates.

A "solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules with water.

The term "protecting group" or "PG" refers to a substituent that reacts with other functional groups, usually to block or protect specific functionality. For example, "amino-protecting group" refers to a substituent attached to the amino group to block or protect the functionality of the amino group in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc). Similarly, a "hydroxyl protecting group" refers to a substituent of a hydroxy group used to block or protect the functionality of the hydroxy group, suitable protecting groups include acetyl and silyl groups. "Carboxyl protecting group" refers to the substituent of carboxyl to block or protect the functionality of carboxyl. General carboxyl protecting groups include -CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2-(trimethylsilane base) ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl phosphino)ethyl, nitroethyl, etc. A general description of protecting groups can be found in: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

The term "treating" any disease or condition as used herein means, in some embodiments, ameliorating the disease or condition (ie, slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to modulating a disease or condition either physically (eg, stabilizing a perceived symptom) or physiologically (eg, stabilizing a parameter of the body), or both. In other embodiments, "treating" refers to preventing or delaying the onset, development or worsening of a disease or condition.

Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids such as acetates, aspartates, benzoates, benzenesulfonates, bromides/hydrobromides, bicarbonates/ Carbonate, Bisulfate/Sulfate, Camphorsulfonate, Chloride/HCl, Chlorophylline Salt, Citrate, Ethionate, Fumarate, Glucoheptonate, Glucose Sugarate, Glucuronate, Hippurate, Hydroiodide/Iodide, Isethionate, Lactate, Lactobionate, Lauryl Sulfate, Malate, Malate salt, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate Salt, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalactonate, propionate, stearate, succinate, sulfosalicylate, tartrate , tosylate and trifluoroacetate.

Inorganic acids from which salts can be derived include, for example, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and the like.

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid , Ethansulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, etc.

Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from Groups I to XII of the Periodic Table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include, for example, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine .

The pharmaceutically acceptable salts of this invention can be synthesized from the parent compound, a basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (such as Na, Ca, Mg or K hydroxides, carbonates, bicarbonates, etc.), or by They are prepared by reacting the free base forms of these compounds with stoichiometric amounts of the appropriate acid. Such reactions are usually carried out in water or organic solvents or a mixture of both. Generally, non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile will be required where appropriate. In, for example, "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., 1985; and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" A further list of suitable salts can be found in Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

In addition, the compounds disclosed in the present invention, including their salts, can also be obtained in the form of their hydrates or in the form of solvents (such as ethanol, DMSO, etc.) containing them for their crystallization. The compounds disclosed herein may inherently or by design form solvates with pharmaceutically acceptable solvents, including water; thus, it is intended that the present invention embrace both solvated and unsolvated forms.

Any structural formulas given herein are also intended to represent non-isotopically enriched as well as isotopically enriched forms of these compounds. Isotopically enriched compounds have structures depicted by the general formulas given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Exemplary isotopes that may be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O , ¹⁸ O, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I.

In another aspect, the compounds of the present invention include isotopically enriched compounds as defined in the present invention, for example, those compounds in which radioactive isotopes such as ³ H, ¹⁴ C and ¹⁸ F are present, or in which non-radioactive isotopes such as ² H and ¹³ C. Such isotopically enriched compounds can be used in metabolic studies (using ¹⁴ C), reaction kinetics studies (using e.g. ² H or ³ H), detection or imaging techniques such as positron emission tomography (PET) or including pharmaceutical or Single-photon emission computed tomography (SPECT) for the determination of substrate tissue distribution may be used in radiation therapy of patients. ¹⁸ F-enriched compounds are particularly ideal for PET or SPECT studies. Isotope-enriched compounds represented by formula (I), formula (I') or formula (II) can be described by conventional techniques familiar to those skilled in the art or in the examples and preparation processes of the present invention using suitable isotope labeling reagents Prepared in place of previously used unlabeled reagents.

^In addition, substitution with heavier isotopes, particularly deuterium (ie,2H or D), may afford certain therapeutic advantages resulting from greater metabolic stability. For example, due to increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It should be understood that deuterium in the present invention is considered as a substituent of the compound of formula (I), formula (I') or formula (II). An isotopic enrichment factor can be used to define the concentration of such heavier isotopes, especially deuterium. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has, for each designated deuterium atom, at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), At least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation) Deuterium incorporation), an isotopic enrichment factor of at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the present invention include those wherein the solvent of crystallization may be isotopically substituted eg _D2O , acetone _- d6, _DMSO -d6.

DESCRIPTION OF THE COMPOUNDS OF THE INVENTION

The aromatic heterocyclic derivatives involved in the present invention, their pharmaceutically acceptable salts, and their pharmaceutical preparations have the ability to antagonize PDE4, especially for the potential use in the treatment of chronic respiratory obstruction.

In one aspect, the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrated Compounds, solvates, metabolites, pharmaceutically acceptable salts or prodrugs:

in:

m is 0, 1, 2, 3 or 4;

p is 0, 1 or 2;

each e is independently 0, 1 or 2;

each f is independently 0, 1 or 2;

X is -N(R ⁸ )-, -O- or -S-;

Y is O or S;

A is a bond or -N(R ⁷ )-;

B is -(CR ^a R ^b ) _p -;

R ¹ is D, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _2-10 heterocyclyl, halogenated C _1-6 alkyl , R ^9a R ⁹ NC _1-6 alkyl-, C _1-6 alkyl-C(=O)-, -C(=O)OR ^9c , -C(=O)-NR ⁹ R ^9a , R ⁹ R ^9a NS(=O) ₂ -, R ^9d -S(=O) ₂ -, R ^9d -S(=O)-C _1-6 alkyl-, R ⁹ R ^9a NC(=O)-C _{1 -6} alkyl-, C _6-10 aryl, C _1-9 heteroaryl, C _3-8 cycloalkyl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl, C _6-10 aryl C _1-6 alkyl or C _1-9 heteroaryl C _1-6 alkyl;

Each R ² is independently H, D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , -S(=O) ₂ Cl, R ^9a R ⁹ N-, -C(=O) -R ^9d , -C(=O)-NR ⁹ R ^9a , -OC(=O)-NR ⁹ R ^9a , -OC(=O)OR ^9c , -N(R ⁹ )-C(=O)- NR ⁹ R ^9a , -N(R ⁹ )-C(=O)OR ^9c , R ^9d -S(=O) ₂ -, R ^9d -S(=O) ₂ -N(R ^9a )-, HOC( =O)-C _1-6 alkoxy-, C _1-6 alkoxy-(CH ₂ ) _e -C(=O)-C _1-6 alkoxy-, C _2-10 heterocyclyl- NH-C _1-6 alkoxy-, C _2-10 heterocyclyl-(CH ₂ ) _e -OC(=O)-C _1-6 alkoxy-, C _2-10 heterocyclyl-(CH ₂ ) _e -NH-C(=O)-C _1-6 alkoxy-, C _3-8 cycloalkyl-(CH ₂ ) _e -NH-C(=O)-C _1-6 alkoxy -, C _6-10 aryl-(CR ^c R ^d ) _f -NH-C _1-6 alkoxy-, C _1-6 alkyl-NH-C(=O)-C _1-6 alkoxy -, R ^e R ^f NC(=O)-C _1-6 alkoxy-, C _1-9 heteroaryl-C _2-10 heterocyclyl-C(=O)-C _1-6 alkoxy -, C _3-8 cycloalkyl-C(=O)-C _2-10 heterocyclyl-C(=O)-C _1-6 alkoxy-, NH ₂ -C(=O)-C _{1 -6} alkoxy-, C _1-6 alkyl-OC(=O)-(CR ^c R ^d ) _f -NH-C(=O)-C _1-6 alkoxy-, NH ₂ -NH- C(=O)-C _1-6 alkoxy-, NH ₂ -C(=O)-(CR ^c R ^d ) _f -NH-C(=O)-C _1-6 alkoxy-, C _1-6 Alkyl-S(=O) ₂ -NH-C(=O)-C _1-6 Alkoxy-, C _1-6 Alkyl-OC(=O)-C _1-6 Alkoxy -, NH ₂ -S(=O) ₂ -NH-C(=O)-C _1-6 alkoxy-, C _2-10 heterocyclyl-C(=O)-C _1-6 alkoxy -, C _6-10 aryl, C _1-9 heteroaryl, C _1-6 alkoxy, amino-substituted C _1-6 alkoxy, halogenated C _1-6 alkoxy, C _1-6 Alkylamino, C _3-8 cycloalkyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _2-10 heterocyclyloxy, C _6-10 aryl C _1-6 alkoxy , C _3-8 cycloalkyloxy or C _3-8 cycloalkylC _1-6 alkoxy; each R ² is independently optionally replaced by one or more R ¹² replaced;

R ³ is D, F, Cl, Br, I, CN, NO ₂ , NH ₂ , OH, COOH, C _1-6 alkylamino, NH ₂ -C _1-6 alkyl-C _1-9 heteroaryl- , NH ₂ -C _1-6 alkyl-C _1-9 heteroaryl-C _1-6 alkyl-, NH ₂ -C _1-6 alkyl-C _6-10 aryl-, NH ₂ -C _{1 -6} alkyl-C _6-10 aryl-C _1-6 alkyl-, C _1-6 alkyl-C(=O)-NH-, R ¹³ OC(=O)-C _1-6 alkyl -C(=O)-NH-, C _3-8 cycloalkyl-C(=O)-NH- or -C(=O)-NR ⁹ R ^9a ;

Each R ⁵ and R ⁶ is independently H, D, F, Cl, Br, I, CN, NO ₂ , NH ₂ , OH, COOH, C _1-6 alkyl, halogenated C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkylamino, C _1-6 alkoxy, halogenated C _1-6 alkoxy, hydroxy substituted C _1-6 alkyl, mercapto substituted C _1-6 alkyl, carboxyl substituted C _1-6 alkyl, NH ₂ -C _1-6 alkyl-C _1-9 heteroaryl-, NH ₂ -C _1-6 alkyl-C _{1- 9} heteroaryl-C _1-6 alkyl-, NH ₂ -C _1-6 alkyl-C _6-10 aryl-, NH ₂ -C _1-6 alkyl-C _6-10 aryl-C _{1 -6} alkyl-, C _3-6 cycloalkyl, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _3-8 cycloalkyl-C (=O)-NH-, -C(=O)-NR ⁹ R ^9a , C _6-10 aryl or C _1-9 heteroaryl;

Or optionally any two of R ³ , R ⁵ and R ⁶ together with the C atoms they are connected to form C=O;

R ⁴ is C _6-10 aryl, C _6-10 aryl-S(=O) ₂ -, C _1-9 heteroaryl, C _1-9 heteroaryl-S(=O) ₂ -, C _6-10 aryl C _1-6 alkyl or C _1-9 heteroaryl C _1-6 alkyl; R ⁴ is optionally substituted by one or more R ¹⁴ ;

each R ⁷ and R ⁸ is independently H, D or C _1-6 alkyl;

Each of R ^a and R ^b is independently H, D, F, Cl, Br, I, CN, OH, NO ₂ , NH ₂ , -COOR ^9c , C _1-6 alkyl, -C(=O)-NR ⁹ R ^9a , -C _1-6 alkyl-C(=O)-NR ⁹ R ^9a , -C(=S)-NH ₂ , amino-substituted C _1-6 alkyl, -NH-C(=O )-R ^9b , -C _1-6 alkyl-NH-C(=O)-R ^9b ,-NH-S(=O) ₂ -C _1-6 alkyl,-C _1-6 alkyl-NH -S(=O) ₂ -C _1-6 alkyl, -NH-S(=O) ₂ -C _3-8 cycloalkyl, -C _1-6 alkyl-NH-S(=O) ₂ - C _3-8 cycloalkyl, -S(=O) ₂ -C _1-6 alkyl, -C _1-6 alkyl-S(=O) ₂ -C _1-6 alkyl, C _6-10 aromatic or C _1-9 heteroaryl; or R ^a , R ^b and the carbon atoms connected to it together form a ring consisting of 3-8 atoms;

each R and R ^is independently H, OH, CN, F, Cl, Br, I or ^C _1-6 alkyl;

Each R ^e and R ^f is independently H, OH or C _1-6 alkyl;

Each of R ⁹ , R ^9a , R ^9b and R ^9d is independently H, D, OH, NH ₂ , -S(=O) ₂ -NH ₂ , -C(=O)-NH ₂ , -C _1-6 Alkyl-C(=O)-NH ₂ ,-C _1-6Alkyl -C(=O)OC _1-6Alkyl ,-C _1-6Alkyl -OC(=O)-C _1-6 Alkyl, C _1-6 alkyl, -S(=O) ₂ -C _1-6 alkyl, -S(=O) ₂ -C _3-8 cycloalkyl, halogenated C _1-6 alkyl, Amino-substituted C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _6-10 aryl, C _2-10 heterocyclyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl C _1-6 alkylamino, C _3-8 cycloalkyl C _1-6 alkyl, C _6-10 aryl C _1-6 alkyl, C _6-10 aryloxy, C _2-10 heterocyclyloxy, C _3-8 cycloalkyloxy, C _6-10 arylamino, C _2-10 heterocyclylamino, C _3-8 cycloalkylamino, C _1-9 heteroaryl or C _3-8 carbocyclic group; or R ⁹ , R ^9a and the nitrogen atom connected to it together form a ring composed of 3-8 atoms; the ring composed of 3-8 atoms, R ⁹ , R ^9a , R ^9b and R ^9d are each independently optionally substituted by one or more R ¹⁵ ;

Each R ^9c is independently H, D, -C _1-6 alkyl-C(=O)-NH ₂ , -C _1-6 alkyl-C(=O)OC _1-6 alkyl, -C _{1 -6} alkyl-OC(=O)-C _1-6 alkyl, C _1-6 alkyl, halogenated C _1-6 alkyl, amino-substituted C _1-6 alkyl, C _6-10 aryl , C _1-9 heteroaryl, C _3-8 cycloalkyl, C _2-10 heterocyclyl, C _3-8 cycloalkyl C _1-6 alkyl, C _6-10 aryl C _1-6 alkane Base or C _3-8 carbocyclyl;

Each R ¹² is independently D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, Halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, halogenated C _1-6 alkylamino, hydroxy substituted C _1-6 alkyl, hydroxy substituted C _1-6 alkoxy or hydroxy Substituted C _1-6 alkylamino;

R ¹³ is H, D or C _1-6 alkyl;

Each R ¹⁴ is independently D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH, -C(=O)-NH ₂ , -C _1-6 alkyl-C(=O )-NH ₂ ,-C _1-6 alkyl-C(=O)OC _1-6 alkyl,-C _1-6 alkyl-OC(=O)-C _1-6 alkyl,C _1-6 Alkyl, C _1-6 alkoxy, C _1-6 alkylamino, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, halogenated C _1-6 alkylamino, hydroxy substituted C _1-6 alkyl, hydroxy substituted C _1-6 alkoxy, hydroxy substituted C _1-6 alkylamino or C _3-6 cycloalkyl;

Each R ¹⁵ is independently D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH, C _1-6 alkyl, C _6-10 aryl, C _1-9 heteroaryl, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl C _1-6 alkyl, C _2-10 heterocyclyl, C _2-10 heterocyclyl C _1-6 alkyl, C _3-8 cycloalkylcarbonyl, C _2-10 heterocyclylcarbonyl, C _6-10 arylcarbonyl or C _{1- 9} heteroarylcarbonyl; and

The R ¹ , R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ^9c , R ^a , R ^b , R ^c , R ^d , R ^e , R ^f , R ¹² , R ¹³ , R ¹⁴ and Each R ¹⁵ is independently optionally substituted by one or more R; wherein each R is independently H, D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH, C _1-6 alkane group or C _1-6 alkoxy group.

Some of these embodiments are, R ¹ is D, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, C _2-6 heterocyclyl, C _{2 -6} heterocyclyl C _1-4 alkyl, halogenated C _1-4 alkyl, -C(=O)-C _1-4 alkyl, -C(=O)OR ^9c , -C(=O) -NR ⁹ R ^9a , R ⁹ R ^9a NC(=O)-C _1-4 alkyl-, C _6-10 aryl, C _6-10 aryl C _1-4 alkyl, C _1-9 heteroaryl Group or C _3-6 cycloalkyl C _1-4 alkyl.

In some embodiments, each R ² is independently H, D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , HOC(=O)-C _1-6 alkoxy-, C _1-4 alkoxy-(CH ₂ ) _e -C(=O)-C _1-6 alkoxy-, C _2-6 heterocyclyl-NH-C _1-6 alkoxy-, C _{2- 6} Heterocyclyl-(CH ₂ ) _e -OC(=O)-C _1-6 Alkoxy-, C _2-6 Heterocyclyl-(CH ₂ ) _e -NH-C(=O)-C _{1 -6} alkoxy-, C _3-6 cycloalkyl-(CH ₂ ) _e -NH-C(=O)-C _1-6 alkoxy-, C _6-10 aryl-(CR ^c R ^d ) _f -NH-C _1-6 alkoxy-, C _1-4 alkyl-NH-C (=O)-C _1-6 alkoxy-, R ^e R ^f NC (= O)-C _{1 -6} alkoxy-, C _1-5 heteroaryl-C _2-6 heterocyclyl-C(=O)-C _1-6 alkoxy-, C _3-6 cycloalkyl-C(=O )-C _2-6 heterocyclyl-C(=O)-C _1-6 alkoxy-, NH ₂ -C(=O)-C _1-6 alkoxy-, C _1-6 alkyl- OC(=O)-(CR ^c R ^d ) _f -NH-C(=O)-C _1-6 alkoxy-, NH ₂ -NH-C(=O)-C _1-6 alkoxy- , NH ₂ -C(=O)-(CR ^c R ^d ) _f -NH-C(=O)-C _1-6 alkoxy-, C _1-4 alkyl-S(=O) ₂ -NH -C(=O)-C _1-6 alkoxy-, C _1-4 alkyl-OC(=O)-C _1-6 alkoxy-, NH ₂ -S(=O) ₂ -NH- C(=O)-C _1-6 alkoxy-, C _2-6 heterocyclyl-C(=O)-C _1-6 alkoxy-, C _6-10 aryl, C _1-5 heterocyclyl Aryl, C _1-6 alkoxy, C _{1-6 alkoxy substituted by amino, halogenated C 1-6 alkoxy} , C _1-4 alkylamino, C _3-6 cycloalkyl, C _{1- 4} alkyl, halogenated C _1-4 alkyl, C _2-6 heterocyclyloxy, C _6-10 aryl C _1-4 alkoxy, C _3-6 cycloalkyloxy or C _{3- 6} cycloalkylC _1-4 alkoxy; each R ² is independently optionally substituted by one or more R ¹² .

In some embodiments, each ^Rc and ^Rd is independently H, OH, CN, F, Cl, Br, I or _C1-4 alkyl.

In some embodiments, each R ^e and R ^f is independently H, OH or C _1-4 alkyl.

In some embodiments, each R ¹² is independently D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, halogenated C _1-4 alkyl, halogenated C _1-4 alkoxy, halogenated C _1-4 alkylamino, hydroxy substituted C _1-4 alkyl, hydroxy substituted C _{1- 4} alkoxy or hydroxy substituted C _1-4 alkylamino.

In some embodiments, R ³ is D, F, Cl, Br, I, CN, NO ₂ , NH ₂ , OH, COOH, C _1-4 alkylamino, NH ₂ -C _1-4 alkyl-C _{1 -5} heteroaryl-, NH ₂ -C _1-4 alkyl-C _1-5 heteroaryl-C _1-4 alkyl-, NH ₂ -C _1-4 alkyl-C _6-10 aryl- , NH ₂ -C _1-4 alkyl-C _6-10 aryl-C _1-4 alkyl-, C _1-4 alkyl-C(=O)-NH-, R ¹³ OC(=O)- C _1-4 alkyl-C(=O)-NH-, C _3-6 cycloalkyl-C(=O)-NH- or -C(=O)-NR ⁹ R ^9a .

^In some of these embodiments, each of R and R is independently H, D, F, ^Cl , Br, I, CN, NO ₂ , NH ₂ , OH, COOH, C _1-4 alkyl, halogenated C _{1 -4} alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkylamino, C _1-4 alkoxy, halogenated C _1-4 alkoxy, hydroxy substituted C _{1- 4} alkyl, C _1-4 alkyl substituted by mercapto, C _1-4 alkyl substituted by carboxy, NH ₂ -C _1-4 alkyl-C _1-5 heteroaryl-, NH ₂ -C _1-4 Alkyl-C _1-5 heteroaryl-C _1-4 alkyl-, NH ₂ -C _1-4 alkyl-C _6-10 aryl-, NH ₂ -C _1-4 alkyl-C _{6- 10} aryl-C _1-4 alkyl-, C _3-6 cycloalkyl, C _6-10 aryl C _1-4 alkyl, C _3-6 cycloalkyl-C(=O)-NH-, -C(=O)-NR ⁹ R ^9a , C _6-10 aryl or C _1-5 heteroaryl.

In some embodiments, optionally any two of R ³ , R ⁵ and R ⁶ together with the C atom to which they are attached form C═O.

In some of these embodiments, each R ⁷ and R ⁸ is independently H, D or C _1-4 alkyl.

Some of these embodiments are, R ¹³ is H, D or C _1-4 alkyl.

Some of the embodiments are that the present invention relates to a compound, which is a compound represented by formula (I') or a stereoisomer, a geometric isomer, a tautomer of a compound represented by formula (I'), Nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs:

in:

X, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ^a , R ^b and p have the meanings described in the present invention;

R ¹¹ is H, C _1-4 alkyl, C _1-4 alkyl-C(=O)-, R ¹³ OC(=O)-C _1-4 alkyl-C(=O)- or C _{3 -6cycloalkyl} -C(=O)-.

Some of the embodiments are that the present invention relates to a compound, which is a compound represented by formula (II) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide Compounds, Hydrates, Solvates, Metabolites, Pharmaceutically Acceptable Salts or Prodrugs:

in:

X, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ^a and R ^b have the meanings described in the present invention;

m is 0, 1, 2 or 3;

R ¹⁰ is H, HOC(=O)-C _1-6 alkyl-, C _1-6 alkoxy-(CH ₂ ) _e -C(=O)-C _1-6 alkyl-, C _{2- 10} Heterocyclyl-NH-C _1-6 Alkyl-, C _2-10 Heterocyclyl-(CH ₂ ) _e -OC(=O)-C _1-6 Alkyl-, C _2-10 Heterocyclyl -(CH ₂ ) _e -NH-C(=O)-C _1-6 alkyl-, C _3-8 cycloalkyl-(CH ₂ ) _e -NH-C(=O)-C _1-6 alkane Base-, C _6-10 aryl-(CR ^c R ^d ) _f -NH-C _1-6 alkyl-, C _1-6 alkyl-NH-C(=O)-C _1-6 alkyl- , R ^e R ^f NC(=O)-C _1-6 alkyl-, C _1-9 heteroaryl-C _2-10 heterocyclyl-C(=O)-C _1-6 alkyl-, C _3-8 Cycloalkyl-C(=O)-C _2-10 Heterocyclyl-C(=O)-C _1-6 Alkyl-, NH ₂ -C(=O)-C _1-6 Alkyl -, C _1-6 alkyl-OC(=O)-(CR ^c R ^d ) _f -NH-C(=O)-C _1-6 alkyl-, NH ₂ -NH-C(=O)- C _1-6 alkyl-, NH ₂ -C(=O)-(CR ^c R ^d ) _f -NH-C(=O)-C _1-6 alkyl-, C _1-6 alkyl-S( =O) ₂ -NH-C(=O)-C _1-6 alkyl-, C _1-6 alkyl-OC(=O)-C _1-6 alkyl-, NH ₂ -S(=O) ₂ -NH-C(=O)-C _1-6 alkyl-, C _2-10 heterocyclyl-C(=O)-C _1-6 alkyl-, amino-substituted C _1-6 alkyl, Halogenated C _1-6 alkyl, C _1-6 alkyl, C _2-10 heterocyclyl, C _6-10 aryl C _1-6 alkyl, C _3-8 cycloalkyl or C _3-8 ring Alkyl C _1-6 alkyl; R ¹⁰ is optionally substituted by one or more R ¹² ; and

R ¹¹ is H, C _1-4 alkyl, C _1-4 alkyl-C(=O)-, R ¹³ OC(=O)-C _1-4 alkyl-C(=O)- or C _{3 -6cycloalkyl} -C(=O)-.

In some embodiments, the pharmaceutically acceptable salt is hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, maleate, succinate, mandelate, fumarate Malonate, Malonate, Malate, 2-Hydroxypropionate, Pyruvate, Oxalate, Glycolate, Salicylate, Glucuronate, Galacturonate, Citrate salt, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, triflate Sulfonates or combinations thereof.

^In some embodiments, R is methyl, ethyl, propyl, isopropyl, halomethyl, haloethyl, halopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclo Hexyl, oxetanyl, oxetanylmethyl, oxetanylethyl, tetrahydrofuryl, tetrahydrofurylmethyl, tetrahydrofurylethyl, phenyl, benzyl, phenethyl, cyclopropylmethyl , cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl or cyclohexylethyl.

_In some embodiments, each R2 is independently H, D, F, Cl, Br, I, CN, _NO2 , OH, ^NH2 , methoxy, ethoxy, propoxy, isopropoxy , butoxy, isobutyloxy, tert-butyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy, cyclopropyl Ethoxy, cyclobutylmethoxy, cyclobutylethoxy, cyclopentylmethoxy, cyclopentylethoxy, cyclohexylmethoxy, cyclohexylethoxy, oxetanyloxy, Tetrahydrofuryloxy, benzyloxy, phenylethoxy, HOC(=O)-C _1-6 alkoxy-, C _1-3 alkoxy-(CH ₂ ) _e -C(=O)- C _1-6 alkoxy-, C _1-4 alkyl-OC(=O)-C _1-6 alkoxy-, C _2-4 heterocyclyl-(CH ₂ ) _e -OC(=O) -C _1-6 alkoxy-, C _2-4 heterocyclyl-C (=O)-C _1-6 alkoxy-, C _1-4 heteroaryl-C _2-4 heterocyclyl-C (=O)-C _1-6 alkoxy-, C _3-6 cycloalkyl-C(=O)-C _2-4 heterocyclyl-C(=O)-C _1-6 alkoxy- , NH ₂ -C(=O)-C _1-6 alkoxy-, NH ₂ -NH-C(=O)-C _1-6 alkoxy-, NH ₂ -C(=O)-(CR ^c R ^d ) _f -NH-C(=O)-C _1-6 alkoxy-, R ^e R ^f NC(=O)-C _1-6 alkoxy-, C _1-4 alkyl-OC (=O)-(CR ^c R ^d ) _f -NH-C(=O)-C _1-6 alkoxy-, NH ₂ -S(=O) ₂ -NH-C(=O)-C _{1 -6} alkoxy-, C _1-3 alkyl-S(=O) ₂ -NH-C(=O)-C _1-6 alkoxy-, C _3-6 cycloalkyl-(CH ₂ ) _e -NH-C(=O)-C _1-6 alkoxy-, C _2-4 heterocyclyl-(CH ₂ ) _e -NH-C(=O)-C _1-6 alkoxy-, Amino-substituted C _1-6 alkoxy, C _2-4 heterocyclyl-NH-C _1-6 alkoxy- or phenyl-(CR ^c R ^d ) _f -NH-C _1-6 alkoxy -; each R ² is independently optionally substituted by one or more R ¹² .

In some embodiments, each ^Rc and ^Rd is independently H, OH, CN, F, Cl, Br, I or _C1-3 alkyl.

In some embodiments, each R ^e and R ^f is independently H, OH or C _1-3 alkyl.

In some embodiments, each R ¹² is independently D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH, methyl, ethyl, propyl, methoxy, ethoxy , propoxy, hydroxy-substituted methyl or halomethyl.

^In some embodiments, each ^R5 and R6 is independently H, D, F, Cl, Br, I, _NH2 , methyl, ethyl, propyl, isopropyl, hydroxy-substituted methyl, benzene base, benzyl or phenethyl.

In some embodiments, R ⁴ is C _6-10 aryl, C _6-10 aryl-S(=O) ₂ -, C _1-9 heteroaryl, C _1-9 heteroaryl-S(= O) ₂ -, C _6-10 aryl C _1-4 alkyl or C _1-9 heteroaryl C _1-4 alkyl; R ⁴ is optionally substituted by one or more R ¹⁴ .

In some embodiments, each R ¹⁴ is independently D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH, -C(=O)-NH ₂ , -C _1-4 alkane -C(=O)-NH ₂ , -C _1-4 alkyl-C(=O)OC _1-4 alkyl, -C _1-4 alkyl-OC(=O)-C _1-4 alkane Base, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, halogenated C _1-4 alkyl, halogenated C _1-4 alkoxy, halogenated C _1-4 alkane Amino, C _1-4 alkyl substituted by hydroxy, C _1-4 alkoxy substituted by hydroxy, C _1-4 alkylamino substituted by hydroxy or C _3-6 cycloalkyl.

Other embodiments are that ^R is phenyl, naphthyl, thiazolyl, thienyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, oxadiazolyl, pyridyl , N-oxypyridin-2-yl, N-oxypyridin-4-yl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl, furo[3,2 -c]pyridyl, furo[3,2-b]pyridyl, furo[2,3-b]pyridyl, furo[2,3-c]pyridyl, benzoxadiazolyl, ind Indolyl, isoindolyl, indazolyl, benzimidazolyl, benzopyrazinyl, benzofuryl, pyridopyrazinyl, 3,4-dihydro-pyridine[3,2-b][ 1,4]oxazinyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuryl, thieno[3,2-b]pyridyl, thieno[2,3- c] pyridyl, thieno[2,3-b]pyridyl, 1,4-benzodioxanyl, 1,2,3,4-tetrahydroquinolin-2-yl or benzenesulfonyl; R ⁴ is optionally substituted with one or more R ¹⁴ .

In other embodiments, each R ¹⁴ is independently D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH, -C(=O)-NH ₂ , -C _1-3 alkane -C(=O)-NH ₂ , -C _1-3 alkyl-C(=O)OC _1-4 alkyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl radical, cyclopentyl, cyclohexyl, methoxy, ethoxy, methylamino or ethylamino.

In some embodiments, each R ^a and R ^b is independently H, D, F, Cl, Br, I, CN, OH, NO ₂ , NH ₂ , -COOR ^9c , C _1-4 alkyl, -C (=O)-NR ⁹ R ^9a ,-C _1-4 alkyl-C(=O)-NR ⁹ R ^9a ,-C(=S)-NH ₂ , amino-substituted C _1-4 alkyl,- NH-C(=O)-R ^9b ,-C _1-4 alkyl-NH-C(=O)-R ^9b ,-NH-S(=O) ₂ -C _1-4 alkyl,-C _{1 -4} Alkyl-NH-S(=O) ₂ -C _1-4 Alkyl, -NH-S(=O) ₂ -C _3-6 Cycloalkyl, -C _1-4 Alkyl-NH-S (=O) ₂ -C _3-6 cycloalkyl, -S(=O) ₂ -C _1-4 alkyl, -C _1-4 alkyl-S(=O) ₂ -C _1-4 alkyl , C _6-10 aryl or C _1-5 heteroaryl.

In some embodiments, R ^a , R ^b and the carbon atoms connected to them together form a ring consisting of 3-6 atoms.

In some embodiments, each R ⁹ , R ^9a and R ^9b is independently H, D, OH, NH ₂ , -S(=O) ₂ -NH ₂ , -C(=O)-NH ₂ , -C _1-4 Alkyl-C(=O)-NH ₂ ,-C _1-4 Alkyl-C(=O)OC _1-6 Alkyl,-C _1-4 Alkyl-OC(=O)-C _1-6 alkyl, C _1-4 alkyl, -S(=O) ₂ -C _1-4 alkyl, -S(=O) ₂ -C _3-6 cycloalkyl, halogenated C _1-4 Alkyl, amino-substituted C _1-4 alkyl, C _1-4 alkoxy, C _1-6 alkylamino, C _6-10 aryl, C _2-6 heterocyclyl, C _3-6 cycloalkane Base, C _3-6 cycloalkyl C _1-4 alkylamino, C _3-6 cycloalkyl C _1-4 alkyl, C _6-10 aryl C _1-4 alkyl, C _6-10 aryloxy Base, C _2-6 heterocyclyloxy, C _3-6 cycloalkyloxy, C _6-10 arylamino, C _2-6 heterocyclylamino, C _3-6 cycloalkylamino, C _{1- 5} heteroaryl or C _3-6 carbocyclyl; R ⁹ , R ^9a and R ^9b are each independently optionally substituted by one or more R ¹⁵ .

Some of these embodiments are, R ⁹ , R ^9a and the nitrogen atom connected thereto together form a ring composed of 3-6 atoms; the ring composed of 3-6 atoms is optionally substituted by one or more R ¹⁵ .

In some embodiments, each R ^9c is independently H, D, -C _1-4 alkyl-C(=O)-NH ₂ , -C _1-4 alkyl-C(=O)OC _1-4 Alkyl, -C _1-4 alkyl-OC(=O)-C _1-6 alkyl, C _1-5 alkyl, halogenated C _1-4 alkyl, amino-substituted C _1-4 alkyl, C _6-10 aryl, C _1-5 heteroaryl, C _3-6 cycloalkyl, C _2-6 heterocyclyl, C _3-6 cycloalkylC _1-4 alkyl, C _6-10 aryl C _1-4 alkyl or C _3-6 carbocyclyl.

In some embodiments, each R ¹⁵ is independently D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH, C _1-4 alkyl, C _6-10 aryl, C _{1 -5} heteroaryl, C _6-10 aryl C _1-4 alkyl, C _1-5 heteroaryl C _1-4 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl C _{1 -4} Alkyl, C _2-6 Heterocyclyl, C _2-6 Heterocyclyl C _1-4 Alkyl, C _3-6 Cycloalkylcarbonyl, C _2-6 Heterocyclylcarbonyl, C _6-10 Aryl C 1-5 heteroaryl carbonyl or C _1-5 heteroaryl carbonyl.

In other embodiments, each R ^a and R ^b is independently H, D, F, Cl, Br, I, CN, OH, NO ₂ , NH ₂ , -COOR ^9c , methyl, ethyl, propyl, Isopropyl, -C(=O)-NR ⁹ R ^9a , -C(=S)-NH ₂ , aminomethyl, aminoethyl, -C _1-3 alkyl-NH-C(=O)- R ^9b , -C _1-3 alkyl-NH-S(=O) ₂ -C _3-6 cycloalkyl, -C _1-3 alkyl-S(=O) ₂ -C _1-3 alkyl, Pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, phenyl, pyridyl or pyrimidinyl.

In some other embodiments, R ^a , R ^b and the carbon atoms connected thereto together form oxetane or 1,3-dioxolane.

In other embodiments, each R ⁹ , R ^9a and R ^9b is independently H, D, OH, NH ₂ , -S(=O) ₂ -NH ₂ , -C(=O)-NH ₂ , -C _1-3 Alkyl-C(=O)-NH ₂ ,-C _1-4 Alkyl-C(=O)OC _1-4 Alkyl,-C _1-3 Alkyl-OC(=O)-C _1-3 alkyl, methyl, ethyl, propyl, isopropyl, -S(=O) ₂ -C _1-3 alkyl, -S(=O) ₂ -cyclopropyl, -S(= O) ₂ -cyclobutyl, -S(=O) ₂ -cyclopentyl, -S(=O) ₂ -cyclohexyl, halogenated C _1-4 alkyl, amino-substituted C _1-4 alkyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Methylamino, Dimethylamino, Ethylamino, Propylamino, Isopropylamino, Phenyl, Cyclopropylmethyl, Cyclobutylmethyl, Cyclo Pentylmethyl, Cyclopropylmethylamino, Cyclobutylmethylamino, Cyclopentylmethylamino, Benzyl, Phenethyl, Phenoxy, Cyclopropyloxy, Cyclobutyloxy, Cyclopentyl Oxygen, phenylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R ⁹ , R ^9a and R ^9b are each independently optionally replaced by One or more R ¹⁵ substitutions.

Some other embodiments are that R ⁹ , R ^9a and the nitrogen atom connected to it together form a ring composed of 3-6 atoms, and the ring composed of 3-6 atoms is azetidine, pyrrolidine, piperidine pyridine, piperazine, morpholine, thiomorpholine, 1-oxo-thiomorpholine or 1,1-dioxo-thiomorpholine; the ring consisting of 3-6 atoms is optionally One or more R ¹⁵ substitutions.

In some other embodiments, each R ^9c is independently H, D, -C _1-3 alkyl-C(=O)-NH ₂ , -C _1-3 alkyl-C(=O)OC _1-3 Alkyl, -C _1-3 alkyl-OC(=O)-C _1-4 alkyl, methyl, ethyl, propyl, isopropyl, halogenated C _1-4 alkyl, amino substituted C _1-4 Alkyl, phenyl, benzyl, phenethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In other embodiments, each R ¹⁵ is independently D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH, methyl, ethyl, propyl, phenyl, pyridyl, pyrimidine Base, thiazolyl, thienyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, oxadiazolyl, benzyl, phenethyl, pyridylmethyl, pyrimidylmethyl , pyridylethyl, pyrimidinylethyl, benzoyl, cyclopropylcarbonyl, cyclobutylcarbonyl or cyclopentylcarbonyl.

Some other embodiments are that R ¹⁰ is H, HOC(=O)-C _1-6 alkyl-, C _1-4 alkoxy-(CH ₂ ) _e -C(=O)-C _1-6 alkane Base-, C _2-6 heterocyclyl-NH-C _1-6 alkyl-, C _2-6 heterocyclyl-(CH ₂ ) _e -OC(=O)-C _1-6 alkyl-, C _2-6 heterocyclyl-(CH ₂ ) _e -NH-C(=O)-C _1-6 alkyl-, C _3-6 cycloalkyl-(CH ₂ ) _e -NH-C(=O) -C _1-6 alkyl-, C _6-10 aryl-(CR ^c R ^d ) _f -NH-C _1-6 alkyl-, C _1-4 alkyl-NH-C(=O)-C _1-6 alkyl-, R ^e R ^f NC(=O)-C _1-6 alkyl-, C _1-5 heteroaryl-C _2-6 heterocyclyl-C(=O)-C _{1- 6} Alkyl-, C _3-6 Cycloalkyl-C(=O)-C _2-6 Heterocyclyl-C(=O)-C _1-6 Alkyl-, NH ₂ -C(=O)- C _1-6 alkyl-, C _1-6 alkyl-OC(=O)-(CR ^c R ^d ) _f -NH-C(=O)-C _1-6 alkyl-, NH ₂ -NH- C(=O)-C _1-6 alkyl-, NH ₂ -C(=O)-(CR ^c R ^d ) _f -NH-C(=O)-C _1-6 alkyl-, C _{1- 4Alkyl} -S(=O) ₂ -NH-C(=O) _-C1-6Alkyl- , _C1-4Alkyl -OC(=O) _-C1-4Alkyl- , _NH2 -S(=O) ₂ -NH-C(=O)-C _1-6 alkyl-, C _2-6 heterocyclyl-C(=O)-C _1-6 alkyl-, amino-substituted C _1-6 alkyl, halogenated C _1-6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, C _2-6 heterocyclyl, C _6-10 aryl C _1-4 alkyl, C _3-6 cycloalkyl or C _3-6 cycloalkyl C _1-4 alkyl; R ¹⁰ is optionally substituted by one or more R ¹² .

In some other embodiments, each ^Rc and ^Rd is independently H, OH, CN, F, Cl, Br, I or _C1-3 alkyl.

In some other embodiments, each R ^e and R ^f is independently H, OH or C _1-3 alkyl.

In other embodiments, each R ¹² is independently D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylamino, halogenated C _1-3 alkyl, halogenated C _1-3 alkoxy, halogenated C _1-3 alkylamino, hydroxy substituted C _1-3 alkyl, hydroxy substituted C _{1- 3} alkoxy or hydroxyl substituted C _1-3 alkylamino.

^In other embodiments, R is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclo Hexyl, Cyclopropylmethyl, Cyclopropylethyl, Cyclobutylmethyl, Cyclobutylethyl, Cyclopentylmethyl, Cyclopentylethyl, Cyclohexylmethyl, Cyclohexylethyl, Oxetane Base, tetrahydrofuryl, benzyl, phenethyl, HOC(=O)-C _1-6 alkyl-, C _1-3 alkoxy-(CH ₂ ) _e -C(=O)-C _1-6 Alkyl-, C _2-4 heterocyclyl-(CH ₂ ) _e -OC(=O)-C _1-6 alkyl-, C _1-4 alkyl-OC(=O)-C _1-4 alkane Base-, C _2-4 heterocyclyl-C(=O)-C _1-6 alkyl-, C _1-4 heteroaryl-C _2-4 heterocyclyl-C(=O)-C _{1- 6} Alkyl-, C _3-6 Cycloalkyl-C(=O)-C _2-4 Heterocyclyl-C(=O)-C _1-6 Alkyl-, NH ₂ -C(=O)- C _1-6 alkyl-, NH ₂ -NH-C(=O)-C _1-6 alkyl-, NH ₂ -C(=O)-(CR ^c R ^d ) _f -NH-C(=O )-C _1-6 alkyl-, R ^e R ^f NC(=O)-C _1-6 alkyl-, C _1-4 alkyl-OC(=O)-(CR ^c R ^d ) _f -NH -C(=O)-C _1-6 alkyl-, NH ₂ -S(=O) ₂ -NH-C(=O)-C _1-6 alkyl-, C _1-3 alkyl-S( =O) ₂ -NH-C(=O)-C _1-6 alkyl-, C _3-6 cycloalkyl-(CH ₂ ) _e -NH-C(=O)-C _1-6 alkyl- , C _2-4 heterocyclyl-(CH ₂ ) _e -NH-C(=O)-C _1-6 alkyl-, amino-substituted C _1-6 alkyl, C _2-4 heterocyclyl-NH -C _1-6 alkyl- or phenyl-(CR ^c R ^d ) _f -NH-C _1-6 alkyl-; R ¹⁰ is optionally substituted by one or more R ¹² .

In some other embodiments, each R ^c and R ^d is independently H, OH, CN, F, Cl, Br, I, methyl, ethyl or propyl.

In other embodiments, each R ^e and R ^f is independently H, OH, methyl, ethyl or propyl.

In other embodiments, each R ¹² is independently D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH, methyl, ethyl, propyl, methoxy, ethoxy , propoxy, hydroxy-substituted methyl or halomethyl.

In some embodiments, the present invention includes but is not limited to compounds with one of the following structures or stereoisomers, geometric isomers, tautomers, nitrogen oxides, and hydrates of compounds with one of the following structures , solvates, metabolites, pharmaceutically acceptable salts or prodrugs:

(note: the compound numbering of above-mentioned specific structure and the compound numbering in the embodiment, the compound numbering to PDE4B2 enzyme inhibitory assay result are all one-to-one correspondence. For example, compound 13 in embodiment 1, to PDE4B2 enzyme inhibitory assay Compound 13 of the results all correspond to compound 13 here.)

The present invention also encompasses the use of the compounds of the present invention and their pharmaceutically acceptable salts for the production of medicinal products for the treatment of respiratory diseases (especially chronic respiratory obstruction), allergy and inflammation, central nervous system (CNS) diseases, pulmonary fibrosis or non-insulin dependent diabetes, including those described herein.

The compounds of the present invention are also useful in the manufacture of a medicament for alleviating, preventing, controlling or treating PDE4-mediated disorders, especially chronic respiratory obstruction.

The present invention includes a pharmaceutical composition comprising a compound represented by formula (I), formula (I') or formula (II) in combination with at least one pharmaceutically acceptable carrier, adjuvant or diluent required effective therapeutic dose.

Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are Belong to the scope of the present invention.

In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes that the substance or composition must be chemically or toxicologically appropriate in relation to the other ingredients making up the formulation and the mammal being used for treatment.

The salts of the compounds of the present invention also include intermediates or formula (I), formula (I') or formula (II) for the preparation or purification of compounds shown in formula (I), formula (I') or formula (II) Salts of isolated enantiomers of the indicated compounds, but not necessarily pharmaceutically acceptable salts.

If the compound of the present invention is basic, the desired salt may be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids and the like. Alternatively use organic acids such as acetic, maleic, succinic, mandelic, fumaric, malonic, pyruvic, oxalic, glycolic and salicylic acids; pyranonic acids such as glucuronic and galactose Alkyd acids; α-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid, ethanesulfonic acid, and many more.

If the compound of the invention is acidic, the desired salts can be prepared by suitable methods, e.g., using inorganic or organic bases, such as ammonia (primary, secondary, tertiary), alkali metal hydroxides or alkaline earth metal hydroxides, etc. Suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia such as primary, secondary and tertiary ammonia, and cyclic ammonia such as piperidine, morpholine and piperazine etc., and inorganic salts obtained from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

Compounds of the present invention and pharmaceutical compositions, formulations and administration

The compounds of the present invention can be produced and formulated as their racemic mixtures, enantiomers, diastereomers, rotamers, N-oxides, polymorphs, solvates and pharmaceutically acceptable Accepted salts and active metabolite forms; compounds containing formula (I), formula (I') or formula (II) or their metabolites, enantiomers, diastereoisomers, N - A pharmaceutical composition of an oxide, polymorph, solvate or pharmaceutically acceptable salt with a pharmaceutically acceptable carrier and optionally included excipients.

The pharmaceutical compositions according to the invention can be produced and administered in dosage units, each unit comprising a certain amount of at least one compound according to the invention and/or at least one physiologically acceptable addition salt thereof. The dosage can vary over very wide ranges, since the compounds are effective even at low dosage levels and are relatively nontoxic. The compound can be administered in therapeutically effective low micromolar doses, which can be increased as needed up to the maximum dose tolerated by the patient.

When available for treatment, a therapeutically effective amount of the compound of formula (I), formula (I') or formula (II) and pharmaceutically acceptable salts thereof may be administered as raw chemicals or as part of a pharmaceutical composition. Active ingredients provided. Therefore, the content of the present invention also provides a pharmaceutical composition, which comprises a therapeutically effective amount of a compound of formula (I), formula (I') or formula (II) or a pharmaceutically acceptable salt thereof and one or more A pharmaceutically acceptable carrier, diluent or excipient.

In fact, according to conventional pharmaceutical compounding techniques, the compound of the present invention or a pharmaceutically acceptable salt thereof can be combined as an active ingredient with a pharmaceutical carrier in an intimately mixed manner. The carrier can take a wide variety of forms depending on the form of preparation desired for administration, eg, oral or parenteral (including intravenous). Thus, the pharmaceutical composition may be presented as discrete units suitable for oral administration such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient. Furthermore, the compositions may be in the form of powders, granules, solutions, suspensions in aqueous liquids, non-aqueous liquids, oil-in-water emulsions or water-in-oil liquid emulsions. In addition to the usual dosage forms shown above, the compound, or a pharmaceutically acceptable salt thereof, may also be administered by controlled release means and/or delivery devices. Said compositions may be prepared by any of the methods known in the pharmaceutical industry. In general, such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then conveniently be brought into the desired form.

The pharmaceutical carrier employed can be solid, liquid or gaseous. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

As used herein, the term "therapeutically effective amount" refers to the total amount of each active ingredient sufficient to show meaningful patient benefit. When a separate active ingredient is administered alone, the term refers to that ingredient alone. When used in combination, the term then refers to combined amounts of the active ingredients that result in a therapeutic effect, whether administered in combination, sequentially or simultaneously. The compounds of formula (I), formula (I') or formula (II) and their pharmaceutically acceptable salts are as described above. The carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. According to another aspect of the present disclosure, there is also provided a method for preparing a pharmaceutical preparation, the method comprising combining a compound of formula (I), formula (I') or formula (II) or a pharmaceutically acceptable salt thereof with a or multiple pharmaceutically acceptable carriers, diluents or excipients. The term "pharmaceutically acceptable" used in the present invention refers to such compounds, raw materials, compositions and/or dosage forms, which are suitable for use in contact with patient tissues without undue toxicity, irritation, etc., within the scope of sound medical judgment. , allergic reactions or other problems and complications commensurate with a reasonable benefit/risk ratio and effective for the intended purpose.

In general, the compounds of the present invention are administered in therapeutically effective amounts by any conventional means of administration for substances exerting similar effects. Suitable dosage ranges are typically 1-500 mg per day, preferably 1-100 mg per day, most preferably 1-30 mg per day, depending on factors such as the severity of the disease being treated, the age and relative health of the subject, the The potency of the compound, the route and form of administration, the indications for which it is administered, and the preference and experience of the relevant medical practitioner. A therapeutically effective amount of a compound of the invention for a given disease can be determined by one of ordinary skill in the art of treating such disease without undue experimentation relying on personal knowledge and the disclosure of this application.

Administration of the compounds of the present invention can be carried out according to the need of the patient, for example, oral administration, nasal administration, parenteral administration (subcutaneous, intravenous, intramuscular, intrasternal and infusion), inhalation administration, Rectal, vaginal, topical, topical, transdermal, and ophthalmic.

Various solid oral dosage forms can be used for the administration of the compounds of the present invention, such as solid dosage forms of tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders. The compounds of the present invention can be administered alone or in combination with various pharmaceutically acceptable carriers, diluents (for example, sucrose, mannitol, lactose, starch) and excipients known in the art, including but not limited to Suspending agents, solubilizers, buffers, binders, disintegrants, preservatives, coloring agents, flavoring agents, lubricants, etc. Timed-release capsules, tablets and gels are also advantageous for administering the compounds of the invention.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients or auxiliaries. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. . Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.1 mg to about 500 mg of active ingredient; and each cachet or capsule preferably contains from about 0.1 mg to about 500 mg of active ingredient. Thus, where one or two tablets, cachets or capsules are taken (once, twice or three times a day), the tablets, cachets or capsules conveniently contain 0.1 mg, 1 mg, 5 mg , 25mg, 50mg, 100mg, 200mg, 300mg, 400mg or 500mg of the active ingredient.

The compounds of the present invention can also be administered in a variety of liquid oral dosage forms, including aqueous and anhydrous solutions, emulsions, suspensions, syrups and elixirs. Such dosage forms may also contain suitable inert diluents known in the art, such as water, and suitable excipients known in the art, such as preservatives, lubricants, sweeteners, flavoring agents. As well as agents for emulsifying and/or suspending the compounds of the invention. The compounds of the present invention may be administered in the form of sterile isotonic solutions by injection, eg, intravenous injection. Other preparations are also possible.

Suppositories for rectal administration of a compound of this invention can be prepared by mixing the compound with suitable excipients such as cocoa butter, salicylates and polyethylene glycols.

Formulations for vaginal administration may be in the form of creams, gels, pastes, foams or sprays containing in addition to the active ingredient such suitable carriers as are known in the art.

For topical administration, the pharmaceutical composition may be a cream, ointment, liniment, lotion, emulsion, suspension, gel, solution, paste, powder suitable for administration to the skin, eyes, ear or nose , spray and drop forms. Topical administration may also include transdermal administration by means of, for example, a transdermal patch.

For the treatment of respiratory diseases, it is preferred that the compounds of the invention are administered by inhalation.

Inhalable preparations include inhalable powders, propellant-containing metered-dose aerosols or propellant-free inhalable formulations. For this purpose, they can be administered directly as powders, preferably in micronized form, or by means of spray solutions or suspensions containing them.

Diluents or carriers, which are generally non-toxic and chemically inert to the compounds of the invention, such as lactose or any other additive suitable for improving the respirable fraction, may be added to the powdered compounds of the invention.

Inhalation aerosols comprising gaseous propellants such as hydrofluoroalkanes may contain the compounds of the invention in solution or dispersion form. Propellant driven formulations may also contain other ingredients such as co-solvents, stabilizers and optionally other excipients.

Propellant-free inhalable formulations containing the compounds of the invention may be in the form of solutions or suspensions in aqueous, alcoholic or hydroalcoholic media, and they may be prepared by spray nebulizers known in the art or by ultrasound. Nebulizer delivery, or by fine-mist nebulizers (soft-mist nebulizers) such as deliver.

The compounds of the invention may be administered as the sole active agent or in combination with other pharmaceutically active ingredients, including those currently used in the treatment of respiratory disorders, e.g., beta2-agonists such as albuterol , formoterol, salmeterol and camoxirol (TA2005); corticosteroids such as budesonide and its epimers, beclomethasone dipropionate, triamcinolone acetonide, fluticasone propionate, fluticasone Nisolide, mometasone furoate, rofluranide, and ciclesonide; and anticholinergic or antimuscarinic agents such as ipratropium, oxitropium, tiotropium, Ronium bromide, revatropate or the compounds disclosed in WO 03/053966.

Preferably, the compound of formula (I), formula (I') or formula (II) is administered alone or in combination with other active ingredients for the prophylaxis and or treatment of respiratory diseases characterized by airway obstruction, such as asthma, chronic bronchitis or chronic obstructive pulmonary disease (COPD).

The treatment method comprising the administration of the compound of the present invention or the pharmaceutical composition further includes the administration of other anti-chronic respiratory obstruction drugs (combined therapy) to the patient, wherein other anti-chronic respiratory obstruction drugs are sodium pyruvate, doxofylline (Doxofylline), Roflumilast, Apremilast, Tetomilast, Tipelukast, Theophylline, Formoterol, Salmeterol , Fluticasone propionate, Salmeterol Xinafoate/Fluticasone Propionate, Rolipram, Piclamist, Cilomilast, CDP-840, Indacaterol, olodaterol, QVA149, Midestine, Zileuton, albuterol, camoxirol, budesonide and Its epimer, beclomethasone dipropionate, triamcinolone acetonide, flunisolide, mometasone furoate, rofluonide, ciclesonide, Ipratropium Bromide, isopropyl Tropium Bromide and Salbutamol Combination, Oxitropium Bromide, Tiotropium Bromide, Glycopyrronium Bromide, Umeclidinium Bromide, Vilanterol, Umeclidinium Bromide/Vilan Umeclidinium/vilanterol, aclidinium bromide, aclidinium bromide/formoterol fumarate compound, LAS40464, LAS100977 (abediterol), AZD-8999, RPL-554, OCID-2987 , CHF-6001, CR-3465, HPP-737, fluticasone furoate/vilanterol compound (fluticasone furoate/vilanterol, FF/VI), benralizumab, ravatorate or their combination.

The term "combined use" or "combination" is to be understood as meaning that the individual components can be administered separately at the same time or more or less simultaneously, or one after the other. In some of these embodiments, one therapeutic agent/pharmaceutical active may be administered in the morning and the other later in the day. In other embodiments, one agent/pharmaceutical active may be administered once a day and the other once a week. It will be appreciated that if the components are administered in immediate succession, the delay in administration of the second component should not be such that the beneficial effects of the combination are lost.

Simultaneous administration may be by any suitable route, and is preferably administered to a subject in need thereof, such as by oral route or intravenous route or intramuscular route or subcutaneous injection, such that the administration Forms have fixed ratios of each therapeutic agent.

More or less simultaneous or sequential administration of each therapeutic agent may be by any suitable route, including but not limited to oral, intravenous, intramuscular, and absorption through mucosal tissues. These therapeutic agents may be administered by the same route or by different routes. For example, both therapeutic agents of the combination can be administered orally.

The compounds of the invention may be included in pharmaceutical compositions. The pharmaceutical composition contains the compound described in the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier; and optionally includes other therapeutic ingredients or adjuvant. Optional additional therapeutic components include, for example, i) leukotriene receptor antagonists, ii) leukotriene biosynthesis inhibitors, iii) corticosteroids, iv) H1 receptor antagonists, v) beta2 adrenergic receptors Agonists, vi) COX-2 selective inhibitors, vii) statins, viiii) non-steroidal anti-inflammatory drugs ("NSAIDs"), and ix) M2/M3 antagonists.

The compositions include those suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most suitable route in a given case will depend on the particular host, and for The nature and severity of the condition for which the active ingredient is administered. The pharmaceutical compositions may conveniently be presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

Creams, ointments, jellies, solutions or suspensions containing the compounds may be used for topical use. For the purposes of the present invention, mouthwashes and mouthwashes are included within the scope of topical use.

Pharmaceutical compositions suitable for parenteral administration may be prepared as solutions or suspensions of the active ingredient in water. Suitable surfactants, such as hydroxypropyl cellulose, may be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Additionally, a preservative can be included to prevent the unwanted growth of microorganisms.

Those pharmaceutical compositions suitable for injectable use include sterile aqueous solutions or dispersions. The compositions may be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid so as to enable easy syringability.

The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be protected against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium including, for example, water, ethanol, polyol (eg, glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

The pharmaceutical composition may be in a form suitable for topical use, such as aerosol, cream, ointment, lotion, dusting powder, and the like. Furthermore, the compositions may be in a form suitable for use in transdermal devices, and such formulations may be prepared by conventional processing methods using the compound or a pharmaceutically acceptable salt thereof. As an example, creams and ointments are prepared by mixing the hydrophilic material and water with about 5% to about 10% by weight of the compound to produce a cream or ointment of the desired consistency.

The present invention provides a method of treating a lung disease (eg, COPD, asthma, or fibrocystic) in a patient in need of such treatment, the method comprising administering to said patient a therapeutically effective amount of at least one of formula (I), formula (I' ) or a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, and at least one compound selected from the group consisting of steroids (such as glucocorticoids), 5-lipoxygenase inhibitors, β- 2 adrenoceptor agonists, α-adrenoceptor agonists, muscarinic M1 antagonists, muscarinic M3 antagonists, muscarinic M2 agonists, NK3 antagonists, LTB4 antagonists, semi- Cystyl leukotriene antagonists, bronchodilators, PDE 4 inhibitors, PDE inhibitors, elastase inhibitors, MMP inhibitors, phospholipase A2 inhibitors, phospholipase D inhibitors, histamine H1 antagonists, group Amine H3 antagonists, dopamine agonists, adenosine A2 agonists, NK1 and NK2 antagonists, GABA-b agonists, nociceptin agonists, expectorants, mucolytics, decongestants, mast cell stabilizers, Antioxidants, anti-IL-8 antibodies, anti-IL-5 antibodies, anti-IgE antibodies, anti-TNF antibodies, IL-10, adhesion molecule inhibitors, growth hormone and other PDE 4 inhibitors.

Non-limiting examples of antihistamine agents for use in combination with compounds represented by formula (I), formula (I') or formula (II) include: astemizole, azatadine, nitrogen Azelastine, acrivastine, brompheniramine, certirizine, chlorpheniramine, clemastine, cyclizine ( cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, doxylamine, dimethindine (dimethindene), ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, Loratadine, levocbastine, mizolastine, equitazine, mianserin, noberastine, meclotide meclizine, norastemizole, picumast, pyrilamine, promethazine, terfenadine, tripyramine (tripelennamine), temelastine, trimeprazine, and triprolidine.

Non-limiting examples of histamine H3 receptor antagonists include: thioperamide, impromidine, burimamide, clobenpropit, impentamine, mifetidine, S- Sopromidine (S-sopromidine), R-sopromidine (R-sopromidine), SKF-91486, GR-175737, GT-2016, UCL-1199 and clozapine. Other compounds can be evaluated for activity at the H3 receptor using known methods, including the guinea pig meninges assay and the guinea pig neurogenic ileal contraction assay, both of which are described in US Patent No. 5,352,707. Another useful assay utilizes rat meninges and is described by West et al., "Identification of Two-H3-Histamine Receptor Subtypes," Molecular Pharmacology, 1990, Vol. 38, 610-613.

The term "leukotriene inhibitor" includes any agent or compound that inhibits, suppresses, delays, or otherwise interacts with the action or activity of a leukotriene. Non-limiting examples of leukotriene inhibitors include: montelukast and its sodium salt; 1-(((R)-(3-(2-(6,7-difluoro-2-quinoline yl)vinyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropaneacetic acid and its sodium salt, which are described in U.S. Patent No. 5,270,324;1 -(((1(R)-3(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-vinyl)phenyl)- 3-(2-(1-Hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid and its sodium salt, which are described in U.S. Patent No. 5,472,964; Pranlukast (pranlukast); zafirlukast; and [2-[[2(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic acid, which Described in US Patent 5,296,495.

Non-limiting examples of beta-adrenoceptor agonists include: albuterol, bitolterol, isoetharine, mataproterenol, perbuterol, salmeterol, terbutaline (terbutaline), isoproterenol, ephedrine, and epinephrine. Non-limiting examples of alpha-adrenoceptor agonists include arylalkylamines (such as phenylpropanolamine and pseudoephedrine), imidazoles (such as naphazoline, oxymetazoline , tetrahydrozoline and xylometazoline) and cycloalkylamines (such as propylhexedrine).

A non-limiting example of a mast cell stabilizer is nedocomil sodium. A non-limiting example of an expectorant is guaifenesin. Non-limiting examples of decongestants are pseudoephedrine, phenylpropanolamine, and phenylephrine.

Non-limiting examples of NK1, NK2 and NK3 tachykinin receptor antagonists include CP-99,994 and SR 48968. Non-limiting examples of muscarinic antagonists include ipratropium bromide and tiatropium bromide.

Non-limiting examples of GABA _B agonists include baclofen and 3-aminopropyl-phosphonic acid. Dopamine agonists include quinpirole, ropinirole, pramipexole, pergolide and bromociptine.

"5-Lipoxygenase inhibitor"includes any agent or compound that inhibits, halts, delays, or interacts with the enzymatic action of 5-lipoxygenase. Non-limiting examples of 5-lipoxygenase inhibitors include zileuton, docbenone, piripost, ICI-D2318, and ABT 761.

Dosage of a compound of this invention depends on a variety of factors, including the particular disease being treated, severity of symptoms, route of administration, frequency of dosage intervals, specific compound used, potency of the compound, toxicological profile, and pharmacokinetics. feature.

The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, formulations intended for oral administration to humans may conveniently contain from about 0.5 mg to about 5 g of active agent compounded with a suitable and convenient amount of carrier material which may comprise from about 5% to about 95% of the total composition. . Unit dosage forms will generally contain from about 1 mg to about 1000 mg of active ingredient, usually 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

Advantageously, they are administered in a dose of 0.01-1000 mg/day, preferably 0.1-500 mg/day.

When administered by inhalation, the compound of the present invention can be administered at a dose of 0.01-10 mg/day, preferably 0.05-5 mg/day, more preferably 0.1-2 mg/day.

Uses of the compounds and pharmaceutical compositions of the present invention

The characteristics of the pharmaceutical composition of the present invention include compounds shown in formula (I), formula (I') or formula (II) or compounds listed in the present invention, and pharmaceutically acceptable carriers, adjuvants or vehicles agent.

The amount of the compound in the compositions of the invention is effective to detectably antagonize PDE4 for the treatment of: pain (e.g., acute pain, acute inflammatory pain, chronic inflammatory pain, and neuropathic pain), acute inflammation, chronic inflammation, rheumatoid arthritis, psoriasis, atopic dermatitis, asthma, COPD, adult respiratory disease, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, Gram Negative bacterial sepsis, toxic shock syndrome, stroke, ischemic reperfusion injury, renal reperfusion injury, glomerulonephritis, Parkinson's disease, Alzheimer's disease, mild cognitive impairment (MCI ), depression, anxiety, graft-versus-host reaction (ie, graft-versus-host disease), allograft rejection (eg, acute allograft rejection and chronic allograft rejection), acute respiratory distress syndrome , delayed allergic reaction, atherosclerosis, cerebral ischemia, osteoarthritis, multiple sclerosis, angiogenesis, osteoporosis, gingivitis, respiratory virus, herpes virus, hepatitis virus, HIV, Kaposi's sarcoma Viral (ie, Kaposi's sarcoma), meningitis, fibrocystic, preterm labor, cough, pruritus, multiple organ dysfunction, psoriatic arthritis, herpes, encephalitis, traumatic brain injury, CNS tumors, interstitial pneumonia , allergies, crystal-induced arthritis, acute pancreatitis, chronic pancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis, eye inflammation, corneal neovascularization, polymyositis, acne, esophagitis, Glossitis, airflow obstruction, airway hypersensitivity (ie, airway hyperresponsiveness), bronchiectasis, bronchiolitis, obstructive bronchiolitis (ie, obstructive bronchiolitis syndrome), chronic bronchitis, cystic fibrosis, Dyspnea, Emphysema, Adult Respiratory Disease, Acute Respiratory Distress Syndrome, Respiratory Viruses, Hypercapnia, Hyperinflation, Hypoxaemia, Hyperoxia-Induced Inflammation, Hypoxia, Pulmonary fibrosis, pulmonary hypertension, peritonitis associated with continuous emergency peritoneal dialysis (CAPD), granulocytic ehrlichiosis, sarcoidosis, small airway disease, airway obstruction, ventilation and perfusion disorders, Wheezing, colds, gout, alcoholic liver disease, lupus, periodontitis, cancer, graft reperfusion injury, early graft rejection (eg, acute allograft rejection), airway hyperresponsiveness, allergic contact dermatitis, Allergic rhinitis, nonallergic rhinitis, patchy alopecia, autoimmune deafness (including, eg, Meniere's disease), autoimmune hemolytic syndrome, autoimmune hepatitis, autoimmune neuropathy, autoimmune Ovarian failure, autoimmune bolus, autoimmune thrombocytopenia, chronic inflammatory demyelinating polyneuropathy, liver cirrhosis, dermatomyositis, diabetes mellitus, drug-induced autoimmunity, endometriosis, fibrotic disease, Gastritis, Goodpasture's syndrome, Graves' disease, Gullain-Barre's disease, Hashimoto's A Adenitis, hepatitis-related autoimmunity, HIV-related autoimmune syndromes and blood disorders, hypophytis, interstitial cystitis, juvenile arthritis, Langerhans cell histiocytosis , lichen planus, metal-induced autoimmunity, myocarditis (including viral myocarditis), myositis, neuropathy (including, for example, IgA neuropathy, membrane neuropathy, and idiopathic neuropathy), nephritic syndrome, optic neuritis, Pancreatitis, postinfectious autoimmunity, primary gallbladder sclerosis, reactive arthritis, ankylosing spondylitis, Reiter's syndrome, reperfusion injury, scleritis, scleroderma, autoimmune disease secondary to blood Conditions (such as anemia), autoimmune diseases associated with silicone implants, Sjogren's syndrome, systemic lupus erythematosus, transverse myelitis, tubulointerstitial nephritis, grapevine Meningitis and leukoplakia, the method comprises administering to the patient an effective amount of at least one compound represented by formula (I), formula (I') or formula (II) or a pharmaceutically acceptable salt or solvate thereof.

An "effective amount" or "effective dose" of a compound or pharmaceutically acceptable composition of the present invention refers to an effective amount for treating or reducing the severity of one or more of the conditions mentioned in the present invention. According to the methods of the present invention, the compounds and compositions may be administered in any amount and by any route of administration effective for treating or lessening the severity of a disease. The exact amount necessary will vary from patient to patient, depending on race, age, general condition of the patient, severity of infection, particular factors, mode of administration, and the like. A compound or composition may be administered in combination with one or more other therapeutic agents, as discussed herein.

General Synthetic Methods for Compounds of the Invention

Generally, the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, wherein the definitions of the substituents are as shown in formula (I), formula (I') or formula (II). The following reaction schemes and examples serve to further illustrate the present invention.

Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare many other compounds of the invention and that other methods for preparing the compounds of the invention are considered to be within the scope of the invention Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by using other known reagents in addition to those described in the present invention, or by incorporating Reaction conditions with some routine modifications. In addition, reactions disclosed herein or known reaction conditions are also recognized to be applicable to the preparation of other compounds of this invention.

In the examples described below, unless indicated otherwise, all temperatures are in degrees Celsius. Reagents were purchased from commercial suppliers such as Linkchem Pharmaceuticals, Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, and were used without further purification unless otherwise indicated. Common reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haiyang Chemical Factory.

Anhydrous tetrahydrofuran was obtained by reflux drying over sodium metal. Anhydrous dichloromethane and chloroform were obtained by refluxing and drying over calcium hydride. Ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide and petroleum ether were dried over anhydrous sodium sulfate before use.

The following reactions were generally carried out under a positive pressure of nitrogen or argon or over anhydrous solvents with a dry tube (unless otherwise indicated), the reaction vials were fitted with suitable rubber stoppers, and the substrate was introduced by syringe. Glassware is dried.

The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory. The test conditions of proton nuclear magnetic resonance spectrum are: under room temperature, Bruker 400MHz or 600MHz nuclear magnetic instrument, with CDC1 ₃ , DMSO-d ₆ , CD ₃ OD or acetone-d ₆ as solvent (reported in ppm) , with TMS (0ppm) or chloroform (7.26ppm) as a reference standard. When multiplets appear, the following abbreviations will be used: s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broadened) peak), dd (doublet of doublets, quartet), dt (doublet of triplets, double triplet). Coupling constants are expressed in Hertz (Hz).

Low-resolution mass spectrometry (MS) data was determined by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30°C), and a G1329A autosampler and G1315B DAD detector were used for For analysis, the ESI source was applied to the LC-MS spectrometer.

Low-resolution mass spectrometry (MS) data was determined by an Agilent 6120 series LC-MS spectrometer equipped with G1311A quaternary pump and G1316A TCC (column temperature maintained at 30°C), and G1329A automatic sampler and G1315D DAD detector were used for analysis , the ESI source was applied to the LC-MS spectrometer.

The above two spectrometers are equipped with Agilent Zorbax SB-C18 column, the specification is 2.1×30mm, 5μm. Injection volume was determined by sample concentration; flow rate was 0.6 mL/min; HPLC peaks were recorded and read by UV-Vis wavelengths at 210 nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (phase A) and 0.1% formic acid in ultrapure water (phase B). Gradient elution conditions are shown in Table 1:

Table 1 Gradient elution conditions

time (min) A(CH₃CN,0.1%HCOOH) B(H₂O,0.1%HCOOH) 0-3 5-100 95-0

time (min) A(CH₃CN,0.1%HCOOH) B(H₂O,0.1%HCOOH) 3-6 100 0 6-6.1 100-5 0-95 6.1-8 5 95

Compound purification was evaluated by Agilent 1100 series high performance liquid chromatography (HPLC), wherein UV detection was at 210nm and 254nm, Zorbax SB-C18 column, specification was 2.1×30mm, 4 μm, 10 minutes, flow rate was 0.6mL/min , 5-95% (0.1% formic acid in acetonitrile solution) of (0.1% formic acid in water), the column temperature was kept at 40°C.

The characterization method of compound purity is: Agilent 1260 preparative high-performance liquid chromatography (Pre-HPLC) or Calesep Pump 250 preparative high-performance liquid chromatography (Pre-HPLC) (column model: NOVASEP, 50/80mm, DAC), at 210nm /254nm with UV detection.

The following abbreviations are used throughout this disclosure:

HOAc Acetic acid

MeCN, CH ₃ CN Acetonitrile

Boc ₂ O di-tert-butyl dicarbonate

CHCl ₃ Chloroform

CDC1 ₃ deuterated chloroform

DMSO dimethyl sulfoxide

DMF N,N-Dimethylformamide

DIPEA N,N-Diisopropylethylamine

DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene

KHMDS Potassium bis(trimethylsilyl)amide

EDCI 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

EtOAc, EA ethyl acetate

EtOH ethanol

Et ₂ O diethyl ether

Fmoc-OSU 9-fluorenylmethyl-N-succinimidyl carbonate

Me-methyl

Et-,CH ₃ CH ₂ - ethyl

Ph-,C ₆ H ₅ -phenyl

Bn-benzyl

HCl hydrogen chloride

HOAT N-Hydroxy-7-azabenzotriazole

HOBT 1-Hydroxybenzotriazole

THF Tetrahydrofuran

MgSO ₄ magnesium sulfate

MgCl ₂ magnesium chloride

MeOH, CH ₃ OH Methanol

CD ₃ OD deuterated methanol

HCHO formaldehyde

CH ₂ Cl ₂ , DCM dichloromethane

mL, m milliliter

M,mol/L mole/liter

PE petroleum ether (60-90℃)

K Potassium

RT room temperature

Rt retention time

NaBH ₃ CN Sodium cyanoborohydride

NaOH sodium hydroxide

Na ₂ CO ₃ sodium carbonate

_{K2CO3potassium carbonate}

NaHCO ₃ sodium bicarbonate

Sodium Na ₂ SO ₄ Sulfate

_H2O water

The following synthetic schemes describe the steps to prepare the compounds of the invention. Unless otherwise stated, each of p, R ^a , R ^b , R ¹ , R ⁵ , R ⁶ , R ⁹ , R ^9a , R ^9b , R ^9c , R ¹⁰ , R ¹¹ , R ¹⁴ and R ¹⁵ has meaning of the above.

Synthetic method one:

The target compound ( 21 ) and target compound ( 22 ) can be prepared by synthetic method 1, wherein n is 0, 1, 2, 3, 4 or 5, and x is 1, 2 or 3. Compound ( 1 ) was condensed with glycine methyl ester hydrochloride to obtain compound ( 2 ), compound ( 2 ) was vulcanized by Lawson's reagent to obtain compound ( 3 ), and compound ( 3 ) was formed under the condition of trimethyloxonium tetrafluoroboric acid Thiomethyl can give compound ( 4 ), compound ( 4 ) can react with acid fluoride compound ( 5-1 ) under basic conditions (such as KHMDS, etc.) to obtain compound ( 5 ), compound ( 5 ) can be reacted under basic conditions (such as LiOH·H ₂ O, NH ₃ ·MeOH, etc.) are hydrolyzed to obtain compound ( 6 ), compound ( 6 ) is condensed with compound ( 20-1 ) to obtain compound ( 20 ), compound ( 20 ) is dissolved in an organic solvent of hydrogen chloride (such as ethyl acetate ester, isopropanol, etc.) to obtain the target compound ( 21 ).

Compound ( 21 ) is further treated with base (such as sodium hydroxide, etc.) to obtain the target compound ( 22 ).

Synthetic method two:

The target compound ( 23 ) can be prepared by Synthesis Method 2, wherein n is 0, 1, 2, 3, 4 or 5. Compound ( 22 ) reacts with R ¹¹ -OH to obtain the target compound ( 23 ).

Synthetic method three:

The target compound ( 25 ) can be prepared by Synthetic Method 3, wherein q is 0, 1, 2, 3 or 4. Compound ( 5 ) was reacted with 4-picoline derivative ( 24-1 ) to obtain compound ( 24 ), and compound ( 24 ) was deprotected in an organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain the target compound ( 25 ).

Synthetic method four:

The target compound ( 28 ) can be prepared by synthetic method IV, wherein q is 0, 1, 2, 3 or 4. Compound ( 6 ) reacts with cyanuric fluoride to obtain compound ( 26 ), compound ( 26 ) reacts with 4-aminopyridine derivatives to obtain compound ( 27 ), and compound ( 27 ) is dissolved in an organic solvent of hydrogen chloride (such as ethyl acetate, iso propanol, etc.) to obtain the target compound ( 28 ).

Synthesis method five:

The target compound ( 30 ) can be prepared by Synthetic Method V, wherein q is 0, 1, 2, 3 or 4. Compound ( 6 ) was reacted with compound ( 29-1 ) to obtain compound ( 29 ), and compound ( 29 ) was deprotected in an organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain the target compound ( 30 ).

Synthetic method six:

The target compound ( 33 ) can be prepared by synthetic method 6, wherein q is 0, 1, 2, 3 or 4, R ^14x is D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH , -C(=O)OC _1-6 alkyl, -C(=O)-NH ₂ , -C _1-6 alkyl-C(=O)-NH ₂ ,-C _1-6 alkyl-C (=O)OC _1-6 alkyl, -C _1-6 alkyl-OC(=O)-C _1-6 alkyl, C _1-6 alkyl, C _1-6 alkoxy, C _{1- 6} alkylamino, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, halogenated C _1-6 alkylamino, hydroxy substituted C _1-6 alkyl, hydroxy substituted C _1-6 alkane Oxygen, C _1-6 alkylamino or C _3-6 cycloalkyl substituted by hydroxy. Compound ( 6 ) was reacted with compound ( 31-1 ) to obtain compound ( 31 ), compound ( 31 ) was hydrolyzed under basic conditions to obtain compound ( 32 ), compound ( 32 ) was dissolved in an organic solvent of hydrogen chloride (such as ethyl acetate, iso propanol, etc.) to obtain the target compound ( 33 ).

Synthetic method seven:

The target compound ( 33 ) can be prepared by synthetic method 7, wherein q is 0, 1, 2, 3 or 4. Compound ( 6 ) was reacted with compound ( 32-1 ) to obtain compound ( 32 ), and compound ( 32 ) was deprotected in an organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain the target compound ( 33 ).

Synthetic method eight:

The target compound ( 35 ) can be prepared by Synthetic Method VIII, wherein n is 0, 1, 2, 3, 4 or 5. Compound ( 26 ) was reacted with aniline derivatives to obtain compound ( 34 ), and compound ( 34 ) was deprotected in an organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain the target compound ( 35 ).

Synthetic method nine:

The target compound ( 37 ) can be prepared by synthetic method 9. Compound ( 6 ) reacts with compound ( 36-1 ) to obtain compound ( 36 ), and compound ( 36 ) is deprotected in an organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain the target compound ( 37 ).

Synthetic method ten:

The target compound ( 39 ) can be prepared by Synthetic Method X, wherein n is 0, 1, 2, 3, 4 or 5. Compound ( 6 ) was reacted with benzenesulfonamide derivatives to obtain compound ( 38 ), and compound ( 38 ) was deprotected in an organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain the target compound ( 39 ).

Synthetic method eleven:

The target compound ( 42-1 ), the target compound ( 42-3 ) and the target compound ( 42-5 ) can be prepared by synthetic method eleven, wherein n is 0, 1, 2, 3, 4 or 5, and R ^x is C _1-6 alkyl or C _3-8 cycloalkyl.

Compound ( 6 ) reacts with compound ( 40-1 ) to obtain compound ( 40 ), compound ( 40 ) obtains compound ( 41 ) under catalytic conditions, compound ( 41 ) in the organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol etc.) to obtain the target compound ( 42-1 ).

Compound ( 41 ) reacts with R ^9b -COOH to obtain compound ( 42-2 ), and compound ( 42-2 ) is deprotected in an organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain the target compound ( 42-3 ).

Compound ( 41 ) was reacted with R ^x -SO ₃ H to obtain compound ( 42-4 ), and compound ( 42-4 ) was deprotected in an organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain the target compound ( 42 -5 ).

Synthetic method twelve:

The target compound ( 46-1 ) and the target compound ( 46 ) can be prepared by synthetic method 12, wherein n is 0, 1, 2, 3, 4 or 5.

Compound ( 6 ) was reacted with compound ( 43-1 ) to obtain compound ( 43 ), compound ( 43 ) was hydrolyzed under basic conditions to obtain compound ( 44 ), compound ( 44 ) was dissolved in an organic solvent of hydrogen chloride (such as ethyl acetate, iso propanol, etc.) to obtain the target compound ( 46-1 ).

Compound ( 44 ) was reacted with NHR ⁹ R ^9a to obtain compound ( 45 ), and compound ( 45 ) was deprotected in an organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain the target compound ( 46 ).

Synthetic method thirteen:

The target compound ( 48 ) can be prepared by synthetic method thirteen, wherein n is 0, 1, 2, 3, 4 or 5, the ring Hy is a ring composed of 3-8 atoms, and s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, x is 1, 2 or 3. Compound ( 44 ) was reacted with compound ( 47-1 ) to obtain compound ( 47 ), and compound ( 47 ) was deprotected in an organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain the target compound ( 48 ).

Synthetic method fourteen:

The target compound ( 50 ) can be prepared by synthetic method 14, wherein n is 0, 1, 2, 3, 4 or 5. Compound ( 44 ) reacts with R ^9c -OH to obtain compound ( 49 ), and compound ( 49 ) is deprotected in an organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain the target compound ( 50 ).

Synthetic method fifteen:

The target compound ( 52 ) can be prepared by synthetic method 15, wherein x is 1, 2 or 3. Compound ( 6 ) was reacted with compound ( 50-1 ) to obtain compound ( 51 ), and compound ( 51 ) was deprotected in an organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain the target compound ( 52 ).

Synthetic method sixteen:

The target compound ( 57 ) can be prepared by synthetic method 16, n is 0, 1, 2, 3, 4 or 5, x is 1, 2 or 3. Compound ( 4 ) and compound ( 53-1 ) are cyclized under basic conditions to obtain compound ( 53 ), and compound ( 53 ) is hydrolyzed under basic conditions (such as LiOH·H ₂ O, NH ₃ ·MeOH, etc.) to obtain compound ( 54 ), compound ( 54 ) was condensed with compound ( 20-1 ) to obtain compound ( 55 ), compound ( 55 ) was debenzylated to obtain compound ( 56 ), and compound ( 56 ) was dissolved in an organic solvent of hydrogen chloride (such as ethyl acetate ester, isopropanol, etc.) to obtain the target compound ( 57 ).

Synthetic method seventeen:

The target compound ( 62 ) can be prepared by Synthetic Method 17, n is 0, 1, 2, 3, 4 or 5. Compound ( 4 ) and compound ( 58-1 ) are cyclized under basic conditions to obtain compound ( 58 ), and compound ( 58 ) is hydrolyzed under basic conditions (such as LiOH·H ₂ O, NH ₃ ·MeOH, etc.) to obtain compound ( 59 ), compound ( 59 ) was condensed with compound ( 20-1 ) to obtain compound ( 60 ), compound ( 60 ) was debenzylated to obtain compound ( 61 ), and compound ( 61 ) was oxidized to obtain the target compound ( 62 ).

Synthetic method eighteen:

The target compound ( 67 ) can be prepared by Synthetic Method 18, n is 0, 1, 2, 3, 4 or 5, x is 1, 2 or 3. Compound ( 2 ) reacts with compound ( 5-1 ) under basic conditions to obtain compound ( 63 ), compound ( 63 ) undergoes ring formation to obtain compound ( 64 ), and compound ( 64 ) is ₂ O, NH ₃ MeOH, etc.) to obtain compound ( 65 ), compound ( 65 ) was condensed with compound ( 20-1 ) to obtain compound ( 66 ), compound ( 66 ) was dissolved in an organic solvent of hydrogen chloride (such as ethyl acetate, iso propanol, etc.) to obtain the target compound ( 67 ).

Synthetic method nineteen:

The target compound ( 82 ) can be prepared by Synthetic Method 19, wherein n is 0, 1, 2, 3, 4 or 5. Compound ( 68 ) was reacted with benzyl bromide to obtain compound ( 69 ), compound ( 69 ) was hydrolyzed under basic conditions (such as NaOH, etc.) to obtain compound ( 70 ), compound ( 70 ) was condensed with glycine methyl ester hydrochloride to obtain compound ( 71 ), compound ( 71 ) was vulcanized by Lawson's reagent to obtain compound ( 72 ), compound ( 72 ) formed a thiomethyl group under the condition of trimethyloxonium tetrafluoroboric acid to obtain compound ( 73 ), compound ( 73 ) was Under neutral conditions (such as KHMDS, etc.) react with acid fluoride compound ( 5-1 ) to obtain compound ( 74 ), and compound ( 74 ) is hydrolyzed under basic conditions (such as LiOH·H ₂ O, NH ₃ ·MeOH, etc.) to obtain compound ( 75 ), compound ( 75 ) was condensed with compound ( 20-1 ) to obtain compound ( 76 ), compound ( 76 ) was reduced to obtain compound ( 77 ), compound ( 77 ) was reacted with 4-bromobutyl acetate to obtain compound ( 78 ), compound ( 78 ) was hydrolyzed under basic conditions to obtain compound ( 79 ), compound ( 79 ) was reacted with 4-toluenesulfonyl chloride to obtain compound ( 80 ), compound ( 80 ) and compound ( 80-1 ) were Compound ( 81 ) was obtained by reaction under acidic conditions, and the target compound ( 82 ) was obtained by reaction of compound ( 81 ) under acidic conditions.

The compounds, pharmaceutical compositions and applications provided by the present invention will be further described below in conjunction with the examples.

Example

Example 1: Compound (S)-5-(1-aminoethyl)-N-(2-chloro-6-fluorobenzyl)-2-(3-(cyclopropylmethoxy)- Synthesis of 4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride

Step 1: Synthesis of the compound 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzamide)methyl acetate

3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid (10g, 38.76mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide salt Acetate (11.1g, 58.14mmol) and N-hydroxy-7-azabenzotriazole (5.28g, 38.76mmol) were added in dichloromethane (50mL), stirred at room temperature for 30min, and methyl glycine hydrochloride was added ( 5.813g, 46.51mmol), and N,N-diisopropylethylamine (27.06mL, 155.04mmol) was added dropwise to the solution at 0°C, stirred at room temperature for 10h, washed with water (25mL×3), and the organic phase After drying with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=2/1) to obtain 11.12 g of white solid, yield: 87%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.47 (s, 1H), 7.29 (dd, J ₁ = 8.3Hz, J ₂ = 1.9Hz, 1H), 7.18 (d, J = 8.3Hz, 1H), 6.68 (t,J _FH ＝75.0Hz,1H),4.22(d,J＝5.0Hz,2H),3.92(d,J＝7.0Hz,2H),3.80(s,3H),1.25-1.32(m,1H ),0.62-0.67(m,2H),0.33-0.37(m,2H);

MS-ESI: m/z 330.2 [M+H] ⁺ .

Step 2: Synthesis of the compound 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzenethiocarboxamide) methyl acetate

Compound 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzamide) methyl acetate (11.12g, 33.77mmol) and Lawson's reagent (13.66g, 33.77mmol) Add tetrahydrofuran (50mL), react at 75°C for 2h, add saturated sodium bicarbonate solution (60mL), extract with ethyl acetate (20mL×3), combine the organic phases, dry over anhydrous sodium sulfate, and conduct column separation of the concentrated solution (petroleum Ether/ethyl acetate (v/v)=2/1) to obtain 10.5 g of yellow solid, yield: 90%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.07(s, 1H), 7.55(d, J=2.0Hz, 1H), 7.24(d, J=2.1Hz, 1H), 7.16(d, J=8.3Hz ,1H),6.68(t,J _FH =75.0Hz,1H),4.56(d,J=4.6Hz,2H),3.94(d,J=7.0Hz,2H),3.85(s,3H),1.27- 1.32(m,1H),0.65-0.67(m,2H),0.36-0.38(m,2H);

MS-ESI: m/z 346.2 [M+H] ⁺ .

Step 3: Synthesis of the compound methyl 2-(((3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)(methylthio)methylene)amino)acetate

At -78°C, compound 2-(3-(cyclopropylmethoxy)-4- (Difluoromethoxy)phenylthiocarboxamide) methyl acetate (5g, 14.48mmol) in dichloromethane (40mL) solution, after stirring at 0°C for 5h, adding saturated sodium bicarbonate solution for washing (25mL×3), The organic phase was dried over anhydrous Na ₂ SO ₄ and the solvent was removed to give 5 g of yellow oil, yield: 96%.

¹ H NMR (400MHz, CDCl _3, Z/E=1:1): δppm 7.16-7.20(m,2H),7.10-7.13(m,2H),6.83-6.87(m,2H),6.65(t, J _FH ＝75.2Hz, 2H), 4.44(s, 2H), 4.15(s, 2H), 3.90(d, J＝6.9Hz, 2H), 3.85(d, J＝6.9Hz, 2H), 3.79(s ,3H),3.72(s,3H),2.45(s,3H),2.16(s,3H),1.27-1.29(m,2H),0.62-0.67(m,4H),0.34-0.36(m,4H );

MS-ESI: m/z 360.1 [M+H] ⁺ .

Step 4: Synthesis of compound (S)-tert-butyl(1-fluoro-1-oxopropan-2-yl)carbamate

Dissolve N-Boc L-alanine (6.5g, 34.4mmol) and triethylamine (5.27mL, 37.83mmol) in dichloromethane (60mL), and add three Polyfluorocyanide (5.62mL, 68.8mmol) was reacted at -10°C for 2h, washed with ice water (20mL×5), the organic phase was dried with anhydrous Na ₂ SO ₄ , and the solvent was removed to obtain 5.84g of a white solid. Yield: 89%.

Step 5: Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of methyl phenyl)oxazole-4-carboxylate

The compound 2-(((3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)(methylthio)methylene)amino)acetic acid methyl ester (5.2g, 14.48mmol ) and compound (S)-(1-fluoro-1-oxopropan-2-yl)carbamate tert-butyl ester (4.15g, 21.72mmol) were dissolved in anhydrous tetrahydrofuran (25mL), at -78°C, To this solution was added dropwise a tetrahydrofuran solution of potassium hexamethyldisilazide (36.2 mL, 36.2 mmol), reacted at -78°C for 1 h, added water (20 mL) to quench the reaction, extracted with ethyl acetate (25 mL×3), After the organic phases were combined, they were dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=3/1) to obtain 5.13 g of a yellow solid, yield: 73% .

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.64(s, 1H), 7.62(d, J=8.4Hz, 1H), 7.23(d, J=8.3Hz, 1H), 6.70(t, J _FH ＝75.0 Hz,1H),5.43-5.47(m,1H),3.98(s,3H),3.96(d,J=7.0Hz,2H),1.54(d,J=7.0Hz,3H),1.43(s,9H ),1.27-1.29(m,1H),0.65-0.68(m,2H),0.36-0.39(m,2H);

MS-ESI: m/z 483.1 [M+H] ⁺ .

Step 6: Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carboxylic acid

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) Methyl oxazole-4-carboxylate (5.13g, 10.63mmol) and lithium hydroxide monohydrate (2.23g, 53.16mmol) were dissolved in a mixed solvent of tetrahydrofuran (40mL) and water (20mL), reacted at 40°C for 2h, Add hydrochloric acid (1M) to adjust the pH value to 1, add ethyl acetate to extract (20mL×3), the organic phases are combined and dried with Na ₂ SO ₄ , and the solvent is removed to obtain 4.8g yellow solid, yield: 96%.

¹ H NMR (600MHz, CD ₃ OD): δppm 7.80 (d, J = 1.8Hz, 1H), 7.66 (dd, J ₁ = 8.3Hz, J ₂ = 1.9Hz, 1H), 7.29 (d, J = 8.3 Hz,1H),6.90(t,J _FH =74.8Hz,1H),5.51(m,1H),4.03(d,J=7.0Hz,2H),1.54(d,J=7.1Hz,3H),1.44 (s,9H),1.35-1.38(m,1H),0.67-0.70(m,2H),0.42-0.44(m,2H);

MS-ESI: m/z 467.3 [MH] ^- .

Step 7: Compound (S)-(1-(4-((2-chloro-6-fluorobenzyl)carbamoyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Synthesis of tert-butyl methoxy)phenyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) oxazole-4-carboxylic acid (0.3g, 0.64mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (183.36mg, 0.96mmol) and N-hydroxy- 7-Azabenzotriazole (130.56mg, 0.96mmol) was dissolved in dichloromethane (10mL), and 2-chloro-6-fluorobenzylamine (0.1mL, 0.77mmol) and N,N-diisopropylethylamine (0.33mL, 1.92mmol), stirred at room temperature for 22h, washed with water (20mL×3), dried the organic phase with anhydrous Na ₂ SO ₄ , removed the solvent, and concentrated Column separation was performed (petroleum ether/ethyl acetate (v/v)=5/1) to obtain 264 mg of white solid, yield: 67%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.59 (dd, J ₁ = 8.3Hz, J ₂ = 1.9Hz, 1H), 7.54 (d, J = 1.8Hz, 1H), 7.47–7.45 (m, 1H) ,7.27(d,J＝4.6Hz,1H),7.24(d,J＝8.4Hz,1H),7.10–7.06(m,1H),6.71(t,J _FH ＝75.0Hz,1H),5.32–5.25 (m,1H),4.87–4.84(m,2H),3.98(d,J=6.9Hz,2H),1.56(d,J=7.0Hz,3H),1.45–1.43(m,9H),1.38– 1.34(m,1H),0.73–0.68(m,2H),0.44–0.40(m,2H).

Step 8: Compound (S)-5-(1-aminoethyl)-N-(2-chloro-6-fluorobenzyl)-2-(3-(cyclopropylmethoxy)-4-(di Synthesis of fluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride

To compound (S)-(1-(4-((2-chloro-6-fluorobenzyl)carbamoyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Base) phenyl) oxazol-5-yl) ethyl) tert-butyl carbamate (0.26g, 0.43mmol) in dichloromethane (2mL) was added HCl in ethyl acetate (4M, 8mL), room temperature Stir for 16 h, filter, and wash with ethyl acetate (15 mL×3) to obtain 128 mg of white solid, yield: 55%.

Compound 13: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.76 (d, J = 1.9Hz, 1H), 7.70 (dd, J ₁ = 8.4Hz, J ₂ = 2.0Hz, 1H), 7.39-7.35 ( m,1H),7.31(d,J=8.2Hz,2H),7.18–7.13(m,1H),6.91(t,J _FH =74.8Hz,1H),5.19–5.14(m,1H),4.81– 4.82(br.s,2H),4.01(d,J=6.9Hz,2H),1.76(d,J=7.0Hz,3H),1.34–1.31(m,1H),0.69–0.66(m,2H) ,0.43–0.41(m,2H);

MS-ESI: m/z 510.2 [M+H-HCl] ⁺ .

Example 2: Compound (S)-5-(1-aminoethyl)-N-(2,4-difluorobenzyl)-2-(3,4-dimethoxyphenyl) Synthesis of Oxazole-4-Carboxamide Hydrochloride

Step 1: Synthesis of compound 3,4-dimethoxybenzoic acid methyl ester

Dissolve methyl 3-hydroxy-4-methoxybenzoate (10g, 54.94mmol) in acetone (50mL), add anhydrous potassium carbonate (15.2g, 110.0mmol) and methyl iodide (6.8mL, 109.2mmol) in sequence , seal the tube, and react at 60°C for 4.5h. Saturated NaCl solution (20 mL) was added, extracted with ethyl acetate (25 mL×3), the organic phases were combined, dried with anhydrous Na ₂ SO ₄ for 1 h, and the solvent was removed to obtain 10.23 g of white solid, yield: 95%.

MS-ESI: m/z 197.1 [M+H] ⁺ .

Step 2: Synthesis of compound 3,4-dimethoxybenzoic acid

The compound 3,4-dimethoxybenzoic acid methyl ester (10.23g, 52.17mmol) was dissolved in a mixed solvent of ethanol (20mL) and water (10mL), and then sodium hydroxide (10.43g, 260.87mmol) was added, React at 60°C for 1.5h, remove ethanol, dissolve the residue with water (20mL), adjust the pH of the solution to about 1 with HCl (1M), extract with ethyl acetate (25mL×3), and combine the organic phases, After drying with anhydrous Na ₂ SO ₄ , the solvent was removed to obtain 9.16 g of white solid, yield: 96.4%.

MS-ESI: m/z 181.1 [MH] ^- .

Step 3: Synthesis of the compound 2-(3,4-dimethoxyphenylamido)methyl acetate

The compound 3,4-dimethoxybenzoic acid (9.16g, 50.33mmol), HOAT (6.85g, 50.33mmol) and EDCI (14.47g, 75.50mmol) were dissolved in DCM (50mL), and stirring was continued at room temperature for 30min Then, add glycine methyl ester hydrochloride (7.58g, 60.40mmol), under ice bath, slowly add DIPEA (35.16mL, 201.32mmol) dropwise, continue stirring at room temperature overnight, add water (30mL), and use Extracted with CH ₂ Cl ₂ (25mL×3), combined the organic phases, dried with anhydrous Na ₂ SO ₄ , removed the solvent, and the concentrated solution was subjected to column separation (Petroleum ether/EtOAc(v/v)=1/1) to obtain 10.82g white solid, yield: 85%.

MS-ESI: m/z 254.1 [M+H] ⁺ .

Step 4: Synthesis of the compound 2-(3,4-dimethoxyphenylthioamido)methyl acetate

The compound 2-(3,4-dimethoxyphenylamido)methyl acetate (2g, 7.90mmol) and Lawson's reagent (3.19g, 7.89mmol) were dissolved in THF (30mL), and the reaction was continued at 75°C After 2h, remove THF, add saturated NaHCO ₃ solution (30mL), then extract with ethyl acetate (25mL×3), combine the organic phases, dry with anhydrous Na ₂ SO ₄ , remove the solvent, and the concentrated solution is subjected to column separation (Petroleum ether/EtOAc (v/v)=2/1), to obtain 1.81 g of yellow solid, yield: 85%.

MS-ESI: m/z 270.1 [M+H] ⁺ .

Step 5: Synthesis of the compound 2-(((3,4-dimethoxyphenyl)(methylthio)methylene)amino)acetic acid methyl ester

At -78°C, a solution of the compound 2-(3,4-dimethoxyphenylthioamido)methyl acetate (2g, 7.43mmol) in dichloromethane (30mL) was slowly added dropwise to trimethyl Oxonium tetrafluoroboric acid (2.20g, 14.87mmol) in dichloromethane (20mL) solution, continue to stir at 0°C for 3h, then add saturated sodium bicarbonate solution to wash (25mL×3), and wash the organic phase with anhydrous _Na2 Drying over SO ₄ and removing the solvent gave 1.89 g of yellow oil, yield: 90%.

MS-ESI: m/z 284.1 [M+H] ⁺ .

Step 6: Synthesis of compound (S)-methyl 5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3,4-dimethoxyphenyl)oxazole-4-carboxylate

The compound 2-(((3,4-dimethoxyphenyl)(methylthio)methylene)amino)methyl acetate (2.5g, 8.83mmol) was mixed with the compound (S)-(1-fluoro- 1-Oxopropan-2-yl) tert-butyl carbamate (2.53g, 13.25mmol) was dissolved in anhydrous tetrahydrofuran (20mL), and at -78°C, potassium hexamethyldisilazide tetrahydrofuran was added dropwise Solution (22.08mL, 22.08mmol), react at -78°C for 1h, add ice water (20mL) to quench the reaction, extract with ethyl acetate (15mL×3), combine organic phases and dry with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=3/1) to obtain 1.61 g of a yellow solid, yield: 45%.

MS-ESI: m/z 407.2 [M+H] ⁺ .

Step 7: Synthesis of compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3,4-dimethoxyphenyl)oxazole-4-carboxylic acid

Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3,4-dimethoxyphenyl)oxazole-4-carboxylic acid methyl ester (2g, 4.92mmol ) and lithium hydroxide monohydrate (1.03g, 24.6mmol) were dissolved in a mixed solvent of tetrahydrofuran (30mL) and water (15mL), reacted at 40°C for 3h, removed tetrahydrofuran, added hydrochloric acid (1M) to adjust the pH value to 1, Add ethyl acetate for extraction (20 mL×3), combine the organic phases and dry with anhydrous Na ₂ SO ₄ , remove the solvent to obtain 1.8 g of yellow solid, yield: 95%.

Step 8: Compound (S)-(1-(4-((2,4-difluorobenzyl)carbamoyl)-2-(3,4-dimethoxyphenyl)oxazol-5-yl ) ethyl) synthetic tert-butyl carbamate

Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3,4-dimethoxyphenyl)oxazole-4-carboxylic acid (0.3g, 0.76mmol) , 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (220mg, 1.15mmol) and N-hydroxy-7-azabenzotriazole (156mg, 1.15mmol) Dissolved in dichloromethane (10mL), stirred at 0°C for 30min, then added dropwise 2,4-difluorobenzylamine (0.11mL, 0.92mmol) and N,N-diisopropylethylamine (0.4mL, 2.3 mmol), stirred at room temperature for 7h, washed with water (10mL×3), the organic phase was dried with Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=4/1), 249 mg of yellow oil were obtained, yield: 63%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.61 (dd, J ₁ = 8.4Hz, J ₂ = 2.0Hz, 1H), 7.50 (d, J = 1.9Hz, 1H), 7.47–7.41 (m, 1H) ,6.95(d,J＝8.4Hz,1H),6.93–6.84(m,2H),5.32–5.28(m,1H),4.69–4.66(m,2H),3.99(s,3H),3.96(s ,3H),1.56(d,J=7.0Hz,3H),1.45(s,9H);

MS-ESI: m/z 518.3 [M+H] ⁺ .

Step 9: Compound (S)-5-(1-aminoethyl)-N-(2,4-difluorobenzyl)-2-(3,4-dimethoxyphenyl)oxazole-4- Synthesis of Formamide Hydrochloride

To compound (S)-(1-(4-((2,4-difluorobenzyl)carbamoyl)-2-(3,4-dimethoxyphenyl)oxazol-5-yl)ethyl Base) tert-butyl carbamate (0.24g, 0.46mmol) in dichloromethane (2mL) solution was added HCl in ethyl acetate solution (4M, 6mL), stirred at room temperature for 2h, filtered, washed with ethyl acetate (15mL×3 ), to obtain 142 mg of white solid, yield: 68%.

Compound 21: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.73 (dd, J ₁ =8.4Hz, J ₂ =2.0Hz, 1H), 7.67 (d, J = 2.0Hz, 1H), 7.52-7.46( m,1H),7.13(d,J=8.5Hz,1H),7.02–6.94(m,2H),5.17–5.13(m,1H),4.65(s,2H),3.93(d,J=3.3Hz ,6H),1.77(d,J=7.0Hz,3H);

MS-ESI: m/z 418.2 [M+H-HCl] ⁺ .

Example 3: Compound (S)-5-(1-aminoethyl)-N-(2,6-difluorobenzyl)-2-(3,4-dimethoxyphenyl) Synthesis of Oxazole-4-Carboxamide Hydrochloride

Step 1: Compound (S)-(1-(4-((2,6-difluorobenzyl)carbamoyl)-2-(3,4-dimethoxyphenyl)oxazol-5-yl ) ethyl) synthetic tert-butyl carbamate

Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3,4-dimethoxyphenyl)oxazole-4-carboxylic acid (0.2g, 0.51mmol) , 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (146mg, 0.77mmol) and N-hydroxy-7-azabenzotriazole (104mg, 0.77mmol) Dissolved in dichloromethane (10mL), stirred at 0°C for 30min, then added dropwise 2,6-difluorobenzylamine (0.07mL, 0.61mmol) and N,N-diisopropylethylamine (0.27mL, 1.53 mmol), stirred at room temperature for 7h, washed with water (10mL× ₃ ), the organic phase was dried with _Na2SO4 , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=5/1), 127 mg of white solid were obtained, yield: 48%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.60 (dd, J ₁ =8.4Hz, J ₂ =2.0Hz, 1H), 7.49 (d, J = 1.9Hz, 1H), 7.33–7.29 (m, 1H) ,6.99–6.93(m,3H),5.32–5.26(m,1H),4.83–4.71(m,2H),3.99(s,3H),3.96(s,3H),1.55(d,J＝7.0Hz ,3H),1.45(s,9H);

MS-ESI: m/z 518.3 [M+H] ⁺ .

Step 2: Compound (S)-5-(1-aminoethyl)-N-(2,6-difluorobenzyl)-2-(3,4-dimethoxyphenyl)oxazole-4- Synthesis of Formamide Hydrochloride

To compound (S)-(1-(4-((2,6-difluorobenzyl)carbamoyl)-2-(3,4-dimethoxyphenyl)oxazol-5-yl)ethyl Base) tert-butyl carbamate (0.12g, 0.23mmol) in dichloromethane (2mL) solution was added HCl in ethyl acetate solution (4M, 4mL), stirred at room temperature for 7h, filtered, washed with ethyl acetate (15mL×3 ), to obtain a white solid 85 mg, yield: 82%.

Compound 22: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.71 (dd, J ₁ =8.4Hz, J ₂ =2.0Hz, 1H), 7.65 (d, J = 2.0Hz, 1H), 7.42-7.36( m,1H),7.12(d,J=8.5Hz,1H),7.02(t,J=8.1Hz,2H),5.17–5.11(m,1H),4.73(s,2H),3.93(d,J =2.9Hz, 6H), 1.76(d, J=7.0Hz, 3H);

MS-ESI: m/z 418.3 [M+H-HCl] ⁺ .

Example 4: Compound (S)-5-(1-aminoethyl)-N-(2-chloro-6-fluorobenzyl)-2-(3,4-dimethoxyphenyl) Synthesis of Oxazole-4-Carboxamide Hydrochloride

Step 1: Compound (S)-(1-(4-((2-chloro-6-fluorobenzyl)carbamoyl)-2-(3,4-dimethoxyphenyl)oxazole-5- Synthesis of tert-butyl) ethyl) carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3,4-dimethoxyphenyl)oxazole-4-carboxylic acid (0.3g, 0.764mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (219.65mg, 1.15mmol) and N-hydroxyl-7-azabenzotriazole (156.4 mg, 1.15mmol) was dissolved in dichloromethane (15mL), and after stirring at 0°C for 30min, 2-chloro-6-fluorobenzylamine (0.12mL, 0.92mmol) and N,N-diisopropylethyl Amine (0.4mL, 2.3mmol), stirred at room temperature for 12h, washed with water (20mL×3), the organic phase was dried with Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v) =6/1), 188 mg of white solid was obtained, yield: 46%.

Step 2: Compound (S)-5-(1-aminoethyl)-N-(2-chloro-6-fluorobenzyl)-2-(3,4-dimethoxyphenyl)oxazole-4 -Synthesis of formamide hydrochloride

To compound (S)-(1-(4-((2-chloro-6-fluorobenzyl)carbamoyl)-2-(3,4-dimethoxyphenyl)oxazol-5-yl) To a solution of tert-butyl ethyl carbamate (0.18g, 0.35mmol) in dichloromethane (2mL) was added HCl in ethyl acetate (4M, 4mL), stirred at room temperature for 17h, filtered, washed with ethyl acetate (15mL× 3), to obtain 138mg of white solid, yield: 61%.

Compound 23: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.70 (dd, J ₁ =8.4Hz, J ₂ =2.0Hz, 1H), 7.64 (d, J = 2.0Hz, 1H), 7.54-7.52( m,1H),7.31–7.26(m,1H),7.18–7.13(m,1H),7.12(d,J＝8.5Hz,1H),5.17–5.12(m,1H),4.82(s,2H) ,4.36(d,J=1.8Hz,2H),3.92(s,6H),1.76(d,J=7.0Hz,3H);

MS-ESI: m/z 434.2 [M+H-HCl] ⁺ .

Example 5: Compound (S)-5-(1-aminoethyl)-N-(2,6-difluorobenzyl)-2-(3-ethoxy-4-methoxy Synthesis of phenyl)oxazole-4-carboxamide hydrochloride

Step 1: Synthesis of the compound 3-ethoxy-4-methoxybenzoic acid methyl ester

3-Hydroxy-4-methoxybenzoic acid methyl ester (10g, 54.9mmol) was dissolved in acetone (50mL), and anhydrous potassium carbonate (15.2g, 109.9mmol) and bromoethane (6.1mL, 82.42mmol) were added successively ), seal the tube, and react at 60°C for 4.5h. Saturated NaCl solution (20 mL) was added, extracted with ethyl acetate (25 mL×3), the organic phases were combined, dried with anhydrous Na ₂ SO ₄ for 1 h, and the solvent was removed to obtain 11.07 g of white solid, yield: 95.9%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.65(d, J=8.4Hz, 1H), 7.53(s, 1H), 6.87(d, J=8.4Hz, 1H), 4.12-4.17(m, 2H) ,3.91(s,3H),3.87(s,3H),1.47(t,J=7.0Hz,3H);

MS-ESI: m/z 211.2 [M+H] ⁺ .

Step 2: Synthesis of compound 3-ethoxy-4-methoxybenzoic acid

The compound 3-ethoxy-4-methoxybenzoic acid methyl ester (11.66g, 55.5mmol) was dissolved in a mixed solvent of ethanol (20mL) and water (10mL), and then sodium hydroxide (11.1g, 277.5 mmol), reacted at 60°C for 1.5h, removed ethanol, dissolved the residue with water (20mL), adjusted the pH value of the solution to about 1 with HCl (1M), extracted with ethyl acetate (25mL×3), and combined organic After phase, it was dried with anhydrous Na ₂ SO ₄ , and the solvent was removed to obtain 10.25 g of white solid, yield: 94.5%.

MS-ESI: m/z 197.2 [M+H] ⁺ .

Step 3: Synthesis of the compound 2-(3-ethoxy-4-methoxybenzamido)methyl acetate

The compound 3-ethoxy-4-methoxybenzoic acid (11.86 g, 60.5 mmol), HOAT (8.229 g, 60.51 mmol) and EDCI (17.336 g, 90.76 mmol) were dissolved in DCM (50 mL) at room temperature After continuing to stir for 30min, add glycine methyl ester hydrochloride (9.076g, 72.61mmol), under ice bath, slowly add DIPEA (42.2mL, 242.0mmol) dropwise, continue stirring overnight at room temperature, add water (30mL) Afterwards, extract with CH ₂ Cl ₂ (25 mL×3), combine the organic phases, dry with anhydrous Na ₂ SO ₄ , remove the solvent, and conduct column separation of the concentrated solution (Petroleum ether/EtOAc (v/v)=1/1 ), to obtain 12.88g white solid, yield: 79.7%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.42(s, 1H), 7.33(d, J=8.3Hz, 1H), 6.87(d, J=8.4Hz, 1H), 6.60(s, 1H), 4.23 (d, J=5.0Hz, 2H), 4.12-4.17(m, 2H), 3.91(s, 3H), 3.80(s, 3H), 1.47(t, J=7.0Hz, 3H);

MS-ESI: m/z 268.1 [M+H] ⁺ .

Step 4: Synthesis of the compound 2-(3-ethoxy-4-methoxyphenylthioamido)methyl acetate

Compound 2-(3-ethoxy-4-methoxybenzamido)methyl acetate (2g, 7.49mmol) and Lawson's reagent (3.03g, 7.49mmol) were dissolved in THF (30mL), at 75°C After continuing to react for 2 h, remove THF, add saturated NaHCO ₃ solution (30 mL), then extract with ethyl acetate (25 mL×3), combine organic phases, dry with anhydrous Na ₂ SO ₄ , remove solvent, and concentrate the solution for column separation (Petroleum ether/EtOAc (v/v)=2/1), 1.7046 g of yellow solid was obtained, yield: 80.4%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.05(s, 1H), 7.54(s, 1H), 7.33(d, J=8.4Hz, 1H), 6.83(d, J=8.4Hz, 1H), 4.56 (d, J=4.4Hz, 2H), 4.13-4.18(m, 2H), 3.90(s, 3H), 3.83(s, 3H), 1.47(t, J=7.0Hz, 3H);

MS-ESI: m/z 284.1 [M+H] ⁺ .

Step 5: Synthesis of the compound 2-(((3-ethoxy-4-methoxyphenyl)(methylthio)methylene)amino)acetate methyl ester

At -78°C, a solution of the compound 2-(3-ethoxy-4-methoxyphenylthioamido)methyl acetate (2g, 7.06mmol) in dichloromethane (30mL) was slowly added dropwise to Trimethyloxonium tetrafluoroboric acid (2.08g, 14.12mmol) in dichloromethane (20mL) solution, after stirring for 3h at 0°C, add saturated sodium bicarbonate solution for washing (25mL×3), and wash the organic phase with Dry over Na ₂ SO ₄ and remove the solvent to obtain 1.89 g of yellow oil, yield: 90%.

Step 6: Compound (S)-methyl 5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3-ethoxy-4-methoxyphenyl)oxazole-4-carboxylate Synthesis

Compound 2-(((3-ethoxy-4-methoxyphenyl)(methylthio)methylene)amino)methyl acetate (2.47g, 8.31mmol) and compound (S)-(1 -Fluoro-1-oxopropan-2-yl) tert-butyl carbamate (2.38g, 12.46mmol) was dissolved in anhydrous tetrahydrofuran (20mL), and at -78°C, hexamethyldisilazylamine was added dropwise Potassium tetrahydrofuran solution (20.78mL, 20.78mmol), react at -78°C for 1h, add ice water (20mL) to quench the reaction, extract with ethyl acetate (15mL×3), combine the organic phases with anhydrous Na ₂ SO ₄ was dried, the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v)=3/1) to obtain 1 g of yellow solid, yield: 28%.

Step 7: Synthesis of compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3-ethoxy-4-methoxyphenyl)oxazole-4-carboxylic acid

Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3-ethoxy-4-methoxyphenyl)oxazole-4-carboxylic acid methyl ester (0.73 g, 1.736mmol) and lithium hydroxide monohydrate (364.25mg, 8.681mmol) were dissolved in a mixed solvent of tetrahydrofuran (20mL) and water (10mL), reacted at 40°C for 3h, removed tetrahydrofuran, added hydrochloric acid (1M) to adjust the pH When the value reached 1, it was extracted with ethyl acetate (20 mL×3), the combined organic phases were dried with anhydrous Na ₂ SO ₄ , and the solvent was removed to obtain 668 mg of a yellow solid, yield: 95%.

Step 8: Compound (S)-(1-(4-((2,6-difluorobenzyl)carbamoyl)-2-(3-ethoxy-4-methoxyphenyl)oxazole- Synthesis of tert-butyl 5-yl)ethyl)carbamate

Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3-ethoxy-4-methoxyphenyl)oxazole-4-carboxylic acid (0.7g, 1.732mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (496.22mg, 2.60mmol) and N-hydroxy-7-azabenzotriazole (353.33 mg, 2.60mmol) was dissolved in dichloromethane (30mL), and after stirring at 0°C for 30min, 2,6-difluorobenzylamine (0.25mL, 2.08mmol) and N,N-diisopropylethylamine were added dropwise (0.91mL, 5.2mmol), stirred at room temperature for 12h, washed with water (20mL×3), the organic phase was dried with Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)= 6/1), to obtain 834.6 mg of white solid, yield: 91%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.58 (dd, J ₁ = 8.4Hz, J ₂ = 2.0Hz, 1H), 7.49 (d, J = 1.9Hz, 1H), 7.32–7.30 (m, 1H) ,6.98–6.92(m,3H),5.30–5.25(m,1H),4.83–4.74(m,2H),4.23–4.17(m,2H),3.94(s,3H),1.55–1.51(m, 6H), 1.45(s, 9H);

MS-ESI: m/z 532.2 [M+H] ⁺ .

Step 9: Compound (S)-5-(1-aminoethyl)-N-(2,6-difluorobenzyl)-2-(3-ethoxy-4-methoxyphenyl)oxazole -Synthesis of 4-formamide hydrochloride

To compound (S)-(1-(4-((2,6-difluorobenzyl)carbamoyl)-2-(3-ethoxy-4-methoxyphenyl)oxazole-5- Base) ethyl) tert-butyl carbamate (0.83g, 1.56mmol) in dichloromethane (10mL) solution was added HCl in ethyl acetate solution (4M, 6mL), stirred at room temperature for 3h, filtered, washed with ethyl acetate ( 20 mL×3), 699.3 mg of white solid was obtained, yield: 96%.

Compound 24: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.70 (dd, J ₁ =8.4Hz, J ₂ =2.0Hz, 1H), 7.63 (d, J = 2.0Hz, 1H), 7.43-7.35( m,1H),7.12(d,J=8.5Hz,1H),7.02(t,J=8.1Hz,2H),5.16–5.11(m,1H),4.73(s,2H),4.18–4.13(m ,2H),3.93(s,3H),1.76(d,J=7.0Hz,3H),1.46(t,J=7.0Hz,3H);

MS-ESI: m/z 432.3 [M+H-HCl] ⁺ .

Example 6: Compound (S)-1-(5-(1-aminoethyl)-2-(3,4-dimethoxyphenyl)oxazol-4-yl)-2- Synthesis of (3,5-dichloropyridin-4-yl)ethanone dihydrochloride

Step 1: Compound (S)-(1-(4-(2-(3,5-dichloropyridin-4-yl)acetyl)-2-(3,4-dimethoxyphenyl)oxazole Synthesis of tert-butyl -5-yl)ethyl)carbamate

Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3,4-dimethoxyphenyl)oxazole-4-carboxylic acid methyl ester (0.2g, 0.49 mmol) and 3,5-dichloro-4-methylpyridine (119.6mg, 0.74mmol) were dissolved in tetrahydrofuran (5mL), stirred at 0°C, and a tetrahydrofuran solution of lithium hexamethyldisilazide (1.476 mL, 1.476mmol), stirred at room temperature for 4h, added saturated ammonium chloride solution (15mL), extracted with ethyl acetate (15mL×3), combined the organic phases and dried them with Na ₂ SO ₄ , removed the solvent, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=4/1), 120 mg of yellow solid was obtained, yield: 45%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.55 (s, 2H), 7.68 (dd, J ₁ = 8.4Hz, J ₂ = 2.0Hz, 1H), 7.58 (d, J = 1.9Hz, 1H), 6.98 (d,J=8.5Hz,1H),5.36–5.30(m,1H),4.85–4.75(m,2H),4.03(s,3H),3.99(s,3H),1.51(d,J=7.1 Hz,3H),1.42(s,9H);

MS-ESI: m/z 536.2 [M+H] ⁺ .

Step 2: Compound (S)-1-(5-(1-aminoethyl)-2-(3,4-dimethoxyphenyl)oxazol-4-yl)-2-(3,5- Synthesis of dichloropyridin-4-yl)ethanone dihydrochloride

To compound (S)-(1-(4-(2-(3,5-dichloropyridin-4-yl)acetyl)-2-(3,4-dimethoxyphenyl)oxazole-5 Add HCl in ethyl acetate (4M, 4mL) to a solution of tert-butyl carbamate (0.11g, 0.21mmol) in dichloromethane (2mL), stir at room temperature for 5h, filter, and wash with ethyl acetate (15 mL×3), 86 mg of yellow solid was obtained, yield: 86%.

Compound 25: ¹ H NMR (400MHz, CD ₃ OD): δppm 8.62(s, 2H), 7.80(dd, J ₁ =8.4Hz, J ₂ =1.8Hz, 1H), 7.71(d, J = 1.8Hz, 1H), 7.16(d, J＝8.4Hz, 1H), 5.21–5.16(m, 1H), 5.00–4.92(m, 2H), 3.97(s, 3H), 3.95(s, 3H), 1.76(d , J=6.9Hz, 3H).

Example 7: Compound (S)-1-(5-(1-aminoethyl)-2-(3-ethoxy-4-methoxyphenyl)oxazole-4- Synthesis of -2-(3,5-dichloropyridin-4-yl)ethanone dihydrochloride

Step 1: Compound (S)-(1-(4-(2-(3,5-dichloropyridin-4-yl)acetyl)-2-(3-ethoxy-4-methoxyphenyl ) Synthesis of oxazol-5-yl) ethyl) tert-butyl carbamate

Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3-ethoxy-4-methoxyphenyl)oxazole-4-carboxylic acid methyl ester (0.2 g, 0.48mmol) and 3,5-dichloro-4-methylpyridine (116.65mg, 0.72mmol) were dissolved in tetrahydrofuran (5mL), stirred at 0°C, and tetrahydrofuran of lithium hexamethyldisilazide was added dropwise solution (1.44mL, 1.44mmol), stirred at room temperature for 2.5h, added saturated ammonium chloride solution (15mL), dichloromethane extracted (20mL), the organic phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was Column separation (petroleum ether/ethyl acetate (v/v)=4/1) yielded 0.16 g of light yellow solid, yield: 61%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.55 (s, 2H), 7.66 (dd, J ₁ = 8.4Hz, J ₂ = 2.0Hz, 1H), 7.58 (d, J = 1.9Hz, 1H), 6.98 (d,J=8.5Hz,1H),5.34–5.29(m,1H),4.85–4.74(m,2H),4.28–4.22(m,2H),3.97(s,3H),1.56(t,J =7.0Hz, 3H), 1.51(d, J=7.1Hz, 3H), 1.42(s, 9H);

MS-ESI: m/z 550.1 [M+H] ⁺ .

Step 2: Compound (S)-1-(5-(1-aminoethyl)-2-(3-ethoxy-4-methoxyphenyl)oxazol-4-yl)-2-(3 , Synthesis of 5-dichloropyridin-4-yl)ethanone dihydrochloride

To compound (S)-(1-(4-(2-(3,5-dichloropyridin-4-yl)acetyl)-2-(3-ethoxy-4-methoxyphenyl)oxa Add HCl in ethyl acetate (4M, 4mL) to a solution of tert-butyl oxazol-5-yl)ethyl)carbamate (0.16g, 0.29mmol) in dichloromethane (2mL), stir at room temperature for 2h, filter, and acetic acid After washing with ethyl ester (15 mL×3), 50 mg of yellow solid was obtained, yield: 40%.

Compound 26: ¹ H NMR (400MHz, CD ₃ OD): δppm 8.57(s, 2H), 7.76(dd, J ₁ =8.4Hz, J ₂ =2.0Hz, 1H), 7.67(d, J = 2.0Hz, 1H),7.14(d,J＝8.5Hz,1H),5.18–5.13(m,1H),4.90–4.87(m,2H),4.20–4.15(m,2H),3.92(s,3H),1.72 (d, J=7.0Hz, 3H), 1.46 (t, J=7.0Hz, 3H).

Example 8: Compound (S)-5-(1-aminoethyl)-N-(3,5-dichloropyridin-4-yl)-2-(3,4-dimethoxy Synthesis of phenyl)oxazole-4-carboxamide dihydrochloride

Step 1: Synthesis of compound (S)-tert-butyl(1-(2-(3,4-dimethoxyphenyl)-4-(fluorocarbonyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3,4-dimethoxyphenyl)oxazole-4-carboxylic acid (0.86g, 2.2mmol) Dissolve triethylamine (0.34mL, 2.42mmol) in dichloromethane (15mL), add cyanuric fluoride (0.36mL, 4.4mmol) dropwise to this solution at -40°C, react at -10°C for 2h, add Washed with ice water (20 mL×4), combined organic phases were dried with Na ₂ SO ₄ , and the solvent was removed to obtain a red solid 0.82 g, yield: 95%.

¹ H NMR (400MHz, d ₆ -DMSO): δppm 7.61 (dd, J ₁ =8.4Hz, J ₂ =2.0Hz, 1H), 7.49 (d, J = 2.0Hz, 1H), 7.17 (d, J = 8.5Hz, 1H), 5.21–5.16(m, 1H), 3.86(d, J=5.1Hz, 6H), 1.48(d, J=7.1Hz, 3H), 1.37(s, 9H);

MS-ESI: m/z 395.2 [M+H] ⁺ .

Step 2: Compound (S)-(1-(4-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(3,4-dimethoxyphenyl)oxazole- Synthesis of tert-butyl 5-yl)ethyl)carbamate

3,5-dichloro-4-aminopyridine (537.9mg, 3.3mmol) and sodium hydride (60%, 132mg, 3.3mmol) were dissolved in tetrahydrofuran (6mL), stirred at room temperature for 1h, at 0°C, to this Compound (S)-(1-(2-(3,4-dimethoxyphenyl)-4-(fluorocarbonyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester ( 0.86g, 2.2mmol) in tetrahydrofuran (9mL), stirred at room temperature for 23h, added saturated ammonium chloride solution (20mL), and extracted with ethyl acetate (20mL×3). The combined organic phases were dried with Na ₂ SO ₄ , the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v)=3/1) to obtain 325 mg of light yellow oil, yield: 27%.

Step 3: Compound (S)-5-(1-aminoethyl)-N-(3,5-dichloropyridin-4-yl)-2-(3,4-dimethoxyphenyl)oxazole -Synthesis of 4-formamide dihydrochloride

To compound (S)-(1-(4-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(3,4-dimethoxyphenyl)oxazole-5- Add HCl in ethyl acetate (4M, 8mL) to a solution of tert-butyl ethyl)carbamate (0.32g, 0.59mmol) in dichloromethane (2mL), stir at room temperature for 1.5h, filter, and wash with ethyl acetate (20 mL×3), 220 mg of yellow solid was obtained, yield: 81%, recrystallized from methanol/ethyl acetate (v/v=1/20), and 110 mg of yellow solid was obtained.

Compound 27: ¹ H NMR (400MHz, CD ₃ OD): δppm 8.72(s, 2H), 7.81(dd, J ₁ =8.4Hz, J ₂ =2.0Hz, 1H), 7.74(d, J = 2.0Hz, 1H), 7.16(d, J=8.5Hz, 1H), 5.29–5.24(m, 1H), 3.96(d, J=6.8Hz, 6H), 1.80(d, J=7.0Hz, 3H);

MS-ESI: m/z 438.2 [M+H-2HCl] ⁺ .

Example 9: Compound (S)-5-(1-aminoethyl)-N-(3,5-dichloropyridin-4-yl)-2-(3-ethoxy-4-methyl Synthesis of oxyphenyl)oxazole-4-carboxamide dihydrochloride

Step 1: Compound (S)-tert-butyl(1-(2-(3-ethoxy-4-methoxyphenyl)-4-(fluorocarbonyl)oxazol-5-yl)ethyl)carbamate Synthesis of esters

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-ethoxy-4-methoxyphenyl)oxazole-4-carboxylic acid ( 0.65g, 1.6 mmol) and triethylamine (0.25mL, 1.76mmol) were dissolved in dichloromethane (10mL), and cyanuric fluoride (0.26mL, 3.2mmol) was slowly added dropwise to this solution at -40°C, React at -10°C for 2 h, add ice water (50 mL) and wash 4-5 times, dry the organic phase with anhydrous Na ₂ SO ₄ , remove the solvent to obtain 577 mg of yellow solid, yield: 88%.

¹ H NMR (400MHz, d ₆ -DMSO): δppm 7.60 (dd, J ₁ =8.4Hz, J ₂ =1.9Hz, 1H), 7.48 (d, J = 2.0Hz, 1H), 7.17 (d, J = 8.6Hz, 1H), 5.26–5.18(m, 1H), 4.14–4.06(m, 2H), 3.85(s, 3H), 1.47(d, J＝7.1Hz, 3H), 1.40–1.38(m, 3H ),1.36–1.31(m,9H);

MS-ESI: m/z 409.3 [M+H] ⁺ .

Step 2: Compound (S)-(1-(4-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(3-ethoxy-4-methoxyphenyl) Synthesis of tert-butyl oxazol-5-yl)ethyl)carbamate

3,5-dichloro-4-aminopyridine (341.23mg, 2.1mmol) and sodium hydride (60%, 84mg, 2.1mmol) were dissolved in tetrahydrofuran (6mL), stirred at room temperature for 1h, and compound (S )-(1-(2-(3-ethoxy-4-methoxyphenyl)-4-(fluorocarbonyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (0.57g, 1.4 mmol) in tetrahydrofuran (9 mL), stirred at room temperature for 14 h, added saturated ammonium chloride solution (20 mL), and extracted with ethyl acetate (20 mL×3). The combined organic phases were dried with Na ₂ SO ₄ , the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v)=3/1) to obtain 240 mg of light yellow solid, yield: 31%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 9.04(s, 1H), 8.62(s, 2H), 7.68–7.65(m, 1H), 7.55(d, J=1.9Hz, 1H), 6.98(d, J＝8.5Hz, 1H), 5.34–5.30(m, 1H), 4.26–4.21(m, 2H), 3.97(s, 3H), 1.60(d, J＝7.0Hz, 3H), 1.44(s, 9H ),1.28(t,J=7.1Hz,3H);

MS-ESI: m/z 552.3 [M+H] ⁺ .

Step 3: Compound (S)-5-(1-aminoethyl)-N-(3,5-dichloropyridin-4-yl)-2-(3-ethoxy-4-methoxyphenyl ) Synthesis of oxazole-4-carboxamide dihydrochloride

To compound (S)-(1-(4-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(3-ethoxy-4-methoxyphenyl)oxazole -5-yl) ethyl) tert-butyl carbamate (0.23g, 0.42mmol) in dichloromethane (2mL) solution was added HCl in ethyl acetate solution (4M, 7mL), stirred at room temperature for 2.5h, filtered, acetic acid After washing with ethyl ester (15 mL×3), 170 mg of a yellow solid was obtained, which was recrystallized using methanol/ethyl acetate (v/v=1/20) to obtain 27.7 mg of a yellow solid.

Compound 28: ¹ H NMR (400MHz, CD ₃ OD): δppm 8.70(s, 2H), 7.79(dd, J ₁ =8.4Hz, J ₂ =2.0Hz, 1H), 7.72(d, J = 1.9Hz, 1H), 7.16(d, J＝8.5Hz, 1H), 5.28–5.23(m, 1H), 4.22–4.17(m, 2H), 3.95(s, 3H), 1.79(d, J＝7.0Hz, 3H ), 1.48(t, J=7.2Hz, 3H);

MS-ESI: m/z 452.9 [M+H-2HCl] ⁺ .

Example 10: Compound (S)-5-(1-aminoethyl)-N-(2-chloro-6-fluorobenzyl)-2-(3-ethoxy-4-methoxy Synthesis of phenyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound (S)-(1-(4-((2-chloro-6-fluorobenzyl)carbamoyl)-2-(3-ethoxy-4-methoxyphenyl)oxazole Synthesis of tert-butyl -5-yl)ethyl)carbamate

Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3-ethoxy-4-methoxyphenyl)oxazole-4-carboxylic acid (0.3g, 0.74mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (212mg, 1.11mmol) and N-hydroxy-7-azabenzotriazole (151mg, 1.11mmol) was dissolved in dichloromethane (10mL), and after stirring at 0°C for 30min, 2-fluoro-6-chlorobenzylamine (0.11mL, 0.89mmol) and N,N-diisopropylethylamine ( 0.39mL, 2.21mmol), stirred at room temperature for 12h, washed with water (10mL×3), the organic phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v) =6/1), 190 mg of white solid was obtained, yield: 47%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.60 (dd, J ₁ =8.4Hz, J ₂ =1.9Hz, 1H), 7.52 (d, J = 1.8Hz, 1H), 7.39–7.29 (m, 1H) ,7.27–7.25(m,1H),7.10–7.05(m,1H),6.94(d,J＝8.5Hz,1H),5.30–5.25(m,1H),4.91–4.84(m,2H),4.23 –4.18(m,2H),3.95(s,1H),1.57–1.51(m,6H),1.45(s,9H);

MS-ESI: m/z 549.2 [M+H] ⁺ .

Step 2: Compound (S)-5-(1-aminoethyl)-N-(2-chloro-6-fluorobenzyl)-2-(3-ethoxy-4-methoxyphenyl)oxa Synthesis of azole-4-carboxamide hydrochloride

To compound (S)-(1-(4-((2-chloro-6-fluorobenzyl)carbamoyl)-2-(3-ethoxy-4-methoxyphenyl)oxazole-5 Add HCl in ethyl acetate (4M, 6mL) to a solution of tert-butyl carbamate (0.19g, 0.35mmol) in dichloromethane (2mL), stir at room temperature for 3h, filter, and wash with ethyl acetate (15mL×3), 92mg of white solid was obtained, yield: 56%.

Compound 29: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.69 (dd, J ₁ =8.4Hz, J ₂ =2.0Hz, 1H), 7.62 (d, J = 2.0Hz, 1H), 7.38-7.35( m,1H),7.33–7.31(m,1H),7.18–7.13(m,1H),7.11(d,J＝8.5Hz,1H),5.17–5.12(m,1H),4.81(s,2H) ,4.17–4.12(m,2H),3.92(s,3H),1.76(d,J＝7.0Hz,3H),1.45(t,J＝7.0Hz,3H);

MS-ESI: m/z 448.2 [M+H-HCl] ⁺ .

Example 11: Compound (S)-5-(1-aminoethyl)-2-(3-cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-(2,6-difluorobenzyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((2,6-difluorobenzyl Synthesis of base) carbamoyl) oxazol-5-yl) ethyl) tert-butyl carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) oxazole-4-carboxylic acid (0.3g, 0.64mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (183.36mg, 0.96mmol) and N-hydroxy- 7-Azabenzotriazole (130.56 mg, 0.96 mmol) was dissolved in dichloromethane (10 mL), and 2,6-difluorobenzylamine (0.1 mL, 0.77 mmol) and N,N-diisopropylethylamine (0.33mL, 1.92mmol), stirred at room temperature for 4h, washed with water (20mL×3), the organic phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was Column separation (petroleum ether/ethyl acetate (v/v)=5/1) yielded 203 mg of white solid, yield: 53%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.59 (dd, J ₁ = 8.3Hz, J ₂ = 1.9Hz, 1H), 7.55 (d, J = 1.9Hz, 1H), 7.35–7.30 (m, 1H) ,7.24(d,J＝8.3Hz,1H),6.98–6.94(m,2H),6.71(t,J _FH ＝75.0Hz,1H),5.35–5.28(m,1H),4.80–4.70(m, 2H), 3.99(d, J＝6.9Hz, 2H), 1.55(d, J＝7.0Hz, 3H), 1.38–1.36(m, 1H), 1.45–1.43(m, 9H), 0.72–0.68(m ,2H),0.43–0.41(m,2H);

MS-ESI: m/z 594.2 [M+H] ⁺ .

Step 2: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2, Synthesis of 6-difluorobenzyl)oxazole-4-carboxamide hydrochloride

To compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((2,6-difluorobenzyl) Add HCl in ethyl acetate (4M, 4mL) to a solution of tert-butyl carbamate (0.2g, 0.34mmol) in dichloromethane (2mL) and stir at room temperature After 14 hours, it was filtered and washed with ethyl acetate (15 mL×3) to obtain 152 mg of white solid, yield: 83%.

Compound 30: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.69 (d, J = 1.9Hz, 1H), 7.61 (dd, J ₁ = 8.4Hz, J ₂ = 1.9Hz, 1H), 7.32-7.28 ( m,1H),7.23(d,J=8.4Hz,1H),6.93(t,J=8.0Hz,2H),6.83(t,J _FH =74.8Hz,1H),5.10–5.05(m,1H) ,4.64(s,2H),3.94(d,J=7.0Hz,2H),1.67(d,J=7.0Hz,3H),1.27–1.24(m,1H),0.61–0.59(m,2H), 0.35–0.32(m,2H);

MS-ESI: m/z 494.3 [M+H-HCl] ⁺ .

Example 12: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-(2-fluorobenzyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((2-fluorobenzyl)amino Synthesis of tert-butyl formyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) oxazole-4-carboxylic acid (0.3g, 0.64mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (183.36mg, 0.96mmol) and N-hydroxy- 7-Azabenzotriazole (130.56mg, 0.96mmol) was dissolved in dichloromethane (10mL), and 2-fluorobenzylamine (0.09mL, 0.77mmol) and N,N-Diisopropylethylamine (0.33mL, 1.92mmol), stirred at room temperature for 7h, washed with water (20mL×3), dried the organic phase with anhydrous Na ₂ SO ₄ , removed the solvent, and the concentrated solution was subjected to column separation ( Petroleum ether/ethyl acetate (v/v)=5/1) to obtain 256 mg of white solid, yield: 69%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.59 (dd, J ₁ =8.3Hz, J ₂ =1.9Hz, 1H), 7.56 (d, J = 1.8Hz, 1H), 7.47–7.43 (m, 1H) ,7.33–7.29(m,1H),7.25(d,J＝8.3Hz,1H),7.18–7.09(m,2H),6.72(t,J _FH ＝75.0Hz,1H),5.32–5.28(m, 1H), 4.74–4.71(m, 2H), 3.99(d, J=7.0Hz, 2H), 1.56(d, J=7.0Hz, 3H), 1.45(s, 9H), 1.41–1.37(m, 1H ),0.73–0.68(m,2H),0.44–0.40(m,2H);

MS-ESI: m/z 576.1 [M+H] ⁺ .

Step 2: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2- Synthesis of fluorobenzyl)oxazole-4-carboxamide hydrochloride

To compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((2-fluorobenzyl)carbamoyl )Oxazol-5-yl)ethyl)carbamate tert-butyl ester (0.25g, 0.43mmol) in dichloromethane (2mL) solution was added HCl in ethyl acetate solution (4M, 8mL), stirred at room temperature for 2h, filtered , washed with ethyl acetate (20 mL×3) to obtain 191 mg of white solid, yield: 87%.

Compound 31: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.80 (d, J = 1.9Hz, 1H), 7.73 (dd, J ₁ = 8.4Hz, J ₂ = 2.0Hz, 1H), 7.45 (td, J ₁ ＝7.6Hz, J ₂ ＝1.5Hz, 1H), 7.33(d, J＝8.3Hz, 2H), 7.19–7.12(m, 2H), 6.92(t, J _FH ＝74.8Hz, 1H), 5.20 –5.14(m,1H),4.69(s,2H),4.03(d,J=6.9Hz,2H),1.77(d,J=7.0Hz,3H),1.38–1.34(m,1H),0.71– 0.66(m,2H),0.44–0.41(m,2H);

MS-ESI: m/z 476.3 [M+H-HCl] ⁺ .

Example 13: Compound (S)-5-(1-aminoethyl)-2-(3-butoxy-4-methoxyphenyl)-N-(2,4-difluoro Synthesis of benzyl)oxazole-4-carboxamide hydrochloride

Step 1: Synthesis of the compound 3-butoxy-4-methoxybenzoic acid methyl ester

Methyl 3-hydroxy-4-methoxybenzoate (10.0g, 54.95mmol), potassium carbonate (15.15g, 109.78mmol) and n-bromobutane (8.85mL, 66.07mmol) were dissolved in N,N- Dimethylformamide (60mL), reacted at 60°C for 4.5h, extracted with ethyl acetate (50mL× ₃ ), combined the organic phases and dried with anhydrous _Na2SO4 , removed the solvent, and the concentrated solution was subjected to column separation (petroleum Ether/ethyl acetate (v/v)=5/1) to obtain 12.89 g of white solid, yield: 99%.

Step 2: Synthesis of compound 3-butoxy-4-methoxybenzoic acid

The compound 3-butoxy-4-methoxybenzoic acid methyl ester (12.89g, 54.16mmol) and sodium hydroxide (6.5g, 162.48mmol) were dissolved in a mixed solvent of ethanol (150mL) and water (50mL) , reacted at 60°C for 1.5h, removed ethanol, adjusted the pH to 1 with hydrochloric acid (1M), extracted with ethyl acetate (50mL×3), combined the organic phases and dried them with anhydrous Na ₂ SO ₄ , and removed the solvent to obtain 12.02 g white solid, yield: 99%.

Step 3: Synthesis of the compound 2-(3-butoxy-4-methoxybenzamide) methyl acetate

Compound 3-butoxy-4-methoxybenzoic acid (12.02g, 53.66mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (15.45g, 80.49mmol) and 1-hydroxybenzotriazole (10.87g, 80.49mmol) were dissolved in dichloromethane (80mL), stirred at room temperature for 0.5h, added glycine methyl ester hydrochloride (8.11g, 64.39mmol ) and N,N-diisopropylethylamine (28.8mL, 160.98mmol), stirred at room temperature for 12h, washed with water (40mL×3), dried the organic phase with Na ₂ SO ₄ , removed the solvent, and the concentrated solution was subjected to column separation ( Petroleum ether/ethyl acetate (v/v)=1/1) to obtain 14.74 g of white solid, yield: 93%.

Step 4: Synthesis of the compound 2-(3-butoxy-4-methoxyphenylthioamide) methyl acetate

The compound 2-(3-butoxy-4-methoxybenzamide) methyl acetate (5.0g, 16.95mmol) and Lawson's reagent (6.85g, 16.95mmol) were dissolved in anhydrous tetrahydrofuran (40mL ), refluxed at 75°C for 2h, added saturated sodium bicarbonate solution (40mL), extracted with ethyl acetate (50mL×3), combined the organic phases and dried them with Na ₂ SO ₄ , removed the solvent, and the concentrated solution was subjected to column separation (petroleum Ether/ethyl acetate (v/v)=3/1) to obtain 5.16 g of yellow solid, yield: 98%.

Step 5: Synthesis of the compound 2-(((3-butoxy-4-methoxyphenyl)(methylthio)methylene)amino)acetate methyl ester

At -78°C, a solution of the compound 2-(3-butoxy-4-methoxyphenylthioamide) methyl acetate (5.16g, 16.60mmol) in dichloromethane (30mL) was slowly added dropwise to Trimethyloxonium tetrafluoroboric acid (4.88g, 33.20mmol) in dichloromethane (20mL) solution, after stirring for 3h at 0°C, add saturated sodium bicarbonate solution for washing (25mL×3), and wash the organic phase with Dry over Na ₂ SO ₄ and remove the solvent to obtain 5.35 g of yellow oil, yield: 99%.

Step 6: Compound (S)-methyl 2-(3-butoxy-4-methoxyphenyl)-5-(1-(tert-butoxycarbonylamino)ethyl)oxazole-4-carboxylate Synthesis

Compound 2-(((3-butoxy-4-methoxyphenyl) (methylthio) methylene) amino) methyl acetate (5.35g, 16.36mmol) and compound (S)-(1 -Fluoro-1-oxopropan-2-yl) tert-butyl carbamate (7.47g, 39.1mmol) was dissolved in anhydrous tetrahydrofuran (20mL), and at -78°C, hexamethyldisilazylamine was added dropwise Potassium tetrahydrofuran solution (32.0mL, 32.0mmol), react at -78°C for 1h, add ice water (20mL) to quench the reaction, extract with ethyl acetate (15mL×3), combine the organic phases with anhydrous Na ₂ SO ₄ was dried, the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=3/1) to obtain 5.02 g of a yellow solid, yield: 68%.

Step 7: Synthesis of compound (S)-2-(3-butoxy-4-methoxyphenyl)-5-(1-(tert-butoxycarbonylamino)ethyl)oxazole-4-carboxylic acid

Compound (S)-2-(3-butoxy-4-methoxyphenyl)-5-(1-(tert-butoxycarbonylamino)ethyl)oxazole-4-carboxylic acid methyl ester (2.47 g, 5.52mmol) and lithium hydroxide monohydrate (1.16g, 27.27mmol) were dissolved in a mixed solvent of tetrahydrofuran (40mL) and water (20mL), reacted at 40°C for 3h, removed tetrahydrofuran, added hydrochloric acid (1M) to adjust the pH When the value reached 1, it was extracted with ethyl acetate (30 mL×3), the combined organic phases were dried with anhydrous Na ₂ SO ₄ , and the solvent was removed to obtain 1.66 g of yellow solid, yield: 70%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.65(d, J=8.4Hz, 1H), 7.60(s, 1H), 6.94(d, J=8.4Hz, 1H), 5.50-5.42(m, 1H) ,4.12(t,J=6.8Hz,2H),3.94(s,3H),1.92-1.85(m,2H),1.59(d,J=7.1Hz,3H),1.57-1.51(m,2H), 1.44(s,9H),1.01(t,J=7.3Hz,3H);

MS-ESI: m/z 435.2 [M+H] ⁺ .

Step 8: Compound (S)-(1-(2-(3-butoxy-4-methoxyphenyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazole- Synthesis of tert-butyl 5-yl)ethyl)carbamate

Compound (S)-2-(3-butoxy-4-methoxyphenyl)-5-(1-(tert-butoxycarbonylamino)ethyl)oxazole-4-carboxylic acid (1.66g, 3.82mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.10g, 5.73mmol) and N-hydroxyl-7-azabenzotriazole (0.77 g, 5.73mmol) was dissolved in dichloromethane (30mL), stirred at room temperature for 0.5h, and 2,4-difluorobenzylamine (0.55mL, 0.90mmol) and N,N-diisopropylethyl Amine (2.05mL, 11.46mmol), stirred at room temperature for 12h, washed with water (20mL×3), the organic phase was dried with Na ₂ SO ₄ , the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v) =6/1), to obtain 694.5 mg of white solid, yield: 40%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.58 (dd, J ₁ =8.4Hz, J ₂ =1.9Hz, 1H), 7.48 (d, J = 1.9Hz, 1H), 7.46-7.40 (m, 1H) ,6.93(d,J=8.4Hz,1H),6.91-6.82(m,2H),5.32-5.28(m,1H),4.68-4.61(m,2H),4.11(t,J=6.8Hz,2H ),3.93(s,3H),1.92-1.85(m,2H),1.55(d,J＝7.1Hz,3H),1.45(s,9H),1.40-1.38(m,2H),1.02(t, J=7.4Hz,3H);

MS-ESI: m/z 560.2 [M+H] ⁺ .

Step 9: Compound (S)-5-(1-aminoethyl)-2-(3-butoxy-4-methoxyphenyl)-N-(2,4-difluorobenzyl)oxazole -Synthesis of 4-formamide hydrochloride

To compound (S)-(1-(2-(3-butoxy-4-methoxyphenyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazole-5- Base) ethyl) tert-butyl carbamate (695 mg, 1.24 mmol) in dichloromethane (3 mL) was added HCl in ethyl acetate solution (4M, 6 mL), stirred at room temperature for 0.5 h, after removing the solvent, washed with methanol/ Ethyl acetate (v/v=1/20) was recrystallized to obtain 344 mg of white solid, yield: 60%.

Compound 33: ¹ H NMR (400MHz, d ₆ -DMSO): δppm 7.67 (dd, J ₁ =8.4Hz, J ₂ =1.9Hz, 1H), 7.63 (d, J = 1.9Hz, 1H), 7.49-7.43 (m, 1H), 7.26-7.20 (m, 1H), 7.18 (d, J = 8.6Hz, 1H), 7.08 (td, J ₁ = 8.5Hz, J ₂ = 1.9Hz, 1H), 5.12-5.08 ( m,1H),4.49(d,J=6.1Hz,2H),4.05(t,J=6.4Hz,2H),3.86(s,3H),1.78-1.71(m,2H),1.63(d,J =6.9Hz, 3H), 1.47-1.44(m, 2H), 0.95(t, J=7.4Hz, 3H);

MS-ESI: m/z 460.3 [M+H-HCl] ⁺ .

Example 14: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of yl)-N-((3,5-dichloropyridin-4-yl)methyl)oxazole-4-carboxamide dihydrochloride

Step 1: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(((3,5-dichloro Synthesis of tert-butyl pyridin-4-yl)methyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) oxazole-4-carboxylic acid (0.3g, 0.64mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (183.36mg, 0.96mmol) and N-hydroxy- 7-Azabenzotriazole (130.56mg, 0.96mmol) was dissolved in dichloromethane (10mL), and the compound (3,5-dichloropyridin-4-yl ) methylamine (136mg, 0.77mmol) in DCM (7mL) and N,N-diisopropylethylamine (0.33mL, 1.92mmol), stirred at room temperature for 17h, washed with water (20mL×3), and the organic phase was washed with The water was dried over Na ₂ SO ₄ , the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v)=5/1) to obtain 263 mg of white solid, yield: 65%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.56 (s, 2H), 7.59 (dd, J ₁ = 8.3Hz, J ₂ = 1.9Hz, 1H), 7.55 (d, J = 1.9Hz, 1H), 7.25 (d,J=8.3Hz,1H),6.71(t,J _FH =75.0Hz,1H),5.32–5.26(m,1H),4.96(d,J=5.7Hz,2H),3.98(d,J ＝7.0Hz,2H),1.56(d,J＝7.0Hz,3H),1.44(s,9H),1.36–1.32(m,1H),0.71–0.68(m,2H),0.44–0.41(m, 2H).

Step 2: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((3 , Synthesis of 5-dichloropyridin-4-yl)methyl)oxazole-4-carboxamide dihydrochloride

To compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(((3,5-dichloropyridine- To a solution of tert-butyl 4-yl)methyl)carbamoyl)oxazol-5-yl)ethyl)carbamate (0.26 g, 0.41 mmol) in dichloromethane (5 mL) was added HCl in ethyl acetate ( 4M, 8mL), stirred at room temperature for 17h, filtered, and washed with ethyl acetate (20mL×3) to obtain 209mg of white solid, yield: 85%.

Compound 34: ¹ H NMR (400MHz, CD ₃ OD): δppm 8.57(s, 2H), 7.77(d, J=1.9Hz, 1H), 7.70(dd, J ₁ =8.4Hz, J ₂ =1.9Hz, 1H), 7.32(d, J＝8.4Hz, 1H), 6.91(t, J＝ _74.8Hz , 1H), 5.18–5.14(m, 1H), 4.92(s, 2H), 4.02(d, J＝ 6.9Hz, 2H), 1.76(d, J=7.0Hz, 3H), 1.36–1.32(m, 1H), 0.70–0.66(m, 2H), 0.44–0.40(m, 2H);

MS-ESI: m/z 528.2 [M+H-2HCl] ⁺ .

Example 15: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-(3-fluorobenzyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((3-fluorobenzyl)amino Synthesis of tert-butyl formyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) oxazole-4-carboxylic acid (0.3g, 0.64mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (183.36mg, 0.96mmol) and N-hydroxy- 7-Azabenzotriazole (130.56mg, 0.96mmol) was dissolved in dichloromethane (10mL), and 3-fluorobenzylamine (0.09mL, 0.77mmol) and N,N-Diisopropylethylamine (0.33mL, 1.92mmol), stirred at room temperature for 5h, washed with water (20mL×3), dried the organic phase with anhydrous Na ₂ SO ₄ , removed the solvent, and the concentrated solution was subjected to column separation ( Petroleum ether/ethyl acetate (v/v)=5/1) to obtain 254 mg of white solid, yield: 69%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.59 (dd, J ₁ = 8.3Hz, J ₂ = 1.9Hz, 1H), 7.55 (d, J = 1.9Hz, 1H), 7.37–7.33 (m, 1H) _FH ＝ 75.0Hz, 1H), 5.32–5.28(m, 1H), 4.67(d, J=6.2Hz, 2H), 3.98(d, J=7.0Hz, 2H), 1.56(s, 3H), 1.45(s, 9H), 1.36–1.32(m,1H), 0.71–0.68(m,2H), 0.44–0.41(m,2H).

Step 2: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(3- Synthesis of fluorobenzyl)oxazole-4-carboxamide hydrochloride

To compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((3-fluorobenzyl)carbamoyl )Oxazol-5-yl)ethyl)carbamate tert-butyl ester (0.25g, 0.43mmol) in dichloromethane (2mL) solution was added HCl in ethyl acetate solution (4M, 8mL), stirred at room temperature for 24h, filtered , washed with ethyl acetate (20 mL×3) to obtain 149 mg of white solid, yield: 68%.

Compound 35: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.72 (d, J = 1.8Hz, 1H), 7.64 (dd, J ₁ = 8.4Hz, J ₂ = 1.9 Hz, 1H), 7.31-7.23 ( m,2H),7.13(d,J＝7.7Hz,1H),7.07–7.04(m,1H),6.95–6.90(m,1H),6.83(t,J _FH ＝74.8Hz,1H),5.12– 5.06(m,1H),4.54(s,2H),3.95(d,J=6.9Hz,2H),1.69(d,J=7.0Hz,3H),1.29–1.25(m,1H),0.62–0.58 (m,2H),0.36–0.32(m,2H);

MS-ESI: m/z 476.3 [M+H-HCl] ⁺ .

Example 16: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-(4-fluorobenzyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((4-fluorobenzyl)amino Synthesis of tert-butyl formyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) oxazole-4-carboxylic acid (0.3g, 0.64mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (183.36mg, 0.96mmol) and N-hydroxy- 7-Azabenzotriazole (130.56mg, 0.96mmol) was dissolved in dichloromethane (10mL), and 4-fluorobenzylamine (0.09mL, 0.77mmol) and N,N-diisopropylethylamine (0.33mL, 1.92mmol), stirred at room temperature for 3h, washed with water (20mL×3), the organic phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation ( Petroleum ether/ethyl acetate (v/v)=5/1) to obtain 250 mg of colorless oil, yield: 68%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.56 (dd, J ₁ =8.3Hz, J ₂ =1.9Hz, 1H), 7.52 (d, J = 1.9Hz, 1H), 7.37–7.33 (m, 2H) ,7.22(d,J=8.3Hz,1H),7.05(t,J=8.7Hz,2H),6.69(t,J _FH =75.0Hz,1H),5.32–5.26(m,1H),4.61(d ,J=6.1Hz,2H),3.96(d,J=7.0Hz,2H),1.54(d,J=7.0Hz,3H),1.43(s,9H),1.36–1.32(m,1H),0.70 –0.65(m,2H),0.41–0.37(m,2H).

Step 2: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(4- Synthesis of fluorobenzyl)oxazole-4-carboxamide hydrochloride

To compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((4-fluorobenzyl)carbamoyl )Oxazol-5-yl)ethyl)carbamate tert-butyl ester (0.25g, 0.43mmol) in dichloromethane (2mL) solution was added HCl in ethyl acetate solution (4M, 8mL), stirred at room temperature for 24h, filtered , washed with ethyl acetate (20 mL×3) to obtain 187 mg of white solid, yield: 78%.

Compound 36: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.79 (d, J = 1.9Hz, 1H), 7.72 (dd, J ₁ = 8.4Hz, J ₂ = 1.9Hz, 1H), 7.45-7.41 ( m,2H),7.33(d,J＝8.4Hz,1H),7.10–7.06(m,2H),6.92(t,J _FH ＝65.5Hz,1H),5.20–5.15(m,1H),4.59( s,2H),4.03(d,J=7.0Hz,2H),1.78(d,J=7.0Hz,3H),1.37–1.32(m,1H),0.70–0.66(m,2H),0.44–0.42 (m,2H);

MS-ESI: m/z 476.1 [M+H-HCl] ⁺ .

Example 17: Compound (S)-5-(1-aminoethyl)-N-benzyl-2-(3-(cyclopropylmethoxy)-4-(difluoromethane Synthesis of oxy)phenyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound (S)-(1-(4-(benzylcarbamoyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole Synthesis of tert-butyl -5-yl)ethyl)carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) oxazole-4-carboxylic acid (0.3g, 0.64mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (183.36mg, 0.96mmol) and N-hydroxy- 7-Azabenzotriazole (130.56mg, 0.96mmol) was dissolved in dichloromethane (10mL), and benzylamine (0.08mL, 0.77mmol) and N, N -Diisopropylethylamine (0.33mL, 1.92mmol), stirred at room temperature for 3h, washed with water (20mL×3), the organic phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ Ethyl acetate (v/v)=5/1), to obtain 200 mg of white solid, yield: 56%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.55 (dd, J ₁ = 8.3Hz, J ₂ = 1.9Hz, 1H), 7.52 (d, J = 1.8Hz, 1H), 7.40–7.38 (m, 4H) ,7.36–7.31(m,1H),7.21(d,J＝8.3Hz,1H),6.69(t,J _FH ＝75.0Hz,1H),5.18–5.15(m,1H),4.65(d,J＝ 6.0Hz, 2H), 3.95(d, J＝7.0Hz, 2H), 1.55(d, J＝7.0Hz, 3H), 1.43(s, 9H), 1.36–1.33(m, 1H), 0.69–0.65( m,2H),0.41–0.37(m,2H);

MS-ESI: m/z 558.2 [M+H] ⁺ .

Step 2: Compound (S)-5-(1-aminoethyl)-N-benzyl-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxa Synthesis of azole-4-carboxamide hydrochloride

To compound (S)-(1-(4-(benzylcarbamoyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-5 Add HCl in ethyl acetate (4M, 7mL) to a solution of tert-butyl carbamate (0.2g, 0.36mmol) in dichloromethane (1mL), stir at room temperature for 18h, filter, and wash with ethyl acetate (15mL×3), 136mg of white solid was obtained, yield: 77%.

Compound 37: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.80 (d, J = 1.9Hz, 1H), 7.72 (dd, J ₁ = 8.4Hz, J ₂ = 2.0Hz, 1H), 7.42-7.39 ( m,2H),7.37–7.31(m,3H),7.30–7.26(m,1H),6.91(t,J _FH ＝74.8Hz,1H),5.20–5.15(m,1H),4.62(s,2H ),4.03(d,J=7.0Hz,2H),1.78(d,J=7.0Hz,3H),1.37–1.32(m,1H),0.71–0.66(m,2H),0.44–0.40(m, 2H);

MS-ESI: m/z 458.1 [M+H-HCl] ⁺ .

Example 18: Compound (S)-5-(1-aminoethyl)-N-((3,5-dichloropyridin-4-yl)methyl)-2-(3-ethoxy Synthesis of 4-methoxyphenyl)oxazole-4-carboxamide dihydrochloride

Step 1: Compound (S)-(1-(4-(((3,5-dichloropyridin-4-yl)methyl)carbamoyl)-2-(3-ethoxy-4-methoxy Synthesis of tert-butyl phenyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3-ethoxy-4-methoxyphenyl)oxazole-4-carboxylic acid (0.25g, 0.62mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (178mg, 0.93mmol) and N-hydroxy-7-azabenzotriazole (127mg, 0.93mmol) was dissolved in dichloromethane (10mL), and after stirring at 0°C for 30min, a solution of compound (3,5-dichloropyridin-4-yl)methanamine (132mg, 0.74mmol) in DCM (4mL) was added dropwise and N,N-diisopropylethylamine (0.32mL, 1.86mmol), stirred at room temperature for 22h, washed with water (20mL×3), dried the organic phase with anhydrous Na ₂ SO ₄ , removed the solvent, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=3/1), 140 mg of white solid was obtained, yield: 40%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.53 (s, 2H), 7.57 (dd, J ₁ = 8.4Hz, J ₂ = 1.8Hz, 1H), 7.47 (d, J = 1.7Hz, 1H), 6.91 (d,J=8.5Hz,1H),5.30–5.24(m,1H),4.93(d,J=5.5Hz,2H),4.20–4.15(m,2H),3.93(s,3H),1.54– 1.49(m,6H),1.42(s,9H).

Step 2: Compound (S)-5-(1-aminoethyl)-N-((3,5-dichloropyridin-4-yl)methyl)-2-(3-ethoxy-4-methanol Synthesis of oxyphenyl)oxazole-4-carboxamide dihydrochloride

To compound (S)-(1-(4-(((3,5-dichloropyridin-4-yl)methyl)carbamoyl)-2-(3-ethoxy-4-methoxybenzene Add HCl in ethyl acetate (4M, 6mL) to a solution of tert-butyl carbamate (0.14g, 0.25mmol) in dichloromethane (1mL) and stir at room temperature for 3h. Filtered and washed with ethyl acetate (15 mL×3) to obtain 100 mg of white solid, yield: 75%.

Compound 38: ¹ H NMR (400MHz, CD ₃ OD): δppm 8.50(s, 2H), 7.60(dd, J ₁ =8.4Hz, J ₂ =2.0Hz, 1H), 7.52(d, J = 2.0Hz, 1H), 7.01(d, J＝8.5Hz, 1H), 5.07–5.04(m, 1H), 4.82(s, 2H), 4.07–4.02(m, 2H), 3.82(s, 3H), 1.65(d ,J=7.0Hz,3H),1.35(t,J=7.0Hz,3H);

MS-ESI: m/z 466.2 [M+H-2HCl] ⁺ .

Example 19: Compound (S)-5-(1-aminoethyl)-N-((3,5-dichloropyridin-4-yl)methyl)-2-(3,4-di Synthesis of Methoxyphenyl)oxazole-4-carboxamide Dihydrochloride

Step 1: Compound (S)-(1-(4-(((3,5-dichloropyridin-4-yl)methyl)carbamoyl)-2-(3,4-dimethoxyphenyl ) Synthesis of oxazol-5-yl) ethyl) tert-butyl carbamate

Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3,4-dimethoxyphenyl)oxazole-4-carboxylic acid (0.3g, 0.77mmol) , 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (220.6mg, 1.16mmol) and N-hydroxyl-7-azabenzotriazole (157.1mg, 1.16 mmol) was dissolved in dichloromethane (10mL), and the compound (3,5-dichloropyridin-4-yl)methylamine (163mg, 0.77mmol) in DCM (5mL) was added dropwise to the solution at 0°C The solution was mixed with N,N-diisopropylethylamine (0.4mL, 2.31mmol), stirred at room temperature for 22h, washed with water (20mL×3), the organic phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column After separation (petroleum ether/ethyl acetate (v/v)=2/1), 378 mg of white solid was obtained, yield: 89%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.53 (s, 2H), 7.58 (dd, J ₁ = 8.4Hz, J ₂ = 2.0Hz, 1H), 7.46 (d, J = 1.9Hz, 1H), 6.92 (d,J=8.5Hz,1H),5.30–5.24(m,1H),4.93(d,J=5.8Hz,2H),3.95(d,J=8.7Hz,6H),1.54(d,J= 7.0Hz, 3H), 1.42(s, 9H);

MS-ESI: m/z 552.1 [M+H] ⁺ .

Step 2: Compound (S)-5-(1-aminoethyl)-N-((3,5-dichloropyridin-4-yl)methyl)-2-(3,4-dimethoxybenzene base) synthesis of oxazole-4-carboxamide dihydrochloride

To compound (S)-(1-(4-(((3,5-dichloropyridin-4-yl)methyl)carbamoyl)-2-(3,4-dimethoxyphenyl)oxa Add HCl in ethyl acetate (4M, 9mL) to a solution of tert-butyl oxazol-5-yl)ethyl)carbamate (0.37g, 0.67mmol) in dichloromethane (2mL), stir at room temperature for 17h, filter, and acetic acid After washing with ethyl ester (20 mL×3), 326 mg of white solid was obtained, yield: 93%.

Compound 39: ¹ H NMR (400MHz, CD ₃ OD): δppm 8.50(s, 2H), 7.55(dd, J ₁ =8.4Hz, J ₂ =2.0Hz, 1H), 7.48(d, J = 1.9Hz, 1H), 6.96(d, J=8.5Hz, 1H), 5.03–4.98(m, 1H), 4.77(s, 2H), 3.76(s, 6H), 1.61(d, J=7.0Hz, 3H);

MS-ESI: m/z 452.2 [M+H-2HCl] ⁺ .

Example 20: Compound (S)-6-((5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl) Synthesis of oxazole-4-carboxamido)methyl)picolinic acid dihydrochloride

Step 1: Synthesis of compound 3-(cyclopropylmethoxy)-4-methoxybenzoic acid methyl ester

Methyl 3-hydroxy-4-methoxybenzoate (5g, 27.4725mmol) was dissolved in DMF (30mL), and anhydrous potassium carbonate (7.58g, 54.945mmol) and bromomethylcyclopropane (3.8mL, 41.204mmol), the tube was sealed, and reacted at 60°C for 4.5h. Add saturated NaCl solution (20mL), extract with ethyl acetate (25mL×3), combine the organic phases and wash with water (30mL× ₃ ), dry the organic phase with anhydrous _Na2SO4 for 1h, remove the solvent to obtain 6.26g white Solid, yield: 96.5%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.66(d, J=8.4Hz, 1H), 7.52(s, 1H), 6.87(d, J=8.4Hz, 1H), 3.92(s, 3H), 3.89 (d,J=7.0Hz,2H),3.87(s,3H),1.32-1.36(m,1H),0.62-0.67(m,2H),0.34-0.38(m,2H);

MS-ESI: m/z 237.1 [M+H] ⁺ .

Step 2: Synthesis of compound 3-(cyclopropylmethoxy)-4-methoxybenzoic acid

Compound 3-(cyclopropylmethoxy)-4-methoxybenzoic acid methyl ester (2g, 8.47mmol) was dissolved in ethanol (20mL), then sodium hydroxide (1.695g, 42.37mmol) was added, at 60 ℃ for 1.5 h, remove ethanol, dissolve the residue with water (20 mL), adjust the pH of the solution to about 1 with HCl (1M), extract with ethyl acetate (25 mL×3), combine the organic phases, and use After drying with water Na ₂ SO ₄ , the solvent was removed to obtain 1.81 g of white solid, yield: 96.2%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.65(d, J=8.4Hz, 1H), 7.52(s, 1H), 7.00(d, J=8.5Hz, 1H), 3.89(s, 3H), 3.86 (d, J=6.9Hz, 2H), 1.24-1.27(m, 1H), 0.58-0.63(m, 2H), 0.33-0.37(m, 2H);

MS-ESI: m/z 223.0 [M+H] ⁺ .

Step 3: Synthesis of the compound 2-(3-(cyclopropylmethoxy)-4-methoxyphenylamido)acetic acid methyl ester

The compound 3-(cyclopropylmethoxy)-4-methoxybenzoic acid (4.5g, 20.27mmol), HOAT (2.759g, 20.27mmol) and EDCI (5.807g, 30.405mmol) were dissolved in DCM (30mL ), after stirring at room temperature for 30min, add glycine methyl ester hydrochloride (3.04g, 24.324mmol), under ice bath, slowly add DIPEA (14mL, 81.08mmol) dropwise, continue stirring overnight at room temperature, add water (30 mL), extracted with CH ₂ Cl ₂ (25 mL×3), combined the organic phases, dried with anhydrous Na ₂ SO ₄ , removed the solvent, and the concentrated solution was subjected to column separation (Petroleum ether/EtOAc (v/v) =1/1), to obtain 3.68g of white solid, yield: 61.9%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.41(s, 1H), 7.34(d, J=8.3Hz, 1H), 6.88(d, J=8.4Hz, 1H), 6.57(s, 1H), 4.23 (d,J=5.0Hz,2H),3.92(s,3H),3.90(d,J=7.0Hz,2H),3.80(s,3H),1.25-1.34(m,1H),0.62-0.66( m,2H),0.35-0.38(m,2H);

MS-ESI: m/z 294.2 [M+H] ⁺ .

Step 4: Synthesis of the compound 2-(3-(cyclopropylmethoxy)-4-methoxyphenylthioamido)acetic acid methyl ester

The compound methyl 2-(3-(cyclopropylmethoxy)-4-methoxyphenylamido)acetate (4 g, 13.64 mmol) and Lawson's reagent (5.52 g, 13.64 mmol) were dissolved in tetrahydrofuran ( 30mL), reacted at 75°C for 2h, added saturated sodium bicarbonate solution (30mL), extracted with ethyl acetate (20mL×3), combined the organic phases and dried with anhydrous sodium sulfate, and the concentrated solution was subjected to column separation ( Petroleum ether/ethyl acetate (v/v)=2/1) to obtain 2.89 g of yellow solid, yield: 68%.

Step 5: Synthesis of the compound 2-(((3-(cyclopropylmethoxy)-4-methoxyphenyl)(methylthio)methylene)amino)acetate methyl ester

At -78°C, compound 2-(3-(cyclopropylmethoxy)-4- Methoxyphenylthioamido) methyl acetate (2.8g, 9.05mmol) in dichloromethane (20mL) solution, stirred at 0 ° C for 3h, then added saturated sodium bicarbonate solution for washing (25mL × 3), organic The phase was dried _over anhydrous _Na2SO4 and the solvent was removed to give 2.8 g of yellow oil, yield: 96%.

Step 6: Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)oxazole-4 -Synthesis of methyl carboxylate

The compound 2-(((3-(cyclopropylmethoxy)-4-methoxyphenyl)(methylthio)methylene)amino)acetate methyl ester (2.8g, 8.66mmol) was mixed with the compound ( S)-(1-fluoro-1-oxopropan-2-yl)carbamate tert-butyl ester (3.3g, 17.32mmol) was dissolved in anhydrous tetrahydrofuran (15mL) Add a tetrahydrofuran solution of potassium hexamethyldisilazide (21.65 mL, 21.65 mmol) dropwise, react at -78°C for 1 h, add water (30 mL) to quench the reaction, extract with ethyl acetate (25 mL×3), and combine the organic phases After drying with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=2/1) to obtain 2.58 g of white solid, yield: 67%.

Step 7: Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)oxa Synthesis of azole-4-carboxylic acid

Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)oxazole-4-carboxy Dissolve methyl ester (2.58g, 5.78mmol) and lithium hydroxide monohydrate (1.21g, 28.9mmol) in a mixed solvent of tetrahydrofuran (20mL) and water (10mL), react at 40°C for 2h, add hydrochloric acid (1M) to adjust The pH value was brought to 1, extracted with ethyl acetate (20 mL×3), the organic phases were combined and dried with Na ₂ SO ₄ , and the solvent was removed to obtain 1.66 g of a yellow solid, yield: 66%.

Step 8: Compound (S)-6-((5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl) Synthesis of ethyl oxazole-4-carboxamido)methyl)picolinate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)oxazole- 4-Carboxylic acid (0.35g, 0.81mmol), compound 6-(aminomethyl) ethyl picolinate (175mg, 0.97mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiethylene Amine hydrochloride (232mg, 1.21mmol) and N-hydroxy-7-azabenzotriazole (165mg, 1.21mmol) were dissolved in dichloromethane (15mL), and added dropwise to the solution at 0°C N,N-Diisopropylethylamine (0.42mL, 2.43mmol), stirred at room temperature for 4h, washed with water (20mL×3), dried the organic phase with anhydrous Na ₂ SO ₄ , removed the solvent, and the concentrated solution was subjected to column separation ( Petroleum ether/ethyl acetate (v/v)=2/1) to obtain 240 mg of yellow solid, yield: 50%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.18(br.s, 1H), 8.07(d, J=7.6Hz, 1H), 7.87(t, J=7.7Hz, 1H), 7.64(d, J= 7.7Hz, 1H), 7.60 (dd, J ₁ =8.4Hz, J ₂ =1.9Hz, 1H), 7.51 (d, J = 1.9Hz, 1H), 6.94 (d, J = 8.5Hz, 1H), 5.32 –5.29(m,1H),4.90–4.88(m,2H),4.54–4.49(m,2H),3.98(d,J＝7.0Hz,2H),3.96(s,3H),1.54(d,J ＝7.0Hz,3H),1.49–1.47(m,3H),1.45(s,9H),1.41–1.39(m,1H),0.73–0.68(m,2H),0.46–0.42(m,2H);

MS-ESI: m/z 595.4 [M+H] ⁺ .

Step 9: Compound (S)-6-((5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl) Synthesis of oxazole-4-carboxamido)methyl)picolinic acid

Compound (S)-6-((5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)oxazole -4-Formylamino) methyl) ethyl picolinate (0.24g, 0.4mmol) and lithium hydroxide monohydrate (0.085g, 2.0mmol) were dissolved in a mixed solvent of tetrahydrofuran (10mL) and water (5mL), React at 40°C for 2h, add hydrochloric acid (1M) to adjust the pH value to 1, add ethyl acetate for extraction (10mL×3), combine the organic phases and dry with Na ₂ SO ₄ , remove the solvent to obtain 0.22g yellow oil, the yield : 95%.

¹ H NMR (400MHz, CD ₃ OD): δppm 8.01–7.92 (m, 2H), 7.63–7.49 (m, 3H), 6.98 (d, J=8.4Hz, 1H), 5.35–5.32 (m, 1H) ,4.68(s,2H),3.83–3.80(m,2H),3.81(s,3H),1.40(d,J＝6.4Hz,3H),1.31–1.30(m,9H),1.23–1.22(m ,1H),0.57–0.52(m,2H),0.30–0.26(m,2H);

MS-ESI: m/z 567.2 [M+H] ⁺ .

Step 10: Compound (S)-6-((5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)oxazole-4-methan Synthesis of amido)methyl)picolinic acid dihydrochloride

To compound (S)-6-((5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)oxazole -4-Formylamino)methyl)picolinic acid (0.22g, 0.39mmol) in dichloromethane (1mL) solution was added HCl in ethyl acetate solution (4M, 8mL), stirred at room temperature for 15min, filtered, ethyl acetate After washing (20 mL×3), 90 mg of white solid was obtained, yield: 43%.

Compound 49: ¹ H NMR (400MHz, CD ₃ OD): δppm 8.35–8.31 (m, 1H), 8.23 (d, J=7.6Hz, 1H), 7.92 (d, J=7.8Hz, 1H), 7.62– 7.59(m,1H),7.52(s,1H),7.00(d,J＝8.5Hz,1H),5.05–5.02(m,1H),4.84(s,2H),3.82–3.80(m,2H) ,3.81(s,3H),1.63(d,J＝6.8Hz,3H),1.20–1.17(m,1H),0.55–0.51(m,2H),0.27–0.23(m,2H);

MS-ESI: m/z 467.3 [M+H-2HCl] ⁺ .

Example 21: Compound (S)-6-((5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Synthesis of yl)phenyl)oxazole-4-carboxamido)methyl)pyridinecarboxylic acid dihydrochloride

Step 1: Compound (S)-6-((5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Synthesis of ethyl methoxy)phenyl)oxazole-4-carboxamido)methyl)picolinate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) oxazole-4-carboxylic acid (0.35g, 0.75mmol), compound 6-(aminomethyl) ethyl picolinate (162mg, 0.90mmol), 1-ethyl-3-(3-dimethylaminopropyl) Carbodiimide hydrochloride (214mg, 1.12mmol) and N-hydroxy-7-azabenzotriazole (152mg, 1.12mmol) were dissolved in dichloromethane (10mL), and the solution was added to the solution at 0°C N,N-diisopropylethylamine (0.4mL, 2.24mmol) was added dropwise, stirred at room temperature for 4h, washed with water (20mL×3), the organic phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was Column separation (petroleum ether/ethyl acetate (v/v)=2/1) gave 250 mg of white solid, yield: 52%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.22(br.s, 1H), 8.08(d, J=7.5Hz, 1H), 7.90–7.87(m, 1H), 7.60(d, J=8.7Hz, 2H), 7.25(d, J＝8.1Hz, 1H), 6.73(t, J _FH ＝75.1Hz, 1H), 5.35–5.30(m, 1H), 4.89(s, 2H), 4.55–4.49(m, 2H), 4.02(d, J=6.8Hz, 2H), 1.55(d, J=7.0Hz, 3H), 1.45(s, 9H), 1.37–1.34(m, 1H), 1.28(t, J=7.1 Hz, 1H), 0.73–0.68(m, 2H), 0.46–0.43(m, 2H).

Step 2: Compound (S)-6-((5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Synthesis of methoxy)phenyl)oxazole-4-carboxamido)methyl)picolinic acid

Compound (S)-6-((5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Base) phenyl) oxazole-4-carboxamido) methyl) ethyl picolinate (0.25g, 0.4mmol) and lithium hydroxide monohydrate (0.08g, 2.0mmol) were dissolved in tetrahydrofuran (10mL) and water ( 5mL) in a mixed solvent, react at 40°C for 2h, add hydrochloric acid (1M) to adjust the pH value to 1, add ethyl acetate for extraction (10mL×3), combine the organic phases and dry with Na ₂ SO ₄ , remove the solvent to obtain 0.23 g yellow oil, yield: 98%.

¹ H NMR (400MHz, CD ₃ OD): δppm 7.99 (d, J = 7.5Hz, 1H), 7.93–7.90 (m, 1H), 7.63–7.55 (m, 3H), 7.17 (d, J = 9.1Hz ,1H),6.78(t,J _FH =74.9Hz,1H),5.38–5.32(m,1H),4.67(s,2H),3.90(d,J=6.9Hz,2H),1.41(d,J ＝6.9Hz,3H),1.31–1.28(m,9H),1.26–1.23(m,1H),0.59–0.54(m,2H),0.33–0.29(m,2H);

MS-ESI: m/z 603.4 [M+H] ⁺ .

Step 3: Compound (S)-6-((5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole Synthesis of -4-formylamino)methyl)picolinic acid dihydrochloride

To compound (S)-6-((5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Base) phenyl) oxazole-4-carboxamido) methyl) picolinic acid (0.23g, 0.38mmol) in dichloromethane (1mL) solution was added HCl ethyl acetate solution (4M, 6mL), stirred at room temperature After 15 min, it was filtered and washed with ethyl acetate (15 mL×3) to obtain 150 mg of white solid, yield: 69%.

Compound 51: ¹ H NMR (400MHz, CD ₃ OD): δppm 8.40(t, J=7.9Hz, 1H), 8.28(d, J=7.7Hz, 1H), 8.19-8.15(m, 1H), 7.99( d,J=8.0Hz,1H),7.70(s,1H),7.64–7.61(m,1H),7.22(d,J=8.4Hz,1H),6.81(t,J _FH =74.7Hz,1H) ,5.12–5.07(m,1H),4.89,4.80(s,s,1H,1H),3.92(d,J＝6.9Hz,2H),1.66(d,J＝7.0Hz,3H),1.26–1.23 (m,1H),0.60–0.55(m,2H),0.33–0.29(m,2H);

MS-ESI: m/z 503.3 [M+H-2HCl] ⁺ .

Example 22: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-N- Synthesis of ((3,5-dichloropyridin-4-yl)methyl)oxazole-4-carboxamide dihydrochloride

Step 1: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-4-(((3,5-dichloropyridine-4- Synthesis of base) methyl) carbamoyl) oxazol-5-yl) ethyl) tert-butyl carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)oxazole- 4-carboxylic acid (0.35g, 0.81mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (232mg, 1.21mmol) and N-hydroxyl-7-aza Benzotriazole (165mg, 1.21mmol) was dissolved in dichloromethane (10mL), and the compound (3,5-dichloropyridin-4-yl)methanamine (172mg ,0.97mmol) in DCM (5mL) and N,N-diisopropylethylamine (0.42mL, 2.43mmol), stirred at room temperature for 4h, washed with water (20mL×3), and the organic phase was washed with anhydrous Na ₂ SO ₄ After drying, the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=2/1) to obtain 280 mg of white solid, yield: 58%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.53 (s, 2H), 7.58 (dd, J ₁ = 8.4Hz, J ₂ = 1.9Hz, 1H), 7.46 (d, J = 1.9Hz, 1H), 6.93 (d,J=8.5Hz,1H),5.30–5.26(m,1H),4.94(d,J=5.7Hz,2H),3.94(s,3H),3.92(d,J=7.0Hz,2H) , 1.55 (d, J=7.0Hz, 3H), 1.44 (s, 9H), 1.39–1.37 (m, 1H), 0.71–0.66 (m, 2H), 0.42–0.38 (m, 2H).

Step 2: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-N-((3,5-di Synthesis of Chloropyridin-4-yl)methyl)oxazole-4-carboxamide Dihydrochloride

To compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-4-(((3,5-dichloropyridin-4-yl) To a solution of tert-butyl methyl)carbamoyl)oxazol-5-yl)ethyl)carbamate (0.28g, 0.47mmol) in dichloromethane (2mL) was added HCl in ethyl acetate (4M, 8mL) , stirred at room temperature for 23 h, filtered and washed with ethyl acetate (20 mL×3) to obtain 240 mg of white solid, yield: 86%.

Compound 52: ¹ H NMR (400MHz, CD ₃ OD): δppm 8.62(s, 2H), 7.70(dd, J ₁ =8.4Hz, J ₂ =2.0Hz, 1H), 7.61(d, J = 2.0Hz, 1H), 7.12(d, J=8.6Hz, 1H), 5.18–5.13(m, 1H), 4.92(s, 2H), 3.93(s, 3H), 3.92(d, J=7.2Hz, 2H), 1.76(d,J=7.0Hz,3H),1.33–1.30(m,1H),0.68–0.63(m,2H),0.40–0.37(m,2H);

MS-ESI: m/z 492.1 [M+H-2HCl] ⁺ .

Example 23: Compound (S)-6-((5-(1-aminoethyl)-2-(3,4-dimethoxyphenyl)oxazole-4-carboxamide Synthesis of base) methyl) picolinic acid dihydrochloride

Step 1: Compound (S)-6-((5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3,4-dimethoxyphenyl)oxazole-4-carboxamido ) methyl) the synthesis of ethyl picolinate

Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3,4-dimethoxyphenyl)oxazole-4-carboxylic acid (0.35g, 0.89mmol) , compound 6-(aminomethyl) ethyl picolinate (193mg, 1.07mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (256mg, 1.34mmol) and N-Hydroxy-7-azabenzotriazole (182mg, 1.34mmol) was dissolved in dichloromethane (15mL), and N,N-diisopropylethylamine ( 0.47mL, 2.68mmol), stirred at room temperature for 12h, washed with water (15mL×3), the organic phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v) =2/1), 360 mg of yellow oil was obtained, yield: 72%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.05(d, J=7.6Hz, 1H), 7.85(t, J=7.6Hz, 1H), 7.60(t, J=8.6Hz, 2H), 7.54(s ,1H),6.92(d,J＝8.4Hz,1H),5.30–5.26(m,1H),4.87–4.85(m,2H),4.51–4.45(m,2H),4.00(s,3H), 3.94(s,3H),1.52(d,J=7.0Hz,3H),1.44(d,J=7.2Hz,3H),1.43(s,9H);

MS-ESI: m/z 555.4 [M+H] ⁺ .

Step 2: Compound (S)-6-((5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3,4-dimethoxyphenyl)oxazole-4-carboxamido ) Synthesis of methyl) picolinic acid

Compound (S)-6-((5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3,4-dimethoxyphenyl)oxazole-4-carboxamido)methanol Base) ethyl picolinate (0.36g, 0.4mmol) and lithium hydroxide monohydrate (0.14g, 3.25mmol) were dissolved in a mixed solvent of tetrahydrofuran (14mL) and water (7mL), reacted at 40°C for 2h, added hydrochloric acid ( 1M) Adjust the pH value to 1, add ethyl acetate for extraction (10 mL×3), combine the organic phases and dry with Na ₂ SO ₄ , remove the solvent to obtain 0.27 g of yellow oil, yield: 79%.

¹ H NMR (400MHz, CD ₃ OD): δppm 8.09(d, J=7.4Hz, 1H), 8.00(t, J=7.7Hz, 1H), 7.71(d, J=7.6Hz, 1H), 7.67( dd,J ₁ =8.4Hz,J ₂ =1.8Hz,1H),7.63(s,1H),7.09(d,J=8.4Hz,1H),5.46–5.44(m,1H),4.79(s,2H ), 3.92(d, J=7.2Hz, 6H), 1.53(d, J=7.1Hz, 3H), 1.42(s, 9H);

MS-ESI: m/z 527.4 [M+H] ⁺ .

Step 3: Compound (S)-6-((5-(1-aminoethyl)-2-(3,4-dimethoxyphenyl)oxazole-4-carboxamido)methyl)picolinic acid Synthesis of dihydrochloride

To compound (S)-6-((5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3,4-dimethoxyphenyl)oxazole-4-carboxamido)methyl Base) into a solution of picolinic acid (0.27g, 0.51mmol) in dichloromethane (1mL), add HCl in ethyl acetate (4M, 9mL), stir at room temperature for 15min, filter, and wash with ethyl acetate (20mL×3) to obtain White solid 210 mg, yield: 82%.

Compound 53: ¹ H NMR (400MHz, CD ₃ OD): δppm 8.57(t, J=7.9Hz, 1H), 8.44(d, J=7.5Hz, 1H), 8.15(d, J=8.0Hz, 1H) ,7.77–7.75(m,1H),7.69(s,1H),7.14(d,J＝8.5Hz,1H),5.21–5.18(m,1H),3.94(s,6H),3.37(s,2H ), 1.77(d, J=7.0Hz, 3H);

MS-ESI: m/z 427.3 [M+H-2HCl] ⁺ .

Example 24: Compound (S)-5-(1-aminoethyl)-N-((3,5-dichloropyridin-4-yl)methyl)-2-(3,4-di Synthesis of Ethoxyphenyl)oxazole-4-carboxamide Dihydrochloride

Step 1: Synthesis of compound 3,4-diethoxybenzoic acid methyl ester

Add methyl 3,4-dihydroxybenzoate (2.0g, 11.90mmol), potassium carbonate (4.93g, 35.70mmol), N,N-dimethylformamide (30mL) and bromoethane ( 2.22mL, 29.75mmol), react at 60°C, stop the reaction after 4.5h, extract with ethyl acetate (50mL×3), combine the organic phases and dry with anhydrous Na ₂ SO ₄ , remove the solvent to obtain 2.0g white solid , Yield: 76%.

Step 2: Synthesis of compound 3,4-diethoxybenzoic acid

Add compound 3, methyl 4-diethoxybenzoate (2.0g, 8.92mmol), sodium hydroxide (1.79g, 44.64 mmol), ethanol (30mL) and water (15mL) into a 100mL two-necked bottle, at 60°C Reaction, stop the reaction after 1.5h, remove ethanol, adjust the pH to 1 with hydrochloric acid (1M), extract with ethyl acetate (50mL×3), combine the organic phases and dry with anhydrous Na ₂ SO ₄ , remove the solvent to obtain 1.85 White solid, yield: 99%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 10.95(br.s, 1H), 7.73(d, J=8.4Hz, 1H), 7.59(s, 1H), 6.89(d, J=8.4Hz, 1H) ,4.17-4.14(m,4H),1.50-1.45(m,6H);

MS-ESI: m/z 211.1 [M+H] ⁺ .

Step 3: Synthesis of the compound 2-(3,4-diethoxybenzamido)methyl acetate

Compound 3,4-diethoxybenzoic acid (6.37g, 30.3mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (8.72g, 45.5mmol) Dissolve 1-hydroxybenzotriazole (6.15g, 45.5mmol) in dichloromethane (80mL), stir at room temperature for 0.5h, add glycine methyl ester hydrochloride (4.57g, 36.4mmol) and N at 0°C, N-Diisopropylethylamine (15.9mL, 91.0mmol), stirred at room temperature for 12h, washed with water (40mL×3), dried the organic phase with Na ₂ SO ₄ , removed the solvent, and the concentrated solution was subjected to column separation (petroleum ether/acetic acid Ethyl ester (v/v)=1/1), to obtain 6.73g of white solid, yield: 79%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.41(s, 1H), 7.31(d, J=8.3Hz, 1H), 6.84(d, J=8.3Hz, 1H), 6.72(br.s, 1H) ,4.19(s,2H),4.14-4.08(m,4H),3.77(s,3H),1.46-1.41(m,6H);

MS-ESI: m/z 282.1 [M+H] ⁺ .

Step 4: Synthesis of the compound 2-(3,4-diethoxyphenylthioamide) methyl acetate

The compound 2-(3,4-diethoxybenzamido)acetate methyl ester (4g, 14.23mmol) and Lawson's reagent (5.75g, 14.23mmol) were added into tetrahydrofuran (60mL), reacted at 75°C for 4h, Add saturated sodium bicarbonate solution (60mL), extract with ethyl acetate (20mL×2), combine the organic phases, dry over anhydrous sodium sulfate, and conduct column separation of the concentrate (petroleum ether/ethyl acetate (v/v)=2 /1), to obtain 4 g of yellow solid, yield: 95%.

Step 5: Synthesis of the compound 2-(((3,4-diethoxyphenyl)(methylthio)methylene)amino)acetate methyl ester

At -78°C, the compound 2-(3,4-diethoxyphenylthioamide was added dropwise to a solution of trimethyloxonium tetrafluoroboric acid (3.98g, 26.90mmol) in dichloromethane (20mL) ) methyl acetate (4g, 13.45mmol) in dichloromethane (30mL), stirred at 0°C for 4h, washed with saturated sodium bicarbonate solution (25mL×3), dried the organic phase with anhydrous Na ₂ SO ₄ , removed solvent to obtain 4 g of yellow oil, yield: 95%.

Step 6: Synthesis of compound (S)-methyl 5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3,4-diethoxyphenyl)oxazole-4-carboxylate

Compound 2-(((3,4-diethoxyphenyl)(methylthio)methylene)amino)methyl acetate (4g, 12.85mmol) was mixed with compound (S)-(1-fluoro-1 -Oxopropan-2-yl) tert-butyl carbamate (4.91g, 25.7mmol) was dissolved in anhydrous tetrahydrofuran (20mL), and hexamethyldisilazylamine was added dropwise to the solution at -78°C Potassium base in tetrahydrofuran (32.1 mL, 32.1 mmol), react at -78°C for 1 h, add water (30 mL) to quench the reaction, extract with ethyl acetate (25 mL×3), combine the organic phases and dry with anhydrous Na ₂ SO ₄ , The solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v)=3/1) to obtain 3.9 g of a yellow solid, yield: 70%.

Step 7: Synthesis of compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3,4-diethoxyphenyl)oxazole-4-carboxylic acid

Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3,4-diethoxyphenyl)oxazole-4-carboxylic acid methyl ester (1.8g, 4.14 mmol) and lithium hydroxide monohydrate (0.87g, 20.71mmol) were dissolved in a mixed solvent of tetrahydrofuran (20mL) and water (10mL), reacted at 40°C for 3h, added hydrochloric acid (1M) to adjust the pH value to 1, and added acetic acid Ethyl ester extraction (20 mL×3), the combined organic phases were dried with Na ₂ SO ₄ , and the solvent was removed to obtain 1.67 g of yellow solid, yield: 96%.

Step 8: Compound (S)-(1-(4-(((3,5-dichloropyridin-4-yl)methyl)carbamoyl)-2-(3,4-diethoxyphenyl ) Synthesis of oxazol-5-yl) ethyl) tert-butyl carbamate

Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3,4-diethoxyphenyl)oxazole-4-carboxylic acid (0.35g, 0.83mmol) , 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (239mg, 1.25mmol) and N-hydroxy-7-azabenzotriazole (170mg, 1.25mmol) Dissolved in dichloromethane (6mL), to this solution was added dropwise at 0°C a solution of (3,5-dichloropyridin-4-yl)methanamine (177mg, 1.0mmol) in DCM (9mL) and N,N-diisopropylethylamine (0.44mL, 2.5mmol), stirred at room temperature for 4h, washed with water (20mL×3), the organic phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation ( Petroleum ether/ethyl acetate (v/v)=2/1) to obtain 270 mg of white solid, yield: 56%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.55 (s, 2H), 7.57 (dd, J ₁ = 8.3Hz, J ₂ = 1.8Hz, 2H), 7.48 (d, J = 1.8Hz, 1H), 6.93 (d,J=8.4Hz,1H),5.30–5.26(m,1H),4.95(d,J=5.6Hz,2H),4.21–4.13(m,4H),1.55(d,J=7.0Hz, 3H), 1.51 (td, J ₁ =7.0 Hz, J ₂ =2.4 Hz, 6H), 1.44 (s, 9H).

Step 9: Compound (S)-5-(1-aminoethyl)-N-((3,5-dichloropyridin-4-yl)methyl)-2-(3,4-diethoxybenzene base) synthesis of oxazole-4-carboxamide dihydrochloride

To compound (S)-(1-(4-(((3,5-dichloropyridin-4-yl)methyl)carbamoyl)-2-(3,4-diethoxyphenyl)oxa To a solution of tert-butyl (azol-5-yl)ethyl)carbamate (0.27g, 0.47mmol) in dichloromethane (4mL) was added HCl in ethyl acetate (4M, 10mL), stirred at room temperature for 20min, filtered, and acetic acid After washing with ethyl ester (20 mL×3), 230 mg of a yellow solid was obtained, yield: 89%.

Compound 54: ¹ H NMR (400MHz, CD ₃ OD): δppm 8.65 (s, 2H), 7.68 (dd, J ₁ = 8.4Hz, J ₂ = 2.0Hz, 2H), 7.63 (d, J = 2.0Hz, 1H), 7.09(d, J＝8.5Hz, 1H), 5.18–5.13(m, 1H), 4.93(s, 2H), 4.19–4.13(m, 4H), 1.75(d, J＝7.0Hz, 3H ), 1.46(td, J ₁ =7.0Hz, J ₂ =1.3Hz, 6H);

MS-ESI: m/z 480.1 [M+H-2HCl] ⁺ .

Example 25: Compound (S)-6-((5-(1-aminoethyl)-2-(3,4-diethoxyphenyl)oxazole-4-carboxamide Synthesis of base) methyl) picolinic acid dihydrochloride

Step 1: Compound (S)-6-((5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3,4-diethoxyphenyl)oxazole-4-carboxamido ) methyl) the synthesis of ethyl picolinate

Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3,4-diethoxyphenyl)oxazole-4-carboxylic acid (0.35g, 0.83mmol) , compound 6-aminomethylpicolinate ethyl ester (180mg, 1.0mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (239mg, 1.25mmol) and N- Hydroxy-7-azabenzotriazole (170mg, 1.25mmol) was dissolved in dichloromethane (10mL), and N,N-diisopropylethylamine (0.44mL , 2.5mmol), stirred at room temperature for 7h, washed with water (20mL×3), the organic phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=2 /1), to obtain 270 mg of white solid, yield: 56%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.21(br.s, 1H), 8.08(d, J=7.6Hz, 1H), 7.88(t, J=7.7Hz, 1H), 7.65(d, J= 7.8Hz,1H),7.58(dd,J ₁ =8.4Hz,J ₂ =1.8Hz,1H),7.55(d,J=1.7Hz,1H),6.93(d,J=8.4Hz,1H),5.32 –5.30(m,1H),4.90–4.89(m,2H),4.54–4.49(m,2H),4.25–4.13(m,4H),1.55–1.47(m,12H),1.45(s,9H) ;

MS-ESI: m/z 583.4 [M+H] ⁺ .

Step 2: Compound (S)-6-((5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3,4-diethoxyphenyl)oxazole-4-carboxamido ) Synthesis of methyl) picolinic acid

Compound (S)-6-((5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3,4-diethoxyphenyl)oxazole-4-carboxamido)methanol Base) ethyl picolinate (0.27g, 0.46mmol) and lithium hydroxide monohydrate (0.097g, 2.32mmol) were dissolved in a mixed solvent of tetrahydrofuran (10mL) and water (5mL), reacted at 40°C for 2h, added hydrochloric acid ( 1M) Adjust the pH to 1, add ethyl acetate for extraction (10 mL×3), combine the organic phases and dry with Na ₂ SO ₄ , remove the solvent to obtain 0.24 g of yellow oil, yield: 93%.

¹ H NMR (400MHz, CD ₃ OD): δppm 8.12 (d, J = 7.4Hz, 1H), 8.05 (t, J = 7.6Hz, 1H), 7.74 (d, J = 7.2Hz, 1H), 7.66– 7.63(m,2H),7.07(d,J=8.3Hz,1H),5.45–5.43(m,1H),4.80(s,2H),4.19–4.13(m,4H),1.54(d,J= 4.5Hz, 3H), 1.48–1.43(m, 6H), 1.42(s, 9H);

MS-ESI: m/z 555.2 [M+H] ⁺ .

Step 3: Compound (S)-6-((5-(1-aminoethyl)-2-(3,4-diethoxyphenyl)oxazole-4-carboxamido)methyl)picolinic acid Synthesis of dihydrochloride

To compound (S)-6-((5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3,4-diethoxyphenyl)oxazole-4-carboxamido)methyl Base) into a solution of picolinic acid (0.24g, 0.43mmol) in dichloromethane (2mL), add HCl in ethyl acetate (4M, 9mL), stir at room temperature for 15min, filter, wash with ethyl acetate (20mL×3), and get Yellow solid 190 mg, yield: 83%.

Compound 55: ¹ H NMR (400MHz, CD ₃ OD): δppm 8.52(t, J=7.9Hz, 1H), 8.40(d, J=7.5Hz, 1H), 8.11(d, J=7.8Hz, 1H) ,7.72(dd,J ₁ =8.4Hz,J ₂ =2.0Hz,1H),7.68(d,J=1.9Hz,1H),7.12(d,J=8.5Hz,1H),5.20–5.18(m, 1H), 5.01(s, 2H), 4.20–4.15(m, 4H), 1.77(d, J=7.0Hz, 3H), 1.47(td, J ₁ =6.9Hz, J ₂ =1.1Hz, 6H);

MS-ESI: m/z 455.3 [M+H-2HCl] ⁺ .

Example 26: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-(2,4-dichlorobenzyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((2,4-dichlorobenzyl Synthesis of base) carbamoyl) oxazol-5-yl) ethyl) tert-butyl carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) oxazole-4-carboxylic acid (0.35g, 0.75mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (214mg, 1.12mmol) and N-hydroxyl-7 -Azabenzotriazole (153mg, 1.12mmol) was dissolved in dichloromethane (10mL), and 2,4-difluorobenzylamine (0.12mL, 0.90mmol) was added dropwise to the solution at 0°C and N,N-diisopropylethylamine (0.4mL, 2.24mmol), stirred at room temperature for 5h, washed with water (10mL×3), the organic phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=6/1), 350 mg of colorless oil was obtained, yield: 75%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.60 (dd, J ₁ = 8.3Hz, J ₂ = 1.9Hz, 1H), 7.56 (d, J = 1.9Hz, 1H), 7.45 (d, J = 2.1Hz ,1H),7.42(d,J＝8.3Hz,1H),7.27–7.25(m,1H),6.72(t,J _FH ＝75.0Hz,1H),5.32–5.28(m,1H),4.73–4.71 (m,2H),3.99(d,J=7.0Hz,2H),1.55(d,J=7.0Hz,3H),1.45(s,9H),1.38–1.35(m,1H),0.73–0.69( m,2H), 0.44–0.40(m,2H).

Step 2: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2, Synthesis of 4-dichlorobenzyl)oxazole-4-carboxamide hydrochloride

To compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((2,4-dichlorobenzyl) Add HCl in ethyl acetate (4M, 10mL) to a solution of tert-butyl carbamate (0.35g, 0.56mmol) in dichloromethane (2mL) and stir at room temperature After 20 min, the solvent was removed to obtain 250 mg of white solid, yield: 79%.

Compound 56: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.81 (d, J = 1.6Hz, 1H), 7.74 (dd, J ₁ = 8.4Hz, J ₂ = 1.7Hz, 1H), 7.47 (d, J＝1.9Hz, 1H), 7.44(d, J＝8.4Hz, 1H), 7.34–7.31(m, 2H), 6.93(t, J _FH ＝74.8Hz, 1H), 5.21–5.19(m, 1H) ,4.68(s,2H),4.03(d,J=6.9Hz,2H),1.80(d,J=7.0Hz,3H),1.64(dd,J ₁ ＝7.2Hz,J ₂ ＝2.8Hz,6H) ,1.37–1.33(m,1H),0.68–0.65(m,2H),0.44–0.40(m,2H);

MS-ESI: m/z 527.2 [M+H-HCl] ⁺ .

Example 27: Compound (S)-5-(1-aminoethyl)-N-(2-chlorobenzyl)-2-(3-(cyclopropylmethoxy)-4- Synthesis of (difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound (S)-(1-(4-((2-chlorobenzyl)carbamoyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of tert-butyl phenyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) oxazole-4-carboxylic acid (0.35g, 0.75mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (214mg, 1.12mmol) and N-hydroxyl-7 -Azabenzotriazole (153mg, 1.12mmol) was dissolved in dichloromethane (10mL), and 2-chlorobenzylamine (0.11mL, 0.90mmol) and N were added dropwise to the solution at 0°C. N-Diisopropylethylamine (0.4mL, 2.24mmol), stirred at room temperature for 5h, washed with water (10mL×3), dried the organic phase with anhydrous Na ₂ SO ₄ , removed the solvent, and the concentrated solution was subjected to column separation (petroleum ether /ethyl acetate (v/v)=6/1) to obtain 310 mg of colorless oil, yield: 70%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.60 (dd, J ₁ = 8.3Hz, J ₂ = 1.9Hz, 1H), 7.56 (d, J = 1.9Hz, 1H), 7.49–7.47 (m, 1H) ,7.44–7.42(m,1H),7.30–7.28(m,1H),7.25(d,J＝8.3Hz,1H),6.72(t,J _FH ＝75.0Hz,1H),5.32–5.28(m, 1H), 4.78–4.76(m, 2H), 3.99(d, J=7.0Hz, 2H), 1.56(d, J=7.0Hz, 3H), 1.45(s, 9H), 1.39–1.34(m, 1H ), 0.73–0.68(m,2H), 0.44–0.40(m,2H).

Step 2: Compound (S)-5-(1-aminoethyl)-N-(2-chlorobenzyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy ) Synthesis of phenyl) oxazole-4-carboxamide hydrochloride

To compound (S)-(1-(4-((2-chlorobenzyl)carbamoyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl )Oxazol-5-yl)ethyl)carbamate tert-butyl ester (0.31g, 0.52mmol) in dichloromethane (1mL) solution was added HCl in ethyl acetate solution (4M, 10mL), stirred at room temperature for 20min, removed The solvent gave 250 mg of white solid, yield: 90%.

Compound 57: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.81 (d, J = 1.9Hz, 1H), 7.74 (dd, J ₁ = 8.4Hz, J ₂ = 1.9Hz, 1H), 7.46-7.42 ( m,2H),7.33–7.29(m,3H),6.92(t,J _FH ＝74.8Hz,1H),5.22–5.17(m,1H),4.72(s,2H),4.03(d,J＝7.0 Hz,2H),1.79(d,J=7.0Hz,3H),1.37–1.33(m,1H),0.69–0.66(m,2H),0.44–0.40(m,2H);

MS-ESI: m/z 492.1 [M+H-HCl] ⁺ .

Example 28: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-(2,6-dichlorobenzyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((2,6-dichlorobenzyl Synthesis of base) carbamoyl) oxazol-5-yl) ethyl) tert-butyl carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) oxazole-4-carboxylic acid (0.35g, 0.75mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (214mg, 1.12mmol) and N-hydroxyl-7 -Azabenzotriazole (153mg, 1.12mmol) was dissolved in dichloromethane (10mL), and 2,6-dichlorobenzylamine (0.12mL, 0.90mmol) was added dropwise to the solution at 0°C and N,N-diisopropylethylamine (0.4mL, 2.24mmol), stirred at room temperature for 4h, washed with water (10mL×3), the organic phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=6/1), 337 mg of white solid was obtained, yield: 72%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.61 (dd, J ₁ =8.3Hz, J ₂ =1.9Hz, 1H), 7.56 (d, J = 1.9Hz, 1H), 7.45 (dd, J ₁ =8.0 Hz, J ₂ ＝1.5Hz, 1H), 7.40(dd, J ₁ ＝7.7Hz, J ₂ ＝1.5Hz, 1H), 7.27–7.22(m, 2H), 6.73(t, J _FH ＝75.0Hz, 1H ),5.32–5.30(m,1H),4.79–4.77(m,2H),3.99(d,J＝7.0Hz,2H),1.55(d,J＝7.0Hz,3H),1.44(s,9H) ,1.37–1.34(m,1H),0.73–0.68(m,2H),0.44–0.40(m,2H).

Step 2: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2, Synthesis of 6-dichlorobenzyl)oxazole-4-carboxamide hydrochloride

To compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((2,6-dichlorobenzyl) Add HCl in ethyl acetate (4M, 10mL) to a solution of tert-butyl carbamate (0.33g, 0.53mmol) in dichloromethane (1mL) and stir at room temperature After 20 min, the solvent was removed to obtain 290 mg of white solid, yield: 97%.

Compound 58: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.81 (d, J = 1.9Hz, 1H), 7.74 (dd, J ₁ = 8.4Hz, J ₂ = 1.9Hz, 1H), 7.50 (dd, J ₁ =7.9Hz, J ₂ =1.5Hz,1H), 7.41–7.39(m,1H),7.34–7.29(m,2H),6.92(t,J _FH =74.8Hz,1H),5.21–5.16( m, 1H), 4.75(s, 2H), 4.04(d, J＝6.9Hz, 2H), 1.78(d, J＝7.0Hz, 3H), 1.37–1.34(m, 1H), 0.71–0.66(m ,2H),0.45–0.41(m,2H);

MS-ESI: m/z 527.1 [M+H-HCl] ⁺ .

Example 29: Compound (S)-5-(1-(cyclopropylcarboxamido)ethyl)-2-(3-(cyclopropylmethoxy)-4- Synthesis of (difluoromethoxy)phenyl)-N-(2,4-difluorobenzyl)oxazole-4-carboxamide

Step 1: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((2,4-difluorobenzyl Synthesis of base) carbamoyl) oxazol-5-yl) ethyl) tert-butyl carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) oxazole-4-carboxylic acid (0.5g, 1.07mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (307.51mg, 1.61mmol) and N-hydroxy- 7-Azabenzotriazole (219mg, 1.61mmol) was dissolved in dichloromethane (10mL), and 2,4-difluorobenzylamine (0.15mL, 1.28mmol) was added dropwise to the solution at 0°C ) and N,N-diisopropylethylamine (0.56mL, 3.21mmol), stirred at room temperature for 4h, washed with water (20mL×3), the organic phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column After separation (petroleum ether/ethyl acetate (v/v)=5/1), 389 mg of white solid was obtained, yield: 61%.

Step 2: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2, Synthesis of 4-difluorobenzyl)oxazole-4-carboxamide hydrochloride

To compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((2,4-difluorobenzyl) Add HCl in ethyl acetate (4M, 12mL) to a solution of tert-butyl carbamate (0.39g, 0.66mmol) in dichloromethane (3mL) and stir at room temperature After 5h, filtered and washed with ethyl acetate (20 mL×3), 269 mg of white solid was obtained, yield: 77%.

¹ H NMR (400MHz, CD ₃ OD): δppm 7.79 (d, J = 1.9Hz, 1H), 7.72 (dd, J ₁ = 8.4Hz, J ₂ = 2.0Hz, 1H), 7.51–7.45 (m, 1H ), 7.33(d, J＝8.4Hz, 1H), 7.02–6.95(m, 2H), 6.92(t, J _FH ＝74.7Hz, 1H), 5.19–5.14(m, 1H), 4.65(s, 2H ),4.03(d,J=7.0Hz,2H),1.77(d,J=7.0Hz,3H),1.38–1.33(m,1H),0.70–0.67(m,2H),0.44–0.41(m, 2H);

MS-ESI: m/z 494.3 [M+H-HCl] ⁺ .

Step 3: Compound (S)-5-(1-(cyclopropylcarboxamido)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl Synthesis of )-N-(2,4-difluorobenzyl)oxazole-4-carboxamide

Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2,4- Difluorobenzyl) oxazole-4-carboxamide hydrochloride (0.25g, 0.47mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (135mg, 0.71 mmol) and N-hydroxy-7-azabenzotriazole (96mg, 0.71mmol) were dissolved in dichloromethane (10mL), and cyclopropanyl formic acid (0.05mL , 0.57mmol) and N,N-diisopropylethylamine (0.33mL, 1.89mmol), stirred at room temperature for 4h, washed with water (20mL×3), the organic phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and concentrated The liquid was subjected to column separation (petroleum ether/ethyl acetate (v/v)=3/2) to obtain 220 mg of white solid, yield: 83%.

Compound 59: ¹ H NMR (400MHz, CDCl ₃ ): δppm 8.79 (d, J = 9.1Hz, 1H), 7.65 (t, J = 6.1Hz, 1H), 7.58 (dd, J ₁ = 8.3Hz, J ₂ =1.9Hz,1H),7.54(d,J=1.8Hz,1H),7.45–7.39(m,1H),7.25(d,J=8.3Hz,1H),6.93–6.87(m,2H),6.72 (t,J _FH =64.4Hz,1H),5.64–5.60(m,1H),4.68(d,J=6.1Hz,2H),3.98(d,J=7.0Hz,2H),1.55(d,J ＝7.0Hz,3H),1.50–1.46(m,1H),1.36–1.30(m,1H),1.01–0.95(m,2H),0.80–0.72(m,2H),0.71–0.68(m,2H ),0.44–0.40(m,2H).

Example 30: Compound (S)-5-(1-aminoethyl)-N-(4-chloro-2-fluorobenzyl)-2-(3-(cyclopropylmethoxy Synthesis of yl)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound (S)-(1-(4-((4-chloro-2-fluorobenzyl)carbamoyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Synthesis of tert-butyl methoxy)phenyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) oxazole-4-carboxylic acid (0.3g, 0.64mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (184mg, 0.96mmol) and N-hydroxyl-7 -Azabenzotriazole (131mg, 0.96mmol) was dissolved in dichloromethane (10mL), and 4-chloro-2-fluorobenzylamine (0.1mL, 0.77mmol) was added dropwise to the solution at 0°C ) and N,N-diisopropylethylamine (0.34mL, 1.92mmol), stirred at room temperature for 15h, washed with water (10mL×3), the organic phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column After separation (petroleum ether/ethyl acetate (v/v)=6/1), 286 mg of white solid was obtained, yield: 73%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.59 (dd, J ₁ = 8.3Hz, J ₂ = 1.9Hz, 1H), 7.56 (d, J = 1.9Hz, 1H), 7.40 (t, J = 8.2Hz ,1H),7.25(d,J＝8.3Hz,1H),7.17–7.13(m,2H),6.72(t,J _FH ＝75.0Hz,1H),5.32(s,1H),4.69–4.66(m ,2H),3.99(d,J=6.9Hz,2H),1.55(d,J=7.0Hz,3H),1.45(s,9H),1.37–1.34(m,1H),0.73–0.68(m, 2H), 0.44–0.41 (m, 2H).

Step 2: Compound (S)-5-(1-aminoethyl)-N-(4-chloro-2-fluorobenzyl)-2-(3-(cyclopropylmethoxy)-4-(di Synthesis of fluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride

To compound (S)-(1-(4-((4-chloro-2-fluorobenzyl)carbamoyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Base) phenyl) oxazol-5-yl) ethyl) tert-butyl carbamate (0.28g, 0.46mmol) in dichloromethane (1mL) solution was added HCl in ethyl acetate solution (4M, 10mL), room temperature After stirring for 20 min, the solvent was removed to obtain 230 mg of white solid, yield: 92%.

Compound 60: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.80 (d, J = 1.9Hz, 1H), 7.73 (dd, J ₁ = 8.4Hz, J ₂ = 1.9Hz, 1H), 7.45 (t, J＝8.3Hz, 1H), 7.33(d, J＝8.4Hz, 1H), 7.24–7.20(m, 2H), 6.92(t, J _FH ＝74.8Hz, 1H), 5.18–5.15(m, 1H) ,4.65(s,2H),4.03(d,J＝7.0Hz,2H),1.78(d,J＝7.0Hz,3H),1.37–1.34(m,1H),0.71–0.66(m,2H), 0.45–0.41(m,2H);

MS-ESI: m/z 510.2 [M+H-HCl] ⁺ .

Example 31: Compound (S)-5-(1-aminopropyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-N- Synthesis of (2,4-difluorobenzyl)oxazole-4-carboxamide hydrochloride

Step 1: Synthesis of compound (S)-2-(tert-butoxycarbonylamino)butanoic acid

Dissolve L-2-aminobutyric acid (2.0g, 19.40mmol) and di-tert-butyl dicarbonate (4.67g, 21.4mmol) in tetrahydrofuran (25mL), and add sodium hydroxide solution (1M, 23mL) dropwise at 0°C ), reacted at room temperature for 12 h, adjusted the pH to 1 with hydrochloric acid (1M), extracted with ethyl acetate (20 mL×3), combined the organic phases, dried with anhydrous Na ₂ SO ₄ , and removed the solvent to obtain 4.4 g of a white solid. Yield: 99%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 10.52(s, 1H), 4.32-4.08(m, 1H), 1.95-1.89(m, 1H), 1.78-1.69(m, 1H), 1.45(s, 9H ), 1.00-0.96(m,3H).

Step 2: Synthesis of compound (S)-tert-butyl(1-fluoro-1-oxobutan-2-yl)carbamate

Dissolve (S)-2-(tert-butoxycarbonylamino)butanoic acid (1.0g, 4.93mmol) and triethylamine (0.8mL, 5.43mmol) in dichloromethane (20mL), drop slowly at -40°C Add cyanuric fluoride (1.0mL, 9.86mmol), continue the reaction at -10°C for 1h, add ice water to wash (20mL×3), dry the organic phase with anhydrous Na ₂ SO ₄ , remove the solvent to obtain 0.89g White solid, yield: 88%.

¹ H NMR (400MHz, d ₆ -DMSO): δppm 4.15-4.13 (m, 1H), 1.78-1.71 (m, 2H), 1.40 (s, 9H), 0.95-0.89 (m, 3H);

MS-ESI: m/z 206.2 [M+H] ⁺ .

Step 3: Compound (S)-5-(1-(tert-butoxycarbonylamino)propyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)oxazole-4 -Synthesis of methyl carboxylate

Compound 2-(((3-(cyclopropylmethoxy)-4-methoxyphenyl)(methylthio)methylene)amino)acetate methyl ester (0.50g, 1.55mmol), compound ( S)-(1-fluoro-1-oxobutan-2-yl) tert-butyl carbamate (0.89g, 4.33mmol) was dissolved in anhydrous tetrahydrofuran (15mL), and at -78°C, six Potassium methyldisilazide tetrahydrofuran solution (6.0mL, 6.00mmol), react at -78°C for 1h, add ice water (20mL) to quench the reaction, extract with ethyl acetate (15mL×3), combine organic The phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v)=4/1) to obtain 0.37 g of a yellow solid, yield: 53%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.65 (dd, J ₁ =8.4Hz, J ₂ =2.0Hz, 1H), 7.56 (d, J = 2.0Hz, 1H), 6.94 (d, J = 8.5Hz ,1H),5.31-5.25(m,1H),4.00(s,3H),3.95(d,J＝7.0Hz,2H),3.95(s,3H),1.93-1.88(m,2H), 1.46( s,9H),1.40-1.35(m,1H),0.97(t,J=7.3Hz,3H),0.72-0.67(m,2H),0.43-0.39(m,2H);

MS-ESI: m/z 461.3 [M+H] ⁺ .

Step 4: Compound (S)-5-(1-(tert-butoxycarbonylamino)propyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)oxazole-4 -Synthesis of carboxylic acids

Compound (S)-5-(1-(tert-butoxycarbonylamino)propyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)oxazole-4-carboxy Dissolve methyl ester (0.37g, 0.81mmol) and lithium hydroxide monohydrate (0.17g, 0.45mmol) in a mixed solvent of tetrahydrofuran (30mL) and water (15mL), react at 40°C for 3h, remove tetrahydrofuran, add The pH was adjusted to 1 with hydrochloric acid (1M), extracted with ethyl acetate (30 mL×3), the organic phases were combined and dried with Na ₂ SO ₄ , and the solvent was removed to obtain 0.34 g of a white solid, yield: 95%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.65(d, J=8.4Hz, 1H), 7.57(s, 1H), 6.95(d, J=8.4Hz, 1H), 5.26-5.24(m, 1H) ,3.96(s,3H),3.95(d,J=6.8Hz,2H),1.96-1.91(m,2H),1.45(s,9H),1.41-1.36(m,1H),0.99(t,J =7.0Hz, 3H), 0.71-0.67(m, 2H), 0.42-0.39(m, 2H);

MS-ESI: m/z 447.1 [M+H] ⁺ .

Step 5: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-4-((2,4-difluorobenzyl)aminomethyl Synthesis of tert-butyl Acyl)oxazol-5-yl)propyl)carbamate

Compound (S)-5-(1-(tert-butoxycarbonylamino)propyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)oxazole-4-carboxy acid (0.15g, 0.34mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.10g, 0.51mmol) and N-hydroxy-7-azabenzo Triazole (0.07g, 0.51mmol) was dissolved in dichloromethane (10mL), stirred at room temperature for 0.5h, and 2,4-difluorobenzylamine (0.05mL, 0.41mmol) and N,N- Diisopropylethylamine (0.18mL, 1.02mmol), stirred at room temperature for 12h, added water (20mL), extracted with dichloromethane (20mL×3), combined the organic phases and dried with Na ₂ SO ₄ , removed the solvent and concentrated The liquid was subjected to column separation (petroleum ether/ethyl acetate (v/v)=5/1) to obtain 0.15 g of white solid, yield: 78%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.60 (dd, J ₁ = 8.4Hz, J ₂ = 2.0Hz, 1H), 7.48 (d, J = 2.0Hz, 1H), 7.46-7.40 (m, 1H) ,6.95(d,J=8.5Hz,1H),6.92-6.84(m,2H),5.13-5.05(m,1H),4.67(t,J=5.8Hz,2H),3.96(d,J=7.0 Hz,2H),3.96(s,3H),1.94-1.86(m,2H),1.46(s,9H),1.39-1.36(m,1H),0.96(t,J＝7.3Hz,3H),0.72 -0.68(m,2H),0.45-0.41(m,2H);

MS-ESI: m/z 572.2 [M+H] ⁺ .

Step 6: Compound (S)-5-(1-aminopropyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-N-(2,4-difluoro Synthesis of benzyl)oxazole-4-carboxamide hydrochloride

To compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-4-((2,4-difluorobenzyl)carbamoyl) Add HCl in ethyl acetate (4M, 6mL) to a solution of tert-butyl oxazol-5-yl)propyl)carbamate (0.15g, 0.26mmol) in dichloromethane (2mL), stir at room temperature for 0.5h, remove After solvent, recrystallize from methanol/ethyl acetate (v/v=1/20) to obtain 117 mg of white solid, yield: 93%.

Compound 66: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.72 (dd, J ₁ =8.4Hz, J ₂ =2.0Hz, 1H), 7.64 (d, J = 1.9Hz, 1H), 7.51-7.45( m,1H),7.13(d,J＝8.5Hz,1H),7.01-6.94(m,2H),5.04-5.01(m,1H),4.64(s,2H), 3.94(d,J＝6.8Hz ,2H),3.94(s,3H),2.21-2.12(m,2H),1.03(t,J＝7.5Hz,3H),0.93-0.86(m,1H),0.68-0.64(m,2H), 0.41-0.37(m,2H);

MS-ESI: m/z 472.1 [M+H-HCl] ⁺ .

Example 32: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-(2,4-difluorophenyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(fluorocarbonyl)oxazole-5- Synthesis of tert-butyl) ethyl) carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) Oxazole-4-carboxylic acid (0.48g, 1.02mmol) and triethylamine (0.16mL, 1.1mmol) were dissolved in dichloromethane (10mL), and tripolyfluoride was added dropwise to the solution at -40°C Cyanide (0.18mL, 2.05mmol), reacted at -10°C for 3h, washed with ice water (20mL×4), dried the organic phase with anhydrous Na ₂ SO ₄ , and removed the solvent to obtain 0.46g of yellow oil, the yield : 96%.

Step 2: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((2,4-difluorobenzene Synthesis of base) carbamoyl) oxazol-5-yl) ethyl) tert-butyl carbamate

2,4-Difluoroaniline (0.16mL, 1.53mmol) and sodium hydride (60%, 61mg, 1.53mmol) were dissolved in tetrahydrofuran (5mL), stirred at room temperature for 0.5h, and compound (S)-(1 -(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(fluorocarbonyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (0.46g, 0.98mmol) in tetrahydrofuran (10mL), stirred at room temperature for 23h, added saturated ammonium chloride solution (20mL), extracted with ethyl acetate (15mL×3), combined the organic phases, and washed with anhydrous Na ₂ SO ₄ After drying, the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=8/1) to obtain 289 mg of white solid, yield: 49%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 9.08(s, 1H), 8.44–8.38(m, 1H), 7.66(dd, J ₁ =8.3Hz, J ₂ =1.9Hz, 1H), 7.61(d, J＝1.9Hz, 1H), 7.29(d, J＝7.4Hz, 1H), 6.99–6.94(m, 2H), 6.74(t, J _FH ＝75.0Hz, 1H), 5.41–5.37(m, 1H) ,4.03(d,J=6.9Hz,2H),1.59(d,J=7.0Hz,3H),1.46(s,9H),1.38–1.35(m,1H),0.75–0.70(m,2H), 0.47–0.43 (m, 2H).

Step 3: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2, Synthesis of 4-difluorophenyl)oxazole-4-carboxamide hydrochloride

To compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((2,4-difluorophenyl) Add HCl in ethyl acetate (4M, 12mL) to a solution of tert-butyl carbamate (0.28g, 0.48mmol) in dichloromethane (2mL) and stir at room temperature After 20 min, the solvent was removed to obtain 238 mg of white solid, yield: 92%.

Compound 73: ¹ H NMR (400MHz, CDCl ₃ ): δppm 7.82 (d, J = 1.7Hz, 1H), 7.75 (dd, J ₁ = 8.4Hz, J ₂ = 1.7Hz, 1H), 7.54–7.49 (m ,1H),7.33(d,J＝8.4Hz,1H),7.34–7.26(m,1H),7.16–7.11(m,2H),6.91(t,J _FH ＝74.7Hz,1H),5.26–5.23 (m,1H),4.04(d,J=6.9Hz,2H),1.78(d,J=7.0Hz,3H),1.34–1.31(m,1H),0.68–0.66(m,2H),0.42– 0.41(m,2H);

MS-ESI: m/z 480.2 [M+H-HCl] ⁺ .

Example 33: Compound (S)-5-(1-aminoethyl)-N-(2,4-difluorobenzyl)-2-(4-(difluoromethoxy)-3- Synthesis of Ethoxyphenyl)oxazole-4-carboxamide Hydrochloride

Step 1: Synthesis of the compound 4-(difluoromethoxy)-3-ethoxybenzoic acid methyl ester

To the sealed tube was added methyl 4-difluoromethoxy-3-hydroxybenzoate (5 g, 22.92 mmol), potassium carbonate (6.33 g, 45.84 mmol), bromoethane (2.58 mL, 34.38 mmol) and N, N'-Dimethylformamide (30 mL), reacted at 60°C for 4 h, filtered with suction, and the filtrate was spin-dried to obtain 5.6 g of brown oil, yield: 96%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.60–7.58 (m, 2H), 7.15 (d, J = 8.7Hz, 1H), 6.65 (t, J _FH = 74.8Hz, 1H), 3.88 (s, 3H ), 4.15–4.10 (m, 2H), 1.44 (t, J=7.0Hz, 3H).

Step 2: Synthesis of compound 4-(difluoromethoxy)-3-ethoxybenzoic acid

The compound 4-(difluoromethoxy)-3-ethoxybenzoic acid methyl ester (5.6g, 22.92mmol), sodium hydroxide (2.73g, 68.23mmol) was dissolved in ethanol (30mL) and water (10mL) In a mixed solvent, react at 60°C for 13h, stop the reaction, remove ethanol, add hydrochloric acid (1M) to adjust the pH to 1, add ethyl acetate (20mL×3) for extraction, dry the organic phase with anhydrous Na ₂ SO ₄ and concentrate to obtain 4.75 g of pale yellow solid, yield: 90%.

¹ H NMR (400MHz, CD ₃ OD): δppm 7.71 (d, J = 1.9Hz, 1H), 7.65 (dd, J ₁ = 8.3Hz, J ₂ = 1.9Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 6.87 (t, J _FH = 74.7Hz, 1H), 4.21–4.15 (m, 2H), 1.46 (t, J = 7.0Hz, 3H).

Step 3: Synthesis of the compound 2-(4-(difluoromethoxy)-3-ethoxybenzamido)acetic acid methyl ester

4-(difluoromethoxy)-3-ethoxybenzoic acid (4.75g, 20.46mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.86 g, 30.69mmol) and N-hydroxy-7-azabenzotriazole (4.17g, 30.69mmol) were dissolved in dichloromethane (35mL), stirred at room temperature for 30min, added glycine methyl ester hydrochloride (3.08g , 24.55mmol), N,N-diisopropylethylamine (11mL, 61.38mmol) was added dropwise at 0°C, stirred at room temperature for 16h, washed with water (40mL×3), the organic phase was dried with Na ₂ SO ₄ , removed The solvent and the concentrate were subjected to column separation (petroleum ether/ethyl acetate (v/v)=2/1) to obtain 6.2 g of light yellow oil, yield: 98%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.99 (s, 1H), 7.49 (d, J = 2.0Hz, 1H), 7.31 (dd, J ₁ = 8.3Hz, J ₂ = 2.0Hz, 1H), 7.14 (d, J＝8.3Hz, 1H), 6.62(t, J _FH ＝74.9Hz, 1H), 4.19(d, J＝3.4Hz, 2H), 4.14–4.08(m, 2H), 1.43(t, J =7.0Hz,3H);

MS-ESI: m/z 304.0 [M+H] ⁺ .

Step 4: Synthesis of the compound 2-(4-(difluoromethoxy)-3-ethoxyphenylthioamide)acetic acid methyl ester

The compound methyl 2-(4-(difluoromethoxy)-3-ethoxybenzamido)acetate (6 g, 19.8 mmol) and Lawson's reagent (8 g, 19.8 mmol) were dissolved in tetrahydrofuran (40 mL) After reacting at 75°C for 4 h, add saturated sodium bicarbonate solution (30 mL), extract with ethyl acetate (20 mL×3), combine the organic phases, dry with anhydrous Na ₂ SO ₄ , and conduct column separation of the concentrate (petroleum ether/ Ethyl acetate (v/v)=4/1) to obtain 6 g of yellow oil, yield: 95%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.59(d, J=2.1Hz, 1H), 7.28–7.25(m, 1H), 7.17(d, J=8.3Hz, 1H), 6.64(t, J _FH =74.9Hz, 1H), 4.57(d, J=4.6Hz, 2H), 4.21–4.16(m, 2H), 3.87(s, 3H), 1.48(t, J=7.0Hz, 3H);

MS-ESI: m/z 320.2 [M+H] ⁺ .

Step 5: Synthesis of the compound methyl 2-(((4-(difluoromethoxy)-3-ethoxyphenyl)(methylthio)methylene)amino)acetate

Trimethyloxonium tetrafluoroboric acid (5.84g, 39.46mmol) was dissolved in dichloromethane (10mL), and compound 2-(4-(difluoromethoxy)-3- Ethoxyphenyl thioamide) methyl acetate (6.3g, 19.73mmol) in dichloromethane (30mL) solution, stirred at 0°C for 5h, washed with saturated sodium bicarbonate solution (25mL×3), the organic phase After drying with anhydrous _Na2SO4 , the solvent was removed to obtain ₆ g of yellow oil, yield: 91%.

Step 6: Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(4-(difluoromethoxy)-3-ethoxyphenyl)oxazole-4- Synthesis of methyl carboxylate

Compound 2-(((4-(difluoromethoxy)-3-ethoxyphenyl)(methylthio)methylene)amino)methyl acetate (6g, 18mmol), compound (S)- (1-Fluoro-1-oxopropan-2-yl) tert-butyl carbamate (6.88g, 36mmol) was dissolved in anhydrous tetrahydrofuran (20mL), stirred at -78°C, and hexamethyldisilazylamine was added dropwise Potassium tetrahydrofuran solution (45mL, 45mmol), react at -78°C for 2h, add saturated sodium bicarbonate solution (35mL) to quench the reaction, extract with ethyl acetate (25mL×3), combine the organic phases and wash with anhydrous Na ₂ SO ₄ was dried, the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=6/1) to obtain 3.1 g of light yellow solid, yield: 38%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.66 (d, J = 1.9Hz, 1H), 7.62 (dd, J ₁ = 8.3Hz, J ₂ = 2.0Hz, 1H), 7.23 (d, J = 8.3Hz ,1H),6.64(t,J _FH ＝74.9Hz,1H),5.48–5.44(m,1H),4.22–4.17(m,2H),3.99(s,3H),1.54(d,J＝7.0Hz ,3H),1.48(t,J=7.0Hz,3H),1.42(s,9H);

MS-ESI: m/z 457.3 [M+H] ⁺ .

Step 7: Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(4-(difluoromethoxy)-3-ethoxyphenyl)oxazole-4- Synthesis of Carboxylic Acids

Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(4-(difluoromethoxy)-3-ethoxyphenyl)oxazole-4-carboxylic acid Methyl ester (3.17g, 6.95mmol) and lithium hydroxide monohydrate (1.46g, 34.73mmol) were dissolved in a mixed solvent of tetrahydrofuran (20mL) and water (10mL), reacted at 40°C for 2h, the solvent tetrahydrofuran was removed, and hydrochloric acid was added (1M) Adjust the pH to 1, extract with ethyl acetate (20 mL×3), combine the organic phases and dry with Na ₂ SO ₄ , remove the solvent to obtain 3 g of yellow solid, yield: 90%.

¹ H NMR (400MHz, CD ₃ OD): δppm 7.82 (d, J = 1.9Hz, 1H), 7.67 (dd, J ₁ = 8.4Hz, J ₂ = 2.0Hz, 1H), 7.29 (d, J = 8.4 Hz,1H),6.87(t,J _FH ＝74.7Hz,1H),5.52–5.50(m,1H),4.25–4.22(m,2H),1.54(d,J＝7.1Hz,3H),1.49( t,J=7.0Hz,3H), 1.45(s,9H).

Step 8: Compound (S)-(1-(4-((2,4-difluorobenzyl)carbamoyl)-2-(4-(difluoromethoxy)-3-ethoxyphenyl ) Synthesis of oxazol-5-yl) ethyl) tert-butyl carbamate

Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(4-(difluoromethoxy)-3-ethoxyphenyl)oxazole-4-carboxylic acid (0.3g, 0.68mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (194mg, 1.02mmol) and N-hydroxyl-7-azabenzotriazepine Dissolve azole (138mg, 1.02mmol) in dichloromethane (10mL), stir at 0°C, add dropwise 2,4-difluorobenzylamine (0.1mL, 0.81mmol) and N,N-diisopropylethylamine (0.35mL, 2.04mmol), stirred at room temperature for 4h, washed with water (20mL×3), the organic phase was dried with Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)= 4/1), 264 mg of colorless oil was obtained, yield: 69%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.60–7.57(m,1H),7.58(s,1H),7.56–7.52(m,1H),7.45–7.41(m,1H),7.25(d,J ＝8.7Hz,1H),6.91–6.85(m,2H),6.66(t,J _FH ＝74.8Hz,1H),5.34–5.31(m,1H),4.68–4.66(m,2H),4.25–4.19 (m, 2H), 1.56 (d, J = 7.0Hz, 3H), 1.52 (t, J = 7.0Hz, 3H), 1.45 (s, 9H).

Step 9: Compound (S)-5-(1-aminoethyl)-N-(2,4-difluorobenzyl)-2-(4-(difluoromethoxy)-3-ethoxybenzene base) synthesis of oxazole-4-carboxamide hydrochloride

To compound (S)-(1-(4-((2,4-difluorobenzyl)carbamoyl)-2-(4-(difluoromethoxy)-3-ethoxyphenyl)oxa Add HCl in ethyl acetate (4M, 10 mL) to a solution of tert-butyl carbamate (260 mg, 0.46 mmol) in dichloromethane (1 mL), stir at room temperature for 20 min, and remove the solvent to obtain White solid 218 mg, yield: 94%.

Compound 74: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.81 (d, J = 1.5Hz, 1H), 7.73 (dd, J ₁ = 8.3Hz, J ₂ = 1.6Hz, 1H), 7.51-7.46 ( m,1H),7.32(d,J＝8.4Hz,1H),7.00–6.94(m,2H),6.88(t,J _FH ＝74.6Hz,1H),5.20–5.15(m,1H),4.65( s,2H),4.27–4.22(m,2H),1.78(d,J=6.9Hz,3H),1.49(t,J=7.0Hz,3H);

MS-ESI: m/z 468.0 [M+H-HCl] ⁺ .

Example 34: Compound (S)-6-((5-(1-aminoethyl)-2-(4-(difluoromethoxy)-3-ethoxyphenyl)oxa Synthesis of azole-4-carboxamide)methyl)picolinic acid dihydrochloride

Step 1: Compound (S)-6-((5-(1-(tert-butoxycarbonylamino)ethyl)-2-(4-(difluoromethoxy)-3-ethoxyphenyl)oxa Synthesis of ethyl azole-4-carboxamide)methyl)picolinate

Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(4-(difluoromethoxy)-3-ethoxyphenyl)oxazole-4-carboxylic acid (0.4g, 0.90mmol), compound 6-(aminoethyl) ethyl picolinate (196mg, 1.085mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (259mg, 1.36mmol) and N-hydroxy-7-azabenzotriazole (184mg, 1.36mmol) were dissolved in dichloromethane (15mL), stirred at 0°C, and N,N-diisopropyl Ethylamine (0.47mL, 2.71mmol), stirred at room temperature for 4h, washed with water (15mL×3), the organic phase was dried with Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/ v)=2/1), 279 mg of white solid was obtained, yield: 51%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.12 (d, J=7.2Hz, 1H), 7.98–7.94 (m, 1H), 7.75–7.72 (m, 1H), 7.67–7.66 (m, 1H), 7.61–7.59(m,1H),7.25(d,J＝8.3Hz,1H),6.67(t,J _FH ＝74.9Hz,1H),5.34–5.31(m,1H),4.97–4.95(m,2H ),4.56–4.50(m,2H),4.28–4.23(m,2H),1.54(t,J＝6.5Hz,6H),1.47(d,J＝7.2Hz,3H),1.45(s,9H) ;

MS-ESI: m/z 605.3 [M+H] ⁺ .

Step 2: Compound (S)-6-((5-(1-(tert-butoxycarbonylamino)ethyl)-2-(4-(difluoromethoxy)-3-ethoxyphenyl)oxa Synthesis of azole-4-carboxamide)methyl)picolinic acid

Compound (S)-6-((5-(1-(tert-butoxycarbonylamino)ethyl)-2-(4-(difluoromethoxy)-3-ethoxyphenyl)oxazole- 4-Carboxamide) methyl) ethyl picolinate (0.28g, 0.46mmol) and lithium hydroxide monohydrate (97mg, 2.32mmol) were added into a mixed solvent of tetrahydrofuran (10mL) and water (5mL), and reacted at 40°C 2h, add hydrochloric acid (1M) to adjust the pH value to 1, add ethyl acetate to extract (10mL×3), combine the organic phases and dry with Na ₂ SO ₄ , remove the solvent to obtain 0.26g white solid, yield: 98%.

¹ H NMR (400MHz, CD ₃ OD): δppm 8.11 (d, J = 7.6Hz, 1H), 8.05–8.02 (br, 1H), 7.74–7.72 (m, 2H), 7.66 (d, J = 8.2Hz ,1H),7.28(d,J＝8.2Hz,1H),6.86(t,J _FH ＝74.7Hz,1H),5.47–5.44(m,1H),4.80(s,2H),4.25–4.20(m ,2H),1.53(d,J=6.8Hz,3H),1.49(t,J=7.1Hz,3H),1.42(s,9H);

MS-ESI: m/z 577.2 [M+H] ⁺ .

Step 3: Compound (S)-6-((5-(1-aminoethyl)-2-(4-(difluoromethoxy)-3-ethoxyphenyl)oxazole-4-carboxamide ) methyl) the synthesis of picolinic acid dihydrochloride

To compound (S)-6-((5-(1-(tert-butoxycarbonylamino)ethyl)-2-(4-(difluoromethoxy)-3-ethoxyphenyl)oxazole- Add HCl in ethyl acetate (4M, 10mL) to a solution of 4-formamide)methyl)picolinic acid (260mg, 0.45mmol) in dichloromethane (1mL), stir at room temperature for 20min, filter, wash with ethyl acetate (20mL ×3), to obtain 210 mg of white solid, yield: 85%.

Compound 75: ¹ H NMR (400MHz, CD ₃ OD): δppm 8.49–8.47(m, 1H), 8.38(d, J=7.5Hz, 1H), 8.08(d, J=7.2Hz, 1H), 7.83( d,J=1.7Hz,1H),7.75(dd,J1 ₌ 8.4Hz,J2=1.8Hz,1H),7.34(d,J=8.3Hz,1H),6.90(t, _JFH = _74.6Hz ,1H),5.22–5.20(m,1H),5.00(s,2H),4.28–4.23(m,2H),1.78(d,J＝6.9Hz,3H),1.50(t,J＝6.9Hz, 3H);

MS-ESI: m/z 477.1 [M+H-2HCl] ⁺ .

Example 35: Compound (S)-5-(1-aminoethyl)-N-(benzofuran-3-ylmethyl)-2-(3-(cyclopropylmethyl) Synthesis of oxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound (S)-(1-(4-((benzofuran-3-ylmethyl)carbamoyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Synthesis of tert-butyl methoxy)phenyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) oxazole-4-carboxylic acid (0.3g, 0.64mmol), compound benzofuran-3-ylmethylamine hydrochloride (141mg, 0.77mmol), 1-ethyl-3-(3-dimethylaminopropyl ) carbodiimide hydrochloride (183mg, 0.96mmol) and N-hydroxy-7-azabenzotriazole (131mg, 0.96mmol) were dissolved in dichloromethane (10mL), stirred at 0°C for 30min, dropwise Add N,N-diisopropylethylamine (0.33mL, 1.92mmol), stir at room temperature for 22h, wash with water (10mL×3), dry the organic phase with Na ₂ SO ₄ , remove the solvent, and the concentrated solution is subjected to column separation ( Petroleum ether/ethyl acetate (v/v)=6/1) to obtain 230 mg of white solid, yield: 60%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.72–7.70(m,2H), 7.58–7.55(m,1H), 7.54–7.52(m,2H), 7.38–7.34(m,1H), 7.30(dd ,J ₁ ＝7.6Hz, J ₂ ＝1.0Hz,1H),7.23(d,J＝8.3Hz,1H),6.71(t,J _FH ＝75.0Hz,1H),5.34–5.30(m,1H), 4.79(d, J=5.8Hz, 2H), 3.96(d, J=7.0Hz, 2H), 1.59(d, J=6.4Hz, 3H), 1.47(s, 9H), 1.35–1.32(m, 1H ), 0.71–0.66(m,2H), 0.42–0.38(m,2H).

Step 2: Compound (S)-5-(1-aminoethyl)-N-(benzofuran-3-ylmethyl)-2-(3-(cyclopropylmethoxy)-4-(di Synthesis of fluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride

To compound (S)-(1-(4-((benzofuran-3-ylmethyl)carbamoyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Base) phenyl) oxazol-5-yl) ethyl) tert-butyl carbamate (0.23g, 0.38mmol) in dichloromethane (2mL) was added HCl in ethyl acetate (4M, 10mL), room temperature After stirring for 20 min, the solvent was removed to obtain 200 mg of white solid, yield: 98%.

Compound 81: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.80 (s, 1H), 7.78–7.76 (m, 2H), 7.70 (dd, J ₁ =8.4Hz, J ₂ =1.9Hz, 1H), 7.48(d, J＝8.2Hz, 1H), 7.34–7.30(m, 2H), 7.27–7.23(m, 1H), 6.90(t, J _FH ＝74.7Hz, 1H), 5.22–5.17(m, 1H ),4.75(s,2H),4.01(d,J＝6.9Hz,2H),1.79(d,J＝7.0Hz,3H),1.34–1.30(m,1H),0.69–0.66(m,2H) ,0.42–0.40(m,2H);

MS-ESI: m/z 498.3 [M+H-HCl] ⁺ .

Example 36: Compound (S)-5-(1-aminoethyl)-N-(benzofuran-3-ylmethyl)-2-(4-(difluoromethoxy Synthesis of yl)-3-ethoxyphenyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound (S)-(1-(4-((benzofuran-3-ylmethyl)carbamoyl)-2-(4-(difluoromethoxy)-3-ethoxybenzene Synthesis of tert-butyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(4-(difluoromethoxy)-3-ethoxyphenyl)oxazole-4-carboxylic acid (0.3g, 0.68mmol), compound benzofuran-3-ylmethylamine hydrochloride (150mg, 0.81mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride Salt (194mg, 1.02mmol) and N-hydroxy-7-azabenzotriazole (138mg, 1.02mmol) were dissolved in dichloromethane (10mL), stirred at 0°C for 30min, and N,N-di Isopropylethylamine (0.35mL, 2.04mmol), stirred at room temperature for 21h, washed with water (10mL×3), the organic phase was dried with Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate ( v/v)=6/1), 220mg of colorless oil was obtained, yield: 57%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.72–7.70(m,2H),7.57–7.55(m,2H),7.55–7.53(m,1H),7.38–7.34(m,1H),7.31–7.29 (m,1H),7.23(d,J=8.8Hz,1H),6.65(t,J _FH =74.8Hz,1H),5.36–5.32(m,1H),4.80(d,J=5.7Hz,2H ), 4.22–4.17 (m, 2H), 1.59 (d, J=7.0Hz, 3H), 1.48 (s, 9H), 1.28 (t, J=7.1Hz, 3H).

Step 2: Compound (S)-5-(1-aminoethyl)-N-(benzofuran-3-ylmethyl)-2-(4-(difluoromethoxy)-3-ethoxy Synthesis of phenyl)oxazole-4-carboxamide hydrochloride

To compound (S)-(1-(4-((benzofuran-3-ylmethyl)carbamoyl)-2-(4-(difluoromethoxy)-3-ethoxyphenyl) To a solution of tert-butyl oxazol-5-yl)ethyl)carbamate (220mg, 0.38mmol) in dichloromethane (1mL) was added HCl in ethyl acetate (4M, 8mL), stirred at room temperature for 20min, and the solvent was removed. 190 mg of pale yellow solid was obtained, yield: 97%.

Compound 87: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.80 (s, 1H), 7.77–7.75 (m, 2H), 7.69 (dd, J ₁ =8.4Hz, J ₂ =1.6Hz, 1H), 7.46(d, J＝8.1Hz, 1H), 7.31–7.28(m, 2H), 7.24(td, J ₁ ＝7.5Hz, J ₂ ＝0.9Hz, 1H), 6.87(t, J _FH ＝74.6Hz, 1H),5.22–5.20(m,1H),4.74(s,2H),4.22–4.17(m,2H),1.81(d,J＝6.9Hz,3H),1.46(t,J＝6.9Hz,3H );

MS-ESI: m/z 472.3 [M+H-HCl] ⁺ .

Example 37: Compound (S)-5-(1-aminoethyl)-2-(4-(difluoromethoxy)-3-ethoxyphenyl)-N-(2, Synthesis of 4-difluorophenethyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound (S)-(1-(2-(4-(difluoromethoxy)-3-ethoxyphenyl)-4-((2,4-difluorophenethyl)aminomethyl Synthesis of tert-butyl Acyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(4-(difluoromethoxy)-3-ethoxyphenyl)oxazole-4-carboxylic acid (0.3g, 0.68mmol), compound 2-(2,4-difluorophenyl)ethylamine (128mg, 0.81mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Hydrochloride (194mg, 1.02mmol) and N-hydroxy-7-azabenzotriazole (138mg, 1.02mmol) were dissolved in dichloromethane (10mL), stirred at 0°C for 30min, and N,N- Diisopropylethylamine (0.35mL, 2.04mmol), stirred at room temperature for 17h, washed with water (10mL×3), the organic phase was dried with Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=6/1), 230 mg of yellow oil was obtained, yield: 58%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.59–7.57(m,2H),7.27–7.22(m,2H),6.87–6.81(m,2H),6.67(t,J _FH ＝70.0Hz,1H) ,5.29–5.25(m,1H),4.25–4.20(m,2H),3.71–3.67(m,2H),2.99(t,J＝7.0Hz,2H), 1.53(t,J＝7.5Hz,6H ),1.46(s,9H);

MS-ESI: m/z 582.3 [M+H] ⁺ .

Step 2: Compound (S)-5-(1-aminoethyl)-2-(4-(difluoromethoxy)-3-ethoxyphenyl)-N-(2,4-difluorobenzene Synthesis of ethyl)oxazole-4-carboxamide hydrochloride

To compound (S)-(1-(2-(4-(difluoromethoxy)-3-ethoxyphenyl)-4-((2,4-difluorophenethyl)carbamoyl) To a solution of tert-butyl oxazol-5-yl)ethyl)carbamate (230mg, 0.40mmol) in dichloromethane (1mL) was added HCl in ethyl acetate (4M, 8mL), stirred at room temperature for 20min, and the solvent was removed. 180 mg of white solid was obtained, yield: 88%.

Compound 88: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.79 (d, J = 1.9Hz, 1H), 7.71 (dd, J ₁ = 8.4Hz, J ₂ = 1.9Hz, 1H), 7.36-7.32 ( m,2H),6.93–6.90(m,2H),6.89(t,J _FH ＝74.6Hz,1H),5.12–5.11(m,1H),4.27–4.22(m,2H),3.66(t,J =7.1Hz, 2H), 2.99(t, J=7.1Hz, 2H), 1.75(d, J=7.0Hz, 3H), 1.50(t, J=7.0Hz, 3H);

MS-ESI: m/z 482.1 [M+H-HCl] ⁺ .

Example 38: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-((2,4-difluorophenyl)sulfonyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(((2,4-difluoro Synthesis of tert-butyl phenyl)sulfonyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) oxazole-4-carboxylic acid (0.3g, 0.64mmol) and N,N'-carbonyldiimidazole (312mg, 1.92mmol) were dissolved in anhydrous tetrahydrofuran (10mL), reacted at 60°C for 30min, cooled to room temperature and pumped The internal gas was blown with nitrogen, and 2,4-difluorobenzenesulfonamide (247mg, 1.28mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14mL, 0.96mmol) were added dropwise Anhydrous tetrahydrofuran (10mL) solution was added, and reacted at 60°C for 12h. After the reaction was stopped, saturated ammonium chloride solution (15mL) was added, extracted with EA (15mL×3), and the organic phase was washed with anhydrous Na ₂ SO ₄ After drying, the concentrate was subjected to column separation (dichloromethane/methanol (v/v)=20/1) to obtain 0.4 g of a yellow solid, yield: 99%.

¹ H NMR (400MHz, CDCl ₃ ): δ(ppm)8.26–8.22(m,1H),7.59–7.54(m,2H),7.27–7.26(m,1H),7.14–7.10(m,1H), 7.02–6.97(m,1H),6.75(t,J _FH ＝74.9Hz,1H),5.28–5.25(m,1H),4.04(d,J＝6.9Hz,2H),1.50(d,J＝7.1 Hz, 3H), 1.39(s, 9H), 1.34–1.33(m, 1H), 0.74–0.72(m, 2H), 0.49–0.45(m, 2H).

Step 2: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((2 , Synthesis of 4-difluorophenyl)sulfonyl)oxazole-4-carboxamide hydrochloride

To compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(((2,4-difluorophenyl )sulfonyl)carbamoyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (0.12g, 0.19mmol) in dichloromethane (2mL) solution was added HCl ethyl acetate solution (4M, 6mL ), stirred at room temperature for 20 min, and removed the solvent to obtain 100 mg of light yellow solid, yield: 93%.

Compound 89: ¹ H NMR (400MHz, CD ₃ OD): δ (ppm) 8.22–8.18 (m, 1H), 7.85 (d, J = 1.8Hz, 1H), 7.74 (dd, J ₁ = 8.4Hz, J ₂ =1.9Hz,1H),7.34(d,J=8.4Hz,1H),7.30–7.23(m,2H),6.93(t,J _FH =74.7Hz,1H),5.14–5.12(m,1H) ,4.06(d,J=7.0Hz,2H),1.70(d,J=7.0Hz,3H),1.38–1.35(m,1H),0.73–0.68(m,2H),0.46–0.42(m,2H );

MS-ESI: m/z 544.2 [M+H-HCl] ⁺ .

Example 39: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-(1-(2,4-difluorophenyl)-2-(methylsulfonyl)ethyl)oxazole-4-carboxamide hydrochloride

Step 1: Synthesis of compound 1-(2,4-difluorophenyl)-2-(methylsulfonyl)ethylamine hydrochloride

At -78°C, add n-butyl lithium in n-hexane (2.4M, 7mL, 16.8mmol) dropwise to a solution of dimethyl sulfone (1.59g, 16.9mmol) in anhydrous tetrahydrofuran (30mL), and at -78°C Stir for 30min. To a solution of 2,4-difluorobenzaldehyde (2g, 14.07mmol) in tetrahydrofuran (15mL) was added dropwise a THF solution of lithium hexamethyldisilazide (1M, 16.9mL, 16.9mmol) at 0°C , stirred for 15 min, added boron trifluoride diethyl ether (3.82 mL, 31 mmol) dropwise at 0°C, stirred for 10 min, then added this solution dropwise to the previous solution of dimethyl sulfone and n-butyllithium at -78°C, stirred at room temperature for 24 h, Stop the reaction, add water (30mL) and potassium carbonate (3g, 21.7mmol) to the solution under ice bath, extract with ethyl acetate (20mL×3), combine the organic phases, dry with anhydrous Na ₂ SO ₄ , concentrate Add dichloromethane (6mL), HCl.EA solution (4M, 12mL), stir at room temperature for 20min, remove the solvent, add water (20mL), wash with petroleum ether (15mL), add sodium hydroxide solution (1M) to the aqueous phase to adjust the pH The value was about 12, extracted with ethyl acetate (20mL×3), combined the organic phases, dried with anhydrous Na ₂ SO ₄ , concentrated to give 0.9g of brown oil, added HCl in ethyl acetate solution (4M, 10mL), Stir at room temperature for 20 min, and remove the solvent to obtain 1 g of brown oil, yield: 27%.

¹ H NMR (400MHz, CD ₃ OD): δ (ppm) 7.71–7.65(m,1H), 7.22–7.14(m,2H), 5.23–5.19(m,1H), 4.00–3.89(m,2H) ,3.09(s,3H);

MS-ESI: m/z 236.2 [M+H-HCl] ⁺ .

Step 2: Compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4- Synthesis of tert-butyl difluorophenyl)-2-(methylsulfonyl)ethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) Oxazole-4-carboxylic acid (0.25g, 0.53mmol), compound 1-(2,4-difluorophenyl)-2-(methylsulfonyl)ethylamine hydrochloride (174mg, 0.64mmol), 1- Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (153mg, 0.80mmol) and N-hydroxy-7-azabenzotriazole (109mg, 0.80mmol) were dissolved in di In methyl chloride (10mL), stir at 0°C for 30min, add N,N-diisopropylethylamine (0.28mL, 1.60mmol) dropwise, stir at room temperature for 17h, add water (10mL×3), wash the organic phase with Na ₂ SO ₄ was dried, the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=2/1) to obtain 94 mg of yellow oil, yield: 26%.

¹ H NMR (400MHz, CDCl ₃ ): δ (ppm) 7.64–7.61 (m, 1H), 7.60–7.58 (m, 2H), 7.54–7.51 (m, 1H), 7.26 (d, J=8.3Hz, 1H),6.98–6.91(m,2H),6.73(t,J _FH ＝75.0Hz,1H),5.95–5.91(m,1H),5.37–5.31(m,1H),4.01–3.99(m,2H ),3.86–3.81(m,1H),3.63–3.56(m,1H),2.87–2.84(m,3H),1.56–1.50(m,3H),1.45(s,9H),1.36–1.33(m ,1H),0.73–0.70(m,2H),0.46–0.43(m,2H).

Step 3: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1- Synthesis of (2,4-difluorophenyl)-2-(methylsulfonyl)ethyl)oxazole-4-carboxamide hydrochloride

To compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4-difluoro To a solution of tert-butyl phenyl)-2-(methylsulfonyl)ethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate (94 mg, 0.14 mmol) in dichloromethane (1 mL) was added HCl Ethyl acetate solution (4M, 4mL), stirred at room temperature for 30min, and the solvent was removed to obtain 77mg of light yellow solid, yield: 91%.

Compound 92: ¹ H NMR (400MHz, CD ₃ OD): δ (ppm) 7.81 (d, J = 1.9Hz, 1H), 7.74 (dd, J ₁ = 8.4Hz, J ₂ = 1.9Hz, 1H), 7.66 –7.60(m,1H),7.34(d,J＝8.4Hz,1H),7.07–7.02(m,2H),6.92(t,J _FH ＝74.7Hz,1H),6.11–6.06(m,1H) ,5.19–5.14(m,1H),3.72–3.68(m,1H),3.08–3.05(m,3H),2.01(s,3H),1.76(d,J＝7.0Hz,3H),1.40–1.34 (m,1H),0.72–0.67(m,2H),0.46–0.42(m,2H);

MS-ESI: m/z 586.3 [M+H-HCl] ⁺ .

Example 40: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(2,2-difluoroethoxy Synthesis of phenyl)-N-(2,4-difluorobenzyl)oxazole-4-carboxamide hydrochloride

Step 1: Synthesis of the compound 3-(cyclopropylmethoxy)-4-(2,2-difluoroethoxy)methyl benzoate

Add methyl 3-cyclopropylmethoxy-4-hydroxybenzoate (5 g, 22.5 mmol), 1-bromo-2,2-difluoroethane (4.89 g, 33.75 mmol), potassium carbonate to the sealed tube (6.22g, 45mmol) and DMF (30mL), react at 60°C for 7h, filter with suction, and concentrate the filtrate to obtain 5.5g of brown liquid, yield: 85%.

¹ H NMR (400MHz, CDCl ₃ ): δ (ppm) 7.62 (dd, J ₁ =8.4Hz, J ₂ =1.9Hz, 1H), 7.56 (d, J = 1.9Hz, 1H), 6.92 (d, J ＝8.4Hz, 1H), 6.31–6.01(m, 1H), 4.28(td, J ₁ ＝13.1Hz, J ₂ ＝4.2Hz, 2H), 3.89(d, J＝8.7Hz, 2H), 3.88(s ,3H),1.35–1.25(m,1H),0.67–0.60(m,2H),0.38–0.34(m,2H);

MS-ESI: m/z 287.2 [M+H] ⁺ .

Step 2: Synthesis of compound 3-(cyclopropylmethoxy)-4-(2,2-difluoroethoxy)benzoic acid

The compound 3-(cyclopropylmethoxy)-4-(2,2-difluoroethoxy)methyl benzoate (5.5g, 19.21mmol) and sodium hydroxide (2.31g, 57.64mmol) were dissolved in In a mixed solvent of ethanol (30mL) and water (15mL), react at 60°C for 3h, remove the solvent ethanol, add hydrochloric acid (1M) to adjust the pH to 1, add ethyl acetate for extraction (25mL×3), and wash the organic phase with anhydrous Dry over Na ₂ SO ₄ and concentrate to give 5.2 g of white solid, yield: 98%.

¹ H NMR (400MHz, CDCl ₃ ): δ (ppm) 7.75 (dd, J ₁ =8.4Hz, J ₂ =2.0Hz, 1H), 7.64 (d, J = 1.9Hz, 1H), 6.99 (d, J ＝8.4Hz, 1H), 6.35–6.05(m, 1H), 4.34(td, J ₁ ＝13.0Hz, J ₂ ＝4.2Hz, 2H), 3.94(d, J＝6.9Hz, 2H), 1.36–1.30 (m,1H),0.71–0.66(m,2H),0.42–0.37(m,2H);

MS-ESI: m/z 273.2 [M+H] ⁺ .

Step 3: Synthesis of the compound 2-(3-(cyclopropylmethoxy)-4-(2,2-difluoroethoxy)benzamido)methyl acetate

The compound 3-(cyclopropylmethoxy)-4-(2,2-difluoroethoxy)benzoic acid (5.2g, 19.1mmol), 1-ethyl-3-(3-dimethylaminopropyl Base) carbodiimide hydrochloride (5.47g, 28.65mmol) and N-hydroxy-7-azabenzotriazole (3.9g, 28.65mmol) were dissolved in dichloromethane (40mL), stirred at room temperature for 30min After that, methyl aminoacetate hydrochloride (2.88g, 22.92mmol) was added, N,N-diisopropylethylamine (10mL, 57.30mmol) was added dropwise at 0°C, stirred at room temperature for 10h, washed with water (30mL), and the organic phase was used After drying over Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=1/1) to obtain 6.19 g of white solid, yield: 94%.

¹ H NMR (400MHz, CDCl ₃ ): δ (ppm) 7.45 (d, J = 2.0Hz, 1H), 7.33 (dd, J ₁ = 8.3Hz, J ₂ = 2.1Hz, 1H), 6.96 (d, J =8.3Hz,1H), 6.67–6.63(m,1H),6.33–6.03(m,1H),4.30(td,J ₁ =13.1Hz,J ₂ =4.2Hz,2H),4.24(d,J= 5.1Hz, 2H), 3.92(d, J=6.9Hz, 2H), 3.82(s, 3H), 1.34–1.29(m, 1H), 0.69–0.64(m, 2H), 0.39–0.35(m, 2H );

MS-ESI: m/z 344.1 [M+H] ⁺ .

Step 4: Synthesis of the compound 2-(3-(cyclopropylmethoxy)-4-(2,2-difluoroethoxy)phenylthioamido)methyl acetate

Compound 2-(3-(cyclopropylmethoxy)-4-(2,2-difluoroethoxy)benzamido)methyl acetate (6.2g, 18.06mmol) and Lawson's reagent (7.3 g, 18.06mmol) was dissolved in tetrahydrofuran (35mL), reacted at 75°C for 2h, added saturated sodium bicarbonate solution (30mL), extracted with ethyl acetate (20mL×3), combined the organic phases with anhydrous Na ₂ SO ₄ After drying, the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v)=2/1) to obtain 6.49 g of a yellow solid, yield: 92%.

¹ H NMR (400MHz, CDCl ₃ ): δ (ppm) 8.09 (br.s, 1H), 7.56 (d, J = 2.2Hz, 1H), 7.32 (dd, J ₁ = 8.4Hz, J ₂ = 2.2Hz ,1H),6.92(d,J=8.4Hz,1H),6.32–6.02(m,1H),4.58(d,J=4.5Hz,2H),4.29(td,J ₁ ＝13.1Hz,J ₂ ＝ 4.2Hz, 2H), 3.93(d, J=7.0Hz, 2H), 3.87(s, 3H), 1.34–1.29(m, 1H), 0.69–0.64(m, 2H), 0.40–0.37(m, 2H );

MS-ESI: m/z 360.2 [M+H] ⁺ .

Step 5: Compound Methyl 2-(((3-(cyclopropylmethoxy)-4-(2,2-difluoroethoxy)phenyl)(methylthio)methylene)amino)acetate Synthesis

At -78°C, compound 2-(3-(cyclopropylmethoxy)-4- (2,2-Difluoroethoxy)phenylthioamido)methyl acetate (3g, 8.35mmol) in dichloromethane (20mL) solution, stirred at 0°C for 3h, washed with saturated sodium bicarbonate solution (25mL) , the organic phase was dried with anhydrous _Na2SO4 , and the solvent was removed to obtain ₃ g of yellow oil, yield: 98%.

Step 6: Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(2,2-difluoroethoxy )Synthesis of phenyl)oxazole-4-carboxylic acid methyl ester

The compound 2-(((3-(cyclopropylmethoxy)-4-(2,2-difluoroethoxy)phenyl)(methylthio)methylene)amino)acetic acid methyl ester (3.1 g, 8.3mmol) and compound (S)-(1-fluoro-1-oxopropan-2-yl)carbamate tert-butyl ester (4g, 20.75mmol) were dissolved in anhydrous tetrahydrofuran (15mL) at -78°C Under certain conditions, a tetrahydrofuran solution (29.05 mL, 29.05 mmol) of potassium hexamethyldisilazide was added dropwise to the solution, reacted at -78°C for 1 h, and after adding saturated sodium chloride solution (30 mL), acetic acid Ethyl ether extraction (20mL×3), the combined organic phases were dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=4/1) to obtain 1.91 g yellow solid, yield: 48%.

¹ H NMR (400MHz, CDCl ₃ ): δ (ppm) 7.64–7.61 (m, 2H), 7.01 (d, J=8.3Hz, 1H), 6.34–6.04 (m, 1H), 5.49–5.45 (m, 1H), 4.32(td, J ₁ ＝13.1Hz, J ₂ ＝4.2Hz, 2H), 4.00(s, 3H), 3.96(d, J＝7.0Hz, 2H), 1.57(d, J＝2.8Hz, 3H),1.45(s,9H),1.35–1.30(m,1H),0.71–0.66(m,2H),0.42–0.38(m,2H);

MS-ESI: m/z 497.2 [M+H] ⁺ .

Step 7: Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(2,2-difluoroethoxy )Synthesis of phenyl)oxazole-4-carboxylic acid

Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(2,2-difluoroethoxy)benzene base) methyl oxazole-4-carboxylate (1.91g, 3.85mmol) and lithium hydroxide monohydrate (0.81g, 19.23mmol) were dissolved in a mixed solvent of tetrahydrofuran (20mL) and water (10mL), and reacted at 40°C 2h, add hydrochloric acid (1M) to adjust the pH value to 1, add ethyl acetate to extract (20mL×3), combine the organic phases and dry with Na ₂ SO ₄ , remove the solvent to obtain 1.62g yellow solid, yield: 87%.

¹ H NMR (400MHz, CDCl ₃ ): δ (ppm) 7.71 (d, J = 2.0Hz, 1H), 7.65 (dd, J ₁ = 8.4Hz, J ₂ = 2.0Hz, 1H), 7.15 (d, J =8.4Hz, 1H), 6.39–6.11(m, 1H), 5.50–5.48(m, 1H), 4.34(td, J ₁ =13.7Hz, J ₂ =3.9Hz, 2H), 3.98(d, J= 6.9Hz, 2H), 1.53(d, J=7.1Hz, 3H), 1.45(s, 9H), 1.34–1.32(m, 1H), 0.69–0.64(m, 2H), 0.43–0.39(m, 2H );

MS-ESI: m/z 481.6 [MH] ^- .

Step 8: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(2,2-difluoroethoxy)phenyl)-4-((2,4 Synthesis of tert-butyl-difluorobenzyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(2,2-difluoroethoxy)benzene base) oxazole-4-carboxylic acid (0.3g, 0.62mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (178mg, 0.93mmol) and N-hydroxy -7-Azabenzotriazole (127mg, 0.93mmol) was dissolved in dichloromethane (10mL), stirred at 0°C, 2,4-difluorobenzylamine (0.09mL, 0.75mmol) was added dropwise after 30min, After stirring at 0°C for 30 min, N,N-diisopropylethylamine (0.33 mL, 1.87 mmol) was added dropwise, stirred at room temperature for 12 h, washed with water (20 mL×3), the organic phase was dried with Na ₂ SO ₄ , and the solvent was removed. The concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v)=4/1) to obtain 230 mg of a yellow solid, yield: 61%.

¹ H NMR (400MHz, CDCl ₃ ): δ (ppm) 7.57 (dd, J ₁ = 8.4Hz, J ₂ = 2.0Hz, 1H), 7.51 (d, J = 1.9Hz, 1H), 7.46–7.40 (m ,1H),7.00(d,J＝8.4Hz,1H),6.91–6.83(m,2H),6.33–6.04(m,1H),5.32–5.30(m,1H),4.67–4.65(m,2H ), 4.31(td, J ₁ ＝13.1Hz, J ₂ ＝4.2Hz, 2H), 3.95(d, J＝7.0Hz, 2H), 1.55(d, J＝7.0Hz, 3H), 1.45(s, 9H ), 1.36–1.32(m,1H), 0.71–0.67(m,2H), 0.43–0.39(m,2H).

Step 9: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(2,2-difluoroethoxy)phenyl)-N Synthesis of -(2,4-difluorobenzyl)oxazole-4-carboxamide hydrochloride

To compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(2,2-difluoroethoxy)phenyl)-4-((2,4-di To a solution of tert-butyl fluorobenzyl)carbamoyl)oxazol-5-yl)ethyl)carbamate (220 mg, 0.36 mmol) in dichloromethane (1 mL) was added HCl in ethyl acetate (4M, 5 mL) , stirred at room temperature for 15 min, filtered, and washed with ethyl acetate (15 mL×3) to obtain 76 mg of white solid, yield: 40%.

Compound 96: ¹ H NMR (400MHz, CD ₃ OD): δ (ppm) 7.66-7.64 (m, 2H), 7.45-7.39 (m, 1H), 7.12 (d, J=8.8Hz, 1H), 6.95- 6.88(m,2H),6.33–6.05(m,1H),5.12–5.07(m,1H),4.58(s,2H),4.30(td,J ₁ =13.7Hz,J ₂ =3.8Hz,2H) ,3.92(d,J=6.9Hz,2H),1.71(d,J=6.9Hz,3H),1.29–1.24(m,1H),0.62–0.58(m,2H),0.36–0.32(m,2H );

MS-ESI: m/z 508.1 [M-HCl+H] ⁺ .

Example 41: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-(1-(2,4-difluorophenyl)ethyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4- Synthesis of tert-butyl difluorophenyl)ethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) oxazole-4-carboxylic acid (0.3g, 0.64mmol), 1-(2', 4'-difluorophenyl) ethylamine (121mg, 0.77mmol), 1-ethyl-3-(3-dimethyl Aminopropyl) carbodiimide hydrochloride (183mg, 0.96mmol) and N-hydroxy-7-azabenzotriazole (131mg, 0.96mmol) were dissolved in dichloromethane (10mL), stirred at 0°C 30min, N,N-diisopropylethylamine (0.34mL, 1.92mmol) was added dropwise, stirred at room temperature for 14h, washed with water (10mL×3), the organic phase was dried with Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column After separation (petroleum ether/ethyl acetate (v/v)=4/1), 270 mg of a colorless oil was obtained, yield: 69%.

¹ H NMR (400MHz, CDCl ₃ ): δ (ppm) 7.63 (dd, J ₁ = 8.3Hz, J ₂ = 1.9Hz, 1H), 7.57 (d, J = 1.8Hz, 1H), 7.38–7.36 (m ,1H),7.26(d,J＝8.4Hz,1H),6.92–6.83(m,2H),6.73(t,J _FH ＝75.0Hz,1H),5.45–5.42(m,1H),4.60–4.54 (m,1H),4.01(d,J＝6.9Hz,2H),1.65–1.64(m,3H),1.55–1.49(m,3H),1.46(s,9H),1.32–1.30(m,1H ), 0.74–0.69(m,2H), 0.46–0.42(m,2H).

Step 2: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1- Synthesis of (2,4-difluorophenyl)ethyl)oxazole-4-carboxamide hydrochloride

To compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4-difluoro To a solution of tert-butyl phenyl)ethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate (270 mg, 0.44 mmol) in dichloromethane (1 mL) was added HCl in ethyl acetate (4M, 5 mL), stirred at room temperature for 2 h, and removed the solvent to obtain 230 mg of white solid, yield: 95%.

Compound 100: ¹ H NMR (400MHz, CD ₃ OD): δ (ppm) 7.83 (d, J = 1.7Hz, 1H), 7.74 (dd, J ₁ = 8.4Hz, J ₂ = 1.7Hz, 1H), 7.55 –7.53(m,1H),7.33(d,J＝8.3Hz,1H),6.99–6.93(m,2H),6.92(t,J _FH ＝74.8Hz,1H),5.52–5.50(m,1H) ,5.16–5.11(m,1H),4.06(d,J＝6.9Hz,2H),1.76(dd,J ₁ ＝7.0Hz,J ₂ ＝2.7Hz,3H),1.63(d,J＝7.0Hz, 3H),1.36–1.32(m,1H),0.71–0.67(m,2H),0.46–0.42(m,2H);

MS-ESI: m/z 508.3 [M+H-HCl] ⁺ .

Example 42: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene base)-N-((S)-1-(2,4-difluorophenyl)-2-(methylsulfonyl)ethyl)oxazole-4-carboxamide hydrochloride and 5-((S) -1-Ammonia Ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((R)-1-(2,4-difluorophenyl) -2-(Methanesulfonate Synthesis of Acyl)ethyl)oxazole-4-carboxamide Hydrochloride

Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-( 1-(2,4-difluorophenyl)-2-(methylsulfonyl)ethyl)oxazole-4-carboxamide hydrochloride was resolved, and the compound 5-((S)-1- Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((S)-1-(2,4-difluorophenyl )-2-(methylsulfonyl)ethyl)oxazole-4-carboxamide hydrochloride (pale yellow solid) and 5-((S)-1-aminoethyl)-2-(3-(cyclopropane methoxy)-4-(difluoromethoxy)phenyl)-N-((R)-1-(2,4-difluorophenyl)-2-(methylsulfonyl)ethyl)oxa Azole-4-carboxamide hydrochloride (pale red solid).

Compound 101: ¹ H NMR (400MHz, CD ₃ OD): δ (ppm) 7.81 (d, J = 1.9Hz, 1H), 7.74 (dd, J ₁ = 8.4Hz, J ₂ = 1.9Hz, 1H), 7.66 –7.60(m,1H),7.34(d,J＝8.4Hz,1H),7.08–7.02(m,2H),6.92(t,J _FH ＝74.7Hz,1H), 6.11–6.07(m,1H) ,5.19–5.14(m,1H),4.07–4.01(m,1H),4.05(d,J＝6.9Hz,2H),3.73–3.68(m,1H),3.06(s,3H),1.75(d ,J＝7.0Hz,3H),1.37–1.33(m,1H),0.72–0.68(m,2H),0.46–0.42(m,2H);

MS-ESI: m/z 586.2[M+H-HCl] ⁺ ;

Compound 102: ¹ H NMR (400MHz, CD ₃ OD): δ (ppm) 7.81 (d, J = 1.8Hz, 1H), 7.74 (dd, J ₁ = 8.4Hz, J ₂ = 1.9Hz, 1H), 7.63 –7.61(m,1H),7.34(d,J＝8.4Hz,1H),7.08–7.02(m,2H),6.92(t,J _FH ＝74.7Hz,1H),6.12–6.08(m,1H) ,5.17–5.15(m,1H),4.08–4.02(m,1H),4.05(d,J＝6.9Hz,2H),3.72–3.68(m,1H),3.07(s,3H),1.76(d ,J＝7.0Hz,3H),1.37–1.33(m,1H),0.72–0.68(m,2H),0.46–0.42(m,2H);

MS-ESI: m/z 586.3 [M+H-HCl] ⁺ .

Example 43: Compound (S)-5-(1-aminoethyl)-2-(3,4-bis(cyclopropylmethoxy)phenyl)-N-(2,4- Synthesis of difluorobenzyl)oxazole-4-carboxamide hydrochloride

Step 1: Synthesis of compound 3,4-bis(cyclopropylmethoxy)methyl benzoate

Methyl 3-cyclopropylmethoxy-4-hydroxybenzoate (5 g, 22.5 mmol), bromomethylcyclopropane (4.56 g, 33.75 mmol), potassium carbonate (6.22 g, 45 mmol) and N,N-Dimethylformamide (30mL), reacted at 60°C for 4.5h, filtered with suction, and the filtrate was desolventized to obtain 5.47g of white solid, yield: 88%.

¹ H NMR (400MHz, CDCl ₃ ): δ (ppm) 7.64 (dd, J ₁ =8.4Hz, J ₂ =2.0Hz, 1H), 7.57 (d, J = 2.0Hz, 1H), 6.89 (d, J ＝8.4Hz,1H),3.94–3.91(m,4H),3.89(s,3H),1.38–1.31(m,2H),0.68–0.62(m,4H),0.41–0.37(m,4H);

MS-ESI: m/z 277.1 [M+H] ⁺ .

Step 2: Synthesis of compound 3,4-bis(cyclopropylmethoxy)benzoic acid

Compound 3,4-bis(cyclopropylmethoxy)methyl benzoate (5.47g, 19.8mmol) and sodium hydroxide (2.38g, 59.4mmol) were dissolved in ethanol (40mL) and mixed with water (20mL) In the solvent, react at 60°C for 3h, remove the solvent ethanol, add hydrochloric acid (1M) to adjust to pH = 1, add ethyl acetate for extraction (25mL×3), dry the organic phase with anhydrous Na ₂ SO ₄ , remove the solvent to obtain a white Solid 4.75g, yield: 91%.

¹ H NMR (400MHz, CDCl ₃ ): δ (ppm) 7.74 (dd, J ₁ =8.4Hz, J ₂ =2.0Hz, 1H), 7.63 (d, J = 2.0Hz, 1H), 6.93 (d, J ＝8.5Hz,1H),3.98–3.94(m,4H),1.38–1.33(m,2H),0.70–0.64(m,4H),0.43–0.38(m,4H);

MS-ESI: m/z 263.2 [M+H] ⁺ .

Step 3: Synthesis of the compound 2-(3,4-bis(cyclopropylmethoxy)benzamido)methyl acetate

Compound 3,4-bis(cyclopropylmethoxy)benzoic acid (4.75g, 18.1mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.21 g, 27.2mmol) and N-hydroxy-7-azabenzotriazole (3.7g, 27.2mmol) were dissolved in dichloromethane (35mL), stirred at room temperature for 30min, and methyl glycine hydrochloride (2.73g, 21.7mmol), N,N-diisopropylethylamine (13mL, 72.4mmol) was added dropwise at 0°C, stirred at room temperature for 10h, washed with water (20mL×3), the organic phase was dried with anhydrous Na ₂ SO ₄ , and the solvent was removed , the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=2/1) to obtain 5.56 g of white solid, yield: 92%.

¹ H NMR (400MHz, CDCl ₃ ): δ (ppm) 7.45 (d, J = 2.1 Hz, 1H), 7.35 (dd, J ₁ = 8.4 Hz, J ₂ = 2.1 Hz, 1 H), 6.91 (d, J =8.4Hz,1H),6.59(br.s,1H),4.25(d,J=4.8Hz,2H),3.93(d,J=6.9Hz,4H),3.82(s,3H),1.38–1.31 (m,2H),0.68–0.62(m,4H),0.41–0.36(m,4H);

MS-ESI: m/z 334.3 [M+H] ⁺ .

Step 4: Synthesis of the compound 2-(3,4-bis(cyclopropylmethoxy)phenylthioamide)acetate methyl ester

The compound methyl 2-(3,4-bis(cyclopropylmethoxy)benzamido)acetate (5.56 g, 16.7 mmol) and Lawson's reagent (6.75 g, 16.7 mmol) were added to tetrahydrofuran (35 mL) , reacted at 75°C for 2h, added saturated sodium bicarbonate solution (40mL), extracted with ethyl acetate (20mL×3), combined the organic phases and dried them with anhydrous Na ₂ SO ₄ , and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate Ester (v/v)=3/1), to obtain 5.8 g of yellow solid, yield: 99%.

¹ H NMR (400MHz, CDCl ₃ ): δ (ppm) 8.06 (br.s, 1H), 7.56 (d, J = 2.2Hz, 1H), 7.37 (dd, J ₁ = 8.4Hz, J ₂ = 2.2Hz ,1H),6.87(d,J=8.4Hz,1H),4.59(d,J=4.5Hz,2H),3.95–3.92(m,4H),3.87(s,3H),1.38–1.31(m, 2H),0.68–0.63(m,4H),0.41–0.37(m,4H);

MS-ESI: m/z 350.2 [M+H] ⁺ .

Step 5: Synthesis of the compound 2-(((3,4-bis(cyclopropylmethoxy)phenyl)(methylthio)methylene)amino)acetate methyl ester

At -78°C, compound 2-(3,4-bis(cyclopropylmethoxy) was added dropwise to a solution of trimethyloxonium tetrafluoroboric acid (3.0g, 20mmol) in dichloromethane (10mL) Dichloromethane (20mL) solution of phenylthioamide) methyl acetate (2.55g, 7.30mmol), react at 0°C for 3h, add saturated sodium bicarbonate solution to wash (45mL), and wash the organic phase with anhydrous Na ₂ SO ₄ After drying, the solvent was removed to obtain 2.39 g of yellow oil, yield: 90%.

Step 6: Compound (S)-2-(3,4-bis(cyclopropylmethoxy)phenyl)-5-(1-((tert-butoxycarbonyl)amino)ethyl)oxazole-4- Synthesis of methyl formate

Compound 2-(((3,4-bis(cyclopropylmethoxy)phenyl)(methylthio)methylene)amino)methyl acetate (2.38g, 6.55mmol) and compound (S)- (1-fluoro-1-oxopropan-2-yl) tert-butyl carbamate (3.6g, 19mmol) was dissolved in anhydrous tetrahydrofuran (10mL), and hexamethasone was added dropwise to the solution at -78°C Potassium disilazide tetrahydrofuran solution (26mL, 26mmol), react at -78°C for 2.5h, add saturated sodium chloride solution (30mL) to quench the reaction, extract with ethyl acetate (20mL×3), combine The organic phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v)=4/1) to obtain 1 g of yellow solid, yield: 31%.

¹ H NMR (400MHz, CDCl ₃ ): δ (ppm) 7.63 (dd, J ₁ =8.4Hz, J ₂ =2.0Hz, 1H), 7.59 (d, J = 2.0Hz, 1H), 6.94 (d, J =8.4Hz,1H),5.47–5.40(m 1H),3.99(s,3H),3.95(t,J=6.6Hz,4H),1.55(d,J=7.0Hz,3H),1.45(s, 9H),1.34–1.30(m,2H),0.71–0.64(m,4H),0.41–0.39(m,4H);

MS-ESI: m/z 487.2 [M+H] ⁺ .

Step 7: Compound (S)-2-(3,4-bis(cyclopropylmethoxy)phenyl)-5-(1-(tert-butoxycarbonylamino)ethyl)oxazole-4-carboxylic acid synthesis

Compound (S)-2-(3,4-bis(cyclopropylmethoxy)phenyl)-5-(1-((tert-butoxycarbonyl)amino)ethyl)oxazole-4-carboxylic acid Esters (1g, 2.1mmol) and lithium hydroxide monohydrate (0.43g, 10mmol) were dissolved in a mixed solvent of tetrahydrofuran (20mL) and water (10mL), reacted at 40°C for 2h, added hydrochloric acid (1M) to adjust the pH value to 1. Add ethyl acetate for extraction (20 mL×3), combine the organic phases and dry with Na ₂ SO ₄ , remove the solvent to obtain 0.97 g of yellow solid, yield: 81%.

¹ H NMR (400MHz, CDCl ₃ ): δ (ppm) 7.59–7.55 (m, 2H), 6.99 (d, J=8.4Hz, 1H), 5.42–5.41 (m, 1H), 3.90–3.87 (m, 4H), 1.46(d, J=7.1Hz, 3H), 1.39(s, 9H), 1.29–1.26(m, 2H), 0.60–0.56(m, 4H), 0.34–0.33(m, 4H);

MS-ESI: m/z 471.1 [MH] ^- .

Step 8: Compound (S)-(1-(2-(3,4-bis(cyclopropylmethoxy)phenyl)-4-((2,4-difluorobenzyl)carbamoyl)oxa Synthesis of tert-butyl (azol-5-yl)ethyl)carbamate

Compound (S)-2-(3,4-bis(cyclopropylmethoxy)phenyl)-5-(1-(tert-butoxycarbonylamino)ethyl)oxazole-4-carboxylic acid (0.34g , 0.73mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (183mg, 0.95mmol) and N-hydroxy-7-azabenzotriazole (130mg , 0.95mmol) was dissolved in dichloromethane (13mL), stirred at 0°C, 2,4-difluorobenzylamine (0.1mL, 0.76mmol) was added dropwise after 30min, N,N-diisopropyl was added dropwise at 0°C Ethylamine (0.33mL, 1.90mmol), stirred at room temperature for 4h, washed with water (10mL×3), the organic phase was dried with Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v )=6/1), 230 mg of yellow oil was obtained, yield: 52%.

¹ H NMR (400MHz, CDCl ₃ ): δ (ppm) 7.56 (dd, J ₁ = 8.4Hz, J ₂ = 2.0Hz, 1H), 7.51 (d, J = 1.9Hz, 1H), 7.44–7.40 (m ,1H),6.94(d,J=8.5Hz,1H),6.91–6.84(m,2H),5.32–5.26(m,1H),4.66(t,J=5.2Hz,2H),3.95(t, J＝6.9Hz, 4H), 1.54(d, J＝7.0Hz, 3H), 1.45(s, 9H), 1.37–1.32(m, 2H), 0.69–0.65(m, 4H), 0.42–0.38(m ,4H).

Step 9: Compound (S)-5-(1-aminoethyl)-2-(3,4-bis(cyclopropylmethoxy)phenyl)-N-(2,4-difluorobenzyl) Synthesis of Oxazole-4-Carboxamide Hydrochloride

To compound (S)-(1-(2-(3,4-bis(cyclopropylmethoxy)phenyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazole- 5-yl) ethyl) tert-butyl carbamate (0.23g, 0.38mmol) in dichloromethane (1.5mL) solution was added HCl in ethyl acetate solution (4M, 4mL), stirred at room temperature for 40min, and the solvent was removed to obtain White solid 100 mg, yield: 47%.

Compound 103: ¹ H NMR (400MHz, CD ₃ OD): δ (ppm) 7.69 (dd, J ₁ =8.4Hz, J ₂ =1.9Hz, 1H), 7.66 (d, J = 1.9Hz, 1H), 7.51 –7.47(m,1H),7.10(d,J＝8.4Hz,1H),7.01–6.94(m,2H),5.15–5.13(m,1H),4.64(s,2H),3.97–3.95(m ,4H),1.76(d,J＝7.0Hz,3H),1.35–1.30(m,2H),0.68–0.64(m,4H),0.43–0.38(m,2H);

MS-ESI: m/z 498.3 [M-HCl+H] ⁺ .

Example 44: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-((3,5-difluoropyridin-2-yl)methyl)oxazole-4-carboxamide dihydrochloride

Step 1: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(((3,5-difluoro Synthesis of tert-butyl pyridin-2-yl)methyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) oxazole-4-carboxylic acid (0.3g, 0.64mmol), 3,5-difluoropyridine-2-methylamine hydrochloride (139mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine Propyl) carbodiimide hydrochloride (183mg, 0.96mmol) and N-hydroxyl-7-azabenzotriazole (131mg, 0.96mmol) were dissolved in dichloromethane (10mL), stirred at 0°C 30min, N,N-diisopropylethylamine (0.45mL, 2.56mmol) was added dropwise, stirred at room temperature for 14h, washed with water (10mL×3), the organic phase was dried with Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column After separation (petroleum ether/ethyl acetate (v/v)=4/1), 120 mg of white solid was obtained, yield: 32%.

¹ H NMR (400MHz, CDCl ₃ ): δ (ppm) 8.38 (d, J = 2.3Hz, 1H), 8.13–8.11 (m, 1H), 7.64 (dd, J ₁ = 8.3Hz, J ₂ = 1.9Hz ,1H),7.60(d,J＝1.9Hz,1H),7.27(d,J＝8.4Hz,1H),6.73(t,J _FH ＝75.0Hz,1H),5.32–5.30(m,1H), 4.86–4.83(m,2H),4.01(d,J=6.9Hz,2H),1.55(d,J=7.0Hz,3H),1.45(s,9H),1.36–1.33(m,1H),0.74 –0.69(m,2H),0.46–0.42(m,2H);

MS-ESI: m/z 595.1 [M+H] ⁺ .

Step 2: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((3 , Synthesis of 5-difluoropyridin-2-yl)methyl)oxazole-4-carboxamide dihydrochloride

To compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(((3,5-difluoropyridine- To a solution of tert-butyl 2-yl)methyl)carbamoyl)oxazol-5-yl)ethyl)carbamate (120mg, 0.20mmol) in dichloromethane (1mL) was added a solution of HCl in ethyl acetate (4M , 4 mL), stirred at room temperature for 2 h, and removed the solvent to obtain 65 mg of white solid, yield: 61%.

Compound 106: ¹ H NMR (400MHz, CD ₃ OD): δ (ppm) 8.34 (d, J = 2.2Hz, 1H), 7.77 (d, J = 1.5Hz, 1H), 7.70 (dd, J ₁ = 8.3 Hz, J ₂ ＝1.5Hz, 1H), 7.63–7.58(m, 1H), 7.30(d, J＝8.3Hz, 1H), 6.89(t, J _FH ＝74.8Hz, 1H), 5.17–5.12(m ,1H),4.78(s,2H),4.01(d,J＝6.9Hz,2H),1.75(d,J＝7.0Hz,3H),1.36–1.29(m,1H),0.68–0.63(m, 2H),0.42–0.38(m,2H);

MS-ESI: m/z 495.1 [M+H-2HCl] ⁺ .

Example 45: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-(2,4-difluorobenzyl)-N-methyloxazole-4-carboxamide hydrochloride

Step 1: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((2,4-difluorobenzyl Synthesis of base) carbamoyl) oxazol-5-yl) ethyl) tert-butyl carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) oxazole-4-carboxylic acid (1.17g, 2.5mmol), 2,4-difluorobenzylamine (0.536g, 3.75mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiethylene Amine hydrochloride (0.72g, 3.75mmol) and N-hydroxy-7-azabenzotriazole (0.51g, 3.75mmol) were dissolved in dichloromethane (20mL), stirred at 0°C for 30min, and N , N-diisopropylethylamine (1.31mL, 7.5mmol), stirred at room temperature for 5h, washed with water (20mL×3), the organic phase was dried with Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ Ethyl acetate (v/v)=4/1) to obtain 800 mg of yellow oil, yield: 54%.

Step 2: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2, Synthesis of 4-difluorobenzyl)-N-methyloxazole-4-carboxamide hydrochloride

Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((2,4-difluorobenzyl) Carbamoyl) oxazol-5-yl) ethyl) tert-butyl carbamate (0.3g, 0.51mmol) and sodium hydride (60%, 30mg, 0.76mmol) were added to anhydrous tetrahydrofuran (10mL), stirred at 0°C , moved to room temperature after 1h, added dropwise a tetrahydrofuran solution of iodomethane (0.76mmol, 10mL), stirred at room temperature, stopped the reaction after 5h, added water (30mL), extracted with ethyl acetate (15mL×3), combined the organic phases with After drying over anhydrous Na ₂ SO ₄ , the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v)=4/1) to obtain 227 mg of light yellow solid, yield: 74%.

Add HCl ethyl acetate solution (4M, 6mL) to the dichloromethane (2mL) solution of 227mg light yellow solid obtained in the previous step, and stop the reaction after stirring at room temperature for 1.5h, remove the solvent to obtain 200mg of white solid, yield: 99 %, is a mixture of two compounds, after resolution to obtain the compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )phenyl)-N-(2,4-difluorobenzyl)-N-methyloxazole-4-carboxamide hydrochloride: light yellow solid 20 mg.

Compound 114: ¹ H NMR (400MHz, CD ₃ OD): δ (ppm) 7.70-7.67(m, 1H), 7.58-7.46(m, 2H), 7.31-7.26(m, 1H), 7.07-6.98(m ,2H),7.02–6.67(m,1H),5.22–5.21(m,1H),4.56–4.54(m,2H),3.99(d,J＝6.7Hz,1H),3.87(d,J＝7.0 Hz,1H),3.45(s,3H),1.75(d,J＝6.9Hz,3H),1.19–1.15(m,1H),0.66–0.64(m,2H),0.41–0.37(m,2H) ;

MS-ESI: m/z 508.3 [M+H-HCl] ⁺ .

Example 46: Compound (S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2,4-di Synthesis of fluorobenzyl)-N-methyl-5-(1-(methylamino)ethyl)oxazole-4-carboxamide hydrochloride

Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((2,4-difluorobenzyl) Carbamoyl) oxazol-5-yl) ethyl) tert-butyl carbamate (0.3g, 0.51mmol) and sodium hydride (60%, 30mg, 0.76mmol) were added to anhydrous tetrahydrofuran (10mL), stirred at 0°C , moved to room temperature after 1h, added dropwise a tetrahydrofuran solution of iodomethane (0.76mmol, 10mL), stirred at room temperature, stopped the reaction after 5h, added water (30mL), extracted with ethyl acetate (15mL×3), combined the organic phases with After drying over anhydrous Na ₂ SO ₄ , the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v)=4/1) to obtain 227 mg of light yellow solid, yield: 74%.

Add HCl ethyl acetate solution (4M, 6mL) to the dichloromethane (2mL) solution of 227mg light yellow solid obtained in the previous step, and stop the reaction after stirring at room temperature for 1.5h, remove the solvent to obtain 200mg of white solid, yield: 99 %, is a mixture of two compounds, after resolution, the compound (S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2, 4-Difluorobenzyl)-N-methyl-5-(1-(methylamino)ethyl)oxazole-4-carboxamide hydrochloride: light yellow solid 20 mg.

Compound 115: ¹ H NMR (400MHz, CD ₃ OD): δ (ppm) 7.74–7.71 (m, 1H), 7.63–7.49 (m, 2H), 7.34–7.29 (m, 1H), 7.10–7.01 (m ,2H),7.08–6.70(m,1H),5.25–5.24(m,1H),5.07–4.97(m,2H),4.03(d,J＝6.9Hz,1H),3.91(d,J＝7.0 Hz,1H),3.48(s,3H),2.76(s,3H),1.79(d,J＝7.0Hz,3H),1.42–1.39(m,1H),0.69–0.67(m,2H),0.44 –0.40(m,2H);

MS-ESI: m/z 522.2 [M+H-HCl] ⁺ .

Example 47: Compound N-(2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)-5-((S)-1-aminoethyl Base)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride and N-(2-amino-1- (2,4-difluorophenyl)-2-oxoethyl)-5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-( Difluoromethoxy Synthesis of yl)phenyl)oxazole-4-carboxamide

Step 1: Synthesis of the compound 2-amino-2-(2,4-difluorophenyl)acetamide

Under nitrogen protection, zinc iodide (0.22g, 0.70mmol) was added to a mixture of 2,4-difluorobenzaldehyde (1g, 7.04mmol) and trimethylsilylcyanane (0.91g, 9.2mmol), room temperature Stir for 15min, add ammonia methanol solution (7M, 10mL) under ice-cooling, react at 40°C for 4h under nitrogen protection, remove the solvent, add ethyl acetate (20mL), wash with water (10mL×3), and wash the organic phase with anhydrous Na ₂ SO ₄ dried, concentrated and added HCl in ethyl acetate solution (4M, 5mL), a solid precipitated, added ethyl acetate (15mL), filtered, and washed 3 times with petroleum ether to obtain a white solid 0.78g, yield: 66%.

¹ H NMR (600MHz, CD ₃ OD): δppm 7.81–7.77(m,1H), 7.31–7.22(m,2H), 6.03(s,1H);

MS-ESI: m/z 169.1 [M+H] ⁺ .

Under ice bath, add the above white solid (0.25g, 1.49mmol) to water (0.1g) and concentrated sulfuric acid (2g), react at 55°C for 4h, move to ice bath, slowly add ammonia water (15mL) and water dropwise (10mL), ethyl acetate (15mL), the organic phase was separated and washed with saturated sodium chloride solution (10mL× ₃ ), dried with anhydrous _Na2SO4 , and concentrated to obtain 190mg of yellow solid, yield: 72% .

¹ H NMR (600MHz, CD ₃ OD): δppm 7.39–7.35(m,1H),7.02(br.s,1H),6.92–6.89(m,1H),6.88–6.84(m,1H),5.75( br.s,1H),4.73(s,1H);

MS-ESI: m/z 187.0 [M+H] ⁺ .

Step 2: Compound ((1S)-1-(4-((2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)carbamoyl)-2-(3- Synthesis of tert-butyl (cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) oxazole-4-carboxylic acid (0.25g, 0.53mmol), compound 2-amino-2-(2,4-difluorophenyl)acetamide (180mg, 0.64mmol), 1-ethyl-3-(3 -Dimethylaminopropyl) carbodiimide hydrochloride (154mg, 0.80mmol) and N-hydroxy-7-azabenzotriazole (109mg, 0.80mmol) were dissolved in dichloromethane (10mL), Add N,N-diisopropylethylamine (0.28mL, 1.60mmol) dropwise to this solution at 0°C, stir at room temperature for 20h, wash with water (10mL×3), and dry the organic phase with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=2/1) to obtain 184 mg of a white solid, yield: 54%.

¹ H NMR (600MHz, CDCl ₃ ): δppm 7.64(dt, J ₁ =8.3Hz, J ₂ =2.0Hz, 1H), 7.61(s, 1H), 7.54–7.49(m, 1H), 7.27(d, J＝8.3Hz,1H),6.96–6.92(m,2H),6.74(t,J _FH ＝75.0Hz,1H),5.94–5.93(m,1H),5.60(br.s,1H),5.34– 5.30(m,1H),4.03(d,J＝7.0Hz,2H),1.53–1.48(m,3H),1.45–1.37(m,9H),1.36–1.33(m,1H),0.73–0.70( m,2H),0.46–0.44(m,2H);

MS-ESI: m/z 637.1 [M+H] ⁺ .

Step 3: Compound N-(2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)-5-((S)-1-aminoethyl)-2-(3 Synthesis of -(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride

To compound ((1S)-1-(4-((2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)carbamoyl)-2-(3-(cyclo Propylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate (0.18g, 0.29mmol) in dichloromethane (4mL) solution Add HCl in ethyl acetate solution (4M, 3mL), stir at room temperature for 20min, remove the solvent to obtain 160mg of white solid, yield: 97%.

Compound 132: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.79(s, 1H), 7.73(d, J=8.3Hz, 1H), 7.61–7.58(m, 1H), 7.33(d, J=8.3 Hz,1H),7.06–7.02(m,2H),6.92(t,J _FH ＝75.0Hz,1H),5.92(s,1H),5.19–5.17(m,1H),4.04–4.03(m,2H ),1.76(d,J＝6.8Hz,3H),1.36–1.32(m,1H),0.69–0.68(m,2H),0.44–0.43(m,2H);

MS-ESI: m/z 537.9 [M+H-HCl] ⁺ .

Step 4: Compound N-(2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)-5-((S)-1-aminoethyl)-2-(3 Synthesis of -(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide

The compound N-(2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)-5-((S)-1-aminoethyl)-2-(3-( Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride (85mg, 0.15mmol) was dissolved in water (10mL), adjusted with NaOH solution (1.0M) pH=9, extracted with dichloromethane (10 mL×3), dried the organic phase with anhydrous Na ₂ SO ₄ , removed the solvent to obtain 75 mg of white solid, yield: 94%.

Compound 325: 1H NMR (400MHz, CD ₃ OD): δppm 7.67(s, 1H), 7.59(d, J=8.3Hz, 1H), 7.46(m, 1H), 7.21(d, J=8.3Hz, 1H ),6.92(m,2H),6.81(t,JF-H=75.0Hz,1H),5.82(s,1H),4.65(m,1H),3.91(m,2H),1.45(d,J= 6.9Hz, 3H), 1.23(m, 1H), 0.54–0.63(m, 2H), 0.28–0.37(m, 2H);

MS-ESI: m/z 509.15 [M+H] ⁺ .

Example 48: Compound N-(2-amino-1-(2,4-difluorophenyl)ethyl)-5-((S)-1-aminoethyl)-2-(3- Synthesis of (cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide dihydrochloride

Step 1: Compound ((1S)-1-(4-((cyano(2,4-difluorophenyl)methyl)carbamoyl)-2-(3-(cyclopropylmethoxy)- Synthesis of tert-butyl 4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) Oxazole-4-carboxylic acid (0.4g, 0.85mmol), compound 2-amino-2-(2,4-difluorophenyl) acetonitrile (210mg, 1.03mmol), 1-ethyl-3-(3- Dimethylaminopropyl) carbodiimide hydrochloride (245mg, 1.28mmol) and N-hydroxy-7-azabenzotriazole (174mg, 1.28mmol) were dissolved in dichloromethane (10mL), 0 N,N-Diisopropylethylamine (0.6mL, 3.42mmol) was added dropwise to the solution at ℃, stirred at room temperature for 5h, washed with water (10mL×3), and the organic phase was dried over anhydrous Na ₂ SO ₄ , The solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v)=6/1) to obtain 218 mg of white solid, yield: 41%.

¹ H NMR (600MHz, CDCl ₃ ): δppm 7.69–7.66 (m, 1H), 7.60–7.57 (m, 2H), 7.26 (d, J=8.2Hz, 1H), 7.04–6.96 (m, 2H), 6.73(t, J _FH ＝74.9Hz, 1H), 6.40(d, J＝8.6Hz, 1H), 5.32–5.30(m, 1H), 4.56–4.53(m, 1H), 4.04–3.99(m, 2H ), 1.58–1.54(m,3H), 1.45(s,9H), 1.34–1.32(m,1H), 0.73–0.71(m,2H), 0.45–0.42(m,2H).

Step 2: Compound ((1S)-1-(4-((2-amino-1-(2,4-difluorophenyl)ethyl)carbamoyl)-2-(3-(cyclopropylmethyl Synthesis of tert-butyl (oxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate

Under ice-bath conditions, the compound ((1S)-1-(4-((cyano(2,4-difluorophenyl)methyl)carbamoyl)-2-(3-(cyclopropylmethoxy base)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate (215mg, 0.35mmol) and nickel chloride (45mg, 0.35mmol) in ethanol (15mL ) solution was added dropwise sodium borohydride (42mg, 1.04mmol) in ethanol (10mL), stirred at room temperature for 8h, added hydrochloric acid (1M, 10mL) to adjust the pH value to about 1, and then added sodium hydroxide solution (2M) Adjust the pH value to about 12, add ethyl acetate (15mL), separate the upper liquid after standing still, remove the organic solvent, extract with ethyl acetate (15mL×3), dry the combined organic phase, and carry out the concentrated solution Column separation (dichloromethane/methanol (v/v)=20/1) gave 82 mg of light yellow solid, yield: 38%.

¹ H NMR (600MHz, CDCl ₃ ): δppm 7.61–7.56(m,2H),7.46–7.42(m,1H),7.25–7.21(m,1H),6.88–6.84(m,2H),6.85–6.60 (m,1H),5.40–5.35(m,1H),4.16–4.12(m,1H),4.00–3.95(m,2H),1.53–1.50(m,3H),1.44–1.35(m,9H) ,1.34–1.31(m,1H),0.70–0.67(m,2H),0.43–0.40(m,2H);

MS-ESI: m/z 623.2 [M+H] ⁺ .

Step 3: Compound N-(2-amino-1-(2,4-difluorophenyl)ethyl)-5-((S)-1-aminoethyl)-2-(3-(cyclopropyl Synthesis of methoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide dihydrochloride

To the compound ((1S)-1-(4-((2-amino-1-(2,4-difluorophenyl)ethyl)carbamoyl)-2-(3-(cyclopropylmethoxy )-4-(Difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate (0.08g, 0.12mmol) in dichloromethane (1mL) solution in dichloromethane (1mL) was added HCl in ethyl acetate The ester solution (4M, 1 mL) was stirred at room temperature for 20 min, and the solvent was removed to obtain 70 mg of white solid, yield: 97%.

Compound 133: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.85–7.83 (m, 1H), 7.76–7.75 (m, 1H), 7.66–7.65 (m, 1H), 7.34 (d, J=8.2Hz ,1H),7.11–7.05(m,2H),6.93(t,J _FH ＝74.7Hz,1H),5.81–5.78(m,1H),5.23–5.16(m,1H),4.07(d,J＝ 6.8Hz, 2H), 3.65–3.62(m, 1H), 3.46–3.44(m, 1H), 1.77(t, J＝5.6Hz, 3H), 1.42–1.37(m, 1H), 0.70–0.69(m ,2H),0.45–0.44(m,2H).

Example 49: Compound 2-(5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of methyl phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetate hydrochloride

Step 1: Synthesis of the compound 2-amino-2-(2,4-difluorophenyl)acetic acid methyl ester hydrochloride

To a solution of 2-amino-2-(2,4-difluorophenyl)acetonitrile (0.35g, 2.08mmol) in methanol (20mL) was added HCl in ethyl acetate (4M, 8mL), and stirred at room temperature for 7h, After reflux for 24h, the solvent was removed to obtain 0.4g of yellow solid, yield: 95%.

¹ H NMR (600MHz, CD ₃ OD): δppm 7.60–7.56(m,1H), 7.21–7.13(m,2H), 3.85(s,3H);

MS-ESI: m/z 202.1 [M+H] ⁺ .

Step 2: Compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Synthesis of yl)phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)methyl acetate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) Oxazole-4-carboxylic acid (0.73g, 1.56mmol), compound 2-amino-2-(2,4-difluorophenyl) methyl acetate hydrochloride (410mg, 1.73mmol), 1-ethyl- 3-(3-Dimethylaminopropyl) carbodiimide hydrochloride (430mg, 2.24mmol) and N-hydroxy-7-azabenzotriazole (310mg, 2.24mmol) were dissolved in dichloromethane ( 25mL), N,N-diisopropylethylamine (1mL, 5.98mmol) was added dropwise to the solution at 0°C, stirred at room temperature for 5h, washed with water (10mL×3), and the organic phase was washed with anhydrous Na ₂ SO ₄ was dried, the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v)=6/1) to obtain 290 mg of white solid, yield: 29%.

¹ H NMR (600MHz, CDCl ₃ ): δppm 8.15 (br.s, 1H), 7.64–7.62 (m, 1H), 7.59 (s, 1H), 7.51–7.46 (m, 1H), 7.26 (d, J ＝8.3Hz,1H),6.94–6.88(m,2H),6.73(t,J _FH ＝75.0Hz,1H),5.99(t,J＝6.5Hz,1H),5.32–5.29(m,1H), 4.03–4.01(m,2H),3.82(s,3H),1.54–1.49(m,3H),1.45(s,9H),1.37–1.34(m,1H),0.73–0.70(m,2H), 0.46–0.43 (m, 2H).

Step 3: Compound 2-(5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole- Synthesis of methyl 4-formamido)-2-(2,4-difluorophenyl)acetate hydrochloride

To compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) To a solution of methyl phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetate (0.1 g, 0.15 mmol) in dichloromethane (1 mL) was added HCl in ethyl acetate The solution (4M, 2mL) was stirred at room temperature for 1.5h, and the solvent was removed to obtain 90mg of white solid, yield: 99%.

Compound 134: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.80(s, 1H), 7.74(d, J=8.4Hz, 1H), 7.59–7.55(m, 1H), 7.34(d, J=8.3 Hz,1H),7.09–7.02(m,2H),6.93(t,J _FH ＝74.7Hz,1H),6.05(s,1H),5.20–5.17(m,1H),4.04(d,J＝7.0 Hz,2H),3.81(s,3H),1.76(d,J＝7.0Hz,3H),1.38–1.34(m,1H),0.71–0.68(m,2H),0.45–0.43(m,2H) ;

MS-ESI: m/z 552.9 [M+H-HCl] ⁺ .

Example 50: Compound 2-(5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid hydrochloride

Step 1: Compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Synthesis of yl)phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid

Compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)methyl acetate (190mg, 0.29mmol) and lithium hydroxide monohydrate (61mg, 1.46mmol) were dissolved in tetrahydrofuran ( 20 mL) and water (10 mL) in a mixed solvent, react at 40°C for 2 h, add hydrochloric acid (1M) to adjust the pH value to 1, add ethyl acetate for extraction (10 mL×3), combine the organic phases and dry with Na ₂ SO ₄ , The solvent was removed to obtain 185 mg of yellow solid, yield: 99%.

¹ H NMR (600MHz, CD ₃ OD): δppm 7.75(s, 1H), 7.69–7.67(m, 1H), 7.58–7.56(m, 1H), 7.30(d, J=8.3Hz, 1H), 7.05 –7.00(m,2H),6.90(t,J _FH ＝74.9Hz,1H),5.93–5.91(m,1H),5.41–5.40(m,1H),4.02(d,J＝6.9Hz,2H) , 1.50 (d, J=7.1Hz, 3H), 1.46–1.36 (m, 9H), 1.34–1.32 (m, 1H), 0.70–0.67 (m, 2H), 0.43–0.41 (m, 2H).

Step 2: Compound 2-(5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole- Synthesis of 4-formamido)-2-(2,4-difluorophenyl)acetic acid hydrochloride

To compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) To a solution of phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid (0.185 g, 0.29 mmol) in dichloromethane (2 mL) was added HCl in ethyl acetate ( 4M, 3mL), stirred at room temperature for 1.5h, and removed the solvent to obtain 165mg of white solid, yield: 99%.

Compound 135: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.79 (s, 1H), 7.74 (dd, J ₁ =8.3Hz, J ₂ =1.5Hz, 1H), 7.60-7.56 (m, 1H), 7.33(d, J＝8.3Hz, 1H), 7.06–7.02(m, 2H), 6.92(t, J _FH ＝74.7Hz, 1H), 5.95(d, J＝2.2Hz, 1H), 5.20–5.15( m,1H),4.04(d,J=6.9Hz,2H),1.76(d,J=7.0Hz,3H),1.37–1.33(m,1H),0.70–0.67(m,2H),0.45–0.42 (m,2H);

MS-ESI: m/z 538.9 [M+H-HCl] ⁺ .

Example 51: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Base)-N-(2-((2,4-difluorobenzyl)amino)-1-(2,4-difluorophenyl)-2-oxoethyl)oxazole-4-carboxamide salt Synthesis

Step 1: Compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((2-((2,4 Synthesis of tert-butyl -difluorobenzyl)amino)-1-(2,4-difluorophenyl)-2-oxoethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

Compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid (0.24g, 0.38mmol), 1-ethyl-3-(3-dimethylaminopropyl) Carbodiimide hydrochloride (108mg, 0.56mmol) and N-hydroxy-7-azabenzotriazole (77mg, 0.56mmol) were dissolved in dichloromethane (10mL), and the solution was added to the solution at 0°C 2,4-difluorobenzylamine (0.06mL, 0.45mmol) and N,N-diisopropylethylamine (0.2mL, 1.13mmol) were added dropwise to , stirred at room temperature for 15h, the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v)=4/1), 210 mg of white solid was obtained, yield: 74%.

¹ H NMR (600MHz, CDCl ₃ ): δppm 7.62(d, J=8.3Hz, 1H), 7.60(s, 1H), 7.50–7.48(m, 1H), 7.26(d, J=8.2Hz, 1H) ,7.26–7.24(m,1H),6.94–6.89(m,2H),6.86–6.79(m,2H),6.74(t,J _FH ＝74.7Hz,1H),6.40–6.36(m,1H), 5.89(d,J=6.8Hz,1H),5.33–5.29(m,1H),4.49–4.49(m,2H),4.02(d,J=6.8Hz,2H),1.52–1.47(m,3H) ,1.44–1.38(m,9H),1.36–1.30(m,1H),0.73–0.70(m,2H),0.46–0.45(m,2H).

Step 2: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2- Synthesis of ((2,4-difluorobenzyl)amino)-1-(2,4-difluorophenyl)-2-oxoethyl)oxazole-4-carboxamide hydrochloride

To compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((2-((2,4-di Fluorobenzyl)amino)-1-(2,4-difluorophenyl)-2-oxoethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (0.21g, 0.27 mmol) in dichloromethane (2 mL) was added HCl in ethyl acetate (4M, 4 mL), stirred at room temperature for 20 min, and the solvent was removed to obtain 190 mg of white solid, yield: 99%.

Compound 136: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.78 (d, J = 1.4Hz, 1H), 7.72 (dd, J ₁ = 8.4Hz, J ₂ = 1.8Hz, 1H), 7.55-7.52 ( m,1H),7.34–7.32(m,2H),7.06–7.00(m,2H),6.94–6.90(m,2H),6.92(t,J _FH ＝74.7Hz,1H),5.96(s,1H ),5.20–5.17(m,1H),4.51–4.40(m,2H),4.02(d,J＝6.9Hz,2H),1.76(t,J＝6.9Hz,3H),1.36–1.32(m, 1H),0.70–0.66(m,2H),0.44–0.41(m,2H);

MS-ESI: m/z 663.9 [M+H-HCl] ⁺ .

Example 52: Compound 5-((S)-1-aminoethyl)-N-(2-(cyclopropylcarboxamido)-1-(2,4-difluorobenzene Synthesis of yl)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound ((1S)-1-(4-((2-(cyclopropylcarboxamido)-1-(2,4-difluorophenyl)ethyl)carbamoyl)-2-( Synthesis of tert-butyl 3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate

The compound ((1S)-1-(4-((2-amino-1-(2,4-difluorophenyl)ethyl)carbamoyl)-2-(3-(cyclopropylmethoxy )-4-(difluoromethoxy) phenyl) oxazol-5-yl) ethyl) tert-butyl carbamate (0.16g, 0.26mmol), cyclopropyl formic acid (0.03mL, 0.31mmol), 1 -Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (74mg, 0.39mmol) and N-hydroxy-7-azabenzotriazole (53mg, 0.39mmol) were dissolved in In dichloromethane (10mL), N,N-diisopropylethylamine (0.13mL, 0.77mmol) was added dropwise to the solution at 0°C, stirred at room temperature for 12h, the solvent was removed, and the concentrated solution was subjected to column separation (petroleum Ether/ethyl acetate (v/v)=2/1) to obtain 100 mg of white solid, yield: 56%.

¹ H NMR (600MHz, CDCl ₃ ): δppm 7.65–7.58(m,2H),7.41–7.37(m,1H),7.26(d,J=8.7Hz,1H),6.92–6.86(m,2H), 6.73(t,J _FH ＝75.0Hz,1H),6.17–6.15(m,1H),5.48–5.46(m,1H),5.32–5.30(m,1H),4.04–3.99(m,2H),3.87 –3.85(m,1H),3.68–3.65(m,1H),1.67–0.61(m,1H),1.56–1.48(m,3H),1.45–1.35(m,9H),1.09–1.05(m, 1H),0.96–0.90(m,2H),0.76–0.70(m,4H),0.45–0.44(m,2H);

MS-ESI: m/z 691.2 [M+H] ⁺ .

Step 2: Compound 5-((S)-1-aminoethyl)-N-(2-(cyclopropylcarboxamido)-1-(2,4-difluorophenyl)ethyl)-2- Synthesis of (3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride

To the compound ((1S)-1-(4-((2-(cyclopropylcarboxamido)-1-(2,4-difluorophenyl)ethyl)carbamoyl)-2-(3- (Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate (0.10 g, 0.14 mmol) in dichloromethane (2 mL) Ethyl acetate solution of HCl (4M, 3mL) was added to the solution, stirred at room temperature for 40min, and the solvent was removed to obtain 90mg of white solid, yield: 99%.

Compound 137: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.84(s, 1H), 7.74(d, J=8.4Hz, 1H), 7.48–7.46(m, 1H), 7.35(d, J=8.4 Hz,1H),7.04–6.97(m,2H),6.93(t,J _FH ＝74.7Hz,1H),5.49–5.47(m,1H),5.13–5.06(m,1H),4.08(d,J ＝6.9Hz,2H),3.79–3.63(m,2H),1.74–1.72(m,3H),1.60–1.55(m,1H),1.38–1.36(m,1H),0.92–0.88(m,2H ),0.77–0.69(m,4H),0.48–0.44(m,2H);

MS-ESI: m/z 591.2 [M+H-HCl] ⁺ .

Example 53: Compound N-(2-Acetamido-1-(2,4-difluorophenyl)ethyl)-5-((S)-1-aminoethyl)- Synthesis of 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound ((1S)-1-(4-((2-Acetamido-1-(2,4-difluorophenyl)ethyl)carbamoyl)-2-(3-(cyclopropyl Synthesis of tert-butyl methoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate

The compound ((1S)-1-(4-((2-amino-1-(2,4-difluorophenyl)ethyl)carbamoyl)-2-(3-(cyclopropylmethoxy )-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (0.20g, 0.32mmol), 1-ethyl-3-(3-dimethylamine Propyl) carbodiimide hydrochloride (92mg, 0.48mmol) and N-hydroxy-7-azabenzotriazole (66mg, 0.48mmol) were dissolved in dichloromethane (10mL), at 0°C Add glacial acetic acid (30mg, 0.39mmol) and N,N-diisopropylethylamine (0.17mL, 0.96mmol) dropwise to this solution respectively, stir at room temperature for 15h, remove the solvent, and conduct column separation of the concentrate (petroleum ether/ Ethyl acetate (v/v)=1/1) to obtain 90 mg of yellow oil, yield: 42%.

¹ H NMR (600MHz, CDCl ₃ ): δppm 7.64–7.63 (m, 2H), 7.39-7.41 (m, 1H), 7.26 (d, J=8.7Hz, 1H), 6.93–6.87 (m, 2H), 6.73(t,J _FH ＝75.0Hz,1H),6.13–6.10(m,1H),5.49–5.48(m,1H),5.32–5.28(m,1H),4.02(d,J＝6.8Hz,2H ),3.84–3.82(m,1H),3.68–3.66(m,1H),2.00(s,3H),1.54–1.50(m,3H),1.44–1.41(m,9H),1.39–1.37(m ,1H),0.73–0.70(m,2H),0.45–0.43(m,2H).

Step 2: Compound N-(2-acetylamino-1-(2,4-difluorophenyl)ethyl)-5-((S)-1-aminoethyl)-2-(3-(cyclopropyl Synthesis of methoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride

To the compound ((1S)-1-(4-((2-acetamido-1-(2,4-difluorophenyl)ethyl)carbamoyl)-2-(3-(cyclopropylmethoxy To a solution of tert-butyl)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate (0.09 g, 0.13 mmol) in dichloromethane (1 mL) was added HCl in acetic acid Ethyl ester solution (4M, 2mL), stirred at room temperature for 20min, and the solvent was removed to obtain 80mg of light yellow solid, yield: 98%.

Compound 138: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.85(s, 1H), 7.77(d, J=8.4Hz, 1H), 7.52–7.48(m, 1H), 7.34(d, J=8.3 Hz,1H),7.03–6.98(m,2H),6.93(t,J _FH ＝74.8Hz,1H),5.53–5.50(m,1H),5.15–5.10(m,1H),4.08(d,J ＝6.9Hz,2H),3.76–3.62(m,2H),1.95(s,3H),1.75(d,J＝6.2Hz,3H),1.42–1.37(m,1H),0.72–0.67(m, 2H),0.47–0.43(m,2H);

MS-ESI: m/z 565.2 [M+H-HCl] ⁺ .

Example 54: Compound 5-((S)-1-aminoethyl)-N-(2-(cyclopropylsulfonylamino)-1-(2,4-difluorobenzene Base) ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride, 5-((S)- 1- Aminoethyl)-N-((S)-2-(cyclopropylsulfonylamino)-1-(2,4-difluorophenyl)ethyl)-2-(3-(cyclopropylmethoxy base)- 4-(Difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride and 5-((S)-1-aminoethyl)-N-((R)-2-(cyclopropyl Sulfonyl Amino)-1-(2,4-difluorophenyl)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4- First Synthesis of Amide Hydrochloride

Step 1: Synthesis of compound 2-amino-2-(2,4-difluorophenyl)acetonitrile hydrochloride

Add zinc iodide (0.68g, 2.11mmol) and ammonia to 2,4-difluorobenzaldehyde (3.0g, 21.1mmol) and cyanotrimethylsilane (2.8g, 27.4mmol) under nitrogen protection at 0°C Methanol solution (7M, 30mL), stirred and reacted at 40°C for 4h, removed the solvent, added ethyl acetate for extraction (10mL×3), combined the organic phases and dried with Na ₂ SO ₄ , removed the solvent, added HCl in ethyl acetate solution (4M, 5mL), a solid was precipitated, filtered, and the solid was washed with ethyl acetate (5mL×3) to obtain 2.9g of a light yellow solid, yield: 68%.

¹ H NMR (400MHz, CD ₃ OD): δppm 7.76–7.82(m,1H), 7.21–7.31(m,2H), 6.03(s,1H);

MS-ESI: m/z 169.15 [M+H-HCl] ⁺ .

Step 2: Compound ((1S)-1-(4-((cyano(2,4-difluorophenyl)methyl)carbamoyl)-2-(3-(cyclopropylmethoxy)- Synthesis of tert-butyl 4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) Oxazole-4-carboxylic acid (0.60g, 1.28mmol), compound 2-amino-2-(2,4-difluorophenyl) acetonitrile hydrochloride (320mg, 1.56mmol), 1-ethyl-3- (3-Dimethylaminopropyl) carbodiimide hydrochloride (380mg, 2.00mmol) and N-hydroxy-7-azabenzotriazole (270mg, 2.00mmol) were dissolved in dichloromethane (20mL) Add N,N-diisopropylethylamine (0.91mL, 5.20mmol) dropwise to the solution at 0°C, stir at room temperature for 5h, add water to wash (10mL×3), and wash the organic phase with anhydrous Na ₂ SO ₄ was dried, the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=6/1) to obtain 330 mg of white solid, yield: 42%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.63–7.69 (m, 1H), 7.58 (d, J=9.5Hz, 2H), 7.25 (d, J=8.2Hz, 1H), 6.94–7.03 (m, 2H),6.72(t,J _FH ＝75.0Hz,1H),6.40(d,J＝8.5Hz,1H),5.25–5.35(m,1H),4.00(d,J＝6.7Hz,2H),1.53 –1.58(m,3H),1.45(s,9H),1.30–1.34(m,1H),0.68–0.72(m,2H),0.40–0.43(m,2H);

MS-ESI: m/z 641.15 [M+Na] ⁺ .

Step 3: Compound ((1S)-1-(4-((2-amino-1-(2,4-difluorophenyl)ethyl)carbamoyl)-2-(3-(cyclopropylmethyl Synthesis of tert-butyl (oxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate

The compound ((1S)-1-(4-((cyano(2,4-difluorophenyl)methyl)carbamoyl)-2-(3-(cyclopropylmethoxy)-4- (Difluoromethoxy) phenyl) oxazol-5-yl) ethyl) tert-butyl carbamate (330 mg, 0.53 mmol) and nickel chloride (68 mg, 0.53 mmol) were dissolved in absolute ethanol (15 mL), Stir at 0°C, add a mixture of absolute ethanol (10mL) and sodium borohydride (101mg, 2.67mmol), react at room temperature for 4h, add dilute hydrochloric acid to adjust pH=1, stir until clear, add NaOH solution (1M) to adjust pH=9 , and extracted with ethyl acetate (10 mL×3), the organic phases were combined and dried with Na ₂ SO ₄ , and the solvent was removed to obtain 300 mg of white solid, yield: 91%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.00 (br.s, 1H), 7.65 (dd, J ₁ = 8.3Hz, J ₂ = 1.7Hz, 1H), 7.59 (d, J = 1.6Hz, 1H) ,7.33–7.42(m,1H),7.27(d,J＝10.2Hz,1H),6.86–6.90(m,2H),6.73(t,J _FH ＝74.9Hz,1H),5.30–5.41(m, 1H),5.25–5.30(m,1H),4.02(d,J＝6.9Hz,2H),1.57–1.78(m,2H),1.49–1.55(m,3H),1.41–1.44(m,9H) ,1.31–1.37(m,1H),0.69–0.74(m,2H),0.42–0.46(m,2H);

MS-ESI: m/z 623.20 [M+H] ⁺ .

Step 4: Compound ((1S)-1-(4-((2-(cyclopropylsulfonylamino)-1-(2,4-difluorophenyl)ethyl)carbamoyl)-2-( Synthesis of tert-butyl 3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate

The compound ((1S)-1-(4-((2-amino-1-(2,4-difluorophenyl)ethyl)carbamoyl)-2-(3-(cyclopropylmethoxy )-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (300mg, 0.48mmol), 1-ethyl-3-(3-dimethylaminopropyl base) carbodiimide hydrochloride (138mg, 0.72mmol) and N-hydroxy-7-azabenzotriazole (98mg, 0.72mmol) were dissolved in dichloromethane (15mL), and heated to Cyclopropanesulfonic acid (71mg, 0.58mmol) and N,N-diisopropylethylamine (0.25mL, 1.44mmol) were added dropwise to this solution, stirred at room temperature for 12h, the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether /ethyl acetate (v/v)=2/1), to obtain 90 mg of white solid, yield: 26%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.15 (br.s, 1H), 7.59–7.63 (m, 2H), 7.43–7.45 (m, 2H), 7.26 (d, J=8.3Hz, 1H), 6.91–6.95(m,2H),6.73(t,J _FH ＝75Hz,1H),5.50–5.56(m,1H),5.27–5.34(m,1H),4.01(d,J＝6.9Hz,2H) ,3.65–3.70(m,2H),2.42–2.50(m,1H),1.50–1.55(m,3H),1.42–1.45(m,9H),1.18–1.22(m,1H),1.00–1.06( m,2H),0.85–0.91(m,2H),0.68–0.73(m,2H),0.41–0.45(m,2H);

MS-ESI: m/z 749.20 [M+Na] ⁺ .

Step 5: Compound 5-((S)-1-aminoethyl)-N-(2-(cyclopropylsulfonylamino)-1-(2,4-difluorophenyl)ethyl)-2- Synthesis of (3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride

Compound ((1S)-1-(4-((2-(cyclopropylsulfonylamino)-1-(2,4-difluorophenyl)ethyl)carbamoyl)-2-(3-( Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate (90mg, 0.124mmol) was dissolved in dichloromethane (2mL) solution , HCl ethyl acetate solution (4M, 4mL) was added, stirred at room temperature for 30min, and the solvent was removed to obtain 70mg of white solid, yield: 85%.

Compound 139: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.86(s, 1H), 7.73(d, J=8.2Hz, 1H), 7.51–7.58(m, 1H), 7.34(d, J=8.3 Hz,1H),6.97–7.06(m,2H),6.92(t,J _FH ＝74.8Hz,1H),5.51(t,J＝6.2Hz,1H),5.09–6.18(m,1H),4.05( d,J=6.8Hz,2H),3.67–3.59(m,2H),2.55–2.63(m,1H),1.75(d,J=6.5Hz,3H),1.07–1.09(m,1H),0.99 –1.05(m,2H),0.86–0.94(m,2H),0.67–0.73(m,2H),0.43–0.47(m,2H);

MS-ESI: m/z 627.15 [M+H-HCl] ⁺ .

Step 6: Compound 5-((S)-1-aminoethyl)-N-((S)-2-(cyclopropylsulfonylamino)-1-(2,4-difluorophenyl)ethyl )-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride and 5-((S)-1-aminoethyl Base)-N-((R)-2-(cyclopropylsulfonylamino)-1-(2,4-difluorophenyl)ethyl)-2-(3-(cyclopropylmethoxy) Synthesis of -4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride

The compound 5-((S)-1-aminoethyl)-N-(2-(cyclopropylsulfonylamino)-1-(2,4-difluorophenyl)ethyl)-2-(3 -(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride (300mg, 0.45mmol) was resolved by preparative chromatography, and the S and R structures were respectively Concentrate the prepared liquid of the type, adjust the pH=9 with NaOH solution (1M), extract with ethyl acetate (10mL×3), combine the organic phases and dry with Na ₂ SO ₄ , remove the solvent, add HCl in ethyl acetate solution ( 4M, 2mL), to give 5-((S)-1-aminoethyl)-N-((S)-2-(cyclopropylsulfonylamino)-1-(2,4-difluorophenyl) Ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride (pale yellow solid 90mg) and 5-( (S)-1-aminoethyl)-N-((R)-2-(cyclopropylsulfonylamino)-1-(2,4-difluorophenyl)ethyl)-2-(3- (Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride (pale yellow solid 85 mg).

Example 55: Compound N-((S)-2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)-5-((S)-1-ammonia Ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride and N-((R)-2- ammonia Base-1-(2,4-difluorophenyl)-2-oxoethyl)-5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy) -4-(difluoro Synthesis of Methoxy)phenyl)oxazole-4-carboxamide Hydrochloride

The compound N-(2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)-5-((S)-1-aminoethyl)-2- (3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride is resolved, and N-((S)-2 -Amino-1-(2,4-difluorophenyl)-2-oxoethyl)-5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy )-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride and N-((R)-2-amino-1-(2,4-difluorophenyl)-2 -Oxoethyl)-5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole- 4-Carboxamide hydrochloride.

Compound 140: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.79 (d, J = 1.9Hz, 1H), 7.73 (dd, J ₁ = 8.4Hz, J ₂ = 1.9Hz, 1H), 7.62-7.58 ( m,1H),7.33(d,J＝8.3Hz,1H),7.07–7.02(m,2H),6.92(t,J _FH ＝75.0Hz,1H),5.92(s,1H),5.20–5.17( m,1H),4.04(d,J=7.0Hz,2H),1.76(d,J=6.8Hz,3H),1.38–1.33(m,1H),0.71–0.68(m,2H),0.45–0.42 (m,2H);

MS-ESI: m/z 537.2[M+H-HCl] ⁺ ;

Compound 141: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.79 (d, J = 1.9Hz, 1H), 7.73 (dd, J ₁ = 8.4Hz, J ₂ = 1.9Hz, 1H), 7.61-7.59 ( m,1H),7.33(d,J＝8.3Hz,1H),7.07–7.03(m,2H),6.92(t,J _FH ＝75.0Hz,1H),5.92(s,1H),5.18–5.14( m,1H),4.03(d,J＝7.0Hz,2H),1.75(d,J＝6.8Hz,3H),1.37–1.33(m,1H),0.71–0.67 (m,2H),0.45–0.42 (m,2H);

MS-ESI: m/z 537.1 [M+H-HCl] ⁺ .

Example 56: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-(1-(2,4-difluorophenyl)-2-(methylamino)-2-oxoethyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4- Synthesis of tert-butyl difluorophenyl)-2-(methylamino)-2-oxoethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

Compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid (0.23g, 0.36mmol), methylamine hydrochloride (29mg, 0.43mmol), 1-ethyl-3 -(3-Dimethylaminopropyl)carbodiimide hydrochloride (104mg, 0.54mmol) and N-hydroxy-7-azabenzotriazole (74mg, 0.54mmol) were dissolved in dichloromethane (10mL ), N,N-diisopropylethylamine (0.25mL, 1.44mmol) was added dropwise to this solution at 0°C, stirred at room temperature for 15h, the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=2/1), 133 mg of white solid was obtained, yield: 56%.

¹ H NMR (600MHz, CDCl ₃ ): δppm 7.55–7.53 (m, 1H), 7.52 (s, 1H), 7.44–7.39 (m, 1H), 7.17 (d, J=8.3Hz, 1H), 6.86– 6.81(m,2H),6.65(t,J _FH ＝75.0Hz,1H),5.86–5.85(m,1H),5.79–5.77(m,1H),5.24–5.20(m,1H),3.94(d ,J＝6.8Hz,2H),2.82–2.80(m,3H),1.44–1.39(m,3H),1.36–1.28(m,9H),1.27–1.24(m,1H),0.64–0.61(m ,2H),0.38–0.33(m,2H);

MS-ESI: m/z 651.9 [M+H] ⁺ .

Step 2: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1- Synthesis of (2,4-difluorophenyl)-2-(methylamino)-2-oxoethyl)oxazole-4-carboxamide hydrochloride

To compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4-difluoro Phenyl)-2-(methylamino)-2-oxoethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate (0.13g, 0.20mmol) in dichloromethane (1mL ) solution was added HCl in ethyl acetate (4M, 2mL), stirred at room temperature for 20 min, and the solvent was removed to obtain 110 mg of a white solid, yield: 94%, which was sent to the preparation for further purification to obtain 80 mg of a white solid.

Compound 144: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.79(s, 1H), 7.72(d, J=8.3Hz, 1H), 7.59–7.55(m, 1H), 7.34(d, J=8.3 Hz,1H),7.07–7.02(m,2H),6.92(t,J _FH ＝74.7Hz,1H),5.90(s,1H),5.19–5.15(m,1H),4.04(d,J＝6.9 Hz,2H),2.80(s,3H),1.75(d,J＝7.0Hz,3H),1.37–1.34(m,1H),0.71–0.68(m,2H),0.45–0.43(m,2H) ;

MS-ESI: m/z 551.1 [M+H-HCl] ⁺ .

Example 57: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Base)-N-(1-(2,4-difluorophenyl)-2-(4-methylpiperazin-1-yl)-2-oxoethyl)oxazole-4-carboxamide disalt salt Synthesis

Step 1: Compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4- Synthesis of tert-butyl difluorophenyl)-2-(4-methylpiperazin-1-yl)-2-oxoethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

Compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid (0.16g, 0.25mmol), 1-ethyl-3-(3-dimethylaminopropyl) Carbodiimide hydrochloride (72mg, 0.38mmol) and N-hydroxy-7-azabenzotriazole (60mg, 0.38mmol) were dissolved in dichloromethane (10mL), and the solution was added to the solution at 0°C 1-Methylpiperazine (0.03mL, 0.30mmol) and N,N-diisopropylethylamine (0.13mL, 0.75mmol) were added dropwise respectively, stirred at room temperature for 15h, the solvent was removed, and the concentrated solution was subjected to column separation (two Chloromethane/methanol (v/v)=20/1) to obtain 60 mg of white solid, yield: 33%.

¹ H NMR (600MHz, CDCl ₃ ): δppm 7.60–7.58 (m, 1H), 7.57–7.56 (m, 1H), 7.53–7.49 (m, 1H), 7.23 (d, J=8.0Hz, 1H), ₍ m,2H),3.98(d,J＝6.9Hz,2H),3.85–3.75(m,2H),2.85–2.75(m,2H),2.62–2.50(m,4H),1.51–1.47(m, 3H), 1.42–1.38(m,9H), 1.35–1.33(m,1H), 0.71–0.68(m,2H), 0.43–0.41(m,2H).

Step 2: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1- Synthesis of (2,4-difluorophenyl)-2-(4-methylpiperazin-1-yl)-2-oxoethyl)oxazole-4-carboxamide dihydrochloride

To compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4-difluoro Phenyl)-2-(4-methylpiperazin-1-yl)-2-oxoethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (0.06g, 0.08 mmol) in dichloromethane (1 mL) was added HCl in ethyl acetate (4M, 2 mL), stirred at room temperature for 20 min, and the solvent was removed to obtain 50 mg of white solid, yield: 91%.

Compound 146: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.79 (d, J = 1.8Hz, 1H), 7.73 (dd, J ₁ = 8.3Hz, J ₂ = 1.5Hz, 1H), 7.60-7.57 ( m,1H),7.34(d,J＝8.3Hz,1H),7.14–7.08(m,2H),6.92(t,J _FH ＝74.7Hz,1H),6.34(s,1H),5.21–5.17( m,1H),4.04(d,J=6.9Hz,2H),3.70–3.40(m,4H),3.30–3.10(m,4H),2.93(s,3H),1.75(d,J=6.8Hz ,3H),1.36–1.33(m,1H),0.71–0.68(m,2H),0.45–0.43(m,2H);

MS-ESI: m/z 620.2 [M+H-2HCl] ⁺ .

Example 58: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Base)-N-(1-(2,4-difluorophenyl)-2-oxo-2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)oxazole-4 -formamide di Synthesis of hydrochloride

Step 1: Compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4- Difluorophenyl)-2-oxo-2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)carbamoyl)oxazol-5-yl)ethyl)carbamic acid tertiary Synthesis of Butyl Ester

Compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid (0.19g, 0.30mmol), 1-(2-pyrimidinyl)piperazine (60mg, 0.36mmol) , 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (86mg, 0.45mmol) and N-hydroxy-7-azabenzotriazole (61mg, 0.45mmol) Dissolve in dichloromethane (10mL), add N,N-diisopropylethylamine (0.16mL, 0.89mmol) dropwise to the solution at 0°C, stir at room temperature for 15h, remove the solvent, and conduct column separation on the concentrate (petroleum ether/ethyl acetate (v/v)=2/1), 220 mg of colorless oil was obtained, yield: 94%.

¹ H NMR (600MHz, CDCl ₃ ): δppm 8.56(d, J=7.3Hz, 1H), 8.33(d, J=4.7Hz, 2H), 7.63(d, J=8.4Hz, 1H), 7.60(s ,1H),7.56–7.55(m,1H),7.25(d,J＝8.3Hz,1H),6.94–6.91(m,2H),6.73(t,J _FH ＝75.0Hz,1H),6.57(t ,J=4.7Hz,1H),6.34(d,J=7.1Hz,1H),5.32–5.29(m,1H),4.02(d,J=6.9Hz,2H),4.00–3.85(m,4H) ,3.72–3.70(m,2H),3.66–3.42(m,4H),1.53–1.49(m,3H),1.45–1.38(m,9H),1.39–1.37(m,1H),0.73–0.70( m,2H),0.46–0.44(m,2H);

MS-ESI: m/z 684.1 [M+H-100] ⁺ .

Step 2: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1- (2,4-difluorophenyl)-2-oxo-2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)oxazole-4-carboxamide dihydrochloride synthesis

To compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4-difluoro Phenyl)-2-oxo-2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate tert-butyl (0.22g, 0.28mmol) in dichloromethane (2mL) was added HCl in ethyl acetate (4M, 4mL), stirred at room temperature for 20min, and the solvent was removed to obtain 200mg of white solid, yield: 99%.

Compound 147: ¹ H NMR (600MHz, CD ₃ OD): δppm 8.56 (d, J = 4.5Hz, 2H), 7.79 (d, J = 1.8Hz, 1H), 7.73 (dd, J ₁ = 8.4Hz, J ₂ =1.7Hz,1H),7.65–7.59(m,1H),7.34(d,J=8.3Hz,2H),7.14–7.09(m,2H),6.96–6.94(m,1H),6.92(t ,J _FH ＝74.7Hz,1H),6.35–6.34(m,1H),5.20–5.16(m,1H),4.10–3.99(m,4H),3.87–3.83(m,4H),3.58–3.56( m,2H),1.76(d,J＝6.9Hz,3H),1.41–1.39(m,1H),0.72–0.67(m,2H),0.46–0.42(m,2H);

MS-ESI: m/z 342.7 [M+2H-2HCl] ²⁺ .

Example 59: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-((2,4-difluorophenyl)(2H-tetrazol-5-yl)methyl)oxazole-4-carboxamide dihydrochloride

Step 1: Compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(((2,4-difluoro Synthesis of tert-butyl phenyl)(2H-tetrazol-5-yl)methyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

To compound ((1S)-1-(4-((cyano(2,4-difluorophenyl)methyl)carbamoyl)-2-(3-(cyclopropylmethoxy)-4- (Difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (160mg, 0.26mmol) and ammonium chloride (20mg, 0.31mmol) in N,N-dimethylformaldehyde Add sodium azide (20mg, 0.31mmol) to the amide (15mL) solution, react at 100°C for 8h, remove the solvent, add water (10mL), adjust the pH value to about 1 with dilute hydrochloric acid (1M), and extract with ethyl acetate ( 15 mL×3), the combined organic phases were dried with anhydrous Na ₂ SO ₄ , concentrated to obtain 160 mg of yellow oil, yield: 93%.

¹ H NMR (600MHz, CDCl ₃ ): δppm 7.59–7.57 (m, 3H), 7.25 (d, J=8.2Hz, 1H), 7.06–7.00 (m, 1H), 6.96–6.84 (m, 2H), 6.73(t, J _FH ＝74.7Hz, 1H), 5.61–5.51(m, 1H), 5.25–5.10(m, 1H), 3.99(d, J＝6.9Hz, 2H), 1.59–1.51(m, 3H ),1.41–1.39(m,9H),1.35–1.33(m,1H),0.71–0.69(m,2H),0.44–0.43(m,2H);

MS-ESI: m/z 562.1 [M-100+H] ⁺ .

Step 2: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((2 , Synthesis of 4-difluorophenyl)(2H-tetrazol-5-yl)methyl)oxazole-4-carboxamide dihydrochloride

To compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(((2,4-difluorophenyl )(2H-tetrazol-5-yl)methyl)carbamoyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (0.16g, 0.24mmol) in dichloromethane (2mL) was added Ethyl acetate solution of HCl (4M, 3 mL), stirred at room temperature for 40 min, and the solvent was removed to obtain 140 mg of yellow solid, yield: 96%.

Compound 148: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.71(s, 1H), 7.64(d, J=8.2Hz, 1H), 7.49–7.45(m, 1H), 7.23(d, J=8.2 Hz,1H),7.02–6.96(m,2H),6.91(s,1H),6.82(t,J _FH =74.7Hz,1H),5.14–5.11(m,1H),3.93(d,J=6.8 Hz,2H),1.68(d,J＝6.5Hz,3H),0.82–0.77(m,1H),0.60–0.57(m,2H),0.33–0.32(m,2H);

MS-ESI: m/z 562.1 [M+H-2HCl] ⁺ .

Example 60: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Base)-N-(1-(2,4-difluorophenyl)-2-oxo-2-(4-(pyridin-4-ylmethyl)piperazin-1-yl)ethyl)oxazole -4-formyl Synthesis of Amine Trihydrochloride

Step 1: Compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4- Difluorophenyl)-2-oxo-2-(4-(pyridin-4-ylmethyl)piperazin-1-yl)ethyl)carbamoyl)oxazol-5-yl)ethyl)amino Synthesis of tert-butyl formate

Compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid (0.23g, 0.36mmol), 1-(4-pyridylmethyl)piperazine (77mg, 0.43mmol ), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (103mg, 0.54mmol) and N-hydroxy-7-azabenzotriazole (74mg, 0.54mmol ) was dissolved in dichloromethane (10mL), and N,N-diisopropylethylamine (0.19mL, 1.08mmol) was added dropwise to the solution at 0°C, stirred at room temperature for 11h, the solvent was removed, and the concentrated solution was subjected to column Separation (ethyl acetate/methanol (v/v)=20/1) gave 260 mg of a colorless oil, yield: 90%.

¹ H NMR (600MHz, CDCl ₃ ): δppm 8.60(d, J=4.1Hz, 2H), 8.52(d, J=6.4Hz, 1H), 7.62(d, J=8.4Hz, 1H), 7.59(s ,1H),7.55–7.49(m,1H),7.36(d,J=3.8Hz,2H),7.25(d,J=8.3Hz,1H),6.96–6.86(m,2H),6.73(t, JFH＝ _75.0Hz ,1H),6.28(d,J＝7.5Hz,1H),5.32–5.29(m,1H),4.01(d,J＝6.9Hz,2H),3.75–3.72(m,2H) ,3.66–3.63(m,1H),3.57(s,2H),3.50–3.45(m,1H),2.53–2.46(m,4H),1.53–1.48(m,3H),1.44(s,9H) ,1.33–1.29(m,1H),0.73–0.68(m,2H),0.46–0.42(m,2H);

MS-ESI: m/z 797.2 [M+H] ⁺ .

Step 2: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1- (2,4-Difluorophenyl)-2-oxo-2-(4-(pyridin-4-ylmethyl)piperazin-1-yl)ethyl)oxazole-4-carboxamide trihydrochloride Salt Synthesis

To compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4-difluoro Phenyl)-2-oxo-2-(4-(pyridin-4-ylmethyl)piperazin-1-yl)ethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate Add HCl in ethyl acetate (4M, 3mL) to a solution of butyl ester (0.26g, 0.33mmol) in dichloromethane (2mL), stir at room temperature for 20min, remove the solvent to obtain 220mg of white solid, yield: 96%.

Compound 150: ¹ H NMR (400MHz, CD ₃ OD): δppm 8.98(s, 2H), 8.37(d, J=5.4Hz, 2H), 7.79(s, 1H), 7.73(d, J=8.4Hz, 1H),7.61–7.55(m,1H),7.34(d,J＝8.4Hz,1H),7.13–7.07(m,2H),6.92(t,J _FH ＝70.6Hz,1H),6.33(s, 1H),5.20–5.16(m,1H),4.58(s,2H),4.04(d,J＝6.9Hz,2H),3.33–3.20(m,8H),1.75(d,J＝7.0Hz,3H ),1.36–1.34(m,1H),0.72–0.67(m,2H),0.46–0.42(m,2H);

MS-ESI: m/z 697.2 [M+H-3HCl] ⁺ .

Example 61: Compound (S)-2-(5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethane Oxy)phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid hydrochloride and (R)-2-(5-((S)-1- Ammonia ethyl Base)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl ) Synthesis of acetic acid hydrochloride

The compound 2-(5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxa Azole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid hydrochloride was prepared and resolved, and the compound (S)-2-(5-((S)- 1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamido)-2-(2,4- Difluorophenyl) acetic acid hydrochloride and (R)-2-(5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(di Fluoromethoxy)phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid hydrochloride.

Compound 153: ¹ H NMR (600MHz, CD ₃ OD): δppm 8.76(s, 1H), 7.71(s, 1H), 7.68(d, J=8.3Hz, 1H), 7.40-7.34(m, 2H), 7.24(t, J _FH ＝75.0Hz, 1H), 7.12(t, J＝8.7Hz, 1H), 6.97(t, J＝7.7Hz, 1H), 5.21(s, 1H), 5.02–4.98(m, 1H), 4.02(d, J＝6.8Hz, 2H), 1.55(d, J＝6.7Hz, 3H), 1.28–1.24(m, 1H), 0.61–0.60(m, 2H), 0.41–0.40(m ,2H);

MS-ESI: m/z 538.2[M+H-HCl] ⁺ ;

Compound 154: ¹ H NMR (400MHz, d ₆ -DMSO): δppm 8.67(s, 1H), 7.65–7.63(m, 2H), 7.35(d, J=8.8Hz, 1H), 7.31–7.27(m, 1H), 7.23(t, J _FH ＝74.0Hz, 1H), 7.12(dd, J ₁ ＝10.0Hz, J ₂ ＝2.5Hz, 1H), 6.99–6.95(m, 1H), 5.16–5.15(m, 1H),5.04–4.99(m,1H),3.98(d,J＝7.0Hz,2H),1.51(d,J＝6.9Hz,3H),1.29–1.25(m,1H),0.63–0.58(m ,2H),0.41–0.38(m,2H);

MS-ESI: m/z 538.2 [M+H-HCl] ⁺ .

Example 62: Compound N-((S)-2-Acetamido-1-(2,4-difluorophenyl)ethyl)-5-((S)-1-Aminoethyl Base)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride and N-((R)-2-acetyl Amino-1-(2,4-difluorophenyl)ethyl)-5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(di flumethoxine Synthesis of yl)phenyl)oxazole-4-carboxamide hydrochloride

The compound N-(2-acetylamino-1-(2,4-difluorophenyl) ethyl)-5-((S)-1-aminoethyl)-2-(3-( Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride is resolved by preparative chromatography to obtain N-((S)-2 -Acetamido-1-(2,4-difluorophenyl)ethyl)-5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4- (Difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride (pale yellow solid) and N-((R)-2-acetylamino-1-(2,4-difluorophenyl) Ethyl)-5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-meth Amide hydrochloride (pale yellow solid).

Compound 158: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.78(s, 1H), 7.71(d, J=8.4Hz, 1H), 7.46–7.41(m, 1H), 7.29(d, J=8.4 Hz,1H),6.98–6.91(m,2H),6.87(t,J _FH ＝74.7Hz,1H),5.47–5.44(m,1H),5.11–5.05(m,1H),4.02(d,J ＝6.9Hz,2H),3.70–3.56(m,2H),1.89(s,3H),1.68(d,J＝7.0Hz,3H),1.35–1.30(m,1H),0.67–0.62(m, 2H),0.41–0.37(m,2H);

MS-ESI: m/z 565.2[M+H-HCl] ⁺ ;

Compound 159: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.85(s, 1H), 7.76(d, J=8.3Hz, 1H), 7.50–7.48(m, 1H), 7.35(d, J=8.3 Hz,1H),7.03–6.98(m,2H),6.93(t,J _FH ＝74.7Hz,1H),5.53–5.51(m,1H),5.11–5.08(m,1H),4.07(d,J ＝7.0Hz,2H),3.75–3.63(m,2H),1.95(s,3H),1.74(d,J＝7.0Hz,3H),1.39–1.37(m,1H),0.72–0.69(m, 2H),0.46–0.44(m,2H);

MS-ESI: m/z 565.2 [M+H-HCl] ⁺ .

Example 63: Compound (S)-2-(5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethane Oxy)phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)methyl acetate hydrochloride and (R)-2-(5-((S)-1 -ammonia Ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamido)-2-(2,4-difluorobenzene Base) Synthesis of Methyl Acetate Hydrochloride

The compound 2-(5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxa Azole-4-carboxamido)-2-(2,4-difluorophenyl) methyl acetate hydrochloride was resolved by preparative chromatography, and compound (S)-2-(5-( (S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamido)-2-( 2,4-Difluorophenyl) methyl acetate hydrochloride (white solid) and compound (R)-2-(5-((S)-1-aminoethyl)-2-(3-(cyclopropyl Methyl methoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetate hydrochloride (white solid) .

Compound 164: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.80(s, 1H), 7.74(d, J=8.3Hz, 1H), 7.59–7.55(m, 1H), 7.34(d, J=8.3 Hz,1H),7.10–7.03(m,2H),6.93(t,J _FH ＝74.7Hz,1H),6.06(s,1H),5.21–5.17(m,1H),4.04(d,J＝6.9 Hz,2H),3.81(s,3H),1.75(d,J＝7.0Hz,3H),1.39–1.36(m,1H),0.71–0.68(m,2H),0.45–0.43(m,2H) ;

MS-ESI: m/z 552.2[M+H-HCl] ⁺ ;

Compound 165: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.80(s, 1H), 7.74(d, J=8.3Hz, 1H), 7.59–7.55(m, 1H), 7.34(d, J=8.3 Hz,1H),7.10–7.03(m,2H),6.93(t,J _FH ＝74.7Hz,1H),6.06(s,1H),5.19–5.16(m,1H),4.04(d,J＝6.9 Hz,2H),3.81(s,3H),1.75(d,J＝7.0Hz,3H),1.38–1.35(m,1H),0.71–0.68(m,2H),0.45–0.43(m,2H) ;

MS-ESI: m/z 552.2 [M+H-HCl] ⁺ .

Example 64: Compound 5-((S)-1-aminoethyl)-N-((S)-2-(cyclopropylcarboxamido)-1-(2,4-difluoro Phenyl)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride and 5- ((S)-1-aminoethyl)-N-((R)-2-(cyclopropylcarboxamido)-1-(2,4-difluorophenyl)ethyl)-2-(3 -(cyclopropyl methyl Synthesis of oxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride

Compound 5-((S)-1-aminoethyl)-N-(2-(cyclopropylcarboxamido)-1-(2,4-difluorophenyl)ethyl)-(2,4-difluorophenyl)ethyl)- 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride was resolved by preparative chromatography to obtain compound 5 -((S)-1-aminoethyl)-N-((S)-2-(cyclopropylcarboxamido)-1-(2,4-difluorophenyl)ethyl)-2-( 3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride (white solid) and 5-((S)-1-aminoethyl )-N-((R)-2-(cyclopropylcarboxamido)-1-(2,4-difluorophenyl)ethyl)-2-(3-(cyclopropylmethoxy)- 4-(Difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride (white solid).

Compound 166: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.84(s, 1H), 7.75(d, J=8.3Hz, 1H), 7.50–7.46(m, 1H), 7.35(d, J=8.3 Hz,1H),7.04–6.98(m,2H),6.94(t,J _FH ＝74.7Hz,1H),5.49–5.47(m,1H),5.15–5.12(m,1H),4.07(d,J =7.0Hz,2H),3.79–3.75(m,1H),3.66–3.63(m,1H),1.72(d,J＝7.0Hz,3H),1.58–1.55(m,1H),1.42–1.39( m,1H),0.93–0.90(m,2H),0.79–0.75(m,2H),0.73–0.70(m,2H),0.47–0.45(m,2H);

MS-ESI: m/z 591.2[M+H-HCl] ⁺ ;

Compound 167: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.84(s, 1H), 7.74(d, J=8.3Hz, 1H), 7.48–7.46(m, 1H), 7.35(d, J=8.3 Hz,1H),7.03–6.98(m,2H),6.94(t,J _FH ＝74.7Hz,1H),5.49–5.47(m,1H),5.10–5.08(m,1H),4.07(d,J ＝7.0Hz,2H),3.77–3.74(m,1H),3.67–3.65(m,1H),1.73(d,J＝7.0Hz,3H),1.57–1.55(m,1H),1.41–1.38( m,1H),1.02–0.99(m,2H),0.80–0.75(m,2H),0.72–0.71(m,2H),0.47–0.46(m,2H);

MS-ESI: m/z 591.2 [M+H-HCl] ⁺ .

Example 65: Compound 5-((S)-1-aminoethyl)-N-(2-(cyclopropylamino)-1-(2,4-difluorophenyl)-2- Synthesis of oxoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride

Step 1: Synthesis of the compound 2-amino-2-(2,4-difluorophenyl)methyl acetate

Dissolve the compound 2-amino-2-(2,4-difluorophenyl)acetonitrile hydrochloride (1.0g, 4.89mmol) in anhydrous methanol (30mL), add HCl in ethyl acetate solution (4M, 8mL) , reacted at 65°C for 24h, spin-dried the solvent, and washed the remaining solid with dichloromethane (10mL×5) to obtain 1.05g of light yellow solid, yield: 91%.

¹ H NMR (600MHz, CD ₃ OD): δppm 7.76–7.82(m,1H), 7.21–7.31(m,2H), 6.03(s,1H), 3.84(s,3H);

MS-ESI: m/z 202.20 [M+H-HCl] ⁺ .

Step 2: Compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Synthesis of methyl)phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) Oxazole-4-carboxylic acid (0.50g, 1.07mmol), compound 2-amino-2-(2,4-difluorophenyl) methyl acetate (380mg, 1.60mmol), 1-ethyl-3-( 3-Dimethylaminopropyl) carbodiimide hydrochloride (409mg, 2.13mmol) and N-hydroxy-7-azabenzotriazole (218mg, 1.60mmol) were dissolved in dichloromethane (20mL) , N,N-diisopropylethylamine (0.75mL, 4.28mmol) was added dropwise to the solution at 0°C, stirred at room temperature for 5h, washed with water (10mL×3), and the organic phase was washed with anhydrous Na ₂ SO ₄ After drying, the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=6/1) to obtain 170 mg of white solid, yield: 25%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.16 (br.s, 1H), 7.62–7.64 (m, 1H), 7.59 (d, J=1.8Hz, 1H), 7.46–7.51 (m, 1H), 7.26(d, J＝8.3Hz, 1H), 6.88–6.95(m, 2H), 6.73(t, J _FH ＝75.1Hz, 1H), 5.98–6.01(m, 1H), 5.25–5.32(m, 1H ),4.02(dd,J＝6.9,1.6Hz,2H),3.82(s,3H),1.49–1.54(m,3H),1.41–1.45(m,9H),1.34–1.37(m,1H), 0.69–0.74(m,2H),0.43–0.47(m,2H);

MS-ESI: m/z 674.10 [M+Na] ⁺ .

Step 3: Compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Synthesis of yl)phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid

Compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)methyl acetate (240mg, 0.37mmol) and LiOH·H ₂ O (77mg, 1.84mmol) were dissolved in THF ( 10 mL) and water (5 mL), stirred at 40°C for 30 min, added dilute hydrochloric acid (1M) to adjust pH = 1, added ethyl acetate for extraction (20 mL×3), combined the organic phases and dried them with Na ₂ SO ₄ to remove the solvent , to obtain 230 mg of white solid, yield: 98%.

¹ H NMR (600MHz, CD ₃ OD): δppm 7.70(s, 1H), 7.61–7.63(m, 1H), 7.50–7.54(m, 1H), 7.24(d, J＝8.3Hz, 1H), 6.94 –7.00(m,2H),6.84(t,J _FH =74.9Hz,1H),5.87(d,J=13.8Hz,1H),5.30–5.38(m,1H),3.97(dd,J=6.9, 2.4Hz, 2H), 1.45(d, J＝7.1Hz, 3H), 1.34–1.36(m, 9H), 1.27–1.31(m, 1H), 0.61–0.65(m, 2H), 0.36–0.39(m ,2H);

MS-ESI: m/z 660.15 [M+Na] ⁺ .

Step 4: Compound ((1S)-1-(4-((2-(cyclopropylamino)-1-(2,4-difluorophenyl)-2-oxoethyl)carbamoyl)- Synthesis of tert-butyl 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate

Compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid (230mg, 0.36mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbon Diimine hydrochloride (138mg, 0.72mmol) and N-hydroxy-7-azabenzotriazole (74mg, 0.54mmol) were dissolved in dichloromethane (15mL), and added to the solution at 0°C Cyclopropylamine (31mg, 0.54mmol) and N,N-diisopropylethylamine (0.19mL, 1.08mmol) were added dropwise, stirred at room temperature for 12h, washed with water (10mL×3), and the organic phase was washed with anhydrous Na ₂ SO ₄ was dried, the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=5/1) to obtain 180 mg of white solid, yield: 74%.

¹ H NMR (600MHz, CDCl ₃ ): δppm 8.42 (br.s, 1H), 7.61–7.64 (m, 2H), 7.48–7.52 (m, 1H), 7.26 (d, J=8.3Hz, 1H), 6.88–6.94(m,2H),6.74(t,J _FH ＝75.1Hz,1H),6.07(s,1H),5.80(d,J＝6.8Hz,1H),5.26–5.33(m,1H), 4.04(d,J=6.9Hz,2H),2.70–2.76(m,1H),1.46–1.53(m,3H),1.40–1.44(m,9H),1.34–1.39(m,1H),0.77– 0.87(m,2H),0.70–0.73(m,2H),0.48–0.59(m,2H),0.44–0.47(m,2H);

MS-ESI: m/z 699.20 [M+Na] ⁺ .

Step 5: Compound 5-((S)-1-aminoethyl)-N-(2-(cyclopropylamino)-1-(2,4-difluorophenyl)-2-oxoethyl) -Synthesis of 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride

To compound ((1S)-1-(4-((2-(cyclopropylamino)-1-(2,4-difluorophenyl)-2-oxoethyl)carbamoyl)-2- (3-(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (175mg, 0.26mmol) in dichloromethane ( 2 mL) solution of ethyl acetate of HCl (4M, 4 mL) was added, stirred at room temperature for 30 min, and the solvent was removed to obtain 160 mg of white solid, yield: 99%.

Compound 168: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.79(s, 1H), 7.72(d, J=8.4Hz, 1H), 7.54–7.58(m, 1H), 7.34(d, J=8.3 Hz,1H),7.03–7.07(m,2H),6.92(t,J _FH ＝74.9Hz,1H),5.85(d,J＝4.6Hz,1H),5.15–5.20(m,1H),4.04( d,J=6.9Hz,2H),2.72–2.75(m,1H),1.75(d,J=7.0Hz,3H),1.32–1.38(m,1H),0.74–0.77(m,2H),0.68 –0.71(m,2H),0.46–0.56(m,2H),0.42–0.45(m,2H);

MS-ESI: m/z 577.20 [M+H-HCl] ⁺ .

Example 66: Compound 2-(5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of benzyl phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetate hydrochloride

Step 1: Compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Synthesis of benzyl)phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetate

Compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid (230mg, 0.36mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbon Diimine hydrochloride (138mg, 0.72mmol) and N-hydroxy-7-azabenzotriazole (74mg, 0.54mmol) were dissolved in dichloromethane (15mL), and added to the solution at 0°C Benzyl alcohol (58mg, 0.54mmol) and N,N-diisopropylethylamine (0.19mL, 1.08mmol) were added dropwise, stirred at room temperature for 12h, washed with water (10mL×3), and the organic phase was washed with anhydrous Na ₂ SO ₄ was dried, the solvent was removed, and the concentrated solution was subjected to column separation (ethyl acetate/petroleum ether (v/v)=8/1) to obtain 63 mg of white solid, yield: 24%.

¹ H NMR (600MHz, CDCl ₃ ): δppm 8.20 (br.s, 1H), 7.60–7.63 (m, 1H), 7.58–7.59 (m, 1H), 7.31–7.35 (m, 5H), 7.24–7.26 (m,2H),6.87–6.91(m,2H),6.73(t,J _FH ＝74.9Hz,1H),6.03(d,J＝7.7Hz,1H),5.27–5.30(m,1H),5.25 (s,2H),4.01(d,J=6.9Hz,2H),1.52(d,J=7.0Hz,3H),1.46(s,9H),1.31–1.39(m,1H),0.70–0.74( m,2H),0.42–0.45(m,2H);

MS-ESI: m/z 750.20 [M+Na] ⁺ .

Step 2: Compound 2-(5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole- Synthesis of Benzyl 4-formylamino)-2-(2,4-difluorophenyl)acetate hydrochloride

To compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) To a solution of benzyl phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetate (63 mg, 0.087 mmol) in dichloromethane (2 mL) was added HCl in ethyl acetate (4M, 4mL), stirred at room temperature for 30min, and removed the solvent to obtain 55mg of white solid, yield: 96%.

Compound 170: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.80(s, 1H), 7.72-7.74(m, 1H), 7.50-7.56(m, 1H), 7.28-7.35(m, 5H), 6.97 –7.08(m,2H),6.92(t,J _FH ＝74.8Hz,1H),6.08(s,1H),5.21–5.32(m,2H),5.15–5.21(m,1H),4.05(d, J＝6.8Hz, 2H), 1.75(d, J＝6.6Hz, 3H), 1.31–1.35(m, 1H), 0.66–0.72(m, 2H), 0.41–0.45(m, 2H);

MS-ESI: m/z 628.10 [M+H-HCl] ⁺ .

Example 67: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Base)-N-((S)-1-(2,4-difluorophenyl)-2-(methylamino)-2-oxoethyl)oxazole-4-carboxamide hydrochloride and 5- ((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((R)-1-(2 ,4-Difluorobenzene Synthesis of yl)-2-(methylamino)-2-oxoethyl)oxazole-4-carboxamide hydrochloride

Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-( 1-(2,4-difluorophenyl)-2-(methylamino)-2-oxoethyl)oxazole-4-carboxamide hydrochloride was resolved by chiral preparative chromatography to obtain compound 5 -((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((S)-1-( 2,4-Difluorophenyl)-2-(methylamino)-2-oxoethyl)oxazole-4-carboxamide hydrochloride (white solid) and 5-((S)-1-aminoethyl Base)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((R)-1-(2,4-difluorophenyl)- 2-(Methylamino)-2-oxoethyl)oxazole-4-carboxamide hydrochloride (white solid).

Compound 171: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.79(s, 1H), 7.73(d, J=8.3Hz, 1H), 7.58–7.55(m, 1H), 7.34(d, J=8.3 Hz,1H),7.07–7.02(m,2H),6.92(t,J _FH ＝74.7Hz,1H),5.90(s,1H),5.20–5.16(m,1H),4.04(d,J＝6.9 Hz,2H),2.80(s,3H),1.75(d,J＝7.0Hz,3H),1.38–1.35(m,1H),0.71–0.68(m,2H),0.45–0.42(m,2H) ;

MS-ESI: m/z 551.2[M+H-HCl] ⁺ ;

Compound 172: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.79(s, 1H), 7.72(d, J=8.3Hz, 1H), 7.58–7.55(m, 1H), 7.34(d, J=8.3 Hz,1H),7.08–7.03(m,2H),6.92(t,J _FH ＝74.7Hz,1H),5.89(s,1H),5.17–5.14(m,1H),4.04(d,J＝6.9 Hz,2H),2.80(s,3H),1.75(d,J＝7.0Hz,3H),1.36–1.34(m,1H),0.71–0.68(m,2H),0.45–0.43(m,2H) ;

MS-ESI: m/z 551.2 [M+H-HCl] ⁺ .

Example 68: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-(1-(2,4-difluorophenyl)-2-(dimethylamino)-2-oxoethyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4- Synthesis of tert-butyl difluorophenyl)-2-(dimethylamino)-2-oxoethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

Compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid (0.35g, 0.55mmol), dimethylamine hydrochloride (54mg, 0.66mmol), 1-ethyl- 3-(3-Dimethylaminopropyl) carbodiimide hydrochloride (158mg, 0.82mmol) and N-hydroxy-7-azabenzotriazole (112mg, 0.82mmol) were dissolved in dichloromethane ( 15mL), N,N-diisopropylethylamine (0.38mL, 2.20mmol) was added dropwise to this solution at 0°C, stirred at room temperature for 4h, the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate Ester (v/v)=3/1), 140 mg of colorless oil was obtained, yield: 38%.

¹ H NMR (600MHz, CDCl ₃ ): δppm 7.62(d, J=8.4Hz, 1H), 7.60(s, 1H), 7.55–7.51(m, 1H), 7.24(d, J=8.3Hz, 1H) ,6.94–6.87(m,2H),6.73(t,J _FH ＝75.1Hz,1H),6.30–6.28(m,1H),5.32–5.28(m,1H),4.02(d,J＝7.0Hz, 2H),3.05–3.04(m,6H),1.55–1.48(m,3H),1.37–1.34(m,1H),0.73–0.70(m,2H),0.44–0.40(m,2H);

MS-ESI: m/z 665.2 [M+H] ⁺ .

Step 2: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1- Synthesis of (2,4-difluorophenyl)-2-(dimethylamino)-2-oxoethyl)oxazole-4-carboxamide hydrochloride

To compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4-difluoro Dichloromethane ( 5 mL) solution of ethyl acetate of HCl (4M, 2 mL) was added, stirred at room temperature for 1.5 h, and the solvent was removed to obtain 110 mg of white solid, yield: 99%.

Compound 173: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.78(s, 1H), 7.72(d, J=8.3Hz, 1H), 7.55–7.51(m, 1H), 7.33(d, J=8.4 Hz,1H),7.10–7.03(m,2H),6.92(t,J _FH ＝74.7Hz,1H),6.26(s,1H),5.18–5.14(m,1H),4.04(d,J＝6.9 Hz,2H),3.03–3.01(m,6H),1.75(d,J＝6.9Hz,3H),1.35–1.32(m,1H),0.71–0.66(m,2H),0.45–0.43(m, 2H);

MS-ESI: m/z 565.2 [M+H-HCl] ⁺ .

Example 69: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Base)-N-(2-((cyclopropylmethyl)amino)-1-(2,4-difluorophenyl)-2-oxoethyl)oxazole-4-carboxamide hydrochloride synthesis

Step 1: Compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((2-((cyclopropyl Synthesis of tert-butyl methyl)amino)-1-(2,4-difluorophenyl)-2-oxoethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

Compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid (0.35g, 0.55mmol), cyclopropanylmethylamine (0.06mL, 0.66mmol), 1-ethyl Base-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (158mg, 0.82mmol) and N-hydroxy-7-azabenzotriazole (112mg, 0.82mmol) were dissolved in dichloro In methane (15mL), N,N-diisopropylethylamine (0.29mL, 1.65mmol) was added dropwise to the solution at 0°C, stirred at room temperature for 4h, the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ Ethyl acetate (v/v)=4/1), to obtain 145 mg of light yellow solid, yield: 38%.

¹ H NMR (600MHz, CDCl ₃ ): δppm 7.63 (d, J = 8.3Hz, 1H), 7.61 (m, 1H), 7.53–7.50 (m, 1H), 7.26 (d, J = 8.3Hz, 1H) ,6.95–6.90(m,2H),6.74(t,J _FH ＝75.0Hz,1H),6.02–6.00(m,1H),5.88–5.87(m,1H),5.33–5.29(m,1H), 4.03(d,J=7.0Hz,2H),3.24–3.21(m,1H),3.15–3.11(m,1H),1.53–1.48(m,3H),1.45–1.40(m,9H),1.37– 1.34(m,1H),0.98–0.94(m,1H),0.73–0.70(m,2H),0.54–0.52(m,2H),0.47–0.44(m,2H),0.21–0.20(m,2H );

MS-ESI: m/z 691.2 [M+H] ⁺ .

Step 2: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2- Synthesis of ((cyclopropylmethyl)amino)-1-(2,4-difluorophenyl)-2-oxoethyl)oxazole-4-carboxamide hydrochloride

To the compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((2-((cyclopropylmethyl )amino)-1-(2,4-difluorophenyl)-2-oxoethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (0.13g, 0.20mmol) Add HCl in ethyl acetate (4M, 2 mL) to a solution of dichloromethane (4 mL), stir at room temperature for 2.5 h, and remove the solvent to obtain 110 mg of white solid, yield: 95%.

Compound 174: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.79(s, 1H), 7.72(d, J=8.3Hz, 1H), 7.60–7.57(m, 1H), 7.34(d, J=8.3 Hz,1H),7.08–7.03(m,2H),6.92(t,J _FH ＝74.7Hz,1H),5.92(d,J＝2.7Hz,1H),5.19–5.15(m,1H),4.04( d,J=6.9Hz,2H),3.15–3.09(m,2H),1.75(d,J=7.0Hz,3H),1.36–1.33(m,1H),1.00–0.97(m,1H),0.71 –0.68(m,2H),0.49–0.47(m,2H),0.45–0.42(m,2H),0.22–0.20(m,2H);

MS-ESI: m/z 591.2 [M+H-HCl] ⁺ .

Example 70: Compound 5-((S)-1-aminoethyl)-N-(2-(cyclopentylformamide)-1-(2,4-difluorophenyl) Synthesis of ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound ((1S)-1-(4-((2-(cyclopentylcarboxamide)-1-(2,4-difluorophenyl)ethyl)carbamoyl)-2-(3 Synthesis of tert-butyl -(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate

The compound ((1S)-1-(4-((2-amino-1-(2,4-difluorophenyl)ethyl)carbamoyl)-2-(3-(cyclopropylmethoxy )-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (0.30g, 0.48mmol), cyclopentanoic acid (66mg, 0.58mmol), 1-ethyl Base-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (140mg, 0.72mmol) and N-hydroxy-7-azabenzotriazole (100mg, 0.72mmol) were dissolved in dichloro In methane (15mL), N,N-diisopropylethylamine (0.34mL, 1.93mmol) was added dropwise to the solution at 0°C, stirred at room temperature for 15h, the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ Ethyl acetate (v/v)=3/1) to obtain 190 mg of colorless oil, yield: 54%.

¹ H NMR (600MHz, CDCl ₃ ): δppm 7.65–7.64 (m, 2H), 7.40–7.37 (m, 1H), 7.26 (d, J=8.7Hz, 1H), 6.92–6.86 (m, 2H), 6.74(t,J _FH ＝75.0Hz,1H),5.95–5.93(m,1H),5.49–5.48(m,1H),5.31–5.28(m,1H),4.03(d,J＝6.9Hz,2H ),3.85–3.81(m,2H),2.53–2.50(m,1H),1.84–1.73(m,4H),1.58–1.55(m,2H),1.53–1.52(m,2H),1.49–1.47 (m,3H),1.46(s,9H),1.38–1.35(m,1H),0.73–0.70(m,2H),0.44–0.43(m,2H);

MS-ESI: m/z 719.2 [M+H] ⁺ .

Step 2: Compound 5-((S)-1-aminoethyl)-N-(2-(cyclopentylcarboxamide)-1-(2,4-difluorophenyl)ethyl)-2-( Synthesis of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride

To the compound ((1S)-1-(4-((2-(cyclopentylformamide)-1-(2,4-difluorophenyl)ethyl)carbamoyl)-2-(3-( Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate (0.19 g, 0.26 mmol) in dichloromethane (4 mL) Add HCl in ethyl acetate solution (4M, 2 mL), stir at room temperature for 1 h, and remove the solvent to obtain 170 mg of white solid, yield: 99%.

Compound 180: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.85(s, 1H), 7.76(d, J=8.3Hz, 1H), 7.50–7.45(m, 1H), 7.35(d, J=8.4 Hz,1H),7.03–7.03(m,2H),6.93(t,J _FH ＝74.7Hz,1H),5.52–5.48(m,1H),5.15–5.08(m,1H),4.08(d,J ＝7.0Hz,2H),3.80–3.72(m,1H),3.67–3.62(m,1H),2.63–2.60(m,1H),1.83–1.79(m,2H),1.74–1.73(m,3H ),1.72–1.69(m,4H),1.60–1.56(m,2H),1.41–1.38(m,1H),0.73–0.68(m,2H),0.47–0.43(m,2H);

MS-ESI: m/z 619.2 [M+H-HCl] ⁺ .

Example 71: Compound N-(2-((S)-2-amino-2-cyclopropylacetamido)-1-(2,4-difluorophenyl)ethyl Base)-5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide Di-salt salt synthesis

Step 1: Compound ((1S)-1-cyclopropyl-2-((2-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-5 -((S)-1-(tert-butoxycarbonylamino)ethyl)oxazole-4-carboxamide)-2-(2,4-difluorophenyl)ethyl)amino)-2-oxoethyl base) synthesis of tert-butyl carbamate

The compound ((1S)-1-(4-((2-amino-1-(2,4-difluorophenyl)ethyl)carbamoyl)-2-(3-(cyclopropylmethoxy )-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (0.30g, 0.48mmol), Boc-L-cyclopropyl glycine (124mg, 0.58mmol ), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (138mg, 0.72mmol) and N-hydroxy-7-azabenzotriazole (98mg, 0.72mmol ) was dissolved in dichloromethane (15mL), and N,N-diisopropylethylamine (0.25mL, 1.45mmol) was added dropwise to the solution at 0°C, stirred at room temperature for 4h, the solvent was removed, and the concentrated solution was subjected to column After separation (petroleum ether/ethyl acetate (v/v)=3/1), 210 mg of white solid was obtained, yield: 53%.

¹ H NMR (600MHz, CDCl ₃ ): δppm 7.65–7.62 (m, 2H), 7.43–7.37 (m, 1H), 7.27 (d, J=8.3Hz, 1H), 6.92–6.87 (m, 2H), 6.73(t, J _FH ＝75.0Hz, 1H), 5.54–5.50(m, 1H), 5.32–5.20(m, 2H), 4.02(d, J＝6.9Hz, 2H), 3.86–3.71(m, 3H ),3.45–3.41(m,1H),1.55–1.49(m,3H),1.46–1.41(m,18H),1.36–1.32(m,1H),1.29–1.27(m,2H),0.73–0.70 (m,2H);

MS-ESI: m/z 820.2 [M+H] ⁺ .

Step 2: The compound N-(2-((S)-2-amino-2-cyclopropylacetamido)-1-(2,4-difluorophenyl)ethyl)-5-((S)- Synthesis of 1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide dihydrochloride

To the compound ((1S)-1-cyclopropyl-2-((2-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-5-( (S)-1-(tert-butoxycarbonylamino)ethyl)oxazole-4-carboxamide)-2-(2,4-difluorophenyl)ethyl)amino)-2-oxoethyl) To a solution of tert-butyl carbamate (0.21g, 0.25mmol) in dichloromethane (4mL) was added HCl in ethyl acetate (4M, 2mL), stirred at room temperature for 1h, and the solvent was removed to obtain a white solid 170mg, yield: 98 %.

Compound 182: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.84(s, 1H), 7.77(d, J=8.3Hz, 1H), 7.59–7.57(m, 1H), 7.35(d, J=8.2 Hz,1H),7.05–6.99(m,2H),6.93(t,J _FH ＝74.7Hz,1H),5.66–5.61(m,1H),5.19–5.11(m,1H),4.07(d,J =6.8Hz,2H),4.03–3.94(m,1H),3.70–3.63(m,1H),3.20–3.17(m,1H),1.75(d,J＝7.0Hz,3H),1.36–1.32( m,1H),0.93–0.87(m,1H),0.71–0.68(m,2H),0.65–0.60(m,2H),0.53–0.50(m,1H),0.47–0.43(m,2H);

MS-ESI: m/z 620.2 [M+H-2HCl] ⁺ .

Example 72: Compound 5-((S)-1-aminoethyl)-N-(2-((S)-2-aminopropionamido)-1-(2,4-difluoro Synthesis of phenyl)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide dihydrochloride

Step 1: Compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4- Synthesis of tert-butyl difluorophenyl)-2-((S)-2-(tert-butoxycarbonylamino)propionamido)ethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

The compound ((1S)-1-(4-((2-amino-1-(2,4-difluorophenyl)ethyl)carbamoyl)-2-(3-(cyclopropylmethoxy )-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)tert-butyl carbamate (0.30g, 0.48mmol), Boc-L alanine (109mg, 0.58mmol), 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (140mg, 0.72mmol) and N-hydroxy-7-azabenzotriazole (100mg, 0.72mmol) dissolved In dichloromethane (15mL), N,N-diisopropylethylamine (0.34mL, 1.93mmol) was added dropwise to this solution at 0°C, stirred at room temperature for 20h, the solvent was removed, and the concentrated solution was subjected to column separation ( Petroleum ether/ethyl acetate (v/v)=2/1) to obtain 195 mg of white solid, yield: 51%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.65–7.63 (m, 2H), 7.40–7.37 (m, 1H), 7.27 (d, J=8.7Hz, 1H), 6.92–6.86 (m, 2H), 6.73(t, J _FH ＝75.0Hz, 1H), 5.50–5.48(m, 1H), 5.34–5.30(m, 1H), 4.17–4.12(m, 1H), 4.02(d, J＝6.9Hz, 2H ),3.81–3.77(m,1H),1.46–1.45(m,3H),1.41–1.40(m,9H),1.38–1.35(m,1H),1.33–1.30(m,3H),1.28–1.23 (m,9H),0.74–0.69(m,2H),0.46–0.42(m,2H);

MS-ESI: m/z 794.2 [M+H] ⁺ .

Step 2: Compound 5-((S)-1-aminoethyl)-N-(2-((S)-2-aminopropanamido)-1-(2,4-difluorophenyl)ethyl Synthesis of )-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide dihydrochloride

To compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4-difluoro Phenyl)-2-((S)-2-(tert-butoxycarbonylamino)propionamido)ethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (0.19g, 0.24 mmol) in dichloromethane (4 mL) was added HCl in ethyl acetate (4M, 2 mL), stirred at room temperature for 0.5 h, and the solvent was removed to obtain 159 mg of white solid, yield: 99%.

Compound 183: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.84(s, 1H), 7.76(d, J=8.3Hz, 1H), 7.58–7.57(m, 1H), 7.35(d, J=8.3 Hz,1H),7.06–7.01(m,2H),6.93(t,J _FH ＝74.8Hz,1H),5.64–5.60(m,1H),5.16–5.11(m,1H),4.07(d,J ＝6.9Hz,2H),3.95–3.89(m,2H),3.70–3.65(m,1H),1.75(d,J＝5.9Hz,3H),1.44–1.40(m,3H),1.38–1.36( m,1H),0.72–0.67(m,2H),0.46–0.44(m,2H);

MS-ESI: m/z 594.2 [M+H-2HCl] ⁺ .

Example 73: Compound 5-((S)-1-aminoethyl)-N-(2-(cyclopentylamino)-1-(2,4-difluorophenyl)-2- Synthesis of oxoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound ((1S)-1-(4-((2-(cyclopentylamino)-1-(2,4-difluorophenyl)-2-oxoethyl)carbamoyl)- Synthesis of tert-butyl 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate

Compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid (280mg, 0.44mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbon Diimine hydrochloride (253mg, 1.32mmol) and N-hydroxy-7-azabenzotriazole (89mg, 0.66mmol) were dissolved in dichloromethane (25mL), and added to the solution at 0°C Cyclopentylamine (75mg, 0.88mmol) and N,N-diisopropylethylamine (0.23mL, 1.32mmol) were added dropwise, stirred at room temperature for 12h, washed with water (10mL×3), and the organic phase was washed with anhydrous Na ₂ SO ₄ was dried, the solvent was removed, and the concentrated solution was subjected to column separation (ethyl acetate/petroleum ether (v/v)=4/1) to obtain 130 mg of white solid, yield: 42%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.40–8.43 (m, 1H), 7.60–7.65 (m, 2H), 7.47–7.53 (m, 1H), 7.26 (d, J=8.3Hz, 1H), 6.87–6.95(m,2H),6.72(t,J _FH ＝75.1Hz,1H),5.81(d,J＝6.8Hz,1H),5.27–5.35(m,1H),4.17–4.25(m,1H ),4.04(d,J＝6.9Hz,2H),1.90–2.06(m,2H),1.56–1.72(m,6H),1.44–1.53(m,3H),1.40–1.44(m,9H), 1.31–1.37(m,1H),0.69–0.74(m,2H),0.43–0.47(m,2H);

MS-ESI: m/z 727.20 [M+Na] ⁺ .

Step 2: Compound 5-((S)-1-aminoethyl)-N-(2-(cyclopentylamino)-1-(2,4-difluorophenyl)-2-oxoethyl) -Synthesis of 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride

To compound ((1S)-1-(4-((2-(cyclopentylamino)-1-(2,4-difluorophenyl)-2-oxoethyl)carbamoyl)-2- (3-(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (130mg, 0.18mmol) in dichloromethane ( 2 mL) solution of ethyl acetate of HCl (4M, 4 mL) was added, stirred at room temperature for 30 min, and the solvent was removed to obtain 115 mg of white solid, yield: 97%.

Compound 184: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.78(s, 1H), 7.71–7.73(m, 1H), 7.54–7.58(m, 1H), 7.34(d, J=8.3Hz, 1H ),7.04–7.07(m,2H),6.92(t,J _FH ＝74.8Hz,1H),5.90(d,J＝4.6Hz,1H),5.15–5.20(m,1H),4.15–4.20(m ,1H),4.04(d,J=6.9Hz,2H),1.90–2.06(m,2H),1.75(d,J=7.0Hz,3H),1.51–1.74(m,5H),1.39–1.44( m,1H),1.37–1.43(m,1H),0.68–0.71(m,2H),0.42–0.45(m,2H);

MS-ESI: m/z 605.20 [M+H-HCl] ⁺ .

Example 74: Compound 5-((S)-1-aminoethyl)-N-(2-(2-cyclopropylacetamido)-1-(2,4-difluorobenzene Base) ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride, 5-((S)- 1- Aminoethyl)-N-((S)-2-(2-cyclopropylacetamido)-1-(2,4-difluorophenyl)ethyl)-2-(3-(cyclopropylmethyl oxygen Base)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride and 5-((S)-1-aminoethyl)-N-((R)-2-( 2-Cyclopropane Acetylamino)-1-(2,4-difluorophenyl)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxa Synthesis of azole-4-carboxamide hydrochloride

Step 1: Compound ((1S)-1-(4-((2-(2-cyclopropylacetamido)-1-(2,4-difluorophenyl)ethyl)carbamoyl)-2- Synthesis of tert-butyl (3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate

The compound ((1S)-1-(4-((2-amino-1-(2,4-difluorophenyl)ethyl)carbamoyl)-2-(3-(cyclopropylmethoxy )-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (0.30g, 0.48mmol), cyclopropaneacetic acid (58mg, 0.58mmol), 1-ethyl Base-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (140mg, 0.72mmol) and N-hydroxy-7-azabenzotriazole (100mg, 0.72mmol) were dissolved in dichloro In methane (15mL), N,N-diisopropylethylamine (0.34mL, 1.93mmol) was added dropwise to the solution at 0°C, stirred at room temperature for 15h, the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ Ethyl acetate (v/v)=3/1), to obtain 168 mg of white solid, yield: 49%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.65–7.63 (m, 2H), 7.42–7.38 (m, 1H), 7.26 (d, J=8.8Hz, 1H), 6.93–6.87 (m, 2H), 6.73(t,J _FH ＝75.0Hz,1H),6.36–6.34(m,1H),5.53–5.50(m,1H),5.32–5.28(m,1H),4.03(d,J＝7.0Hz,2H ),3.85–3.81(m,1H),3.76–3.71(m,1H),2.18–2.14(m,2H),1.55–1.48(m,3H),1.45–1.41(m,9H),1.37–1.34 (m,1H),1.33–1.30(m,1H),0.92–0.88(m,2H),0.74–0.69(m,2H),0.57–0.55(m,2H),0.46–0.42(m,2H) ;

MS-ESI: m/z 705.2 [M+H] ⁺ .

Step 2: Compound 5-((S)-1-aminoethyl)-N-(2-(2-cyclopropylacetamido)-1-(2,4-difluorophenyl)ethyl)-2 -(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride, 5-((S)-1-aminoethyl)- N-((S)-2-(2-cyclopropylacetamido)-1-(2,4-difluorophenyl)ethyl)-2-(3-(cyclopropylmethoxy)-4 -(Difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride and 5-((S)-1-aminoethyl)-N-((R)-2-(2-cyclopropane Acetylamino)-1-(2,4-difluorophenyl)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole- Synthesis of 4-Formamide Hydrochloride

To the compound ((1S)-1-(4-((2-(2-cyclopropylacetamido)-1-(2,4-difluorophenyl)ethyl)carbamoyl)-2-(3 -(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate (0.16g, 0.23mmol) in dichloromethane (4mL ) solution was added HCl ethyl acetate solution (4M, 2mL), stirred at room temperature for 0.5h, and the solvent was removed to obtain 5-((S)-1-aminoethyl)-N-(2-(2-cyclopropyl Acetylamino)-1-(2,4-difluorophenyl)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4 - Formamide hydrochloride: white solid 170 mg, yield: 99%.

Compound 5-((S)-1-aminoethyl)-N-(2-(2-cyclopropylacetamido)-1-(2,4-difluorophenyl)ethyl)-2-( 3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride was resolved by chiral preparative chromatography to obtain compound 5-((S )-1-aminoethyl)-N-((S)-2-(2-cyclopropylacetamido)-1-(2,4-difluorophenyl)ethyl)-2-(3-( Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride (pale yellow solid) and 5-((S)-1-aminoethyl)- N-((R)-2-(2-cyclopropylacetamido)-1-(2,4-difluorophenyl)ethyl)-2-(3-(cyclopropylmethoxy)-4 -(Difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride (white solid).

Compound 187: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.79(s, 1H), 7.71(d, J=8.4Hz, 1H), 7.46–7.40(m, 1H), 7.29(d, J=8.3 Hz,1H),6.98–6.91(m,2H),6.87(t,J _FH ＝74.7Hz,1H),5.49–5.46(m,1H),5.06–5.01(m,1H),4.02(d,J =6.9Hz,2H),3.72–3.62(m,2H),2.04(d,J=7.1Hz,2H),1.68(d,J=6.9Hz,3H),1.35–1.30(m,1H),1.30 –1.26(m,1H),0.67–0.62(m,2H),0.45–0.37(m,4H),0.10–0.06(m,2H);

MS-ESI: m/z 605.2[M+H-HCl] ⁺ ;

Compound 188: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.79(s, 1H), 7.71(d, J=8.4Hz, 1H), 7.46–7.40(m, 1H), 7.29(d, J=8.3 Hz,1H),6.98–6.91(m,2H),6.87(t,J _FH ＝74.7Hz,1H),5.49–5.46(m,1H),5.06–5.01(m,1H),4.02(d,J =6.9Hz,2H),3.72–3.62(m,2H),2.04(d,J=7.1Hz,2H),1.68(d,J=6.9Hz,3H),1.35–1.30(m,1H),1.30 –1.26(m,1H),0.67–0.62(m,2H),0.45–0.37(m,4H),0.10–0.06(m,2H);

MS-ESI: m/z 605.2 [M+H-HCl] ⁺ .

Example 75: Compound (2S)-2-(2-(5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(di Synthesis of isopropyl hydrochloride of fluoromethoxy)phenyl)oxazole-4-carboxamide)-2-(2,4-difluorophenyl)acetamido)propionate

Step 1: Synthesis of compound L-alanine isopropyl ester hydrochloride

Boc-L-alanine (1g, 5.29mmol), isopropanol (0.49mL, 6.34mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride ( 1.52g, 7.93mmol) and N-hydroxy-7-azabenzotriazole (1.08g, 7.93mmol) were dissolved in dichloromethane (20mL), and N was added dropwise to this solution at 0°C, N-Diisopropylethylamine (3.7mL, 21.14mmol), stirred at room temperature for 16h, washed with water (10mL×3), dried the organic phase with anhydrous Na ₂ SO ₄ , removed the solvent, and the concentrated solution was subjected to column separation (petroleum ether /ethyl acetate (v/v)=10/1), to obtain 630 mg of colorless liquid N-Boc-L-alanine isopropyl ester, yield: 51%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 5.05–5.01 (m, 1H), 4.24–4.21 (m, 1H), 1.44 (s, 9H), 1.34 (d, J=7.2Hz, 3H), 1.23 ( t,J=6.6Hz,6H);

MS-ESI: m/z 254.1 [M+23].

To compound N-Boc-L-alanine isopropyl ester (0.25g, 1.08mmol) in dichloromethane (3mL) solution was added HCl in ethyl acetate solution (4M, 8mL), stirred at room temperature for 5h, the solvent was removed, 181 mg of a colorless oil was obtained, yield: 99%.

¹ H NMR (400MHz, CD ₃ OD): δppm 5.06–5.00 (m, 1H), 4.00–3.94 (m, 1H), 1.45 (d, J=7.2Hz, 3H), 1.24–1.22 (m, 6H) ;

MS-ESI: m/z 132.2 [M+H-HCl] ⁺ .

Step 2: Compound (2S)-2-(2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)- Synthesis of isopropyl 4-(difluoromethoxy)phenyl)oxazole-4-carboxamide)-2-(2,4-difluorophenyl)acetamido)propionate

Compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid (0.23g, 0.36mmol), L-alanine isopropyl ester hydrochloride (72mg, 0.43mmol ), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (104mg, 0.54mmol) and N-hydroxy-7-azabenzotriazole (74mg, 0.54mmol ) was dissolved in dichloromethane (15mL), and N,N-diisopropylethylamine (0.25mL, 1.44mmol) was added dropwise to the solution at 0°C, stirred at room temperature for 12h, the solvent was removed, and the concentrated solution was subjected to column After separation (petroleum ether/ethyl acetate (v/v)=3/1), 118 mg of light yellow solid was obtained, yield: 43%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.65–7.62 (m, 1H), 7.61–7.60 (m, 1H), 7.52–7.48 (m, 1H), 7.26 (d, J=8.2Hz, 1H), 6.95–6.90(m,2H),6.73(t,J _FH ＝74.5Hz,1H),6.53–6.52(m,1H),5.92(d,J＝7.2Hz,1H),5.33–5.29(m,1H ),5.09–4.99(m,1H),4.57–4.49(m,1H),4.03(d,J＝6.9Hz,2H),1.53–1.50(m,3H),1.42–1.36(m,9H), 1.28(t,J=7.1Hz,6H),1.24–1.20(m,3H),0.74–0.69(m,2H),0.47–0.43(m,2H);

MS-ESI: m/z 751.2 [M+H] ⁺ .

Step 3: Compound (2S)-2-(2-(5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Synthesis of )phenyl)oxazole-4-carboxamide)-2-(2,4-difluorophenyl)acetamido)isopropyl propionate hydrochloride

To compound (2S)-2-(2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4- (Difluoromethoxy)phenyl)oxazole-4-carboxamide)-2-(2,4-difluorophenyl)acetamido)isopropyl propionate (0.11g, 0.15mmol) in dichloromethane (3 mL) was added HCl in ethyl acetate solution (4M, 4 mL), stirred at room temperature for 3 h, and the solvent was removed to obtain 100 mg of light yellow solid, yield: 97%.

Example 76: Compound 5-((S)-1-aminoethyl)-N-(2-(4-(cyclopropylcarbonyl)piperazin-1-yl)-1-(2, 4-Difluorophenyl)-2-oxoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide Synthesis of hydrochloride

Step 1: Compound ((1S)-1-(4-((2-(4-(cyclopropylcarbonyl)piperazin-1-yl)-1-(2,4-difluorophenyl)-2- Oxoethyl)carbamoyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate tert-butyl Synthesis of esters

Compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid (210mg, 0.33mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbon Diimine hydrochloride (126mg, 0.66mmol) and N-hydroxy-7-azabenzotriazole (67mg, 0.49mmol) were dissolved in dichloromethane (15mL), and added to the solution at 0°C Add cyclopropyl(piperazin-1-yl)methanone hydrochloride (94mg, 0.49mmol) and N,N-diisopropylethylamine (0.23mL, 0.99mmol) dropwise, stir at room temperature for 12h, and wash with water (10mL×3), the organic phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (ethyl acetate/petroleum ether (v/v)=2/1) to obtain 160 mg of white solid, yield : 63%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.51(d, J=6.6Hz, 1H), 7.60–7.64(m, 2H), 7.52–7.57(m, 1H), 7.26(d, J=8.3Hz, 1H),6.88–6.95(m,2H),6.73(t,J _FH ＝75.1Hz,1H),6.32(d,J＝7.3Hz,1H),5.27–5.34(m,1H),4.02(d, J＝6.9Hz,2H),3.35–3.82(m,8H),1.67–1.74(m,1H),1.48–1.53(m,3H),1.40–1.45(m,9H),1.32–1.36(m, 1H),0.86–0.93(m,2H),0.78–0.83(m,2H),0.69–0.73(m,2H),0.42–0.47(m,2H);

MS-ESI: m/z 796.20 [M+Na] ⁺ .

Step 2: Compound 5-((S)-1-aminoethyl)-N-(2-(4-(cyclopropylcarbonyl)piperazin-1-yl)-1-(2,4-difluorobenzene Synthesis of yl)-2-oxoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride

To the compound ((1S)-1-(4-((2-(4-(cyclopropylcarbonyl)piperazin-1-yl)-1-(2,4-difluorophenyl)-2-oxo Ethyl)carbamoyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester ( 85 mg, 0.11 mmol) in dichloromethane (2 mL) was added HCl in ethyl acetate (4M, 2 mL), stirred at room temperature for 30 min, and the solvent was removed to obtain 75 mg of white solid, yield: 96%.

Compound 199: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.77-7.79(m, 1H), 7.71-7.74(m, 1H), 7.61-7.55(m, 1H), 7.33(d, J=8.3Hz ,1H),7.08–7.14(m,2H),6.92(t,J _FH ＝75.1Hz,1H),6.31(s,1H),5.14–5.21(m,1H),4.04(d,J＝6.8Hz ,2H),3.18–3.87(m,8H),1.89–2.00(m,1H),1.76(d,J＝6.8Hz,3H),1.34–1.39(m,1H),0.81–0.91(m,4H ),0.67–0.71(m,2H),0.42–0.46(m,2H);

MS-ESI: m/z 674.20 [M+H-HCl] ⁺ .

Example 77: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-(1-(2,4-difluorophenyl)-2-hydrazino-2-oxoethyl)oxazole-4-carboxamide dihydrochloride

Step 1: Compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4- Synthesis of tert-butyl difluorophenyl)-2-hydrazino-2-oxoethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

To compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Add hydrazine hydrate (80%, 1mL) to a solution of methyl phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetate (250mg, 0.38mmol) in methanol (20mL) , reacted at 60°C for 2.5h, and obtained 240 mg of white solid after removing the solvent, yield: 96%.

¹ H NMR (600MHz, CDCl ₃ ): δppm 7.63–7.61(m,1H),7.60(s,1H),7.53–7.48(m,1H),7.26(d,J＝8.3Hz,1H),6.95– 6.88(m,2H),6.74(t,J _FH ＝75.0Hz,1H),5.92(d,J＝7.6Hz,1H),5.35–5.30(m,1H),4.02–4.01(m,2H), 1.54–1.47(m,3H),1.46–1.41(m,9H),1.37–1.34(m,1H),0.73–0.70(m,2H),0.46–0.40(m,2H);

MS-ESI: m/z 552.2 [M+H-100] ⁺ .

Step 2: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1- Synthesis of (2,4-difluorophenyl)-2-hydrazino-2-oxoethyl)oxazole-4-carboxamide dihydrochloride

To compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4-difluoro A solution of tert-butyl phenyl)-2-hydrazino-2-oxoethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate (0.24 g, 0.37 mmol) in dichloromethane (4 mL) Add HCl in isopropanol solution (7M, 4mL), stir at room temperature for 1.5h, and remove the solvent to obtain 220mg of light yellow solid, yield: 95%.

Compound 202: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.80-7.79(m, 1H), 7.75-7.72(m, 1H), 7.68-7.63(m, 1H), 7.33(d, J=8.4Hz ,1H),7.14–7.07(m,2H),6.92(t,J _FH ＝74.7Hz,1H),6.09–6.08(m,1H),5.24–5.19(m,1H),4.04(d,J＝ 6.9Hz,2H),1.79–1.76(m,3H),1.38–1.33(m,1H),0.71–0.66(m,2H),0.45–0.41(m,2H);

MS-ESI: m/z 552.2 [M+H-2HCl] ⁺ .

Example 78: Compound (S)-2-(5-(5-(5-((S)-1-aminoethyl)-4-((2,4-difluorobenzyl)aminomethyl Synthesis of isopropyl (acyl)oxazol-2-yl)-2-(difluoromethoxy)phenoxy)pentanamide)propionate hydrochloride

Step 1: Synthesis of the compound 3-(benzyloxy)-4-(difluoromethoxy)methyl benzoate

Methyl 3-hydroxy-4-(difluoromethoxy)benzoate (5.0 g, 22.94 mmol), potassium carbonate (6.33 g, 45.88 mmol) and benzyl bromide (3.3 mL, 27.53 mmol) were dissolved in N, N-dimethylformamide (60mL), reacted at 60°C for 4.5h, added water (40mL), extracted with ethyl acetate (50mL×3), combined the organic phases and dried them with anhydrous Na ₂ SO ₄ to remove The solvent and the concentrate were subjected to column separation (petroleum ether/ethyl acetate (v/v)=5/1) to obtain 6.99 g of white solid, yield: 99%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.75(s, 1H), 7.68(d, J=8.2Hz, 1H), 7.48-7.38(m, 5H), 7.24(d, J=8.3Hz, 1H) ,6.67(t,J _FH ＝74.6Hz,1H),5.20(s,2H),3.93(s,3H);

MS-ESI: 309.0 [M+H] ⁺ .

Step 2: Synthesis of compound 3-(benzyloxy)-4-(difluoromethoxy)benzoic acid

The compound 3-(benzyloxy)-4-(difluoromethoxy)methyl benzoate (6.99g, 22.69mmol) and sodium hydroxide (2.27g, 56.74mmol) were dissolved in ethanol (60mL) and water ( 30 mL) in a mixed solvent, react at 60°C for 1.5 h, remove ethanol, adjust the pH to 1 with hydrochloric acid (1M), extract with ethyl acetate (50 mL×3), combine the organic phases and dry with anhydrous Na ₂ SO ₄ , and the solvent was removed to obtain 6.70 g of white solid, yield: 99%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.80(s, 1H), 7.68(d, J=8.4Hz, 1H), 7.49(d, J=7.0Hz, 2H), 7.43-7.35(m, 3H) ,7.26(d,J=8.4Hz,1H),6.88(t,JFH= _74.5Hz ,1H),5.23(s,2H);

MS-ESI: 293.1[MH] ^- .

Step 3: Synthesis of the compound 2-(3-(benzyloxy)-4-(difluoromethoxy)benzamido)acetic acid methyl ester

Compound 3-(benzyloxy)-4-(difluoromethoxy)benzoic acid (6.70g, 22.79mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide salt Salt (6.60g, 34.19mmol) and 1-hydroxybenzotriazole (4.62g, 34.19mmol) were dissolved in dichloromethane (60mL), stirred at room temperature for 0.5h, added glycine methyl ester hydrochloride ( 3.44g, 27.35mmol) and N,N-diisopropylethylamine (12.25mL, 68.37mmol), stirred at room temperature for 12h, washed with water (40mL×3), dried the organic phase with Na ₂ SO ₄ , removed the solvent and concentrated The liquid was subjected to column separation (petroleum ether/ethyl acetate (v/v)=1/1) to obtain 7.95 g of white solid, yield: 96%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.62(s, 1H), 7.47-7.33(m, 6H), 7.24(d, J=8.3Hz, 1H), 6.67(br.s, 1H), 6.65( t, J _FH ＝74.5Hz, 1H), 5.20(s, 2H), 4.25(d, J＝5.0Hz, 2H), 3.83(s, 3H);

MS-ESI: m/z 366.2 [M+H] ⁺ .

Step 4: Synthesis of the compound 2-(3-(benzyloxy)-4-(difluoromethoxy)phenylthioamide)acetic acid methyl ester

The compound 2-(3-(benzyloxy)-4-(difluoromethoxy)benzamido)methyl acetate (7.95g, 21.80mmol) and Lawson's reagent (8.80g, 21.80mmol) were dissolved in In tetrahydrofuran (60mL), reflux and stir at 75°C for 2h, add saturated sodium bicarbonate solution (40mL), extract with ethyl acetate (50mL×3), combine the organic phases and dry with Na ₂ SO ₄ , remove the solvent, and concentrate Column separation (petroleum ether/ethyl acetate (v/v)=3/1) was carried out to obtain 8.33 g of yellow solid, yield: 99%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.08 (br.s, 1H), 7.69 (s, 1H), 7.50-7.28 (m, 6H), 7.21 (d, J=8.3Hz, 1H), 6.64 ( t, J _FH ＝74.7Hz, 1H), 5.21(s, 2H), 4.57(d, J＝4.5Hz, 2H), 3.88(s, 3H);

MS-ESI: m/z 380.0 [MH] ^- .

Step 5: Synthesis of the compound 2-(((3-(benzyloxy)-4-(difluoromethoxy)phenyl)(methylthio)methylene)amino)acetate methyl ester

At -78°C, the compound 2-(3-(benzyloxy)-4-(difluoromethoxy)phenylthioamide) acetate (8.33g, 21.87mmol) in dichloromethane (30mL ) solution was slowly added dropwise to a solution of trimethyloxonium tetrafluoroboric acid (6.47g, 43.74mmol) in dichloromethane (20mL), and after stirring for 3h at 0°C, saturated sodium bicarbonate solution was added to wash (25mL×3 ), the organic phase was dried with anhydrous Na ₂ SO ₄ , and the solvent was removed to obtain 8.55 g of yellow oil, yield: 99%.

MS-ESI: m/z 396.2 [M+H] ⁺ .

Step 6: Compound (S)-2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-5-(1-((tert-butoxycarbonyl)amino)ethyl)oxa Synthesis of Methyl Azole-4-carboxylate

The compound 2-(((3-(benzyloxy)-4-(difluoromethoxy)phenyl)(methylthio)methylene)amino)acetic acid methyl ester (3.45g, 8.74mmol), compound (S)-(1-Fluoro-1-oxopropan-2-yl) tert-butyl carbamate (4.45g, 23.30mmol) was dissolved in anhydrous tetrahydrofuran (30mL), and at -78°C, six Potassium methyldisilazide tetrahydrofuran solution (30.00mL, 30.00mmol), react at -78°C for 1h, add ice water (20mL) to quench the reaction, extract with ethyl acetate (15mL×3), combine organic The phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v)=4/1) to obtain 3.78 g of a yellow solid, yield: 83%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.80(s, 1H), 7.68(d, J=8.4Hz, 1H), 7.50-7.36(m, 5H), 7.29(d, J=8.3Hz, 1H) ,6.66(t,J _FH ＝74.7Hz,1H),5.68(br.s,1H),5.53-5.45(m,1H),5.23(s,2H),4.01(s,3H),1.57(d, J=7.0Hz, 3H), 1.45(s, 9H).

Step 7: Compound (S)-2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-5-(1-((tert-butoxycarbonyl)amino)ethyl)oxa Synthesis of azole-4-carboxylic acid

Compound (S)-2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-5-(1-((tert-butoxycarbonyl)amino)ethyl)oxazole- Methyl 4-carboxylate (0.55g, 1.06mmol) and lithium hydroxide monohydrate (0.22g, 5.30mmol) were dissolved in a mixed solvent of tetrahydrofuran (20mL) and water (10mL), and reacted at 40°C for 3h to remove tetrahydrofuran , adding hydrochloric acid (1M) to adjust the pH value to 1, adding ethyl acetate to extract (30mL×3), the organic phases were combined and dried with Na ₂ SO ₄ , and the solvent was removed to obtain 0.53 mg of white solid, yield: 99%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.80 (s, 1H), 7.68 (d, J = 8.4Hz, 1H), 7.51–7.35 (m, 5H), 7.29 (d, J = 8.4Hz, 1H) ,6.66(t,J _FH ＝74.7Hz,1H),5.68(br.s,1H),5.53–5.46(m,1H),5.23(s,2H),1.57(d,J＝7.0Hz,3H) ,1.45(s,9H);

MS-ESI: m/z 449.2 [M-55].

Step 8: Compound (S)-(1-(2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-4-((2,4-difluorobenzyl)amino Synthesis of tert-butyl formyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-5-(1-((tert-butoxycarbonyl)amino)ethyl)oxazole- 4-Formic acid (0.53g, 1.05mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.31g, 1.60mmol) and N-hydroxyl-7-aza Benzotriazole (0.22g, 1.60mmol) was dissolved in dichloromethane (15mL), stirred at room temperature for 0.5h, 2,4-difluorobenzylamine (0.15mL, 1.26mmol) and N, N-Diisopropylethylamine (0.58mL, 3.20mmol), stirred at room temperature for 12h, added water (15mL), extracted with dichloromethane (20mL×3), combined the organic phases and dried with Na ₂ SO ₄ to remove the solvent , the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=5/1) to obtain 211.0 mg of white solid, yield: 38%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.69(s, 1H), 7.63(d, J=8.4Hz, 1H), 7.56(br.s, 1H), 7.50-7.36(m, 6H), 7.28( d,J=8.3Hz,1H),6.92-6.85(m,2H),6.56(t,J _FH =74.6Hz,1H),5.32(br.s,1H),5.24(s,2H),4.73- 4.63(m,2H),1.56(d,J=7.0Hz,3H),1.45(s,9H);

MS-ESI: m/z 574.1 [M-55] ⁺ .

Step 9: Compound (S)-(1-(4-((2,4-difluorobenzyl)carbamoyl)-2-(4-(difluoromethoxy)-3-hydroxyphenyl)oxa Synthesis of tert-butyl (azol-5-yl)ethyl)carbamate

Compound (S)-(1-(2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-4-((2,4-difluorobenzyl)carbamoyl ) oxazol-5-yl) ethyl) tert-butyl carbamate (2.53g, 4.02mmol) and nickel chloride (782mg, 6.03mmol) were dissolved in ethanol (20mL), sodium borohydride (688mg, 18.09mmol) was added ) in ethanol (20mL), stirred at room temperature for 3h, adjusted the pH to 1 with hydrochloric acid (1M), then adjusted the pH to 14 with sodium hydroxide, filtered, removed the ethanol, extracted with ethyl acetate (20mL×3), combined The organic phase was dried with Na ₂ SO ₄ , the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v)=3/1) to obtain 1.719 g of white solid, yield: 80%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.60-7.57(m, 2H), 7.45-7.38(m, 2H), 7.16(d, J=8.3Hz, 1H), 6.88-6.84(m, 2H), 6.65(t, J _FH ＝73.6Hz, 1H), 5.31(s, 1H), 4.69-4.59(m, 2H), 1.53(d, J＝7.0Hz, 3H), 1.44(s, 9H);

MS-ESI: 540.3 [M+H] ⁺ .

Step 10: Compound (S)-5-(5-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-4-((2,4-difluorobenzyl)carbamoyl)oxa Synthesis of Methyl Azol-2-yl)-2-(Difluoromethoxy)phenoxy)valerate

To compound (S)-(1-(4-((2,4-difluorobenzyl)carbamoyl)-2-(4-(difluoromethoxy)-3-hydroxyphenyl)oxazole- Potassium carbonate (290mg, 2.07mmol) was added to a DMF (10mL) solution of 5-yl) ethyl) tert-butyl carbamate (560mg, 1.04mmol) and methyl 5-bromovalerate (304mg, 1.56mmol), 60 The reaction was sealed at ℃ for 5 h, after the solvent was removed, water (10 mL) was added, extracted with ethyl acetate (15 mL), the organic phase was dried with anhydrous Na ₂ SO ₄ , and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/ v)=4/1), 448 mg of colorless oil was obtained, yield: 66%.

Step 11: Compound (S)-5-(5-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-4-((2,4-difluorobenzyl)carbamoyl)oxa Synthesis of azole-2-yl)-2-(difluoromethoxy)phenoxy)valeric acid

To compound (S)-5-(5-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazole- Add lithium hydroxide monohydrate (80mg , 1.91mmol), reacted at 40°C for 2h, added hydrochloric acid solution (1M) to adjust the pH to about 1, added ethyl acetate for extraction (15mL×3), dried the organic phase with anhydrous Na ₂ SO ₄ , concentrated to obtain 240 mg Color oil, yield: 98%.

Step 12: Compound (S)-2-(5-(5-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-4-((2,4-difluorobenzyl Synthesis of isopropyl)carbamoyl)oxazol-2-yl)-2-(difluoromethoxy)phenoxy)pentanamide)propionate

Compound (S)-5-(5-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazole- 2-yl)-2-(difluoromethoxy)phenoxy)valeric acid (0.25g, 0.39mmol), compound L-alanine isopropyl ester hydrochloride (80mg, 0.47mmol), 1-ethyl Base-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (112mg, 0.59mmol) and N-hydroxy-7-azabenzotriazole (80mg, 0.59mmol) were dissolved in dichloro In methane (15mL), N,N-diisopropylethylamine (0.27mL, 1.56mmol) was added dropwise to the solution at 0°C, stirred at room temperature for 4h, washed with water (10mL×3), and the organic phase was washed with The water was dried over Na ₂ SO ₄ , the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v)=1/1) to obtain 235 mg of a colorless oil, yield: 80%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.60–7.58(m, 2H), 7.47-7.41(m, 1H), 7.24(d, J=8.0Hz, 1H), 6.91–6.84(m, 2H), 6.65(t,J _FH ＝74.5Hz,1H),6.14–6.12(m,1H),5.09–5.03(m,1H),4.69–4.67(m,2H),4.58–4.54(m,1H),4.17 –4.13(m,2H),2.36(t,J=6.9Hz,2H),1.95–1.89(m,4H),1.56(d,J=7.0Hz,3H),1.45(s,9H),1.40( d, J=7.2Hz, 3H), 1.27(t, J=5.8Hz, 6H);

MS-ESI: m/z 753.2 [M+H] ⁺ .

Step 13: Compound (S)-2-(5-(5-(5-((S)-1-aminoethyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazole Synthesis of -2-yl)-2-(difluoromethoxy)phenoxy)pentanamide)propionate isopropyl hydrochloride

To compound (S)-2-(5-(5-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-4-((2,4-difluorobenzyl) To a solution of isopropyl carbamoyl)oxazol-2-yl)-2-(difluoromethoxy)phenoxy)pentanamide)propionate (0.22g, 0.29mmol) in dichloromethane (3mL) was added HCl in isopropanol solution (4M, 3mL), stirred at room temperature for 40min, and the solvent was removed to obtain 192mg of white solid, yield: 94%.

Compound 198: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.82(s, 1H), 7.73(d, J=8.4Hz, 1H), 7.52-7.46(m, 1H), 7.33(d, J=8.3 Hz,1H),7.01–6.94(m,2H),6.89(t,J _FH ＝74.5Hz,1H),5.21–5.15(m,1H),5.01–4.95(m,1H),4.65(s,2H ),4.36–4.30(m,1H),4.20(t,J＝6.0Hz,2H),2.38–2.34(m,2H),1.94–1.83(m,4H),1.78(d,J＝7.0Hz, 3H), 1.37(d, J=7.3Hz, 3H), 1.24(t, J=6.6Hz, 6H);

MS-ESI: m/z 653.3 [M+H-HCl] ⁺ .

Example 79: Compound 2-(5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of ethyl phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetate hydrochloride

Step 1: Compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Synthesis of ethyl)phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetate

Compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid (0.25g, 0.39mmol) and N,N'-carbonyldiimidazole (197mg, 1.17mmol) were added without In water tetrahydrofuran (20mL), react at 60°C for 0.5h, cool to room temperature, add absolute ethanol (22mg, 0.47mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene ( 0.09mL, 0.59mmol), react at 60°C for 8h, add saturated ammonium chloride solution (15mL), extract with ethyl acetate (10mL×3), add the organic phase and dry it with Na ₂ SO ₄ , remove the solvent, and the concentrated solution is subjected to column separation (petroleum ether/ethyl acetate (v/v)=4/1), 200 mg of white solid was obtained, yield: 76%.

¹ H NMR (600MHz, CDCl ₃ ): δppm 7.63(d, J=8.3Hz, 1H), 7.59(s, 1H), 7.51–7.48(m, 1H), 7.26(d, J=8.3Hz, 1H) ,6.94–6.88(m,2H),6.73(t,J _FH ＝75.0Hz,1H),5.98–5.96(m,1H),5.32–5.30(m,1H),5.20–5.18(m,1H), 4.56–4.54(m,1H),4.32–4.25(m,2H),4.02(d,J＝6.7Hz,2H),1.56–1.49(m,3H),1.46(s,9H),1.38–1.35( m,1H),1.28–1.27(m,3H),0.73–0.70(m,2H),0.46–0.45(m,2H);

MS-ESI: m/z 566.2 [M+H-100] ⁺ .

Step 2: Compound 2-(5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole- Synthesis of ethyl 4-formamido)-2-(2,4-difluorophenyl)acetate hydrochloride

To compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) A solution of ethyl phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetate (0.2 g, 0.30 mmol) in dichloromethane (4 mL) was added with HCl in isopropanol The solution (7M, 2 mL) was stirred at room temperature for 40 min, and the solvent was removed to obtain 180 mg of white solid, yield: 99%.

Compound 207: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.80(s, 1H), 7.74(d, J=8.3Hz, 1H), 7.60–7.56(m, 1H), 7.33(d, J=8.3 Hz,1H),7.09–7.03(m,2H),6.92(t,J _FH ＝74.7Hz,1H),6.01(s,1H),5.20–5.18(m,1H),4.63–4.62(m,1H ), 4.28(q, J=7.1Hz, 2H), 4.05(d, J=6.9Hz, 2H), 1.76(d, J=6.7Hz, 3H), 1.62(d, J=7.2Hz, 3H), 1.36–1.34(m,1H),1.25(t,J＝7.2Hz,3H),0.70–0.67(m,2H),0.45–0.43(m,2H);

MS-ESI: m/z 566.2 [M+H-HCl] ⁺ .

Example 80: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Base)-N-((S)-1-(2,4-difluorophenyl)-2-hydrazino-2-oxoethyl)oxazole-4-carboxamide dihydrochloride and 5-( (S)- 1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((R)-1-(2,4-difluoro Phenyl)-2- Synthesis of hydrazino-2-oxoethyl)oxazole-4-carboxamide dihydrochloride

Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-( 1-(2,4-difluorophenyl)-2-hydrazino-2-oxoethyl)oxazole-4-carboxamide dihydrochloride was resolved by chiral preparative chromatography to obtain compound 5- ((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((S)-1-(2 ,4-difluorophenyl)-2-hydrazino-2-oxoethyl)oxazole-4-carboxamide dihydrochloride (white solid) and 5-((S)-1-aminoethyl) -2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((R)-1-(2,4-difluorophenyl)-2- Hydrazino-2-oxoethyl)oxazole-4-carboxamide dihydrochloride (pale yellow solid).

Compound 208: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.79(s, 1H), 7.73(d, J=8.3Hz, 1H), 7.66–7.62(m, 1H), 7.34(d, J=8.3 Hz,1H),7.13–7.08(m,2H),6.92(t,J _FH ＝74.7Hz,1H),6.08(s,1H),5.25–5.23(m,1H),4.03(d,J＝6.9 Hz,2H),1.76(d,J=7.0Hz,3H),1.36–1.33(m,1H),0.71–0.68(m,2H),0.44–0.42(m,2H);

MS-ESI: m/z 552.2[M+H-2HCl] ⁺ ;

Compound 209: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.79(s, 1H), 7.73(d, J=8.3Hz, 1H), 7.67–7.63(m, 1H), 7.33(d, J=8.3 Hz,1H),7.13–7.08(m,2H),6.92(t,J _FH ＝74.7Hz,1H),6.07(s,1H),5.21–5.17(m,1H),4.03(d,J＝6.9 Hz,2H),1.76(d,J=6.8Hz,3H),1.35–1.31(m,1H),0.70–0.67(m,2H),0.44–0.42(m,2H);

MS-ESI: m/z 552.2 [M+H-2HCl] ⁺ .

Example 81: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-(1-(2,4-difluorophenyl)-2-(methoxyamino)-2-oxoethyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4- Synthesis of tert-butyl difluorophenyl)-2-(methoxyamino)-2-oxoethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

Compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid (0.25g, 0.39mmol), methoxyamine hydrochloride (40mg, 0.47mmol), 1- Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (112mg, 0.59mmol) and N-hydroxy-7-azabenzotriazole (80mg, 0.59mmol) were dissolved in di In methyl chloride (15mL), N,N-diisopropylethylamine (0.27mL, 1.57mmol) was added dropwise to the solution at 0°C, stirred at room temperature for 15h, the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether /ethyl acetate (v/v)=2/1) to obtain 130 mg of colorless oil, yield: 49%.

¹ H NMR (600MHz, CDCl ₃ ): δppm 7.63–7.60 (m, 2H), 7.56–7.55 (m, 1H), 7.26 (d, J=8.2Hz, 1H), 6.96–6.88 (m, 2H), 6.74(t, J _FH ＝75.0Hz, 1H), 5.87–5.84(m, 1H), 5.36–5.31(m, 1H), 4.02(d, J＝6.8Hz, 2H), 3.81(s, 3H), 1.54–1.49(m,3H),1.45–1.41(m,9H),1.36–1.33(m,1H),0.73–0.70(m,2H),0.45–0.44(m,2H);

MS-ESI: m/z 567.1 [M+H-100] ⁺ .

Step 2: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1- Synthesis of (2,4-difluorophenyl)-2-(methoxyamino)-2-oxoethyl)oxazole-4-carboxamide hydrochloride

To compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4-difluoro Dichloromethane ( 3mL) was added in isopropanol solution of HCl (7M, 2mL), stirred at room temperature for 30min, and the solvent was removed to obtain 110mg of a light yellow solid with a yield of 95%, which was sent to the preparation for further purification to obtain 80mg of a white solid.

Compound 211: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.79(s, 1H), 7.73(d, J=8.3Hz, 1H), 7.63–7.61(m, 1H), 7.34(d, J=8.3 Hz,1H),7.07–7.03(m,2H),6.92(t,J _FH ＝74.7Hz,1H),5.87–5.86(m,1H),5.20–5.17(m,1H),4.04(d,J ＝6.8Hz,2H),3.72(s,3H),1.77–1.75(m,3H),1.36–1.31(m,1H),0.70–0.67(m,2H),0.44–0.43(m,2H);

MS-ESI: m/z 567.2 [M+H-HCl] ⁺ .

Example 82: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-(1-(2,4-difluorophenyl)-2-(2-isopropylhydrazine)-2-oxoethyl)oxazole-4-carboxamide dihydrochloride

Step 1: Compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4- Synthesis of tert-butyl difluorophenyl)-2-(2-isopropylhydrazine)-2-oxoethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

Compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid (0.25g, 0.39mmol), isopropylhydrazine hydrochloride (59mg, 0.47mmol), 1- Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (112mg, 0.59mmol) and N-hydroxy-7-azabenzotriazole (80mg, 0.59mmol) were dissolved in di In methyl chloride (15mL), N,N-diisopropylethylamine (0.27mL, 1.57mmol) was added dropwise to the solution at 0°C, stirred at room temperature for 20h, the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether /ethyl acetate (v/v)=2/1) to obtain 148 mg of a colorless oil, yield: 54%.

¹ H NMR (600MHz, CDCl ₃ ): δppm 7.63 (d, J = 8.3Hz, 1H), 7.60 (s, 1H), 7.55–7.51 (m, 1H), 7.26 (d, J = 8.3Hz, 1H) ,6.96–6.90(m,2H),6.74(t,J _FH ＝75.0Hz,1H),5.89(d,J＝7.4Hz,1H),5.34–5.31(m,1H),4.02(d,J＝ 6.7Hz, 2H), 1.53–1.49(m, 3H), 1.45–1.41(m, 9H), 1.35-1.38(m, 1H), 1.04(d,J=5.9Hz,3H), 0.99(d,J =6.2Hz,3H),0.73–0.70(m,2H),0.46–0.43(m,2H);

MS-ESI: m/z 694.2 [M+H] ⁺ .

Step 2: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1- Synthesis of (2,4-difluorophenyl)-2-(2-isopropylhydrazine)-2-oxoethyl)oxazole-4-carboxamide dihydrochloride

To compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4-difluoro Diphenyl)-2-(2-isopropylhydrazine)-2-oxoethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (0.14g, 0.21mmol) HCl in isopropanol (7M, 2mL) was added to the methyl chloride (3mL) solution, stirred at room temperature for 40min, and the solvent was removed to obtain 120mg of a white solid with a yield of 92%, which was sent to the preparation for further purification to obtain 63mg of a white solid.

Compound 212: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.79(s, 1H), 7.74–7.66(m, 2H), 7.33(d, J=8.0Hz, 1H), 7.13–7.10(m, 2H ),6.91(t,J _FH ＝74.7Hz,1H),6.06–6.05(m,1H),5.21–5.18(m,1H),4.03(d,J＝6.6Hz,2H),3.70–3.67(m ,1H),1.78–1.76(m,3H),1.35–1.33(m,1H),1.33–1.30(m,6H),0.69–0.67(m,2H),0.43–0.42(m,2H);

MS-ESI: m/z 594.3 [M+H-2HCl] ⁺ .

Example 83: Compound 5-((S)-1-aminoethyl)-N-(2-(cyclopropanesulfonamide)-1-(2,4-difluorophenyl)-2- Synthesis of oxoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound ((1S)-1-(4-((2-(cyclopropanesulfonamide)-1-(2,4-difluorophenyl)-2-oxoethyl)carbamoyl)- Synthesis of tert-butyl 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate

Compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid (0.3g, 0.47mmol) and N,N'-carbonyldiimidazole (236mg, 1.41mmol) were added without In water tetrahydrofuran (15mL), react at 60°C for 0.5h, cool to room temperature, add cyclopropanesulfonamide (114mg, 0.94mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11mL, 0.71mmol), react at 60°C for 15h, add saturated ammonium chloride solution (15mL), extract with ethyl acetate (10mL×3), add organic phase and dry with Na ₂ SO ₄ , remove the solvent to obtain 340mg Yellow oil, yield: 97%.

¹ H NMR (600MHz, CDCl ₃ ): δppm 7.61–7.58(m,2H),7.53–7.50(m,1H),7.30(d,J=8.3Hz,1H),7.25–7.21(m,2H), 6.80–6.78(m,1H),6.85–6.59(m,1H),5.73–5.72(m,1H),5.37–5.36(m,1H),4.03–3.98(m,2H),2.61–2.58(m ,1H),1.50(d,J＝6.9Hz,3H),1.42–1.39(m,9H),1.33–1.30(m,1H),1.21–1.19(m,2H),1.15–1.13(m,1H ),1.05–1.03(m,2H),0.70–0.66(m,2H),0.46–0.42(m,2H);

MS-ESI: m/z 641.1 [M+H-100] ⁺ .

Step 2: Compound 5-((S)-1-aminoethyl)-N-(2-(cyclopropanesulfonamide)-1-(2,4-difluorophenyl)-2-oxoethyl) -Synthesis of 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride

To compound ((1S)-1-(4-((2-(cyclopropanesulfonamide)-1-(2,4-difluorophenyl)-2-oxoethyl)carbamoyl)-2- (3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (0.34g, 0.46mmol) in dichloromethane (4mL) was added in isopropanol solution of HCl (7M, 3mL), stirred at room temperature for 1.5h, and the solvent was removed to obtain 310mg of oil, yield: 99%, which was sent for preparation and purification to obtain 100mg of white solid.

Compound 214: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.78(s, 1H), 7.72(d, J=8.3Hz, 1H), 7.59–7.55(m, 1H), 7.32(d, J=8.3 Hz,1H),7.12–7.08(m,2H),6.91(t,J _FH ＝74.7Hz,1H),5.97(d,J＝7.0Hz,1H),5.23–5.19(m,1H),4.02( d,J=6.8Hz,2H),3.03–2.99(m,1H),1.77(d,J=6.7Hz,3H),1.35–1.32(m,1H),1.30–1.29(m,2H),1.23 –1.19(m,1H),1.18–1.14(m,2H),0.69–0.66(m,2H),0.42–0.41(m,2H);

MS-ESI: m/z 641.1 [M+H-HCl] ⁺ .

Example 84: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-(1-(2,4-difluorophenyl)-2-ureidoethyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4- Synthesis of tert-butyl difluorophenyl)-2-ureidoethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

The compound ((1S)-1-(4-((2-amino-1-(2,4-difluorophenyl)ethyl)carbamoyl)-2-(3-(cyclopropylmethoxy )-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate (200mg, 0.32mmol) and triethylamine (0.44mL, 3.2mmol) were dissolved in anhydrous In tetrahydrofuran (10mL), trimethylsilyl isocyanate (0.43mL, 3.2mmol) was added dropwise to this solution, stirred at room temperature for 2h, added ice water (5mL), extracted with ethyl acetate (10mL×3), anhydrous sulfuric acid After drying over sodium, the solvent was removed, and the concentrate was subjected to column separation (dichloromethane/methanol (v/v)=40/1) to obtain 90 mg of white solid, yield: 42%.

¹ H NMR (600MHz, CDCl ₃ ): δppm 7.75–7.78(m,1H),7.69–7.71(m,1H),7.50–7.54(m,1H),7.30(d,J＝8.3Hz,1H), 6.98–7.03(m,2H),6.90(t,J _FH ＝75.0Hz,1H),5.36–5.45(m,2H),4.03–4.06(m,2H),3.58–3.72(m,2H),1.47 –1.50(m,3H),1.42(s,9H),1.31–1.37(m,1H),0.68–0.71(m,2H),0.43–0.46(m,2H);

MS-ESI: m/z 666.20 [M+H] ⁺ .

Step 2: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1- Synthesis of (2,4-difluorophenyl)-2-ureidoethyl)oxazole-4-carboxamide hydrochloride

To compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4-difluoro To a solution of tert-butyl phenyl)-2-ureidoethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate (190 mg, 0.31 mmol) in dichloromethane (4 mL) was added HCl in ethyl acetate The ester solution (3.7M, 2 mL) was stirred at room temperature for 30 min, and the solvent was removed to obtain 170 mg of white solid, yield: 99%.

Compound 215: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.84(s, 1H), 7.77-7.79(m, 1H), 7.49-7.53(m, 1H), 7.33-7.35(m, 1H), 6.98 –7.02(m,2H),6.93(t,J _FH ＝75.1Hz,1H),5.45–5.48(m,1H),5.09–5.16(m,1H),4.08(d,J＝6.8Hz,2H) ,3.58–3.68(m,2H),1.73–1.75(m,3H),1.35–1.39(m,1H),0.68–0.71(m,2H),0.44–0.47(m,2H);

MS-ESI: m/z 566.20 [M+H-HCl] ⁺ .

Example 85: Compound (2S)-2-(2-(5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(di Synthesis of methyl fluoromethoxy)phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetamido)propionate hydrochloride

Step 1: Compound (2S)-2-(2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)- Synthesis of methyl 4-(difluoromethoxy)phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetamido)propionate

Compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid (230mg, 0.36mmol), alanine methyl ester hydrochloride (75mg, 0.54mmol), 1- Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (138mg, 0.72mmol) and N-hydroxy-7-azabenzotriazole (74mg, 0.54mmol) were dissolved in di In methyl chloride (15mL), N,N-diisopropylethylamine (0.19mL, 1.08mmol) was added dropwise to the solution at 0°C, stirred at room temperature for 12h, washed with water (10mL×3), and used for the organic phase After drying over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrate was subjected to column separation (ethyl acetate/petroleum ether (v/v)=8/1) to obtain 190 mg of white solid, yield: 79%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.30–8.35 (m, 1H), 7.60–7.64 (m, 2H), 7.47–7.53 (m, 1H), 7.26 (d, J=8.3Hz, 1H), 6.89–6.93(m,2H),6.73(t,J _FH ＝74.9Hz,1H),5.93(d,J＝7.3Hz,1H),5.28–5.34(m,1H),4.57–4.63(m,1H ),4.02(d,J＝6.9Hz,2H),3.78(s,1.5H),3.72(s,1.5H),1.77(s,3H),1.46–1.53(m,3H),1.39–1.44( m,9H),1.27–1.35(m,1H),0.69–0.73(m,2H),0.43–0.47(m,2H);

MS-ESI: m/z 723.15 [M+H] ⁺ .

Step 2: Compound (2S)-2-(2-(5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Synthesis of )phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetamido)propionic acid methyl ester hydrochloride

To compound (2S)-2-(2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4- (Difluoromethoxy)phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetamido)propanoic acid methyl ester (190mg, 0.26mmol) in dichloromethane ( 2 mL) solution of ethyl acetate of HCl (4M, 4 mL) was added, stirred at room temperature for 30 min, and the solvent was removed to obtain 170 mg of white solid, yield: 98%.

Compound 217: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.77–7.78(m,1H),7.70–7.73(m,1H),7.59–7.64(m,1H),7.32–7.34(m,1H) ,7.03–7.06(m,2H),6.92(td,J＝74.8,3.4Hz,1H),5.99(d,J＝1.8Hz,1H),5.16–5.21(m,1H),4.45–4.51(m ,1H),4.02–4.04(m,2H),3.75(s,1.5H),3.69(s,1.5H),1.78(d,J=6.8Hz,3H),1.38(dd,J ₁ ＝23.3Hz ,J ₂ =7.3Hz,3H),1.32–1.35(m,1H),0.67–0.70(m,2H),0.41–0.45(m,2H);

MS-ESI: m/z 623.20 [M+H-HCl] ⁺ .

Example 86: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Base)-N-(1-(2,4-difluorophenyl)-2-(methanesulfonamide)-2-oxoethyl)oxazole-4-carboxamide hydrochloride, 5-((S )-1- Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((S)-1-(2,4-difluorophenyl )-2-(A Sulfonamide)-2-oxoethyl)oxazole-4-carboxamide hydrochloride and 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)- 4-(Difluoromethoxy)phenyl)-N-((R)-1-(2,4-difluorophenyl)-2-(methylsulfonamide)-2-oxoethyl)oxazole -4-A Synthesis of Amide Hydrochloride

Step 1: Compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4- Synthesis of tert-butyl difluorophenyl)-2-(methylsulfonamide)-2-oxoethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

Compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid (0.25g, 0.39mmol), N,N'-carbonyldiimidazole (197mg, 1.17mmol) was added without In water tetrahydrofuran (10mL), react at 60°C for 0.5h, cool to room temperature, add methylsulfonamide (75mg, 0.78mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.09mL, 0.59mmol), anhydrous tetrahydrofuran (8mL), react at 60°C for 10h, add saturated ammonium chloride solution (15mL), extract with ethyl acetate (10mL×3), add Na ₂ SO ₄ to the organic phase After drying, the solvent was removed to obtain 280 mg of white solid, yield: 99%.

¹ H NMR (600MHz, CDCl ₃ ): δppm 7.59–7.57(m,1H), 7.53–7.51(m,1H), 7.24–7.21(m,1H), 7.20(s,1H), 6.75(br.s ,1H),6.85–6.59(m,1H),5.74–5.73(m,1H),4.00–3.97(m,2H),3.11–3.00(m,3H),1.45(d,J＝6.0Hz,3H ),1.43–1.39(m,9H),1.33–1.30(m,1H),0.70–0.65(m,2H),0.42–0.36(m,2H);

MS-ESI: m/z 615.1 [M-100+H] ⁺ .

Step 2: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1- (2,4-Difluorophenyl)-2-(methylsulfonamide)-2-oxoethyl)oxazole-4-carboxamide hydrochloride, 5-((S)-1-aminoethyl) -2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((S)-1-(2,4-difluorophenyl)-2- (Methanesulfonamide)-2-oxoethyl)oxazole-4-carboxamide hydrochloride and 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy )-4-(difluoromethoxy)phenyl)-N-((R)-1-(2,4-difluorophenyl)-2-(methanesulfonamide)-2-oxoethyl) Synthesis of Oxazole-4-Carboxamide Hydrochloride

To compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4-difluoro Dichloromethane ( 4mL) was added in isopropanol solution of HCl (7M, 3mL), stirred at room temperature for 1h, and the solvent was removed to obtain the compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethyl Oxy)-4-(difluoromethoxy)phenyl)-N-(1-(2,4-difluorophenyl)-2-(methanesulfonamide)-2-oxoethyl)oxazole - 4-Carboxamide hydrochloride: white solid 291 mg, yield: 99%.

Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1-(2 , 4-difluorophenyl)-2-(methanesulfonamide)-2-oxoethyl)oxazole-4-carboxamide hydrochloride was sent to preparative chromatography for resolution to obtain compound 5-((S)-1 -aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((S)-1-(2,4-difluorobenzene Base)-2-(methylsulfonamide)-2-oxoethyl)oxazole-4-carboxamide hydrochloride (pale yellow solid 65 mg) and 5-((S)-1-aminoethyl)-2 -(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((R)-1-(2,4-difluorophenyl)-2-(methyl Sulfonamide)-2-oxoethyl)oxazole-4-carboxamide hydrochloride (white solid 70 mg).

Compound 219: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.78(s, 1H), 7.72(d, J=8.4Hz, 1H), 7.58–7.52(m, 1H), 7.32(d, J=8.3 Hz,1H),7.12–7.06(m,2H),6.91(t,J _FH ＝75.0Hz,1H),5.97(s,1H),5.23–5.21(m,1H),4.01(d,J＝6.9 Hz,2H),1.78(d,J=6.9Hz,3H),1.35–1.32(m,1H),0.70–0.65(m,2H),0.43–0.40(m,2H);

MS-ESI: m/z 615.2[M+H-HCl] ⁺ ;

Compound 220: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.78 (d, J = 1.7Hz, 1H), 7.72 (dd, J ₁ = 8.3Hz, J ₂ = 1.8Hz, 1H), 7.58-7.52 ( m,1H),7.33(d,J＝8.4Hz,1H),7.13–7.06(m,2H),6.91(t,J _FH ＝75.0Hz,1H),5.96(s,1H),5.23–5.18( m,1H),4.01(d,J=6.9Hz,2H),1.77(d,J=7.0Hz,3H),1.36–1.32(m,1H),0.70–0.65(m,2H),0.43–0.39 (m,2H);

MS-ESI: m/z 615.1 [M+H-HCl] ⁺ .

Example 87: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-(1-(2,4-difluorophenyl)-2-(3-methylurea)ethyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4- Synthesis of tert-butyl difluorophenyl)-2-(3-methylureido)ethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

Dissolve triethylamine (39mg, 0.39mmol) and N,N'-carbonyldiimidazole (CDI) (78mg, 0.48mmol) in anhydrous DMF (2mL), add compound ((1S)-1-(4-( (2-Amino-1-(2,4-difluorophenyl)ethyl)carbamoyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl )oxazol-5-yl)ethyl)carbamate tert-butyl ester (200mg, 0.32mmol) in anhydrous DMF (3mL) solution, stirred at room temperature for 30min, then added methylamine hydrochloride (26mg, 0.38mmol), 60°C Stop the reaction after reacting for 1h, remove the solvent DMF, add water (5mL), extract with ethyl acetate (10mL×3), dry over anhydrous sodium sulfate, remove the solvent, and the concentrated solution is subjected to column separation (petroleum ether/ethyl acetate (v/v )=1/1), 100 mg of white solid was obtained, yield: 46%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.60–7.64(m,2H),7.38–7.44(m,1H),7.24–7.26(m,1H),6.87–6.92(m,2H),6.73(t ,J _FH ＝75.0Hz,1H),5.35–5.46(m,2H),4.00–4.03(m,2H),3.70–3.77(m,1H),3.59–3.64(m,1H),2.77(d, J=4.7Hz,3H),1.49–1.54(m,3H),1.41–1.45(m,9H),1.32–1.36(m,1H),0.69–0.73(m,2H),0.41–0.45(m, 2H);

MS-ESI: m/z 680.20 [M+H] ⁺ .

Step 2: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1- Synthesis of (2,4-difluorophenyl)-2-(3-methylureido)ethyl)oxazole-4-carboxamide hydrochloride

To compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4-difluoro A solution of tert-butyl phenyl)-2-(3-methylureido)ethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate (95 mg, 0.14 mmol) in dichloromethane (1 mL) Add HCl in ethyl acetate solution (4M, 2 mL), stir at room temperature for 30 min, remove the solvent to obtain 85 mg of white solid, yield: 99%.

Compound 221: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.86(s, 1H), 7.77(d, J=8.2Hz, 1H), 7.46–7.50(m, 1H), 7.34(d, J=8.2 Hz,1H),6.96–7.01(m,2H),6.93(t,J _FH ＝74.8Hz,1H),5.41–5.44(m,1H),5.08–5.13(m,1H),4.08(d,J ＝6.8Hz,2H),3.59–3.66(m,2H),2.71(s,3H),1.73–1.75(m,3H),1.34–1.39(m,1H),0.68–0.71(m,2H), 0.43–0.46(m,2H);

MS-ESI: m/z 580.20 [M+H-HCl] ⁺ .

Example 88: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-(2-(3-(cyclopropylmethyl)ureido)-1-(2,4-difluorophenyl)ethyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((2-(3-(cyclo Synthesis of tert-butyl propylmethyl)ureido)-1-(2,4-difluorophenyl)ethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

Dissolve triethylamine (0.1mL, 0.72mmol) and N,N'-carbonyldiimidazole (CDI) (120mg, 0.72mmol) in anhydrous DMF (2mL), add compound ((1S)-1-(4- ((2-Amino-1-(2,4-difluorophenyl)ethyl)carbamoyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Base) oxazol-5-yl) ethyl) tert-butyl carbamate (300mg, 0.48mmol) in anhydrous DMF (3mL) solution, stirred at room temperature for 30min and then added cyclopropylmethylamine (52mg, 0.72mmol), 60 After reacting at ℃ for 1 h, the reaction was stopped, the solvent DMF was removed, water (5 mL), extracted with ethyl acetate (10 mL×3), dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/ v)=1/1), 170 mg of white solid was obtained, yield: 49%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.63–7.66 (m, 2H), 7.38–7.44 (m, 1H), 7.26 (d, J=8.8Hz, 1H), 6.81–6.89 (m, 2H), 6.92(t,J _FH ＝75.1Hz,1H),5.26–5.46(m,2H),4.02–4.04(m,2H),3.70–3.77(m,1H), 3.59–3.64(m,1H),3.01 –3.10(m,2H),1.49–1.54(m,3H),1.40–1.45(m,9H),1.31–1.38(m,2H),0.69–0.73(m,2H),0.40–0.43(m, 4H), 0.14–0.17(m, 2H).

Step 2: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2- Synthesis of (3-(cyclopropylmethyl)ureido)-1-(2,4-difluorophenyl)ethyl)oxazole-4-carboxamide hydrochloride

To compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((2-(3-(cyclopropylmethoxy) Methyl)ureido)-1-(2,4-difluorophenyl)ethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (165mg, 0.27mmol) HCl ethyl acetate solution (4M, 2mL) was added to the methane (1mL) solution, stirred at room temperature for 30min, and the solvent was removed to obtain 150mg of white solid, yield: 97%.

Compound 222: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.86(s, 1H), 7.77(d, J=8.2Hz, 1H), 7.46–7.50(m, 1H), 7.34(d, J=8.2 Hz,1H),6.96–7.01(m,2H),6.93(t,J _FH ＝75.1Hz,1H),5.40–5.43(m,1H),5.10–5.16(m,1H),4.08(d,J ＝6.8Hz,2H),3.58–3.68(m,2H),2.96–3.06(m,2H),1.74(d,J＝6.5Hz,3H),1.33–1.40(m,2H),0.68–0.71( m,2H),0.44–0.47(m,2H),0.37–0.43(m,2H),0.13–0.17(m,2H);

MS-ESI: m/z 620.20 [M+H-HCl] ⁺ .

Example 89: Compound N-(2-((2-amino-2-oxoethyl)amino)-1-(2,4-difluorophenyl)-2-oxo Ethyl)-5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-meth Amide salt salt synthesis

Step 1: Compound 2-(2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(di Synthesis of methyl fluoromethoxy)phenyl)oxazole-4-carboxamide)-2-(2,4-difluorophenyl)acetamide)acetate

Compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid (0.25g, 0.39mmol), glycine methyl ester hydrochloride (60mg, 0.47mmol), 1-ethyl Base-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (113mg, 0.59mmol) and N-hydroxy-7-azabenzotriazole (80mg, 0.59mmol) were dissolved in dichloro In methane (15mL), N,N-diisopropylethylamine (0.27mL, 1.57mmol) was added dropwise to the solution at 0°C, stirred at room temperature for 16h, the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ Ethyl acetate (v/v)=2/1) to obtain 187 mg of colorless oil, yield: 67%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.64–7.61(m,2H),7.53–7.51(m,1H),7.26(d,J＝8.6Hz,1H), 6.94–6.91(m,2H), 6.74(t,J _FH ＝71.6Hz,1H),6.48–6.45(m,1H),5.98–5.96(m,1H),5.32–5.30(m,1H),4.12–4.08(m,2H),4.03 (d,J＝6.8Hz,2H),3.77(s,3H),1.54–1.48(m,3H),1.44–1.38(m,9H),1.35–1.32(m,1H),0.74–0.71(m ,2H),0.46–0.44(m,2H);

MS-ESI: m/z 609.2 [M+H-100] ⁺ .

Step 2: Compound ((1S)-1-(4-((2-((2-amino-2-oxoethyl)amino)-1-(2,4-difluorophenyl)-2-oxo Substituting ethyl)carbamoyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate tert-butyl Synthesis

To compound 2-(2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethane Oxygen)phenyl)oxazole-4-carboxamide)-2-(2,4-difluorophenyl)acetamide)methyl acetate (0.25g, 0.35mmol) in anhydrous methanol (7mL) was added Ammonia in methanol solution (7M, 8mL), reaction at 75°C for 5h, the solvent was removed, and the concentrated solution was subjected to column separation (dichloromethane/methanol (v/v)=20/1) to obtain 170 mg of a light yellow solid, Yield: 69%.

¹ H NMR (600MHz, CDCl ₃ ): δppm 7.59–7.57(m,1H),7.56(s,1H),7.50–7.46(m,1H),7.24(d,J＝8.2Hz,1H),6.93– 6.89(m,1H),6.86–6.83(m,1H),6.72(t,J _FH ＝75.0Hz,1H),6.41–6.39(m,1H),5.89(t,J＝7.4Hz,1H), 5.65–5.63(m,1H),5.41–5.39(m,1H),4.04–3.97(m,2H),3.95–3.93(m,2H),1.56–1.51(m,3H),1.46–1.41(m ,9H),1.34–1.31(m,1H),0.70–0.69(m,2H),0.41–0.40(m,2H);

MS-ESI: m/z 594.1 [M+H-100] ⁺ .

Step 3: Compound N-(2-((2-amino-2-oxoethyl)amino)-1-(2,4-difluorophenyl)-2-oxoethyl)-5-(( Synthesis of S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride

To compound ((1S)-1-(4-((2-((2-amino-2-oxoethyl)amino)-1-(2,4-difluorophenyl)-2-oxoethyl Base)carbamoyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)tert-butyl carbamate (0.16 g, 0.24mmol) of dichloromethane (4mL) and methanol (4mL) was added in isopropanol solution of HCl (7M, 3mL), stirred at room temperature for 2h, and the solvent was removed to obtain a white solid 148mg, yield: 97 %, sent to preparation for further purification to obtain 60 mg of white solid.

Compound 223: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.79-7.78(m, 1H), 7.73-7.71(m, 1H), 7.65-7.62(m, 1H), 7.33(d, J=8.3Hz ,1H),7.07–7.03(m,2H),6.92(t,J _FH ＝74.7Hz,1H),6.01(s,1H),5.20–5.17(m,1H),4.04–3.99(m,3H) ,3.85–3.82(m,1H),1.76(d,J＝7.0Hz,3H),1.36–1.33(m,1H),0.70–0.67(m,2H),0.44–0.41(m,2H);

MS-ESI: m/z 594.2 [M+H-HCl] ⁺ .

Example 90: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-(quinolin-2-ylmethyl)oxazole-4-carboxamide dihydrochloride

Step 7: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((quinolin-2-ylmethyl Synthesis of base) carbamoyl) oxazol-5-yl) ethyl) tert-butyl carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) oxazole-4-carboxylic acid (0.3g, 0.64mmol), 2-quinolinemethylamine (121mg, 0.77mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride Salt (184mg, 0.96mmol) and N-hydroxy-7-azabenzotriazole (217mg, 1.60mmol) were dissolved in dichloromethane (15mL), and N,N -Diisopropylethylamine (0.45mL, 2.56mmol), stirred at room temperature for 16h, removed the solvent, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=3/1) to obtain 366mg of a white solid, Yield: 94%.

¹ H NMR (600MHz, CDCl ₃ ): δppm 8.20 (d, J = 8.4Hz, 1H), 8.13 (d, J = 8.5Hz, 1H), 7.86 (d, J = 8.0Hz, 1H), 7.79–7.76 (m,1H),7.66–7.65(m,2H),7.59(t,J=7.4Hz,1H),7.48(d,J=8.4Hz,1H),7.28(d,J=8.6Hz,2H) ,7.12–7.11(m,1H),6.74(t,J _FH ＝75.0Hz,1H),5.34–5.30(m,1H),4.98–4.97(m,2H),4.03(d,J＝7.0Hz, 2H), 1.58(d, J=7.0Hz, 3H), 1.46(s, 9H), 1.41–1.37(m, 1H), 0.74–0.71(m, 2H), 0.46–0.44(m, 2H);

MS-ESI: m/z 609.3 [M+H] ⁺ .

Step 2: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(quinoline Synthesis of -2-ylmethyl)oxazole-4-carboxamide dihydrochloride

To compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((quinolin-2-ylmethyl) Add HCl in ethyl acetate (4M, 4mL) to a solution of tert-butyl carbamate (0.36g, 0.59mmol) in dichloromethane (8mL) and stir at room temperature After 40 min, the solvent was removed to obtain 77 mg of white solid, yield: 24%.

Compound 225: ¹ H NMR (600MHz, CD ₃ OD): δppm 9.15(d, J=8.5Hz, 1H), 8.37–8.35(m, 2H), 8.22(t, J=7.7Hz, 1H), 8.11( d,J=8.5Hz,1H),8.00(t,J=7.6Hz,1H),7.84(s,1H),7.77(d,J=8.3Hz,1H),7.35(d,J=8.3Hz, 1H), 6.93(t, J _FH ＝74.7Hz, 1H), 5.20–5.19(m, 2H), 4.05(d, J＝6.8Hz, 2H), 1.77(d, J＝6.8Hz, 3H), 1.37 –1.34(m,1H),0.71–0.68(m,2H),0.45–0.42(m,2H);

MS-ESI: m/z 509.2 [M+H-2HCl] ⁺ .

Example 91: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Base)-N-(1-(2,4-difluorophenyl)-2-oxo-2-(aminosulfonylamino)ethyl)oxazole-4-carboxamide hydrochloride, 5- ((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((S)-1-(2 ,4-Difluorobenzene Base)-2-oxo-2-(aminosulfonylamino)ethyl)oxazole-4-carboxamide hydrochloride and 5-((S)-1-aminoethyl)-2-(3- (Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((R)-1-(2,4-difluorophenyl)-2-oxo-2-( Sulfamoyl Synthesis of amino)ethyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4- Synthesis of tert-butyl difluorophenyl)-2-oxo-2-(aminosulfonylamino)ethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

Compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid (0.25g, 0.39mmol) and N,N'-carbonyldiimidazole (197mg, 1.17mmol) were added without In tetrahydrofuran (20mL) in water, react at 60°C for 0.5h, cool to room temperature, add sulfonamide (151mg, 1.57mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.09 mL, 0.59mmol), reacted at 60°C for 15h, added saturated ammonium chloride solution (15mL), extracted with ethyl acetate (10mL×3), added the organic phase and dried it with Na ₂ SO ₄ , removed the solvent, and the concentrated solution was subjected to column Separation (dichloromethane/methanol (v/v)=40/1) gave 212 mg of a colorless oil, yield: 75%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.54-7.60(m, 3H), 7.23(d, J=8.3Hz, 1H), 6.91(s, 1H), 6.80-6.85(m, 1H), 6.72( t,J _FH ＝74.7Hz,1H),6.00(s,1H),5.32(s,1H),3.93-4.00(m,2H),1.51-1.57(m,3H),1.32-1.35(m,1H ),1.26-1.30(m,9H),0.67-0.72(m,2H),0.41-0.43(m,2H);

MS-ESI: m/z 616.0 [M+H-100] ⁺ .

Step 2: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1- (2,4-Difluorophenyl)-2-oxo-2-(aminosulfonylamino)ethyl)oxazole-4-carboxamide hydrochloride, 5-((S)-1-aminoethyl )-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((S)-1-(2,4-difluorophenyl)-2 -Oxo-2-(aminosulfonylamino)ethyl)oxazole-4-carboxamide hydrochloride and 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethyl) Oxygen)-4-(difluoromethoxy)phenyl)-N-((R)-1-(2,4-difluorophenyl)-2-oxo-2-(aminosulfonylamino) Synthesis of ethyl)oxazole-4-carboxamide hydrochloride

To compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4-difluoro Phenyl)-2-oxo-2-(aminosulfonylamino)ethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (0.20g, 0.27mmol) in dichloromethane (4mL) solution was added HCl in isopropanol (7M, 3mL), stirred at room temperature for 3h, and the solvent was removed to obtain 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethyl Oxygen)-4-(difluoromethoxy)phenyl)-N-(1-(2,4-difluorophenyl)-2-oxo-2-(aminosulfonylamino)ethyl)oxa Azole-4-carboxamide hydrochloride: oil 167 mg, yield: 93%.

Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1-(2 ,4-difluorophenyl)-2-oxo-2-(aminosulfonylamino)ethyl)oxazole-4-carboxamide hydrochloride was prepared and resolved to obtain compound 5-((S)-1 -aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((S)-1-(2,4-difluorobenzene Base)-2-oxo-2-(aminosulfonylamino)ethyl)oxazole-4-carboxamide hydrochloride (white solid 54 mg) and 5-((S)-1-aminoethyl)-2 -(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((R)-1-(2,4-difluorophenyl)-2-oxo -2-(Aminosulfonylamino)ethyl)oxazole-4-carboxamide hydrochloride (white solid 55 mg).

Compound 226: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.78(s, 1H), 7.71(d, J=8.3Hz, 1H), 7.56-7.59(m, 1H), 7.32(d, J=8.3 Hz,1H),7.05-7.09(m,2H),6.92(t,J _FH ＝74.7Hz,1H),5.96(s,1H),5.20-5.22(m,1H),4.01(d,J＝6.9 Hz,2H),1.77(d,J=7.0Hz,3H),1.33-1.35(m,1H),0.66-0.69(m,2H),0.41-0.43(m,2H);

MS-ESI: m/z 616.1[M+H-HCl] ⁺ ;

Compound 227: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.78(s, 1H), 7.71(d, J=8.3Hz, 1H), 7.56-7.58(m, 1H), 7.33(d, J=8.3 Hz, 1H), 7.05-7.10(m, 2H), 6.92(t, J _FH ＝74.7Hz, 1H), 5.95(s, 1H), 5.19-5.20(m, 1H), 4.01(d, J＝7.0 Hz,2H),1.77(d,J=7.0Hz,3H),1.33-1.36(m,1H),0.66-0.70(m,2H),0.40-0.43(m,2H);

MS-ESI: m/z 616.1 [M+H-HCl] ⁺ .

Example 92: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene base)-N-((S)-1-(2,4-difluorophenyl)-2-(hydroxylamino)-2-oxoethyl)oxazole-4-carboxamide hydrochloride and 5- ((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((R)-1-(2 ,4-Difluorobenzene Synthesis of -2-(hydroxylamino)-2-oxoethyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4- Synthesis of tert-butyl difluorophenyl)-2-(hydroxylamino)-2-oxoethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

Potassium hydroxide (52mg, 0.92mmol) was added to a solution of hydroxylamine hydrochloride (43mg, 0.61mmol) in methanol (20mL), reacted at 40°C for 0.5h, after stopping the reaction, compound 2-(5-( (S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4- Methyl formamido)-2-(2,4-difluorophenyl)acetate (200mg, 0.31mmol), react at 65°C for 4h, filter, remove the solvent from the filtrate, add hydrochloric acid (1M) to adjust the pH value to about 2 , adding ethyl acetate for extraction (10 mL×3), the organic phase was dried with anhydrous Na ₂ SO ₄ , and the solvent was removed to obtain a yellow solid 180 mg, yield: 89%.

¹ H NMR (600MHz,d ₆ -DMSO): δppm 7.67–7.62(m,2H),7.60–7.57(m,1H),7.40–7.37(m,1H),7.31–7.27(m,1H),7.22 (t,J _FH ＝74.0Hz,1H),7.13–7.09(m,1H),5.36–5.30(m,1H),4.01–3.98(m,2H),1.42–1.35(m,9H),1.30– 1.28(m,1H),0.62–0.60(m,2H),0.41–0.39(m,2H);

MS-ESI: m/z 553.2 [M+H-100] ⁺ .

Step 2: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((S )-1-(2,4-difluorophenyl)-2-(hydroxylamino)-2-oxoethyl)oxazole-4-carboxamide hydrochloride and 5-((S)-1-ammonia Ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((R)-1-(2,4-difluorophenyl) Synthesis of -2-(hydroxylamino)-2-oxoethyl)oxazole-4-carboxamide hydrochloride

To compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4-difluoro Dichloromethane (4mL ) solution was added HCl in isopropanol solution (7M, 3mL), stirred at room temperature for 1.5h, and the solvent was removed to obtain 216mg of yellow solid, yield: 99%, sent to preparative chromatography to obtain compound 5-((S)- 1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((S)-1-(2,4-difluoro Phenyl)-2-(hydroxylamino)-2-oxoethyl)oxazole-4-carboxamide hydrochloride (50 mg, white solid) and 5-((S)-1-aminoethyl)-2 -(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((R)-1-(2,4-difluorophenyl)-2-(hydroxylamine yl)-2-oxoethyl)oxazole-4-carboxamide hydrochloride (90 mg, yellow solid).

Compound 229: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.79(s, 1H), 7.72(d, J=8.0Hz, 1H), 7.64–7.62(m, 1H), 7.33(d, J=8.3 Hz,1H),7.07–7.02(m,2H),6.92(t,J _FH ＝74.7Hz,1H),5.90(s,1H),5.20–5.19(m,1H),4.03(d,J＝6.9 Hz,2H),1.76(d,J=6.7Hz,3H),1.36–1.33(m,1H),0.70–0.67(m,2H),0.45–0.41(m,2H);

MS-ESI: m/z 553.1[M+H-HCl] ⁺ ;

Compound 230: MS-ESI: m/z 553.1 [M+H-HCl] ⁺ .

Example 93: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-(1-(2,4-difluorophenyl)-2-oxo-2-ureidoethyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4- Synthesis of tert-butyl difluorophenyl)-2-oxo-2-ureidoethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

Compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid (0.25g, 0.39mmol), N,N-carbonyldiimidazole (197mg, 1.17mmol) was added to anhydrous In tetrahydrofuran (20mL), react at 60°C for 0.5h, cool to room temperature, add urea (94mg, 1.57mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.09mL, 0.59mmol), reacted at 60°C for 24h, added saturated ammonium chloride solution (15mL), extracted with ethyl acetate (10mL×3), added the organic phase and dried it with Na ₂ SO ₄ , removed the solvent, and the concentrated solution was subjected to column separation ( Petroleum ether/ethyl acetate (v/v)=2/1) to obtain 80 mg of yellow solid, yield: 30%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.26–8.21 (m, 1H), 7.67 (dd, J ₁ = 8.3Hz, J ₂ = 1.9Hz, 1H), 7.61 (d, J = 1.9Hz, 1H) ,7.31(d,J＝8.3Hz,1H),7.14–7.09(m,1H),7.04–6.98(m,1H),6.75(t,J _FH ＝74.9Hz,1H),5.38–5.34(m, 1H), 4.03(d, J＝7.0Hz, 2H), 1.60(d, J＝7.2Hz, 3H), 1.44(s, 9H), 1.38–1.36(m, 1H), 0.76–0.71(m, 2H ),0.48–0.44(m,2H).

Step 2: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1- Synthesis of (2,4-difluorophenyl)-2-oxo-2-ureidoethyl)oxazole-4-carboxamide hydrochloride

To compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4-difluoro A solution of tert-butyl phenyl)-2-oxo-2-ureidoethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate (0.07 g, 0.11 mmol) in dichloromethane (4 mL) Add HCl in isopropanol solution (7M, 3mL), stir at room temperature for 1 h, and remove the solvent to obtain 65 mg of light yellow solid, yield: 93%.

Compound 231: ¹ H NMR (600MHz, CD ₃ OD): δppm 8.02–7.98(m, 1H), 7.75(s, 1H), 7.74–7.72(m, 1H), 7.34(d, J=8.3Hz, 1H ),7.27–7.23(m,1H),7.13(t,J＝8.3Hz,1H),6.95(t,J _FH ＝74.6Hz,1H),5.37–5.34(m,1H),4.04(d,J =6.8Hz,2H),1.82(d,J=7.0Hz,3H),1.37–1.35(m,1H),0.73–0.69(m,2H),0.47–0.45(m,2H);

MS-ESI: m/z 580.1 [M+H-HCl] ⁺ .

Example 94: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-(2-(3-cyclopropylureido)-1-(2,4-difluorophenyl)ethyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((2-(3-cyclopropyl Synthesis of tert-butyl ureido)-1-(2,4-difluorophenyl)ethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

Dissolve triethylamine (101mg, 1.01mmol) and N,N'-carbonyldiimidazole (CDI) (162mg, 1.01mmol) in anhydrous DMF (2mL), add ((1S)-1-(4-(( 2-Amino-1-(2,4-difluorophenyl)ethyl)carbamoyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) Oxazol-5-yl) ethyl) tert-butyl carbamate (250mg, 0.4mmol) in anhydrous DMF (3mL) solution, stirred at room temperature for 30min, then added cyclopropylamine (57mg, 1.01mmol), reacted at 60°C for 1h, then stopped Reaction, remove the solvent DMF, add water (5mL), extract with ethyl acetate (10mL×3), dry over anhydrous sodium sulfate, remove the solvent, and concentrate the solution for column separation (petroleum ether/ethyl acetate (v/v)=1/ 1), to obtain 180 mg of white solid, yield: 64%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.50 (br.s, 1H), 7.62–7.67 (m, 2H), 7.37–7.43 (m, 1H), 7.26 (d, J=8.3Hz, 1H), 6.68–6.92(m,2H),6.73(t,J _FH ＝75.0Hz,1H),5.48–5.53(m,1H),5.32–5.40(m,1H),5.23–5.34(m,1H),4.74 –4.79(m,1H),4.02(d,J＝6.9Hz,2H),3.71–3.84(m,2H),2.37–2.41(m,1H),1.47–1.54(m,3H),1.41–1.45 (m,9H),1.32–1.40(m,1H),0.67–0.76(m,4H),0.48–0.57(m,2H),0.42–0.46(m,2H);

MS-ESI: m/z 706.25 [M+H] ⁺ .

Step 2: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2- Synthesis of (3-cyclopropylureido)-1-(2,4-difluorophenyl)ethyl)oxazole-4-carboxamide hydrochloride

To compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((2-(3-cyclopropylurea Dichloromethane (1 mL) of tert-butyl)-1-(2,4-difluorophenyl)ethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate (170mg, 0.24mmol) Ethyl acetate solution of HCl (4M, 2 mL) was added to the solution, stirred at room temperature for 30 min, and the solvent was removed to obtain 150 mg of white solid, yield: 97%.

Compound 232: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.86(s, 1H), 7.78(d, J=8.3Hz, 1H), 7.49–7.53(m, 1H), 7.34(d, J=8.2 Hz,1H),6.96–7.02(m,2H),6.93(t,J _FH ＝74.8Hz,1H),5.47–5.50(m,1H),5.09–5.16(m,1H),4.08(d,J =6.8Hz,2H),3.63–3.73(m,2H),2.42–2.45(m,1H),1.75(d,J＝6.6Hz,3H),1.33–1.39(m,1H),0.66–0.71( m,4H),0.42–0.47(m,4H);

MS-ESI: m/z 606.30 [M+H-HCl] ⁺ .

Example 95: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-(1-(2,4-difluorophenyl)-2-morpholinyl-2-oxoethyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4- Synthesis of tert-butyl difluorophenyl)-2-morpholinyl-2-oxoethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

Compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid (0.25g, 0.39mmol), morpholine (41mg, 0.47mmol), 1-ethyl-3- (3-Dimethylaminopropyl)carbodiimide hydrochloride (112mg, 0.59mmol) and N-hydroxy-7-azabenzotriazole (133mg, 0.98mmol) were dissolved in dichloromethane (15mL) In this solution, N,N-diisopropylethylamine (0.27mL, 1.57mmol) was added dropwise to the solution at 0°C, stirred at room temperature for 15h, the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate ( v/v)=2/1), 267 mg of colorless oil was obtained, yield: 96%.

¹ H NMR (600MHz, CDCl ₃ ): δppm 8.51(d, J=7.4Hz, 1H), 7.62(d, J=8.4Hz, 1H), 7.60(s, 1H), 7.56–7.53(m, 1H) ,7.25(d,J＝8.3Hz,1H),6.96–6.94(m,1H),6.92–6.88(m,1H),6.73(t,J _FH ＝75.1Hz,1H),6.29–6.28(m, 1H),5.32–5.29(m,1H),4.02(d,J＝6.9Hz,2H),3.73–3.60(m,6H),3.44–3.36(m,2H),1.53–1.48(m,3H) ,1.45–1.38(m,9H),1.35–1.33(m,1H),0.73–0.70(m,2H),0.46–0.44(m,2H);

MS-ESI: m/z 707.3 [M+H] ⁺ .

Step 2: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1- Synthesis of (2,4-difluorophenyl)-2-morpholinyl-2-oxoethyl)oxazole-4-carboxamide hydrochloride

To compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-(2,4-difluoro Phenyl)-2-morpholinyl-2-oxoethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate (0.25g, 0.35mmol) in dichloromethane (4mL) A solution of HCl in isopropanol (7M, 3 mL) was added to the solution, stirred at room temperature for 1 h, and the solvent was removed to obtain 210 mg of a white solid, yield: 91%.

Compound 233: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.78-7.77(m, 1H), 7.73-7.71(m, 1H), 7.58-7.55(m, 1H), 7.33(d, J=8.3Hz ,1H),7.11–7.06(m,2H),6.92(t,J _FH ＝74.7Hz,1H),6.27(s,1H),5.19–5.16(m,1H),4.03(d,J＝6.9Hz ,2H),3.71–3.58(m,6H),3.37–3.35(m,1H),3.29–3.27(m,1H),1.77–1.75(m,3H),1.36–1.34(m,1H),0.70 –0.68(m,2H),0.44–0.43(m,2H);

MS-ESI: m/z 607.2 [M+H-HCl] ⁺ .

Example 96: Compound (S)-2-(5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethane Oxy)phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)ethyl acetate hydrochloride and (R)-2-(5-((S)-1 -ammonia Ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamido)-2-(2,4-difluorobenzene Base) Synthesis of Ethyl Acetate Hydrochloride

Compound 2-(5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxa Azole-4-carboxamido)-2-(2,4-difluorophenyl)ethyl acetate hydrochloride was sent to preparative chromatographic resolution, and compound (S)-2-(5-((S) was obtained after resolution )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamido)-2-(2, 4-Difluorophenyl) ethyl acetate hydrochloride and (R)-2-(5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4 -(Difluoromethoxy)phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)ethyl acetate hydrochloride.

Compound 238: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.80(s, 1H), 7.74(d, J=8.3Hz, 1H), 7.60–7.56(m, 1H), 7.34(d, J=8.3 Hz,1H),7.07–7.03(m,2H),6.92(t,J _FH ＝75.0Hz,1H),6.02(s,1H),5.20–5.19(m,1H),4.28(q,J＝7.1 Hz, 2H), 4.05(d, J=6.9Hz, 2H), 1.76(d, J=6.9Hz, 3H), 1.36–1.34(m, 1H), 1.25(t, J=7.1Hz, 3H), 0.71–0.68(m,2H),0.44–0.43(m,2H);

MS-ESI: m/z 566.2[M+H-HCl] ⁺ ;

Compound 239: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.80(s, 1H), 7.74(d, J=8.3Hz, 1H), 7.59–7.57(m, 1H), 7.34(d, J=8.3 Hz,1H),7.09–7.03(m,2H),6.92(t,J _FH ＝75.0Hz,1H),6.02(s,1H),5.18–5.16(m,1H),4.28(q,J＝7.1 Hz, 2H), 4.04(d, J=6.9Hz, 2H), 1.76(d, J=6.9Hz, 3H), 1.37–1.34(m, 1H), 1.25(t, J=7.1Hz, 3H), 0.71–0.68(m,2H),0.45–0.43(m,2H);

MS-ESI: m/z 566.2 [M+H-HCl] ⁺ .

Example 97: Compound N-(2-amino-1-(2,4-difluorophenyl)-2-thioethyl)-5-((S)-1-aminoethyl Base)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride, N-((S)-2-amino - 1-(2,4-difluorophenyl)-2-thioethyl)-5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4 -(difluoromethoxy Base) phenyl) oxazole-4-carboxamide hydrochloride and N-((R)-2-amino-1-(2,4-difluorophenyl)-2-thioethyl)-5- Synthesis of ((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride to make

Step 1: Compound ((1S)-1-(4-((2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)carbamoyl)-2-(3- Synthesis of tert-butyl (cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate

Compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid methyl ester (240mg, 0.37mmol), ammonia methanol solution (7M, 5.3mL, 37mmol) was dissolved in anhydrous Methanol (10mL), in a 100mL sealed tube, was stirred at 60°C for 1h, the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=1/1) to obtain 157mg of a white solid, product Rate: 67%.

¹ H NMR (600MHz, CD ₃ OD): δppm 8.34–8.38(m,1H),7.61–7.64(m,2H),7.48–7.54(m,1H),7.27(d,J＝8.3Hz,1H) ,6.91–6.95(m,2H),6.74(t,J _FH ＝75.0Hz,1H),5.93–6.00(m,2H),5.58(br.s,1H),5.29–5.34(m,1H), 4.04(d,J=6.9Hz,2H),1.48–1.53(m,3H),1.40–1.45(m,9H),1.28–1.36(m,1H),0.70–0.74(m,2H),0.44– 0.47(m,2H);

MS-ESI: m/z 637.20 [M+H] ⁺ .

Step 2: Compound ((1S)-1-(4-((2-amino-1-(2,4-difluorophenyl)-2-thioethyl)carbamoyl)-2-(3- Synthesis of tert-butyl (cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate

The compound ((1S)-1-(4-((2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)carbamoyl)-2-(3-(cyclo Propylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate (200mg, 0.32mmol) and Lawesson's reagent (140mg , 0.35mmol) was dissolved in tetrahydrofuran (10mL), stirred and refluxed at 75°C for 30min, the solvent was removed, the residue was added with water (10mL), extracted with ethyl acetate (10mL×3), the organic phase was dried with anhydrous Na ₂ SO ₄ , removed The solvent and the concentrate were subjected to column separation (ethyl acetate/petroleum ether (v/v)=4/1) to obtain 118 mg of light yellow solid, yield: 58%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.78–8.82(m,1H),7.59–7.67(m,2H),7.28(d,J＝8.3Hz,1H), 6.88–6.94(m,2H), 6.74(t, J _FH ＝75.0Hz, 1H), 6.19–6.26(m, 1H), 5.30–5.42(m, 1H), 4.04(d, J＝6.9Hz, 2H), 1.48–1.52(m, 3H ), 1.39–1.45(m,9H), 1.28–1.36(m,1H), 0.70–0.74(m,2H), 0.43–0.47(m,2H). Step 3: Compound N-(2-amino-1-(2,4-difluorophenyl)-2-thioethyl)-5-((S)-1-aminoethyl)-2-(3 Synthesis of -(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride

To compound ((1S)-1-(4-((2-amino-1-(2,4-difluorophenyl)-2-thioethyl)carbamoyl)-2-(3-(cyclo Propylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate (110 mg, 0.17 mmol) in dichloromethane (2 mL) was added Ethyl acetate solution of HCl (4M, 2 mL), stirred at room temperature for 20 min, and the solvent was removed to obtain 95 mg of a light yellow solid, yield: 96%.

Compound 236: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.80(s, 1H), 7.73–7.75(m, 1H), 7.66–7.70(m, 1H), 7.34(d, J=8.3Hz, 1H ),6.98–7.04(m,2H),6.92(t,J _FH ＝75.0Hz,1H),6.19(s,1H),5.14–5.20(m,1H),4.04(d,J＝6.9Hz,2H ),1.77(d,J＝7.0Hz,3H),1.32–1.37(m,1H),0.67–0.70(m,2H),0.42–0.45(m,2H);

MS-ESI: m/z 553.20 [M+H-HCl] ⁺ .

Step 4: Compound N-((S)-2-amino-1-(2,4-difluorophenyl)-2-thioethyl)-5-((S)-1-aminoethyl)- 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride and N-((R)-2-amino-1- (2,4-difluorophenyl)-2-thioethyl)-5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-( Synthesis of difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride

The compound N-(2-amino-1-(2,4-difluorophenyl)-2-thioethyl)-5-((S)-1-aminoethyl)-2-(3-( Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride (270mg, 0.46mmol) was subjected to preparative chromatographic resolution, and S and R configurations were respectively The preparation solution was concentrated, adjusted to pH=9 with NaOH solution (1M), extracted with ethyl acetate (10mL×3), the organic phases were combined and dried with Na ₂ SO ₄ , the solvent was removed, and ethyl acetate solution of HCl (4M, 2mL), the S configuration compound N-((S)-2-amino-1-(2,4-difluorophenyl)-2-thioethyl)-5-((S)-1-amino Ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride (light yellow solid 68mg); R configuration Compound N-((R)-2-amino-1-(2,4-difluorophenyl)-2-thioethyl)-5-((S)-1-aminoethyl)-2-( 3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride (pale yellow solid 100 mg).

Compound 244: MS-ESI: m/z 553.20[M+H-HCl] ⁺ ;

Compound 245: MS-ESI: m/z 553.20 [M+H-HCl] ⁺ .

Example 98: Compound (2-(5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Synthesis of (yl)phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetoxy)methyl trimethyl acetate hydrochloride to make

Step 1: Compound (2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of oxy)phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetoxy)methyl trimethyl acetate

Compound 2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid (500mg, 0.78mmol) and potassium hydroxide (44mg, 0.78mmol) were dissolved in absolute ethanol (5mL) reaction at 40°C for 15min, remove the solvent, add DMF (5mL) and chloromethyl pivalate (0.34mL, 2.34mmol), stir at room temperature for 4h, add ice water (10mL), extract with ethyl acetate (10mL× 3), the organic phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=10/1) to obtain 450 mg of light yellow solid, yield: 76 %.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.11–8.15 (m, 1H), 7.59–7.63 (m, 2H), 7.46–7.52 (m, 1H), 7.26 (d, J=8.3Hz, 1H), 6.88–6.94(m,2H),6.73(t,J _FH ＝75.0Hz,1H),6.02–6.03(m,1H),5.93(d,J＝5.5Hz,1H),5.77(d,J＝5.5 Hz,1H),5.29–5.33(m,1H),4.01–4.04(m,2H),1.48–1.54(m,3H),1.41–1.45(m,9H),1.31–1.35(m,1H), 1.16(s,9H),0.69–0.74(m,2H),0.41–0.47(m,2H);

MS-ESI: m/z 774.20 [M+Na] ⁺ .

Step 2: Compound (2-(5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole Synthesis of -4-formamido)-2-(2,4-difluorophenyl)acetoxy)methyl trimethyl acetate hydrochloride

To the compound (2-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )phenyl)oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetoxy)methyltrimethylacetate (260mg, 0.35mmol) in dichloromethane (2mL ) solution was added HCl ethyl acetate solution (4M, 4mL), stirred at room temperature for 30min, and the solvent was removed to obtain 230mg of white solid, yield: 96%.

Compound 271: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.80 (d, J = 1.8Hz, 1H), 7.74 (dd, J ₁ = 8.4Hz, J ₂ = 1.9Hz, 1H), 7.59 (dd, J ₁ ＝14.8Hz, J ₂ ＝8.4Hz, 1H), 7.34(d, J＝8.3Hz, 1H), 7.02–7.10(m, 2H), 6.92(t, J _FH ＝75.1Hz, 1H), 6.07 (s,1H),5.95(dd,J ₁ =5.7Hz,J ₂ =1.8Hz,1H),5.75(dd,J ₁ =5.7Hz,J ₂ =1.5Hz,1H),5.15–5.22(m, 1H), 4.05(d, J=6.9Hz, 2H), 1.76(dd, J ₁ ＝6.9Hz, J ₂ ＝1.1Hz, 3H), 1.31–1.38(m, 1H), 1.15(s, 9H), 0.67–0.72(m,2H),0.41–0.46(m,2H);

MS-ESI: m/z 652.10 [M+H-HCl] ⁺ .

Example 99: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Base)-N-(2,4-difluorobenzyl)oxazole-4-carboxamide hydrochloride and (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethyl) oxygen Synthesis of yl)-4-(difluoromethoxy)phenyl)-N-(2,4-difluorobenzyl)oxazole-4-carboxamide

Step 1: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((2,4-difluorobenzyl Synthesis of base) carbamoyl) oxazol-5-yl) ethyl) tert-butyl carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) oxazole-4-carboxylic acid (300mg, 0.64mmol), HOAT (130.8mg, 0.961mmol) and EDCI (183.7mg, 0.961mmol) were dissolved in DCM (25mL), and after stirring for 30min at room temperature, 2, 4-Difluorobenzylamine (109.9mg, 0.769mmol), under ice-cooling, slowly add DIPEA (0.35mL, 1.923mmol) dropwise, continue stirring at room temperature overnight, add water (25mL), wash with CH ₂ Cl ₂ Extraction (25mL×3), after combining the organic phases, drying with anhydrous Na ₂ SO ₄ , removing the solvent, and the concentrated solution was subjected to column separation (Petroleum ether/EtOAc (v/v)=5/1) to obtain 316.4 mg of white solid , Yield: 83.2%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.57 (dd, J ₁ =8.3Hz, J ₂ =1.9Hz, 1H), 7.53 (d, J = 1.8Hz, 1H), 7.39-7.44 (d, 1H) ,7.23(d,J=8.3Hz,1H),6.82-6.89(m,2H),6.70(t,J=75.0Hz,1H),5.27-5.30(m,1H),4.65(brs,2H), 3.97(d,J=6.9Hz,2H),1.53(d,J=7.0Hz,3H),1.43(s,9H),1.28-1.29(m,1H),0.66-0.71(m,2H),0.39 -0.42(m,2H);

MS-ESI: m/z 494.0 [M-100+H] ⁺ .

Step 2: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2, Synthesis of 4-difluorobenzyl)oxazole-4-carboxamide hydrochloride

Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((2,4-difluorobenzyl) Carbamoyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (316.4mg, 0.533mmol) was dissolved in CH ₂ Cl ₂ (2mL) ^, then HCl.EA (4M, 3mL) was added and reacted at room temperature After 2 hours, after removing the solvent, CH ₂ Cl ₂ was added to just dissolve the crude product, and a large amount of ethyl acetate was added to precipitate a large amount of white solid, which was filtered and dried to obtain 250 mg of white solid, yield: 88.6%.

Compound 7: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.70(s, 1H), 7.63(dd, J ₁ =8.3Hz, J ₂ =1.9Hz, 1H), 7.37-7.41(m, 1H), 7.24(d, J=8.3Hz, 1H), 6.86-6.92(m, 2H), 6.82(t, J=75.0Hz, 1H), 5.07(q, J=7.0Hz, 1H), 4.55(s, 2H ),3.94(d,J=7.0Hz,2H),1.68(d,J=7.0Hz,3H),1.24-1.28(m,1H),0.58-0.61(m,2H),0.32-0.34(m, 2H);

MS-ESI: m/z 494.0 [M-HCl+H] ⁺ .

Step 3: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2, Synthesis of 4-difluorobenzyl)oxazole-4-carboxamide

Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2,4- Difluorobenzyl)oxazole-4-carboxamide hydrochloride (150mg, 0.28mmol) was dissolved in water (10mL), adjusted to pH=9 with aqueous NaOH (1.0M), extracted with ethyl acetate (10mL×3) , the organic phase was dried with anhydrous Na ₂ SO ₄ , and the solvent was removed to obtain a white solid 130 mg, yield: 94%.

Compound 313: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.66 (d, J = 1.9Hz, 1H), 7.58 (dd, J ₁ = 8.3Hz, J ₂ = 2.0Hz, 1H), 7.33-7.37 ( m,1H),7.18(d,J=8.3Hz,1H),6.83–6.89(m,2H),6.78(t,J _FH =75.0Hz,1H),4.65(q,J=6.9Hz,1H) ,4.50(s,2H),3.91(d,J＝6.9Hz,2H),1.44(d,J＝6.9Hz,3H),1.21–1.27(m,1H),0.55–0.59(m,2H), 0.29–0.33(m,2H);

MS-ESI: m/z 494.30 [M+H] ⁺ .

Example 100: Compound N-((S)-2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)-5-((S)-1- Synthesis of aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide

The compound N-((S)-2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)-5-((S)-1-aminoethyl)-2- (3-(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride (150mg, 0.28mmol) was dissolved in water (10mL) and washed with NaOH The aqueous solution (1.0 M) was adjusted to pH=9, extracted with dichloromethane (10 mL×3), the organic phase was dried with anhydrous Na ₂ SO ₄ , and the solvent was removed to obtain 110 mg of white solid, yield: 79%.

Compound 322: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.57–7.69(m,2H),7.41–7.52(m,1H),7.17–7.24(m,1H),6.87–6.97(m,2H) ,6.81(t,J _FH ＝75.0Hz,1H),5.82(s,1H),4.85–4.90(m,1H),3.88–3.93(m,2H),1.58(d,J＝6.6Hz,3H) ,1.17–1.30(m,1H),0.54–0.63(m,2H),0.28–0.37(m,2H);

MS-ESI: m/z 536.95 [M+H] ⁺ .

Example 101: Compound (S)-5-(1-aminoethyl)-2-(3,4-diethoxyphenyl)-N-(2,4-difluorobenzyl base) synthesis of oxazole-4-carboxamide hydrochloride

Step 1: Compound (S)-(1-(2-(3,4-diethoxyphenyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazol-5-yl ) ethyl) synthetic tert-butyl carbamate

Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3,4-diethoxyphenyl)oxazole-4-carboxylic acid (176mg, 0.41mmol), 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (118.8mg, 0.62mmol) and N-hydroxy-7-azabenzotriazole (83.8mg, 0.62mmol ) was dissolved in dichloromethane (10mL), stirred at room temperature for 0.5h, and 2,4-difluorobenzylamine (0.06mL, 0.49mmol) and N,N-diisopropylethylamine (0.22 mL, 1.23mmol), stirred at room temperature for 12h, added water (20mL), extracted with dichloromethane (20mL×3), combined the organic phases and dried with Na ₂ SO ₄ , removed the solvent, and the concentrated solution was subjected to column separation (petroleum ether/ Ethyl acetate (v/v)=5/1), to obtain 149 mg of white solid, yield: 67%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.52(d, J=8.4Hz, 1H), 7.46(s, 1H), 7.41-7.35(m, 1H), 6.89(d, J=8.4Hz, 1H) ,6.86-6.78(m,2H),5.29-5.25(m,1H),4.63-4.60(m,2H),4.16-4.10(m,4H),1.52(d,J＝7.0Hz,3H),1.48 -1.44(m,6H),1.42(s,9H);

MS-ESI: m/z 546.2 [M+H] ⁺ .

Step 2: Compound (S)-5-(1-aminoethyl)-2-(3,4-diethoxyphenyl)-N-(2,4-difluorobenzyl)oxazole-4- Synthesis of Formamide Hydrochloride

To compound (S)-(1-(2-(3,4-diethoxyphenyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazol-5-yl)ethyl Base) tert-butyl carbamate (100mg, 0.18mmol) in dichloromethane (2mL) solution was added HCl in ethyl acetate solution (4M, 5mL), stirred at room temperature for 0.5h, after removing the solvent, washed with methanol/ethyl acetate (v/v=1/20) recrystallized to obtain 75 mg of white solid, yield: 92%.

Compound 3: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.67(d, J=8.4Hz, 1H), 7.63(s, 1H), 7.48-7.42(m, 1H), 7.07(d, J=8.4 Hz,1H),6.98-6.91(m,2H),5.12-5.09(m,1H),4.62(s,2H),4.17-4.11(m,4H),1.74(d,J＝6.6Hz,3H) ,1.46-1.42(m,6H);

MS-ESI: m/z 446.2 [M+H-HCl] ⁺ .

Example 102: Compound (S)-5-(1-aminoethyl)-2-(3-(benzyloxy)-4-methoxyphenyl)-N-(2,4- Synthesis of difluorobenzyl)oxazole-4-carboxamide hydrochloride

Step 1: Synthesis of the compound 3-benzyloxy-4-methoxybenzoic acid methyl ester

Methyl 3-hydroxy-4-methoxybenzoate (10.00g, 54.93mmol), potassium carbonate (15.66g, 113.30mmol) and benzyl bromide (7.8mL, 66.07mmol) were dissolved in N,N-dimethyl Dimethyl formamide (60mL), reacted at 60°C for 4.5h, added water (40mL), extracted with ethyl acetate (50mL×3), combined the organic phases and dried them with anhydrous Na ₂ SO ₄ , removed the solvent, and concentrated Column separation (petroleum ether/ethyl acetate (v/v)=5/1) was carried out to obtain 11.2 g of white solid, yield: 75%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.69(d, J=8.4Hz, 1H), 7.62(s, 1H), 7.46(d, J=7.3Hz, 2H), 7.40-7.31(m, 3H) ,6.91(d,J＝8.4Hz,1H),5.18(s,2H),3.93(s,3H),3.85(s,3H);

MS-ESI: m/z 273.1 [M+H] ⁺ .

Step 2: Synthesis of compound 3-benzyloxy-4-methoxybenzoic acid

The compound 3-benzyloxy-4-methoxybenzoic acid methyl ester (11.2g, 41.18mmol) and sodium hydroxide (8.89g, 222.3mmol) were dissolved in a mixed solvent of ethanol (150mL) and water (50mL) , reacted at 60°C for 1.5h, removed ethanol, adjusted the pH to 1 with hydrochloric acid (1M), extracted with ethyl acetate (50mL×3), combined the organic phases and dried them with anhydrous Na ₂ SO ₄ , and removed the solvent to obtain 8.51 g white solid, yield: 80%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.69(d, J=8.4Hz, 1H), 7.62(s, 1H), 7.46(d, J=7.3Hz, 2H), 7.40-7.31(m, 3H) ,6.91(d,J＝8.4Hz,1H),5.18(s,2H),3.85(s,3H);

MS-ESI: m/z 259.2 [M+H] ⁺ .

Step 3: Synthesis of the compound 2-(3-(benzyloxy)-4-methoxybenzamido)methyl acetate

Compound 3-benzyloxy-4-methoxybenzoic acid (8.51g, 33.0mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (9.62g, 50.2mmol), 1-hydroxybenzotriazole (6.69g, 49.5mmol) was dissolved in dichloromethane (80mL), stirred at room temperature for 0.5h, and glycine methyl ester hydrochloride (4.97g, 39.6mmol) was added at 0°C and N,N-diisopropylethylamine (17.8mL, 102.3mmol), stirred at room temperature for 12h, washed with water (40mL×3), the organic phase was dried with Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum Ether/ethyl acetate (v/v)=1/1) to obtain 9.88 g of white solid, yield: 91%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.47-7.44(m, 3H), 7.38-7.35(m, 3H), 7.32-7.28(m, 1H), 6.89(d, J=8.4Hz, 1H), 6.57(br.s,1H),5.16(s,2H),4.20(d,J=5.0Hz,2H),3.91(s,3H),3.80(s,3H);

MS-ESI: m/z 330.2 [M+H] ⁺ .

Step 4: Synthesis of the compound 2-(3-(benzyloxy)-4-methoxyphenylthioamide)acetic acid methyl ester

The compound 2-(3-(benzyloxy)-4-methoxybenzamido)acetic acid methyl ester (2.5g, 7.59mmol) and Lawson's reagent (3.07g, 7.59mmol) were dissolved in tetrahydrofuran (40mL) reflux at 75°C for 2 h, add saturated sodium bicarbonate solution (40 mL), extract with ethyl acetate (50 mL×3), combine the organic phases and dry with Na ₂ SO ₄ , remove the solvent, and the concentrated solution is subjected to column separation ( Petroleum ether/ethyl acetate (v/v)=3/1) to obtain 2.55 g of yellow solid, yield: 97%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.02 (br.s, 1H), 7.59 (s, 1H), 7.47-7.45 (m, 2H), 7.39-7.28 (m, 4H), 6.84 (d, J =8.4Hz,1H),5.17(s,2H),4.54(m,J=4.6Hz,2H),3.90(s,3H),3.83(s,3H);

MS-ESI: m/z 346.2 [M+H] ⁺ .

Step 5: Synthesis of the compound methyl 2-(((3-(benzyloxy)-4-methoxyphenyl)(methylthio)methylene)amino)acetate

At -78°C, a solution of the compound 2-(3-(benzyloxy)-4-methoxyphenylthioamide)acetic acid methyl ester (2.55g, 7.39mmol) in dichloromethane (30mL) was slowly dropped Add trimethyloxonium tetrafluoroboric acid (1.31g, 8.87mmol) in dichloromethane solution (20mL), continue to stir at 0°C for 3h, add saturated sodium bicarbonate solution for washing (25mL×3), organic phase _After drying with anhydrous _Na2SO4 , the solvent was removed to obtain 2.1 g of yellow oil, yield: 80%.

MS-ESI: m/z 360.1 [M+H] ⁺ .

Step 6: Compound (S)-2-(3-(Benzyloxy)-4-methoxyphenyl)-5-(1-(tert-butoxycarbonylamino)ethyl)oxazole-4-carboxylic acid Synthesis of methyl esters

Compound 2-(((3-(benzyloxy)-4-methoxyphenyl)(methylthio)methylene)amino)methyl acetate (2.47g, 8.31mmol) and compound (S)- (1-Fluoro-1-oxopropan-2-yl) tert-butyl carbamate (2.38g, 12.46mmol) was dissolved in anhydrous tetrahydrofuran (20mL), and hexamethyldi The tetrahydrofuran solution of potassium silylamide (20.78mL, 20.78mmol), reacted at -78°C for 1h, added ice water (20mL) to quench the reaction, extracted with ethyl acetate (15mL×3), combined the organic phases with After drying over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=3/1) to obtain 1 g of yellow solid, yield: 28%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.68-7.64 (m, 2H), 7.50-7.48 (m, 2H), 7.41-7.30 (m, 3H), 6.95 (d, J=8.4Hz, 1H), 5.69(br.s,1H),5.47-5.43(m,1H),5.20(s,2H),3.97(s,3H),3.93(s,3H),1.53(d,J=7.0Hz,3H) ,1.39(s,9H);

MS-ESI: m/z 483.1 [M+H] ⁺ .

Step 7: Compound (S)-2-(3-(Benzyloxy)-4-methoxyphenyl)-5-(1-(tert-butoxycarbonylamino)ethyl)oxazole-4-carboxylic acid Synthesis

Compound (S)-2-(3-(benzyloxy)-4-methoxyphenyl)-5-(1-(tert-butoxycarbonylamino)ethyl)oxazole-4-carboxylic acid methyl ester (390mg, 0.81mmol) and lithium hydroxide monohydrate (172mg, 4.1mmol) were dissolved in a mixed solvent of tetrahydrofuran (20mL) and water (10mL), reacted at 40°C for 3h, removed tetrahydrofuran, added hydrochloric acid (1M) Adjust the pH value to 1, add ethyl acetate for extraction (30 mL×3), combine the organic phases and dry with Na ₂ SO ₄ , remove the solvent to obtain 352 mg of white solid, yield: 93%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.69-7.66(m, 2H), 7.51(d, J=7.2Hz, 1H), 7.42-7.34(m, 3H), 6.97(d, J=8.3Hz, 1H),5.72(br.s,1H),5.43-5.41(m,1H),5.22(s,2H),3.95(s,3H),1.58(d,J＝7.0Hz,3H), 1.45(s ,9H);

MS-ESI: m/z 467.2 [MH] ^- .

Step 8: Compound (S)-(1-(2-(3-(benzyloxy)-4-methoxyphenyl)-4-((2,4-difluorobenzyl)carbamoyl)oxa Synthesis of tert-butyl (azol-5-yl)ethyl)carbamate

Compound (S)-2-(3-(benzyloxy)-4-methoxyphenyl)-5-(1-(tert-butoxycarbonylamino)ethyl)oxazole-4-carboxylic acid (352mg , 0.75mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (215.7mg, 1.13mmol) and N-hydroxyl-7-azabenzotriazole ( 152.7mg, 1.13mmol) was dissolved in dichloromethane (10mL), stirred at room temperature for 0.5h, and 2,4-difluorobenzylamine (0.10mL, 0.90mmol) and N,N-diisopropyl Ethylamine (0.40mL, 2.25mmol), stirred at room temperature for 12h, added water (20mL), extracted with dichloromethane (20mL×3), combined the organic phases and dried with Na ₂ SO ₄ , removed the solvent, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=6/1), 320 mg of white solid was obtained, yield: 72%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.60-7.54(m, 2H), 7.48(d, J=7.2Hz, 2H), 7.44-7.36(m, 3H), 7.32(d, J=7.2Hz, 1H), 6.94(d, J＝8.5Hz, 1H), 6.90-6.82(m, 2H), 5.28-5.26(m, 1H), 5.25(s, 2H), 4.66-4.63(m, 2H), 3.93 (s,3H),1.52(d,J=7.0Hz,3H),1.25(s,9H);

MS-ESI: m/z 594.0 [M+H] ⁺ .

Step 9: Compound (S)-5-(1-aminoethyl)-2-(3-(benzyloxy)-4-methoxyphenyl)-N-(2,4-difluorobenzyl) Synthesis of Oxazole-4-Carboxamide Hydrochloride

To compound (S)-(1-(2-(3-(benzyloxy)-4-methoxyphenyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazole- 5-yl) ethyl) tert-butyl carbamate (300mg, 0.51mmol) in dichloromethane (2mL) solution was added HCl in ethyl acetate solution (4M, 5mL), stirred at room temperature for 0.5h, after removing the solvent, use Methanol/ethyl acetate (v/v=1/20) recrystallized to obtain 230 mg of white solid, yield: 92%.

Compound 6: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.73-7.71(m, 2H), 7.48-7.44(m, 3H), 7.39-7.31(m, 3H), 7.13(d, J=8.1Hz ,1H),6.99-6.92(m,2H),5.17(s,2H),5.13-5.08(m,1H),4.62(s,2H),3.92(s,3H),1.73(d,J＝7.0 Hz, 3H).

Example 103: Compound (S)-5-(1-aminoethyl)-N-(2,4-difluorobenzyl)-2-(3-nitro-4-methoxy Synthesis of phenyl)oxazole-4-carboxamide hydrochloride

Step 1: Synthesis of the compound 2-(3-nitro-4-methoxybenzamido)methyl acetate

3-nitro-4-methoxybenzoic acid (5.0g, 25.4mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (7.3g, 38.1mmol ) and 1-hydroxybenzotriazole (5.15g, 38.1mmol) were dissolved in dichloromethane (30mL), stirred at room temperature for 0.5h, glycine methyl ester hydrochloride (3.83g, 30.5mmol) and N , N-diisopropylethylamine (13.3mL, 76.2mmol), stirred at room temperature for 12h, added water (30mL), extracted with dichloromethane (40mL×3), combined the organic phases and dried with Na ₂ SO ₄ to remove The solvent and the concentrate were subjected to column separation (petroleum ether/ethyl acetate (v/v)=1/1) to obtain 6.34 g of white solid, yield: 95%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.28(s, 1H), 8.04-8.00(m, 1H), 7.14-6.99(m, 1H), 6.88(br.s, 1H), 4.24-4.21(m ,2H),4.00(s,3H),3.80(s,3H);

MS-ESI: m/z 269.0 [M+H] ⁺ .

Step 2: Synthesis of the compound 2-(3-nitro-4-methoxyphenylthioamide) methyl acetate

The compound 2-(3-nitro-4-methoxybenzamido) methyl acetate (2.0g, 7.46mmol) and Lawson's reagent (3.02g, 7.46mmol) were dissolved in tetrahydrofuran (20mL), 75 Stir at reflux for 2 h, add saturated sodium bicarbonate solution (30 mL), extract with ethyl acetate (50 mL×3), combine organic phases and dry with Na ₂ SO ₄ , remove the solvent, and the concentrated solution is subjected to column separation (petroleum ether/ Ethyl acetate (v/v)=3/1), to obtain 2.1 g of yellow solid, yield: 98%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.33(s, 1H), 8.10(d, J=8.9Hz, 1H), 7.11(d, J=8.9Hz, 1H), 4.57(d, J=4.6Hz ,2H),4.02(s,3H),3.86(s,3H);

MS-ESI: m/z 285.1 [M+H] ⁺ .

Step 3: Synthesis of the compound 2-(((3-nitro-4-methoxyphenyl)(methylthio)methylene)amino)acetate methyl ester

At -78°C, a solution of the compound 2-(3-nitro-4-methoxyphenylthioamide) methyl acetate (0.5g, 1.76mmol) in dichloromethane (20mL) was slowly added dropwise to three Methyloxonium tetrafluoroboric acid (0.39g, 2.64mmol) in dichloromethane (20mL) solution, continue stirring at 0°C for 3h, add saturated sodium bicarbonate solution for washing (25mL×3), and wash the organic phase with anhydrous Drying over Na ₂ SO ₄ and removing the solvent gave 0.495 g of yellow oil, yield: 95%.

MS-ESI: m/z 299.0 [M+H] ⁺ .

Step 4: Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3-nitro-4-methoxyphenyl)oxazole-4-carboxylic acid methyl ester synthesis

Compound 2-(((3-nitro-4-methoxyphenyl)(methylthio)methylene)amino)methyl acetate (0.495g, 1.66mmol), compound (S)-(1- Fluoro-1-oxopropan-2-yl) tert-butyl carbamate (0.476g, 2.49mmol) was dissolved in anhydrous tetrahydrofuran (20mL), and at -78°C, hexamethyldisilazylamine was added dropwise Potassium tetrahydrofuran solution (6.6mL, 6.6mmol), react at -78°C for 1h, add ice water (20mL) to quench the reaction, extract with ethyl acetate (15mL×3), combine the organic phases with anhydrous Na ₂ SO ₄ was dried, the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v)=3/1) to obtain 0.213 g of a yellow solid, yield: 32%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.51(s, 1H), 8.27(d, J=8.9Hz, 1H), 7.18(d, J=8.9Hz, 1H), 5.59(br.s, 1H) ,5.49-5.45(m,1H),4.04(s,3H),3.98(s,3H),1.55(d,J=7.0Hz,3H),1.42(s,9H);

MS-ESI: m/z 422.1 [M+H] ⁺ .

Step 5: Synthesis of compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3-nitro-4-methoxyphenyl)oxazole-4-carboxylic acid

Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3-nitro-4-methoxyphenyl)oxazole-4-carboxylic acid methyl ester (0.24g ,0.57mmol) and lithium hydroxide monohydrate (0.068g, 2.85mmol) were dissolved in a mixed solvent of tetrahydrofuran (20mL) and water (10mL), reacted at 40°C for 3h, removed tetrahydrofuran, added hydrochloric acid (1M) to adjust the pH When the value reached 1, it was extracted with ethyl acetate (30 mL×3), the organic phases were combined and dried with Na ₂ SO ₄ , and the solvent was removed to obtain 0.211 mg of white solid, yield: 91%.

Step 6: Compound (S)-(1-(4-((2,4-difluorobenzyl)carbamoyl)-2-(3-nitro-4-methoxyphenyl)oxazole-5 Synthesis of -yl) ethyl) tert-butyl carbamate

Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3-nitro-4-methoxyphenyl)oxazole-4-carboxylic acid (211mg, 0.52mmol ), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (149.5mg, 0.78mmol) and N-hydroxy-7-azabenzotriazole (105.4mg, 0.78mmol) was dissolved in dichloromethane (10mL), stirred at room temperature for 0.5h, and 2,4-difluorobenzylamine (0.08mL, 0.63mmol) and N,N-diisopropylethylamine ( 0.27mL, 1.56mmol), stirred at room temperature for 12h, added water (15mL), extracted with dichloromethane (20mL×3), combined the organic phases and dried them with Na ₂ SO ₄ , removed the solvent, and the concentrated solution was subjected to column separation (petroleum ether /ethyl acetate (v/v)=6/1), to obtain 190 mg of white solid, yield: 70%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.48(s, 1H), 8.14(d, J=8.8Hz, 1H), 7.44-7.38(m, 1H), 7.17(d, J=8.9Hz, 1H) ,6.89-6.82(m,2H),6.74(br.s,1H),5.30(t,J=7.0Hz,1H),4.64(d,J=4.2Hz,2H),4.03(s,3H), 1.53(d,J=7.0Hz,3H),1.42(s,9H);

MS-ESI: m/z 533.0 [M+H] ⁺ .

Step 7: Compound (S)-5-(1-aminoethyl)-N-(2,4-difluorobenzyl)-2-(3-nitro-4-methoxyphenyl)oxazole- Synthesis of 4-Formamide Hydrochloride

To compound (S)-(1-(4-((2,4-difluorobenzyl)carbamoyl)-2-(3-nitro-4-methoxyphenyl)oxazol-5-yl ) Ethyl) tert-butyl carbamate (190mg, 0.36mmol) in dichloromethane (2mL) solution was added HCl in ethyl acetate solution (4M, 3mL), stirred at room temperature for 0.5h, after removing the solvent, with methanol / acetic acid Ethyl ester (v/v=1/20) was recrystallized to obtain 144 mg of white solid, yield: 93%.

Compound 10: ¹ H NMR (400MHz, CDCl ₃ ): δppm 8.49(s, 1H), 8.16(d, J=8.7Hz, 1H), 7.62-7.58(m, 1H), 7.41-7.39(m, 1H) ,7.19(d,J=8.9Hz,1H),6.90-6.87(m,1H),4.99-4.96(m,1H),4.63(d,J=6.0Hz,2H),4.05(s,3H), 1.74(d,J=7.0Hz,3H);

MS-ESI: m/z 433.2 [M+H-HCl] ⁺ .

Example 104: Compound 5-(aminomethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-N-(2,4- Synthesis of difluorobenzyl)oxazole-4-carboxamide hydrochloride

Step 1: Synthesis of the compound (2-fluoro-2-oxoethyl) tert-butyl carbamate

N-Boc-glycine (2.5g, 14.29mmol) and triethylamine (2.15mL, 15.72mmol) were dissolved in dichloromethane (20mL), and cyanuric fluoride (2.7mL, 28.58 mmol), continued the reaction at -10°C for 1 h, washed with ice water (20 mL×3), dried the organic phase with anhydrous Na ₂ SO ₄ , and removed the solvent to obtain 2.12 g of white solid, yield: 84%.

¹ H NMR (400 MHz, d ₆ -DMSO): δ ppm 7.54-7.51 (m, 1H), 4.03-4.00 (m, 2H), 1.39 (s, 9H).

Step 2: Compound 5-((tert-butoxycarbonylamino)methyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)oxazole-4-carboxylic acid methyl ester synthesis

Compound 2-(((3-(cyclopropylmethoxy)-4-methoxyphenyl)(methylthio)methylene)amino)acetic acid methyl ester (1.99g, 6.16mmol), compound ( 2-Fluoro-2-oxoethyl) tert-butyl carbamate (2.18g, 12.32mmol) was dissolved in anhydrous tetrahydrofuran (30mL), and at -78°C, potassium hexamethyldisilazide was added dropwise Tetrahydrofuran solution (18.48mL, 18.48mmol), react at -78°C for 1h, add ice water (20mL) to quench the reaction, extract with ethyl acetate (15mL×3), combine the organic phases with anhydrous Na ₂ SO ₄ was dried, the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=2/1) to obtain 0.57 g of a yellow solid, yield: 25%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.66 (dd, J ₁ = 8.4Hz, J ₂ = 2.0Hz, 1H), 7.55 (d, J = 2.0Hz, 1H), 6.92 (d, J = 8.5Hz ,1H),5.28(br.s,1H),4.72(d,J=5.7Hz,2H),3.97(s,3H),3.93(s,3H),3.92(d,J=6.0Hz,2H) ,1.46(s,9H),1.39-1.35(m,1H),0.69-0.64(m,2H),0.40-0.36(m,2H);

MS-ESI: m/z 433.3 [M+H] ⁺ .

Step 3: Synthesis of compound 5-((tert-butoxycarbonylamino)methyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)oxazole-4-carboxylic acid

The compound 5-((tert-butoxycarbonylamino)methyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)oxazole-4-carboxylic acid methyl ester (0.57g , 1.32mmol) and lithium hydroxide monohydrate (0.28g, 6.60mmol) were dissolved in a mixed solvent of tetrahydrofuran (20mL) and water (10mL), reacted at 40°C for 3h, removed tetrahydrofuran, added hydrochloric acid (1M) to adjust The pH value was brought to 1, extracted with ethyl acetate (30 mL×3), the organic phases were combined and dried with Na ₂ SO ₄ , and the solvent was removed to obtain 0.54 g of white solid, yield: 99%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.64 (dd, J ₁ =8.4Hz, J ₂ =1.9Hz, 1H), 7.56 (s, 1H), 6.93 (d, J = 8.5Hz, 1H), 5.36 (br.s,1H),4.71-4.64(m,2H),3.94(s,3H),3.93(d,J=7.1Hz,2H),1.47(s,9H),1.37-1.35(m,1H ),0.69-0.65(m,2H),0.40-0.38(m,2H);

MS-ESI: m/z 419.1 [M+H] ⁺ .

Step 4: Compound ((2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazole-5 Synthesis of -yl) methyl) tert-butyl carbamate

Compound 5-((tert-butoxycarbonylamino)methyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)oxazole-4-carboxylic acid (0.21g, 0.48 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.14g, 0.72mmol) and N-hydroxy-7-azabenzotriazole (0.10g , 0.72mmol) was dissolved in dichloromethane (10mL), stirred at room temperature for 0.5h, and 2,4-difluorobenzylamine (0.06mL, 0.58mmol) and N,N-diisopropylethylamine were added dropwise at 0°C (0.25mL, 1.44mmol), stirred at room temperature for 12h, added water (15mL), extracted with dichloromethane (20mL×3), combined the organic phases and dried with Na ₂ SO ₄ , removed the solvent, and the concentrated solution was subjected to column separation (petroleum Ether/ethyl acetate (v/v)=3/1) to obtain 0.26 g of white solid, yield: 97%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.59 (dd, J ₁ =8.4Hz, J ₂ =2.0Hz, 1H), 7.46 (d, J = 2.0Hz, 1H), 7.43-7.37 (m, 1H) ,6.92(d,J=8.5Hz,1H),6.89-6.81(m,2H),4.70(d,J=6.2Hz,2H),4.63(d,J=6.2Hz,2H),3.93(s, 3H), 3.92(d, J=6.9Hz, 2H), 1.46(s, 9H), 1.38-1.35(m, 1H), 0.70-0.65(m, 2H), 0.41-0.38(m, 2H);

MS-ESI: m/z 544.2 [M+H] ⁺ .

Step 5: Compound 5-(aminomethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-N-(2,4-difluorobenzyl)oxazole- Synthesis of 4-Formamide Hydrochloride

To the compound ((2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazol-5-yl ) Methyl) tert-butyl carbamate (0.26g, 0.48mmol) in dichloromethane (3mL) solution was added HCl in ethyl acetate solution (4M, 4mL), stirred at room temperature for 0.5h, after removing the solvent, with methanol / Ethyl acetate (v/v=1/20) was recrystallized to obtain 210 mg of white solid, yield: 91%.

Compound 15: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.69 (dd, J ₁ =8.4Hz, J ₂ =2.0Hz, 1H), 7.61 (d, J = 2.0Hz, 1H), 7.48-7.42( m,1H),7.09(d,J=8.5Hz,1H),6.98-6.90(m,2H),4.61(s,2H),4.58(s,2H),3.91(d,J=6.9Hz,2H ),3.91(s,3H),1.34-1.26(m,1H),0.65-0.61(m,2H),0.38-0.34(m,2H);

MS-ESI: m/z 444.1 [M+H-HCl] ⁺ .

Example 105: Compound (R)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-N- Synthesis of (2,4-difluorobenzyl)oxazole-4-carboxamide hydrochloride

Step 1: Synthesis of compound (R)-tert-butyl(1-fluoro-1-oxopropan-2-yl)carbamate

N-Boc-R-alanine (1.0g, 5.29mmol) and triethylamine (0.8mL, 5.82mmol) were dissolved in dichloromethane (20mL), and cyanuric fluoride ( 1.0mL, 10.58mmol), continued the reaction at -10°C for 1h, washed with ice water (20mL×3), dried the organic phase with anhydrous Na ₂ SO ₄ , removed the solvent to obtain 0.82g of white solid, yield: 81%.

¹ H NMR (400 MHz, d ₆ -DMSO): δ ppm 4.33-4.26 (m, 1H), 1.39 (s, 9H), 1.35 (d, J = 7.2 Hz, 3H).

Step 2: Compound (R)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)oxazole-4 -Synthesis of methyl carboxylate

Compound 2-(((3-(cyclopropylmethoxy)-4-methoxyphenyl)(methylthio)methylene)amino)acetate methyl ester (0.5g, 1.55mmol), compound ( R)-(1-fluoro-1-oxopropan-2-yl)carbamate tert-butyl ester (0.59g, 3.1mmol) was dissolved in anhydrous tetrahydrofuran (20mL), and at -78°C, six Potassium methyldisilazide tetrahydrofuran solution (6.2mL, 6.2mmol), react at -78°C for 1h, add ice water (20mL) to quench the reaction, extract with ethyl acetate (15mL×3), combine organic The phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v)=2/1) to obtain 0.34 g of a yellow solid, yield: 50%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.63(d, J=8.4Hz, 1H), 7.54(s, 1H), 6.92(d, J=8.4Hz, 1H), 5.46-5.42(m, 1H) ,3.97(s,3H),3.94(s,3H),3.93(d,J=7.0Hz,2H),1.53(d,J=7.0Hz,3H),1.42(s,9H),1.27-1.24( m,1H),0.69-0.65(m,2H),0.40-0.37(m,2H);

MS-ESI: m/z 447.3 [M+H] ⁺ .

Step 3: Compound (R)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)oxazole-4 -Synthesis of carboxylic acids

Compound (R)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)oxazole-4-carboxy Dissolve methyl ester (0.34g, 0.76mmol) and lithium hydroxide monohydrate (0.16g, 3.8mmol) in a mixed solvent of tetrahydrofuran (20mL) and water (10mL), react at 40°C for 3h, remove tetrahydrofuran, add The pH value was adjusted to 1 with hydrochloric acid (1M), extracted with ethyl acetate (30 mL×3), the organic phases were combined and dried with Na ₂ SO ₄ , and the solvent was removed to obtain 310 mg of white solid, yield: 94%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.62(d, J=8.4Hz, 1H), 7.54(s, 1H), 6.93(d, J=8.4Hz, 1H), 5.40-5.36(m, 1H) ,3.94(s,3H),3.93(d,J=7.0Hz,2H),1.57(d,J=7.1Hz,3H),1.44(s,9H),1.27-1.25(m,1H),0.68- 0.66(m,2H),0.40-0.38(m,2H);

MS-ESI: m/z 433.3 [M+H] ⁺ .

Step 4: Compound (R)-(1-(2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-4-((2,4-difluorobenzyl)aminomethyl Synthesis of tert-butyl Acyl)oxazol-5-yl)ethyl)carbamate

Compound (R)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)oxazole-4-carboxy acid (0.31g, 0.72mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.21g, 1.08mmol) and N-hydroxyl-7-azabenzo Triazole (0.15g, 1.08mmol) was dissolved in dichloromethane (10mL), stirred at room temperature for 0.5h, and 2,4-difluorobenzylamine (0.10mL, 0.86mmol) and N,N- Diisopropylethylamine (0.38mL, 2.16mmol), stirred at room temperature for 12h, added water (15mL), extracted with dichloromethane (20mL×3), combined the organic phases and dried with Na ₂ SO ₄ , removed the solvent and concentrated The liquid was subjected to column separation (petroleum ether/ethyl acetate (v/v)=5/1) to obtain 0.29 g of white solid, yield: 73%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.57 (d, J=8.4Hz, 1H), 7.54 (br.s, 1H), 7.45-7.38 (m, 2H), 6.93-6.80 (m, 2H), 5.29-5.27(m,1H),4.65-4.62(m,2H),3.93(s,3H),3.92(d,J=6.9Hz,2H),1.52(d,J=7.0Hz,3H),1.43 (s,9H),1.25-1.23(m,1H),0.69-0.66(m,2H),0.42-0.38(m,2H);

MS-ESI: m/z 558.2 [M+H] ⁺ .

Step 5: Compound (R)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-N-(2,4-difluoro Synthesis of benzyl)oxazole-4-carboxamide hydrochloride

To compound (R)-(1-(2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-4-((2,4-difluorobenzyl)carbamoyl) Add HCl in ethyl acetate (4M, 5mL) to a solution of tert-butyl oxazol-5-yl)ethyl)carbamate (0.29g, 0.52mmol) in dichloromethane (3mL), stir at room temperature for 0.5h, remove After solvent, recrystallize from methanol/ethyl acetate (v/v=1/20) to obtain 184 mg of white solid, yield: 78%.

Compound 16: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.69 (dd, J ₁ =8.4Hz, J ₂ =2.0Hz, 1H), 7.61 (d, J = 2.0Hz, 1H), 7.48-7.42( m,1H),7.10(d,J＝8.5Hz,1H),6.99-6.91(m,2H),5.14-5.09(m,1H),4.61(s,2H),3.91(s,3H),3.91 (d, J=6.9Hz, 2H), 1.73(d, J=7.0Hz, 3H), 1.32-1.28(m, 1H), 0.66-0.61(m, 2H), 0.38-0.34(m, 2H);

MS-ESI: m/z 458.1 [M+H-HCl] ⁺ .

Example 106: Compound (S)-5-(1-amino-2-methylpropyl)-2-(3-(cyclopropylmethoxy)-4-methoxy Synthesis of phenyl)-N-(2,4-difluorobenzyl)oxazole-4-carboxamide hydrochloride

Step 1: Synthesis of compound (S)-tert-butyl(1-fluoro-3-methyl-1-oxobutan-2-yl)carbamate

N-Boc-L-valine (3.1g, 14.29mmol) and triethylamine (2.2mL, 15.72mmol) were dissolved in dichloromethane (20mL), and cyanuric fluoride ( 2.7mL, 28.58mmol), continued the reaction at -10°C for 1h, washed with ice water (20mL×3), dried the organic phase with anhydrous Na ₂ SO ₄ , removed the solvent to obtain 3.01g of white solid, yield: 96%.

¹ H NMR (400 MHz, d ₆ -DMSO): δ ppm 4.10-4.06 (m, 1H), 2.12-2.03 (m, 1H), 1.45 (s, 9H), 0.97-0.94 (m, 6H).

Step 2: Compound (S)-5-(1-(tert-butoxycarbonylamino)-2-methylpropyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl ) Synthesis of methyl oxazole-4-carboxylate

Compound 2-(((3-(cyclopropylmethoxy)-4-methoxyphenyl)(methylthio)methylene)amino)acetate methyl ester (2.2 g, 6.80 mmol) and compound ( S)-(1-fluoro-3-methyl-1-oxobutan-2-yl)carbamate tert-butyl ester (2.98g, 13.60mmol) was dissolved in anhydrous tetrahydrofuran (40mL) at -78°C Add dropwise a tetrahydrofuran solution of potassium hexamethyldisilazide (20.4mL, 20.40mmol), react at -78°C for 1h, add ice water (20mL) to quench the reaction, extract with ethyl acetate (15mL× 3), after merging the organic phases, use anhydrous Na ₂ SO ₄ to dry, remove the solvent, and concentrate the liquid for column separation (petroleum ether/ethyl acetate (v/v)=6/1), obtain 1.13g yellow solid, yield : 38%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.63 (dd, J ₁ =8.4Hz, J ₂ =2.0Hz, 1H), 7.54 (d, J = 2.0Hz, 1H), 6.93 (d, J = 8.5Hz ,1H),5.11-5.07(m,1H),3.94(d,J＝6.9Hz,2H),3.93(s,3H),3.89(s,3H),1.44(s,9H),1.36-1.33( m,1H),1.04(d,J=6.6Hz,3H),0.89(d,J=6.7Hz,3H),0.68-0.63(m,2H),0.40-0.35(m,2H);

MS-ESI: m/z 475.3 [M+H] ⁺ .

Step 3: Compound (S)-5-(1-(tert-butoxycarbonylamino)-2-methylpropyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl ) Synthesis of oxazole-4-carboxylic acid

Compound (S)-5-(1-(tert-butoxycarbonylamino)-2-methylpropyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)oxa Methyl azole-4-carboxylate (1.13g, 2.38mmol) and lithium hydroxide monohydrate (0.50g, 11.92mmol) were dissolved in a mixed solvent of tetrahydrofuran (40mL) and water (20mL), and reacted at 40°C for 3h , remove tetrahydrofuran, add hydrochloric acid (1M) to adjust the pH value to 1, add ethyl acetate to extract (30mL×3), the organic phases are combined and dried with Na ₂ SO ₄ , the solvent is removed to obtain 0.47g white solid, yield: 43 %.

MS-ESI: m/z 461.3 [M+H] ⁺ .

Step 4: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-4-((2,4-difluorobenzyl)aminomethyl Synthesis of tert-butyl Acyl)oxazol-5-yl)-2-methylpropyl)carbamate

Compound (S)-5-(1-(tert-butoxycarbonylamino)-2-methylpropyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)oxa Azole-4-carboxylic acid (0.20g, 0.43mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.12g, 0.65mmol) and N-hydroxyl-7 -Azabenzotriazole (0.09g, 0.65mmol) was dissolved in dichloromethane (10mL), stirred at room temperature for 0.5h, and 2,4-difluorobenzylamine (0.06mL, 0.52mmol) was added dropwise at 0°C and N,N-diisopropylethylamine (0.23mL, 1.30mmol), stirred at room temperature for 12h, added water (15mL), extracted with dichloromethane (20mL×3), combined organic phases and dried with Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=5/1) to obtain 0.23 g of a white solid, yield: 93%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.57 (dd, J ₁ =8.4Hz, J ₂ =2.0Hz, 1H), 7.45 (d, J = 2.0Hz, 1H), 7.42-7.38 (m, 1H) ,6.92(d,J＝8.5Hz,1H),6.89-6.82(m,2H),4.90-4.85(m,1H),4.66-4.64(m,2H),3.93(s,3H),3.94(d ,J=5.3Hz,2H),2.20-2.11(m,1H),1.44(s,9H),1.36-1.35(m,1H),1.02(d,J=6.7Hz,3H),0.86(d, J=6.7Hz, 3H), 0.71-0.66(m, 2H), 0.43-0.39(m, 2H);

MS-ESI: m/z 586.2 [M+H] ⁺ .

Step 5: Compound (S)-5-(1-amino-2-methylpropyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-N-(2 , Synthesis of 4-difluorobenzyl)oxazole-4-carboxamide hydrochloride

To compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-4-((2,4-difluorobenzyl)carbamoyl) To a solution of tert-butyl oxazol-5-yl)-2-methylpropyl)carbamate (0.29g, 0.50mmol) in dichloromethane (2mL) was added HCl in ethyl acetate (4M, 8mL), room temperature Stir for 0.5 h, remove the solvent, and recrystallize from methanol/ethyl acetate (v/v=1/20) to obtain 246 mg of white solid, yield: 94%.

Compound 17: ¹ H NMR (400MHz, CDCl ₃ ): δppm 7.74-7.71(m, 1H), 7.59(d, J=8.4Hz, 1H), 7.46(s, 1H), 7.44-7.40(m, 1H) ,6.94-6.91(m,1H),6.89-6.84(m,1H),4.80-4.75(m,1H),4.66-4.63(m,2H),3.95(s,3H),3.94(d,J= 7.0Hz, 2H), 2.70-2.68(m, 1H), 1.41–1.34(m, 1H), 1.13(d, J=5.7Hz, 3H), 1.00(d, J=5.6Hz, 3H), 0.72- 0.67(m,2H),0.44–0.41(m,2H);

MS-ESI: m/z 486.1 [M+H-HCl] ⁺ .

Example 107: Compound (S)-5-(1-amino-2-phenylethyl)-2-(3-(cyclopropylmethoxy)-4-methoxy Synthesis of phenyl)-N-(2,4-difluorobenzyl)oxazole-4-carboxamide hydrochloride

Step 1: Synthesis of compound (S)-tert-butyl(1-fluoro-1-oxo-3-phenylpropan-2-yl)carbamate

Dissolve N-Boc-L-phenylalanine (3.6g, 14.29mmol) and triethylamine (2.2mL, 15.72mmol) in dichloromethane (20mL), and slowly add trifluoromethane dropwise at -40°C Cyanide (2.7mL, 28.58mmol), continued to react at -10°C for 1h, washed with ice water (20mL×3), dried the organic phase with anhydrous Na ₂ SO ₄ , and removed the solvent to obtain 3.07g of a white solid, product Rate: 85%.

¹ H NMR (400MHz, d ₆ -DMSO): δppm 7.32-7.22 (m, 5H), 4.50-4.44 (m, 1H), 3.11-2.98 (m, 2H), 1.35 (s, 9H);

MS-ESI: m/z 266.0 [MH] ^- .

Step 2: Compound (S)-5-(1-(tert-butoxycarbonylamino)-2-phenylethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl ) Synthesis of methyl oxazole-4-carboxylate

Compound 2-(((3-(cyclopropylmethoxy)-4-methoxyphenyl)(methylthio)methylene)amino)acetate methyl ester (2.1 g, 6.50 mmol) and compound ( S)-(1-fluoro-1-oxo-3-phenylpropan-2-yl)carbamate tert-butyl ester (3.47g, 13.00mmol) was dissolved in anhydrous tetrahydrofuran (40mL) at -78°C , dropwise added a tetrahydrofuran solution of potassium hexamethyldisilazide (19.5mL, 19.50mmol), reacted at -78°C for 1h, added ice water (20mL) to quench the reaction, extracted with ethyl acetate (15mL×3 ), combined the organic phases with anhydrous Na ₂ SO ₄ dried, removed the solvent, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=3/1) to obtain 0.95g yellow solid, yield: 28%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.51 (d, J = 6.7Hz, 1H), 7.42 (s, 1H), 7.23-7.11 (m, 5H), 6.90 (d, J = 8.5Hz, 1H) ,5.63-5.57(m,1H),3.94(s,3H),3.92(s,3H),3.90(d,J＝7.0Hz,2H),3.15-3.10(m,2H),1.40(s,9H ),1.34-1.31(m,1H),0.70-0.64(m,2H),0.40-0.36(m,2H);

MS-ESI: m/z 523.3 [M+H] ⁺ .

Step 3: Compound (S)-5-(1-(tert-butoxycarbonylamino)-2-phenylethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl ) Synthesis of oxazole-4-carboxylic acid

Compound (S)-5-(1-(tert-butoxycarbonylamino)-2-phenylethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)oxa Methyl azole-4-carboxylate (0.95g, 1.82mmol) and lithium hydroxide monohydrate (0.38g, 9.10mmol) were dissolved in a mixed solvent of tetrahydrofuran (40mL) and water (20mL), and reacted at 40°C for 3h , remove tetrahydrofuran, add hydrochloric acid (1M) to adjust the pH value to 1, add ethyl acetate to extract (30mL×3), the organic phases are combined and dried with Na ₂ SO ₄ , the solvent is removed to obtain 0.90g white solid, yield: 97 %.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.25-7.14(m, 7H), 6.90(d, J=8.5Hz, 1H), 5.94(br.s, 1H), 5.57-5.55(m, 1H), 3.93(s,3H),3.91(d,J＝7.1Hz,2H),3.21-3.18(m,2H),1.39(s,9H),1.34-1.31(m,1H),0.70-0.65(m, 2H),0.41-0.37(m,2H);

MS-ESI: m/z 509.2 [M+H] ⁺ .

Step 4: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-4-((2,4-difluorobenzyl)aminomethyl Synthesis of tert-butyl Acyl)oxazol-5-yl)-2-phenylethyl)carbamate

Compound (S)-5-(1-(tert-butoxycarbonylamino)-2-phenylethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)oxa Azole-4-carboxylic acid (0.20g, 0.40mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.14g, 0.72mmol) and N-hydroxyl-7 -Azabenzotriazole (0.10g, 0.72mmol) was dissolved in dichloromethane (10mL), stirred at room temperature for 0.5h, and 2,4-difluorobenzylamine (0.06mL, 0.48mmol) was added dropwise at 0°C and N,N-diisopropylethylamine (0.25mL, 1.44mmol), stirred at room temperature for 12h, added water (15mL), extracted with dichloromethane (20mL×3), combined organic phases and dried with Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=5/1) to obtain 0.24 g of a white solid, yield: 94%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.53-7.48 (m, 1H), 7.43-7.37 (m, 2H), 7.22-7.18 (m, 2H), 7.15-7.11 (m, 3H), 6.91-6.83 (m,3H),5.43-5.37(m,1H),4.71-4.60(m,2H),3.92(s,3H),3.89(d,J＝7.0Hz,2H),3.23-3.10(m,2H ),1.40(s,9H),1.36-1.34(m,1H),0.71-0.66(m,2H),0.42-0.38(m,2H);

MS-ESI: m/z 534.1 [M+H-100] ⁺ .

Step 5: Compound (S)-5-(1-amino-2-phenylethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-N-(2 , Synthesis of 4-difluorobenzyl)oxazole-4-carboxamide hydrochloride

To compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-4-((2,4-difluorobenzyl)carbamoyl) To a solution of tert-butyl oxazol-5-yl)-2-phenylethyl)carbamate (0.24g, 0.38mmol) in dichloromethane (3mL) was added HCl in ethyl acetate (4M, 4mL), room temperature Stir for 0.5 h, remove the solvent, and recrystallize from methanol/ethyl acetate (v/v=1/20) to obtain 150 mg of white solid, yield: 70%.

Compound 19: ¹ H NMR (400MHz, CD ₃ OD) δppm 7.58 (dd, J ₁ =8.4Hz, J ₂ =2.0Hz, 1H), 7.48 (d, J = 2.0Hz, 1H), 7.39-7.33(m ,1H),7.26–7.20(m,3H),7.15–7.13(m,2H),7.07(d,J＝8.5Hz,1H),6.99–6.91(m,2H),5.32–5.29(m,1H ),4.56(s,2H),3.90(s,3H),3.88(d,J＝7.0Hz,2H),3.44-3.34(m,2H),1.33–1.25(m,1H),0.66–0.61( m,2H),0.38–0.34(m,2H);

MS-ESI: m/z 534.1 [M+H-HCl] ⁺ .

Example 108: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-N- Synthesis of (3,5-dichloropyridin-4-yl)oxazole-4-carboxamide dihydrochloride

Step 1: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-4-(fluorocarbonyl)oxazol-5-yl)ethyl ) Synthesis of tert-butyl carbamate

Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)oxazole-4-carboxy Acid (0.30g, 0.70mmol) and triethylamine (0.10mL, 0.77mmol) were dissolved in dichloromethane (10mL), and cyanuric fluoride (0.20mL, 1.40 mmol), reacted at -10°C for 1 h, washed with ice water (20 mL×3), dried the organic phase with anhydrous Na ₂ SO ₄ , and removed the solvent to obtain 282 mg of white solid, yield: 93%.

¹ H NMR (400MHz, d ₆ -DMSO): δppm 7.59 (dd, J ₁ =8.4Hz, J ₂ =1.9Hz, 1H), 7.45 (d, J = 2.0Hz, 1H), 7.17 (d, J = 8.6Hz, 1H), 5.22–5.18(m, 1H), 3.90(d, J=7.0Hz, 2H), 3.87(s, 3H), 1.47(d, J=7.0Hz, 3H), 1.37(s, 9H),1.27–1.25(m,1H),0.62–0.58(m,2H),0.38–0.35(m,2H);

MS-ESI: m/z 435.2 [M+H] ⁺ .

Step 2: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-4-((3,5-dichloropyridin-4-yl ) carbamoyl) oxazol-5-yl) ethyl) synthesis of tert-butyl carbamate

Dissolve 3,5-dichloro-4-aminopyridine (162mg, 1.00mmol) and sodium hydride (60%, 80mg, 2.00mmol) in tetrahydrofuran (5mL), stir at room temperature for 1h, and add compound (S) dropwise at 0°C -(1-(2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-4-(fluorocarbonyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester ( 282mg, 0.65mmol) in tetrahydrofuran (9mL), stirred at room temperature for 12h, added saturated ammonium chloride solution (20mL), extracted with ethyl acetate (20mL×3), combined organic phases were dried with Na ₂ SO ₄ , and the solvent was removed , the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=5/1) to obtain 40 mg of white solid, yield: 11%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.78(s, 2H), 7.74–7.65(m, 2H), 7.21(d, J=8.4Hz, 1H), 5.18– 4.95(m, 1H), 3.93– 3.88(m,5H),1.65(d,J＝7.0Hz,3H),1.37(s,9H),1.24–1.22(s,1H),0.65–0.54(m,2H),0.41–0.30(m, 2H);

MS-ESI: m/z 577.1 [M+H] ⁺ .

Step 3: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-N-(3,5-dichloro Synthesis of pyridin-4-yl)oxazole-4-carboxamide dihydrochloride

To compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-4-((3,5-dichloropyridin-4-yl)amino Formyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (316mg, 0.55mmol) in dichloromethane (2mL) solution was added HCl in ethyl acetate solution (4M, 6mL), stirred at room temperature for 0.5h , after removing the solvent, recrystallized from methanol/ethyl acetate (v/v=1/20) to obtain 135 mg of white solid, yield: 52%.

Compound 41: ¹ H NMR (400MHz, d ₆ -DMSO): δppm 8.78(s, 2H), 7.73(d, J=8.5Hz, 1H), 7.66(s, 1H), 7.21(d, J=8.6Hz ,1H),5.11–5.07(m,1H),3.92(d,J＝7.0Hz,2H),3.88(s,3H),1.65(d,J＝7.0Hz,3H),1.30–1.26(m, 1H),0.63–0.58(m,2H),0.38–0.35(m,2H);

MS-ESI: m/z 477.0 [M+H-2HCl] ⁺ .

Example 109: Compound (S)-5-(1-aminoethyl)-N-(3,5-dichloropyridin-4-yl)-2-(3,4-diethoxy Synthesis of phenyl)oxazole-4-carboxamide dihydrochloride

Step 1: Synthesis of compound (S)-tert-butyl(1-(2-(3,4-diethoxyphenyl)-4-(fluorocarbonyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3,4-diethoxyphenyl)oxazole-4-carboxylic acid (1.02g, 2.42mmol) Dissolve triethylamine (0.37mL, 2.66mmol) in dichloromethane (20mL), slowly add cyanuric fluoride (0.46mL, 4.84mmol) dropwise at -40°C, and continue the reaction at -10°C for 1h, Washed with ice water (20 mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , and the solvent was removed to obtain 1.00 g of white solid, yield: 97%.

¹ H NMR (400MHz, d ₆ -DMSO): δppm 7.57 (dd, J ₁ =8.4Hz, J ₂ =1.9Hz, 1H), 7.48 (d, J = 2.0Hz, 1H), 7.16 (d, J = 8.5Hz, 1H), 5.21–5.19(m, 1H), 4.28–3.97(m, 4H), 1.47(d, J=7.0Hz, 3H), 1.39–1.23(m, 15H);

MS-ESI: m/z 423.3 [M+H] ⁺ .

Step 2: Compound (S)-(1-(4-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(3,4-diethoxyphenyl)oxazole- Synthesis of tert-butyl 5-yl)ethyl)carbamate

Dissolve 3,5-dichloro-4-aminopyridine (469mg, 2.84mmol) and sodium hydride (60%, 114mg, 2.84mmol) in tetrahydrofuran (5mL), stir at room temperature for 1h, and add compound (S) dropwise at 0°C -(1-(2-(3,4-diethoxyphenyl)-4-(fluorocarbonyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (1.00g, 2.37mmol) in tetrahydrofuran (10mL) solution, stirred at room temperature for 12h, washed with saturated ammonium chloride solution (20mL× ₃ ), the organic phase was dried with _Na2SO4 , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v )=5/1), to obtain 264 mg of white solid, yield: 20%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.63 (s, 2H), 7.65 (dd, J ₁ = 8.4Hz, J ₂ = 2.0Hz, 1H), 7.57 (d, J = 2.0Hz, 1H), 6.97 (d,J=8.5Hz,1H),5.40–5.27(m,1H),4.26–4.18(m,4H),1.60(d,J=7.0Hz,3H),1.55–1.51(m,6H), 1.44(s,9H);

MS-ESI: m/z 565.1 [M+H] ⁺ .

Step 3: Compound (S)-5-(1-aminoethyl)-N-(3,5-dichloropyridin-4-yl)-2-(3,4-diethoxyphenyl)oxazole -Synthesis of 4-formamide dihydrochloride

To compound (S)-(1-(4-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(3,4-diethoxyphenyl)oxazole-5- Base) ethyl) tert-butyl carbamate (264mg, 0.47mmol) in dichloromethane (2mL) solution was added HCl in ethyl acetate solution (4M, 6mL), stirred at room temperature for 0.5h, after removing the solvent, washed with methanol/ Ethyl acetate (v/v=1/20) was recrystallized to obtain 161 mg of white solid, yield: 74%.

Compound 45: ¹ H NMR (400MHz, d ₆ -DMSO): δppm 8.77(s, 2H), 7.71(s, 1H), 7.72(d, J=6.9Hz, 1H), 7.19(d, J=9.0Hz ,1H),5.14–5.04(m,1H),4.20–4.06(m,4H),1.65(d,J＝7.0Hz,3H),1.40–1.35(m,6H);

MS-ESI: m/z 465.2 [M+H-2HCl] ⁺ .

Example 110: Compound (S)-5-(1-aminoethyl)-N-(2,4-difluorobenzyl)-2-(3-hydroxy-4-methoxy Synthesis of phenyl)oxazole-4-carboxamide hydrochloride

Step 1: Synthesis of the compound 4-methoxy-3-(4-methoxybenzyloxy)methyl benzoate

Methyl 3-hydroxy-4-methoxybenzoate (10.00g, 54.95mmol), potassium carbonate (32.80g, 238.00mmol) and p-methoxybenzyl bromide (23.70g, 166.00mmol) were dissolved in N, N-dimethylformamide (60mL), reacted at 60°C for 4.5h, added water (40mL), extracted with ethyl acetate (50mL×3), combined the organic phases and dried them with anhydrous Na ₂ SO ₄ to remove The solvent and the concentrate were subjected to column separation (petroleum ether/ethyl acetate (v/v)=5/1) to obtain 16.2 g of light yellow solid, yield: 97%.

MS-ESI: m/z 303.3 [M+H] ⁺ .

Step 2: Synthesis of compound 4-methoxy-3-(4-methoxybenzyloxy)benzoic acid

The compound 4-methoxy-3-(4-methoxybenzyloxy)methyl benzoate (16.20g, 53.64mmol), lithium hydroxide monohydrate (6.80g, 162.00mmol) was dissolved in tetrahydrofuran (60mL ) and water (30mL), reacted at 40°C for 1.5h, removed tetrahydrofuran, adjusted the pH to 1 with hydrochloric acid (1M), extracted with ethyl acetate (50mL×3), combined the organic phases with anhydrous Na Drying over ₂ SO ₄ and removing the solvent gave 15.01 g of white solid, yield: 97%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.78 (dd, J ₁ =8.4Hz, J ₂ =2.0Hz, 1H), 7.69 (d, J = 1.9Hz, 1H), 7.42 (d, J = 8.7Hz ,2H),6.95–6.92(m,3H),5.14(s,2H),3.83(s,6H);

MS-ESI: m/z 287.3 [MH] ^- .

Step 3: Synthesis of the compound 2-(4-methoxy-3-(4-methoxybenzyloxy)benzamido)methyl acetate

Compound 4-methoxy-3-(4-methoxybenzyloxy)benzoic acid (13.0g, 45.10mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Hydrochloride (13.0g, 67.65mmol) and 1-hydroxybenzotriazole (9.13g, 67.65mmol) were dissolved in dichloromethane (80mL), stirred at room temperature for 0.5h, and glycine methyl ester hydrochloride was added at 0°C (6.83g, 54.20mmol) and N,N-diisopropylethylamine (24.3mL, 135.30mmol), stirred at room temperature for 12h, washed with water (40mL×3), dried the organic phase with Na ₂ SO ₄ , removed the solvent, The concentrate was subjected to column separation (dichloromethane/methanol (v/v)=50/1) to obtain 9.5 g of white solid, yield: 62%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.47(s, 1H), 7.38-7.34(m, 3H), 6.90-6.86(m, 3H), 6.60(br.s, 1H), 5.08(s, 2H ), 4.21(d, J=5.0Hz, 2H), 3.89(s, 3H), 3.80(s, 3H), 3.79(s, 3H);

MS-ESI: m/z 360.2 [M+H] ⁺ .

Step 4: Synthesis of the compound 2-(4-methoxy-3-(4-methoxybenzyloxy)phenylthioamide)acetic acid methyl ester

Compound 2-(4-methoxy-3-(4-methoxybenzyloxy)benzamido)methyl acetate (2.0g, 5.57mmol) was dissolved in Lawson's reagent (2.25g, 5.57mmol) In tetrahydrofuran (40mL), reflux at 75°C and stir for 2h, add saturated sodium bicarbonate solution (40mL), extract with ethyl acetate (50mL×3), combine the organic phases and dry with Na ₂ SO ₄ , remove the solvent, and concentrate The liquid was subjected to column separation (petroleum ether/ethyl acetate (v/v)=1/1) to obtain 2.05 g of yellow viscous liquid, yield: 98%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.63(s, 1H), 7.43-7.39(m, 3H), 6.92(d, J=8.7Hz, 2H), 6.87(d, J=8.4Hz, 1H) ,5.13(s,2H),4.58(d,J=4.5Hz,2H),3.92(s,3H),3.87(s,3H),3.82(s,3H);

MS-ESI: m/z 376.2 [M+H] ⁺ .

Step 5: Synthesis of the compound 2-(((4-methoxy-3-(4-methoxybenzyloxy)phenyl)(methylthio)methylene)amino)acetate methyl ester

Under the condition of -78°C, the compound 2-(4-methoxy-3-(4-methoxybenzyloxy)phenylthioamide)acetic acid methyl ester (2.05g, 5.47mmol) was dissolved in dichloromethane ( 30mL) solution was slowly added dropwise to a solution of trimethyloxonium tetrafluoroboric acid (1.62g, 10.94mmol) in dichloromethane (20mL), and after stirring at 0°C for 3h, saturated sodium bicarbonate solution was added to wash (25mL× 3), the organic phase was dried with anhydrous Na ₂ SO ₄ , and the solvent was removed to obtain 2.24 g of yellow oil, yield: 99%.

MS-ESI: m/z 390.1 [M+H] ⁺ .

Step 6: Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(4-methoxy-3-(4-methoxybenzyloxy)phenyl)oxazole -Synthesis of methyl 4-carboxylate

The compound 2-(((4-methoxy-3-(4-methoxybenzyloxy)phenyl)(methylthio)methylene)amino)acetic acid methyl ester (2.24g, 5.47mmol) and Compound (S)-(1-fluoro-1-oxopropan-2-yl)carbamate tert-butyl ester (2.34g, 12.25mmol) was dissolved in anhydrous tetrahydrofuran (20mL), and was added dropwise at -78°C Potassium hexamethyldisilazide tetrahydrofuran solution (16.4mL, 16.4mmol), react at -78°C for 1h, add ice water (20mL) to quench the reaction, extract with ethyl acetate (15mL×3), combine The organic phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v)=2/1) to obtain 347 mg of a yellow solid, yield: 14%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.69-7.67(m, 2H), 7.42(d, J=8.6Hz, 2H), 6.96-6.90(m, 3H), 5.49-5.45(m, 1H), 5.14(s,2H),3.99(s,3H),3.93(s,3H),3.83(s,3H),1.55(d,J=7.0Hz,3H),1.45(s,9H);

MS-ESI: m/z 513.3 [M+H] ⁺ .

Step 7: Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(4-methoxy-3-(4-methoxybenzyloxy)phenyl)oxazole -Synthesis of 4-carboxylic acid

Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(4-methoxy-3-(4-methoxybenzyloxy)phenyl)oxazole-4 -Methyl carboxylate (374mg, 0.73mmol) and lithium hydroxide monohydrate (153mg, 0.95mmol) were dissolved in a mixed solvent of tetrahydrofuran (30mL) and water (15mL), reacted at 40°C for 3h, removed tetrahydrofuran, added The pH value was adjusted to 1 with hydrochloric acid (1M), extracted with ethyl acetate (30 mL×3), the organic phases were combined and dried with Na ₂ SO ₄ , and the solvent was removed to obtain 230 mg of white solid, yield: 64%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.68-7.66(m, 2H), 7.43(d, J=8.7Hz, 2H), 7.00-6.89(m, 3H), 5.44-5.40(m, 1H), 5.15(s,2H),3.94(s,3H),3.83(s,3H),1.59(d,J=7.0Hz,3H),1.45(s,9H);

MS-ESI: m/z 499.3 [M+H] ⁺ .

Step 8: Compound (S)-(1-(4-((2,4-difluorobenzyl)carbamoyl)-2-(4-methoxy-3-(4-methoxybenzyloxy) ) phenyl) oxazol-5-yl) ethyl) synthesis of tert-butyl carbamate

Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(4-methoxy-3-(4-methoxybenzyloxy)phenyl)oxazole-4 -Carboxylic acid (230mg, 0.46mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (133mg, 0.69mmol) and N-hydroxyl-7-azabenzo Triazole (93mg, 0.69mmol) was dissolved in dichloromethane (15mL), stirred at room temperature for 0.5h, and 2,4-difluorobenzylamine (0.07mL, 0.55mmol) and N,N-di Isopropylethylamine (0.25mL, 1.38mmol), stirred at room temperature for 12h, added water (15mL), extracted with dichloromethane (20mL×3), combined the organic phases and dried with Na ₂ SO ₄ , removed the solvent, and concentrated Column separation was performed (petroleum ether/ethyl acetate (v/v)=3/1) to obtain 154 mg of white solid, yield: 55%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.60 (dd, J ₁ =8.3Hz, J ₂ =2.0Hz, 1H), 7.58 (d, J = 1.8Hz, 1H), 7.44-7.41 (m, 3H) ,6.96-6.84(m,5H),5.32–5.28(m,1H),5.15(s,2H),4.68-4.65(m,2H),3.94(s,3H),3.83(s, 3H),1.55 (d, J=7.0Hz, 3H), 1.46(s, 9H);

MS-ESI: m/z 624.3 [M+H] ⁺ .

Step 9: Compound (S)-5-(1-aminoethyl)-N-(2,4-difluorobenzyl)-2-(3-hydroxy-4-methoxyphenyl)oxazole-4 -Synthesis of formamide hydrochloride

To compound (S)-(1-(4-((2,4-difluorobenzyl)carbamoyl)-2-(4-methoxy-3-(4-methoxybenzyloxy)benzene Add HCl in ethyl acetate (4M, 8mL) to a solution of tert-butyl carbamate (154mg, 0.25mmol) in dichloromethane (2mL) and stir at room temperature for 0.5h. After removing the solvent, recrystallize from methanol/ethyl acetate (v/v=1/20) to obtain 81 mg of white solid, yield: 62%.

Compound 47: ¹ H NMR (400MHz, CDCl ₃ ): δppm 7.74-7.70(m, 1H), 7.55(s, 1H), 7.47(d, J=8.0Hz, 1H), 7.43-7.38(m, 1H) ,6.90-6.81(m,2H),5.03(br.s,1H),4.60(d,J=5.3Hz,2H),3.89(s,3H),1.89(d,J=5.2Hz,3H);

MS-ESI: m/z 404.1 [M+H-HCl] ⁺ .

Example 111: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopentyloxy)-4-methoxyphenyl)-N-((3, Synthesis of 5-dichloropyridin-4-yl)methyl)oxazole-4-carboxamide dihydrochloride

Step 1: Compound (S)-(1-(2-(3-(cyclopentyloxy)-4-methoxyphenyl)-4-(((3,5-dichloropyridin-4-yl) Synthesis of tert-butyl methyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopentyloxy)-4-methoxyphenyl)oxazole-4-carboxylic acid ( 0.30g, 0.67mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.19g, 1.00mmol) and N-hydroxyl-7-azabenzotriazepam Azole (0.14g, 1.00mmol) was dissolved in dichloromethane (15mL), stirred at room temperature for 0.5h, and the compound (3,5-dichloropyridin-4-yl)methanamine (0.14g, 0.81mmol) was added dropwise at 0°C ) and N,N-diisopropylethylamine (0.18mL, 2.01mmol), stirred at room temperature for 12h, added water (15mL), extracted with dichloromethane (20mL×3), combined the organic phases with Na ₂ SO ₄ After drying, the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=2/1) to obtain 330 mg of white solid, yield: 82%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.54 (s, 2H), 7.56 (dd, J ₁ = 8.4Hz, J ₂ = 2.0Hz, 1H), 7.47 (d, J = 2.0Hz, 1H), 6.92 (d,J=8.5Hz,1H),5.30–5.28(m,1H),4.95(d,J=5.8Hz,2H),4.91–4.82(m,1H),3.91(s,3H),1.99– 1.84(m,6H),1.70–1.60(m,2H),1.55(d,J=7.0Hz,3H),1.44(s,9H);

MS-ESI: m/z 605.2 [M+H] ⁺ .

Step 2: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopentyloxy)-4-methoxyphenyl)-N-((3,5-dichloropyridine Synthesis of -4-yl)methyl)oxazole-4-carboxamide dihydrochloride

To compound (S)-(1-(2-(3-(cyclopentyloxy)-4-methoxyphenyl)-4-(((3,5-dichloropyridin-4-yl)methyl ) carbamoyl) oxazol-5-yl) ethyl) tert-butyl carbamate (330mg, 0.55mmol) in dichloromethane (2mL) solution was added HCl ethyl acetate solution (4M, 8mL), stirred at room temperature After 0.5 h, after removing the solvent, recrystallize from methanol/ethyl acetate (v/v=1/20) to obtain 242 mg of white solid, yield: 88%.

Compound 70: ¹ H NMR (400MHz, CD ₃ OD): δppm 8.71(s, 2H), 7.70(d, J=8.4Hz, 1H), 7.61(s, 1H), 7.11(d, J=8.5Hz, 1H), 5.19–5.14(m,1H), 4.94(s,2H), 4.93–4.90(m,1H), 3.91(s,3H), 2.04–1.80(m,6H), 1.77(d,J= 7.0Hz, 3H), 1.69–1.65(s, 2H);

MS-ESI: m/z 505.1 [M+H-2HCl] ⁺ .

Example 112: Compound 5-(2-aminopropyl-2-yl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)- Synthesis of N-(2,4-difluorobenzyl)oxazole-4-carboxamide hydrochloride

Step 1: Synthesis of the compound (1-fluoro-2-methyl-1-oxopropan-2-yl)carbamate tert-butyl ester

Dissolve N-Boc-2-aminoisobutyric acid (3.5g, 14.97mmol) and triethylamine (2.3mL, 16.50mmol) in dichloromethane (30mL), slowly add tripolyfluoride dropwise at -40°C Cyanide (2.5mL, 29.94mmol), continued to react at -10°C for 1h, washed with ice water (20mL×3), dried the organic phase with anhydrous Na ₂ SO ₄ , and removed the solvent to obtain 2.80g of a white solid, product Rate: 91%.

¹ H NMR (400 MHz, d ₆ -DMSO): δ ppm 1.40 (s, 6H), 1.39 (s, 9H).

Step 2: Compound 5-(2-(tert-butoxycarbonylamino)propan-2-yl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)oxazole-4- Synthesis of methyl carboxylate

Compound 2-(((3-(cyclopropylmethoxy)-4-methoxyphenyl)(methylthio)methylene)amino)acetate methyl ester (1.85 g, 5.73 mmol) and compound ( 1-Fluoro-2-methyl-1-oxopropan-2-yl) tert-butyl carbamate (2.80g, 13.66mmol) was dissolved in anhydrous tetrahydrofuran (30mL), and at -78°C, six Potassium methyldisilazide tetrahydrofuran solution (20.00mL, 20.00mmol), react at -78°C for 1h, add ice water (20mL) to quench the reaction, extract with ethyl acetate (15mL×3), combine organic The phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v)=3/1) to obtain 323 mg of a yellow solid, yield: 15%.

MS-ESI: m/z 461.3 [M+H] ⁺ .

Step 3: Compound 5-(2-(tert-butoxycarbonylamino)propan-2-yl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)oxazole-4- Synthesis of Carboxylic Acids

Compound 5-(2-(tert-butoxycarbonylamino)propan-2-yl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)oxazole-4-carboxylic acid Methyl ester (323mg, 0.70mmol) and lithium hydroxide monohydrate (147mg, 3.5mmol) were dissolved in a mixed solvent of tetrahydrofuran (30mL) and water (15mL), reacted at 40°C for 3h, removed tetrahydrofuran, added hydrochloric acid (1M ) to adjust the pH value to 1, add ethyl acetate to extract (30mL×3), combine the organic phases and dry with Na ₂ SO ₄ , remove the solvent to obtain 309 mg of white solid, yield: 99%.

MS-ESI: m/z 445.3 [MH] ^- .

Step 4: Compound (2-(2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazole Synthesis of tert-butyl -5-yl)propan-2-yl)carbamate

Compound 5-(2-(tert-butoxycarbonylamino)propan-2-yl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)oxazole-4-carboxylic acid (309mg, 0.70mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (203mg, 1.05mmol) and N-hydroxy-7-azabenzotriazole (142mg, 1.05mmol) was dissolved in dichloromethane (20mL), stirred at room temperature for 0.5h, and 2,4-difluorobenzylamine (0.10mL, 0.84mmol) and N,N-diisopropyl Ethylamine (0.38mL, 2.10mmol), stirred at room temperature for 12h, added water (15mL), extracted with dichloromethane (20mL×3), combined the organic phases and dried with Na ₂ SO ₄ , removed the solvent, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=5/1), 30 mg of white solid was obtained, yield: 7.5%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.60 (dd, J ₁ =8.4Hz, J ₂ =2.0Hz, 1H), 7.51 (d, J = 1.9Hz, 1H), 7.47–7.40 (m, 1H) ,6.94(d,J=8.5Hz,1H),6.90–6.82(m,2H),4.65(d,J=6.2Hz,2H),3.96(d,J=6.9Hz,2H),3.96(s, 3H),1.83(s,6H),1.43–1.38(m,1H),1.35(s,9H),0.72–0.68(m,2H),0.44–0.40(m,2H);

MS-ESI: m/z 572.2 [M+H] ⁺ .

Step 5: Compound 5-(2-aminopropyl-2-yl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-N-(2,4-difluoro Synthesis of benzyl)oxazole-4-carboxamide hydrochloride

To the compound (2-(2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazole-5 -yl) propan-2-yl) tert-butyl carbamate (36mg, 0.06mmol) in dichloromethane (1mL) solution was added HCl in ethyl acetate solution (4M, 3mL), stirred at room temperature for 0.5h, after removing the solvent , recrystallized from methanol/ethyl acetate (v/v=1/20) to obtain 18.5 mg of white solid, yield: 66%.

Compound 71: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.70 (dd, J ₁ =8.4Hz, J ₂ =2.0Hz, 1H), 7.63 (d, J = 2.0Hz, 1H), 7.51-7.45( m,1H),7.13(d,J=8.5Hz,1H),7.02–6.94(m,2H),4.67(s,2H),3.94(s,3H),3.94(d,J=6.9Hz,2H ),1.85(s,6H),1.35–1.32(m,1H),0.71–0.62(m,2H),0.43–0.32(m,2H);

MS-ESI: m/z 472.2 [M+H-HCl] ⁺ .

Example 113: Compound 5-((S)-1-aminoethyl)-N-(2,4-difluorobenzyl)-2-(4-(difluoromethoxy)- Synthesis of 3-((tetrahydrofuran-3-yl)oxy)phenyl)oxazole-4-carboxamide hydrochloride

Step 1: Synthesis of the compound 4-(difluoromethoxy)-3-((tetrahydrofuran-3-yl)oxy)methyl benzoate

Methyl 3-hydroxy-4-(difluoromethoxy)benzoate (2.0g, 9.18mmol), potassium carbonate (2.54g, 18.38mmol) and 3-bromotetrahydrofuran (2.1g, 13.9mmol) were dissolved in N , N-dimethylformamide (50mL), reacted at 60°C for 4.5h, added water (40mL), extracted with ethyl acetate (50mL×3), combined organic phases and dried with anhydrous Na ₂ SO ₄ , The solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v)=5/1) to obtain 2.48 g of a white solid, yield: 94%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.68 (dd, J ₁ = 8.4Hz, J ₂ = 1.9Hz, 1H), 7.60 (d, J = 1.9Hz, 1H), 7.23 (d, J = 8.4Hz ,1H),6.63(t,J _FH ＝74.4Hz,1H),5.08-5.04(m,1H),4.06-3.99(m,3H),3.97-3.95(m,1H),3.93(s,3H) ,2.33-2.17(m,2H);

MS-ESI: 289.2[M+H] ⁺ .

Step 2: Synthesis of compound 4-(difluoromethoxy)-3-((tetrahydrofuran-3-yl)oxy)benzoic acid

The compound methyl 4-(difluoromethoxy)-3-((tetrahydrofuran-3-yl)oxy)benzoate (2.48g, 8.62mmol) and sodium hydroxide (0.83g, 20.65mmol) were dissolved in ethanol (40mL) and water (20mL) in a mixed solvent, reacted at 60°C for 1.5h, removed ethanol, adjusted the pH to 1 with hydrochloric acid (1M), extracted with ethyl acetate (50mL×3), combined the organic phases and used Water Na ₂ SO ₄ dried, and the solvent was removed to obtain 2.24 g of white solid, yield: 95%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.76 (dd, J ₁ = 8.4Hz, J ₂ = 1.9Hz, 1H), 7.65 (d, J = 1.9Hz, 1H), 7.26 (d, J = 8.4Hz ,1H),6.65(t,J _FH ＝74.2Hz,1H),5.10-5.07(m,1H),4.08–4.02(m,3H),4.01-3.97(m,1H),2.33-2.20(m, 2H);

MS-ESI: 273.0[MH] ^- .

Step 3: Synthesis of the compound 2-(4-(difluoromethoxy)-3-((tetrahydrofuran-3-yl)oxy)benzamido)acetic acid methyl ester

Compound 4-(difluoromethoxy)-3-((tetrahydrofuran-3-yl)oxy)benzoic acid (2.24g, 8.20mmol), 1-ethyl-3-(3-dimethylaminopropyl ) carbodiimide hydrochloride (2.37g, 12.30mmol) and 1-hydroxybenzotriazole (1.67g, 12.30mmol) were dissolved in dichloromethane (40mL), stirred at room temperature for 0.5h, and glycine was added at 0°C Methyl ester hydrochloride (1.33g, 9.84mmol) and N,N-diisopropylethylamine (4.4mL, 24.60mmol), stirred at room temperature for 12h, washed with water (20mL×3), and the organic phase was washed with Na ₂ SO ₄ After drying, the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=1/1) to obtain 2.56 g of colorless liquid, yield: 91%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.48 (d, J = 1.9Hz, 1H), 7.33 (dd, J ₁ = 8.3Hz, J ₂ = 1.9Hz, 1H), 7.20 (d, J = 8.3Hz ,1H),6.85(br.s,1H),6.60(t,J _FH ＝74.4Hz,1H),5.07-5.04(m,1H),4.23(d,J＝4.9Hz,2H),4.01-3.97 (m,3H),3.95-3.90(m,1H),3.81(s,3H),2.30-2.14(m,2H);

MS-ESI: m/z 346.0 [M+H] ⁺ .

Step 4: Synthesis of the compound 2-(4-(difluoromethoxy)-3-((tetrahydrofuran-3-yl)oxy)phenylthioamide)acetic acid methyl ester

Compound 2-(4-(difluoromethoxy)-3-((tetrahydrofuran-3-yl)oxy)benzamido)acetic acid methyl ester (2.56g, 7.42mmol) and Lawson's reagent (2.98g , 7.42mmol) was dissolved in tetrahydrofuran (40mL), stirred under reflux at 75°C for 2h, added saturated sodium bicarbonate solution (30mL), extracted with ethyl acetate (50mL×3), combined organic phases and dried with Na ₂ SO ₄ , The solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v)=1/1) to obtain 2.45 g of a yellow solid, yield: 92%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.59 (d, J = 2.0Hz, 1H), 7.29 (dd, J ₁ = 8.3Hz, J ₂ = 2.1Hz, 1H), 7.20 (d, J = 8.3Hz ,1H),6.60(t,J _FH ＝74.6Hz,1H),5.09-5.07(m,1H),4.58(d,J＝4.4Hz,2H),4.05-3.99(m,3H),3.97-3.94 (m,1H),3.88(s,3H),2.33-2.17(m,2H);

MS-ESI: m/z 362.0 [M+H] ⁺ .

Step 5: Compound 2-(((4-(difluoromethoxy)-3-((tetrahydrofuran-3-yl)oxy)phenyl)(methylthio)methylene)amino)acetate methyl ester synthesis

At -78°C, the compound 2-(4-(difluoromethoxy)-3-((tetrahydrofuran-3-yl)oxy)phenylthioamide)acetic acid methyl ester (2.45g, 6.79mmol) A solution of dichloromethane (30mL) was slowly added dropwise to a solution of trimethyloxonium tetrafluoroboric acid (2.00g, 13.58mmol) in dichloromethane (20mL), and after stirring for 3h at 0°C, saturated sodium bicarbonate was added The solution was washed (25 mL×3), the organic phase was dried with anhydrous Na ₂ SO ₄ , and the solvent was removed to obtain 2.53 g of yellow oil, yield: 99%.

Compound 77-5: MS-ESI: m/z 376.2 [M+H] ⁺ .

Step 6: Compound 5-((S)-1-(tert-butoxycarbonylamino)ethyl)-2-(4-(difluoromethoxy)-3-((tetrahydrofuran-3-yl)oxy) Synthesis of methyl phenyl)oxazole-4-carboxylate

Compound 2-(((4-(difluoromethoxy)-3-((tetrahydrofuran-3-yl)oxy)phenyl)(methylthio)methylene)amino)acetic acid methyl ester (2.53g , 6.75mmol), compound (S)-(1-fluoro-1-oxopropan-2-yl)carbamate tert-butyl ester (2.60g, 13.5mmol) was dissolved in anhydrous tetrahydrofuran (30mL), -78°C Under certain conditions, a tetrahydrofuran solution (27.0 mL, 27.0 mmol) of potassium hexamethyldisilazide was added dropwise, reacted at -78°C for 1 h, quenched with ice water (20 mL), extracted with ethyl acetate (15 mL ×3), combined the organic phases and dried them with anhydrous Na ₂ SO ₄ , removed the solvent, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=1/1) to obtain 1.45 g of a yellow solid. Rate: 45%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.68 (dd, J ₁ = 8.3Hz, J ₂ = 1.9Hz, 1H), 7.65 (s, 1H), 7.27 (d, J = 8.3Hz, 1H), 6.62 (t,J _FH ＝74.5Hz,1H),5.50-5.46(m,1H),5.15-5.13(m,1H),4.06–4.03(m,3H),4.01(s,3H),3.98-3.94( m,1H),2.34-2.20(m,2H),1.57(d,J=7.0Hz,3H),1.45(s,9H);

MS-ESI: m/z 499.3 [M+H] ⁺ .

Step 7: Compound 5-((S)-1-(tert-butoxycarbonylamino)ethyl)-2-(4-(difluoromethoxy)-3-((tetrahydrofuran-3-yl)oxy) Synthesis of phenyl)oxazole-4-carboxylic acid

Compound 5-((S)-1-(tert-butoxycarbonylamino)ethyl)-2-(4-(difluoromethoxy)-3-((tetrahydrofuran-3-yl)oxy)phenyl ) Methyl oxazole-4-carboxylate (1.45g, 2.92mmol) and lithium hydroxide monohydrate (0.62g, 14.6mmol) were dissolved in a mixed solvent of tetrahydrofuran (50mL) and water (25mL), at 40°C React for 3h, remove tetrahydrofuran, add hydrochloric acid (1M) to adjust the pH value to 1, add ethyl acetate to extract (30mL×3), combine the organic phases and dry with Na ₂ SO ₄ , remove the solvent to obtain 1.29g white solid, the yield : 92%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.68-7.66 (m, 2H), 7.28 (d, J = 8.7Hz, 1H), 6.62 (t, J _FH = 74.6Hz, 1H), 5.63 (br.s ,1H),5.47-5.44(m,1H),5.16-5.18(m,1H),4.06-3.94(m,4H),2.36-2.20(m,2H),1.61(d,J＝4.8Hz,3H ), 1.45(s,9H).

Step 8: Compound ((1S)-1-(4-((2,4-difluorobenzyl)carbamoyl)-2-(4-(difluoromethoxy)-3-((tetrahydrofuran-3 Synthesis of -yl)oxy)phenyl)oxazol-5-yl)ethyl)carbamate tert-butyl

Compound 5-((S)-1-(tert-butoxycarbonylamino)ethyl)-2-(4-(difluoromethoxy)-3-((tetrahydrofuran-3-yl)oxy)phenyl ) oxazole-4-carboxylic acid (0.20g, 0.42mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.12g, 0.63mmol) and N-hydroxy -7-Azabenzotriazole (0.09g, 0.63mmol) was dissolved in dichloromethane (15mL), stirred at room temperature for 0.5h, and 2,4-difluorobenzylamine (0.06mL, 0.51 mmol) and N,N-diisopropylethylamine (0.23mL, 1.26mmol), stirred at room temperature for 12h, added water (15mL), extracted with dichloromethane (20mL×3), combined the organic phases with Na ₂ SO ₄ was dried, the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=3/1) to obtain 183.0 mg of a white solid, yield: 72%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.63 (dd, J ₁ =8.4Hz, J ₂ =1.9Hz, 1H), 7.55 (br.s, 1H), 7.49-7.42 (m, 1H), 7.27( d,J=8.4Hz,1H),6.92-6.84(m,2H),6.62(t,J _FH =74.5Hz,1H),5.32(br.s,1H),5.14-5.11(m,1H), 4.73-4.63(m,2H),4.10-3.95(m,4H),2.34-2.20(m,2H),1.56(d,J=7.0Hz,3H),1.45(s,9H);

MS-ESI: m/z 610.2 [M+H] ⁺ .

Step 9: Compound 5-((S)-1-aminoethyl)-N-(2,4-difluorobenzyl)-2-(4-(difluoromethoxy)-3-((tetrahydrofuran- Synthesis of 3-yl)oxy)phenyl)oxazole-4-carboxamide hydrochloride

To the compound ((1S)-1-(4-((2,4-difluorobenzyl)carbamoyl)-2-(4-(difluoromethoxy)-3-((tetrahydrofuran-3-yl )oxy)phenyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (183mg, 0.30mmol) in dichloromethane (1mL) was added HCl in ethyl acetate (4M, 3mL), Stir at room temperature for 0.5 h, remove the solvent, and recrystallize with methanol/ethyl acetate (v/v=1/20) to obtain 160 mg of white solid, yield: 95%.

Compound 77: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.79-7.75(m, 2H), 7.52-7.46(m, 1H), 7.36(d, J=8.3Hz, 1H), 6.99-6.94(m ,2H),6.88(t,J _FH ＝74.3Hz,1H),5.24-5.22(m,1H),5.19-5.14(m,1H),4.66(s,2H),4.07-3.99(m,3H) ,3.97-3.92(m,1H),2.38-2.30(m,1H),2.23-2.17(m,1H),1.78(d,J=7.0Hz,3H);

MS-ESI: m/z 510.1 [M+H-HCl] ⁺ .

Example 114: Compound (S)-5-(5-(5-(1-aminoethyl)-4-((2,4-difluorobenzyl)carbamoyl)oxa Synthesis of (2-methoxy)ethyl (azol-2-yl)-2-(difluoromethoxy)phenoxy)pentanoate hydrochloride

Step 1: Compound (S)-5-(5-(5-(1-(tert-butoxycarbonylamino)ethyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazole- Synthesis of (2-methoxy)ethyl 2-yl)-2-(difluoromethoxy)phenoxy)pentanoate

Compound (S)-5-(5-(5-(1-(tert-butoxycarbonylamino)ethyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazole-2- Base)-2-(difluoromethoxy)phenoxy)pentanoic acid (253mg, 0.40mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (116mg , 0.60mmol) and N-hydroxy-7-azabenzotriazole (82mg, 0.60mmol) were dissolved in dichloromethane (10mL), stirred at room temperature for 0.5h, and ethylene glycol monomethyl ether was added dropwise at 0°C (0.05mL, 0.60mmol) and N,N-diisopropylethylamine (0.22mL, 1.20mmol), stirred at room temperature for 12h, added water (15mL), extracted with dichloromethane (20mL×3), combined organic phase After drying with Na ₂ SO ₄ , the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v)=3/1) to obtain 190 mg of white solid, yield: 68%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.60–7.57(m,1H),7.57(s,1H),7.47–7.41(m,1H),7.24(d,J＝8.2Hz,1H),6.91– 6.84(m,2H),6.64(t,J _FH ＝74.6Hz,1H),5.33–5.28(m,1H),4.68–4.66(m,2H),4.27–4.24(m,2H),4.16–4.13 (m,2H),3.62–3.60(m,2H),3.40(s,3H),2.49(t,J＝6.9Hz,2H),1.95–1.87(m,4H),1.56(d,J＝7.0 Hz,3H),1.44(s,9H);

MS-ESI: m/z 698.3 [M+H] ⁺ .

Step 2: Compound (S)-5-(5-(5-(1-aminoethyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazol-2-yl)-2 Synthesis of (2-methoxy) ethyl (difluoromethoxy) phenoxy) pentanoate hydrochloride

To compound (S)-5-(5-(5-(1-(tert-butoxycarbonylamino)ethyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazole-2- To a solution of (2-methoxy)ethyl)-2-(difluoromethoxy)phenoxy)pentanoate (190 mg, 0.27 mmol) in dichloromethane (1 mL) was added a solution of HCl in ethyl acetate ( 4M, 3mL), stirred at room temperature for 0.5h, removed the solvent, and recrystallized with methanol/ethyl acetate (v/v=1/20) to obtain 139mg of white solid, yield: 82%.

Compound 97: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.81 (d, J = 1.9Hz, 1H), 7.73 (dd, J ₁ = 8.4Hz, J ₂ = 1.9Hz, 1H), 7.52-7.46 ( m,1H),7.34(d,J＝8.4Hz,1H),7.02–6.94(m,2H),6.88(t,J _FH ＝74.4Hz,1H),5.20–5.14(m,1H),4.65( s,2H),4.24–4.18(m,4H),3.62–3.60(m,2H),3.37(s,3H),2.49(t,J＝7.0Hz,2H),1.95–1.85(m,4H) ,1.78(d,J=7.0Hz,3H);

MS-ESI: m/z 598.2 [M+H-HCl] ⁺ .

Example 115: Compound (S)-5-(5-(5-(1-aminoethyl)-4-((2,4-difluorobenzyl)carbamoyl)oxa Synthesis of Methyl Azol-2-yl)-2-(Difluoromethoxy)phenoxy)valerate Hydrochloride

To compound (S)-5-(5-(5-(1-(tert-butoxycarbonylamino)ethyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazole-2- Add HCl in ethyl acetate (4M, 3mL) to a solution of methyl 2-(difluoromethoxy)phenoxy)valerate (90mg, 0.14mmol) in dichloromethane (1mL) and stir at room temperature After 0.5 h, after removing the solvent, recrystallize from methanol/ethyl acetate (v/v=1/20) to obtain 70 mg of white solid, yield: 92%.

Compound 99: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.79(s, 1H), 7.71(d, J=8.2Hz, 1H), 7.50–7.44(m, 1H), 7.31(d, J=8.3 Hz,1H),7.01–6.89(m,2H),6.86(t,J _FH ＝74.5Hz,1H),5.17–5.15(m,1H),4.63(s,2H),4.25–4.11(m,2H ),3.66(s,3H),2.45(t,J=7.1Hz,2H),1.94–1.79(m,4H),1.76(d,J=7.0Hz,3H);

MS-ESI: m/z 554.1 [M+H-HCl] ⁺ .

Example 116: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-((tetrahydrofuran-3- Synthesis of yl)oxy)phenyl)-N-(2,4-difluorobenzyl)oxazole-4-carboxamide hydrochloride

Step 1: Synthesis of the compound 3-(cyclopropylmethoxy)-4-((tetrahydrofuran-3-yl)oxy)methyl benzoate

Methyl 3-cyclopropylmethoxy-4-hydroxybenzoate (2.0g, 9.00mmol), potassium carbonate (3.73g, 27.00mmol) and 3-bromotetrahydrofuran (2.72g, 18.00mmol) were dissolved in N, N-dimethylformamide (40mL), reacted at 60°C for 4.5h, added water (40mL), extracted with ethyl acetate (50mL×3), combined the organic phases and dried with anhydrous Na ₂ SO ₄ to remove The solvent and the concentrate were subjected to column separation (petroleum ether/ethyl acetate (v/v)=5/1) to obtain 2.87 g of white solid, yield: 100%.

¹ H NMR (400MHz, CDCl ₃ ) δppm 7.63 (dd, J ₁ =8.4Hz, J ₂ =2.0Hz, 1H), 7.56 (d, J = 1.9Hz, 1H), 6.85 (d, J = 8.4Hz, 1H),5.05–5.02(m,1H),4.06–4.00(m,3H),3.95–3.91(m,1H),3.89(s,3H),3.88(d,J＝6.7Hz,2H),2.23 –2.19(m,2H),1.34–1.28(m,1H),0.66–0.61(m,2H),0.38–0.34(m,2H);

MS-ESI: 293.3 [M+H] ⁺ .

Step 2: Synthesis of compound 3-(cyclopropylmethoxy)-4-((tetrahydrofuran-3-yl)oxy)benzoic acid

The compound 3-(cyclopropylmethoxy)-4-((tetrahydrofuran-3-yl)oxy)methyl benzoate (2.87g, 9.83mmol) and sodium hydroxide (0.98g, 24.5mmol) were dissolved in In a mixed solvent of ethanol (40mL) and water (20mL), react at 60°C for 1.5h, remove ethanol, adjust the pH to 1 with hydrochloric acid (1M), extract with ethyl acetate (50mL×3), and combine the organic phases _After drying with anhydrous _Na2SO4 , the solvent was removed to obtain 2.66 g of white solid, yield: 97%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.74 (d, J ₁ =8.4Hz, J ₂ =2.0Hz, 1H), 7.63 (d, J = 2.0Hz, 1H), 6.89 (d, J = 8.5Hz ,1H),5.09–5.05(m,1H),4.09–4.03(m,3H),3.98–3.93(m,1H),3.91(d,J＝6.8Hz,2H),2.27–2.22(m,2H ),1.36–1.29(m,1H),0.68–0.63(m,2H),0.40–0.37(m,2H);

MS-ESI: 279.0 [M+H] ⁺ .

Step 3: Synthesis of the compound 2-(3-(cyclopropylmethoxy)-4-((tetrahydrofuran-3-yl)oxy)benzamido)acetic acid methyl ester

Compound 3-(cyclopropylmethoxy)-4-((tetrahydrofuran-3-yl)oxy)benzoic acid (2.66g, 9.57mmol), 1-ethyl-3-(3-dimethylaminopropyl Carbodiimide hydrochloride (2.77g, 14.36mmol) and 1-hydroxybenzotriazole (1.94g, 14.36mmol) were dissolved in dichloromethane (40mL), stirred at room temperature for 0.5h, and added at 0°C Glycine methyl ester hydrochloride (1.44g, 11.48mmol) and N,N-diisopropylethylamine (5.15mL, 28.72mmol), stirred at room temperature for 12h, washed with water (20mL×3), and the organic phase was washed with Na ₂ SO ₄ was dried, the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=1/1) to obtain 2.87 g of a white solid, yield: 86%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.43 (d, J = 2.0Hz, 1H), 7.34 (dd, J ₁ = 8.3Hz, J ₂ = 2.1Hz, 1H), 6.86 (d, J = 8.3Hz ,1H),6.68(br.s,1H),5.04–5.01(m,1H),4.23(d,J＝5.1Hz,2H),4.07–4.00(m,3H),3.96–3.93(m,1H ),3.89(d,J＝6.8Hz,2H),3.81(s,3H),2.23–2.18(m,2H),1.34–1.27(m,1H),0.66–0.61(m,2H),0.37– 0.34(m,2H);

MS-ESI: m/z 350.1 [M+H] ⁺ .

Step 4: Synthesis of the compound 2-(3-(cyclopropylmethoxy)-4-((tetrahydrofuran-3-yl)oxy)phenylthioamide)acetic acid methyl ester

The compound 2-(3-(cyclopropylmethoxy)-4-((tetrahydrofuran-3-yl)oxy)benzamido)acetic acid methyl ester (2.87g, 8.22mmol) and Lawson's reagent (3.32 g, 8.22mmol) was dissolved in tetrahydrofuran (40mL), stirred under reflux at 75°C for 2h, added saturated sodium bicarbonate solution (30mL), extracted with ethyl acetate (50mL×3), combined organic phases and dried with Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=1/2) to obtain 2.22 g of a yellow solid, yield: 74%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.11 (br.s, 1H), 7.53 (d, J = 2.2Hz, 1H), 7.34 (dd, J ₁ = 8.4Hz, J ₂ = 2.2Hz, 1H) ,6.82(d,J=8.4Hz,1H),5.04–5.00(m,1H),4.58(d,J=4.6Hz,2H),4.06–3.99(m,3H),3.95–3.92(m,1H ),3.90(d,J＝6.9Hz,2H),3.85(s,3H),2.22–2.17(m,2H),1.34–1.28(m,1H),0.66–0.61(m,2H),0.38– 0.35(m,2H);

MS-ESI: m/z 366.2 [M+H] ⁺ .

Step 5: Compound Methyl 2-(((3-(cyclopropylmethoxy)-4-((tetrahydrofuran-3-yl)oxy)phenyl)(methylthio)methylene)amino)acetate Synthesis

At -78°C, the compound 2-(3-(cyclopropylmethoxy)-4-((tetrahydrofuran-3-yl)oxy)phenylthioamide)acetic acid methyl ester (2.22g, 6.08mmol ) in dichloromethane (30mL) was slowly added dropwise to a solution of trimethyloxonium tetrafluoroboric acid (1.80g, 12.20mmol) in dichloromethane (20mL), and after stirring for 3h at 0°C, saturated bicarbonate was added Washed with sodium solution (25 mL×3), the organic phase was dried with anhydrous Na ₂ SO ₄ , and the solvent was removed to obtain 2.31 g of yellow oil, yield: 93%.

MS-ESI: m/z 380.1 [M+H] ⁺ .

Step 6: Compound 5-((S)-1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopropylmethoxy)-4-((tetrahydrofuran-3-yl)oxy )Synthesis of phenyl)oxazole-4-carboxylic acid methyl ester

Compound 2-(((3-(cyclopropylmethoxy)-4-((tetrahydrofuran-3-yl)oxy)phenyl)(methylthio)methylene)amino)acetic acid methyl ester (2.31 g, 6.09mmol) and compound (S)-(1-fluoro-1-oxopropan-2-yl)carbamate tert-butyl ester (2.85g, 12.20mmol) were dissolved in anhydrous tetrahydrofuran (30mL), -78 Under the condition of ℃, a tetrahydrofuran solution (25.0 mL, 25.00 mmol) of potassium hexamethyldisilazide was added dropwise, reacted at -78 ℃ for 1 h, added ice water (20 mL) to quench the reaction, and extracted with ethyl acetate ( 15mL×3), the combined organic phases were dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=2/1) to obtain 1.39 g of a yellow solid, Yield: 45%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.62 (dd, J ₁ =8.3Hz, J ₂ =1.9Hz, 1H), 7.59 (d, J = 2.2Hz, 1H), 6.90 (d, J = 8.3Hz ,1H),5.50-5.42(m,1H),5.06-5.02(m,1H),4.06-4.04(m,3H),3.99(s,3H),3.95-3.92(m,1H),3.93(d ,J=6.8Hz,2H),2.24-2.19(m,2H),1.55(d,J=7.0Hz,3H),1.44(s,9H),1.32–1.29(m,1H),0.68-0.63( m,2H),0.40-0.36(m,2H);

MS-ESI: m/z 503.2 [M+H] ⁺ .

Step 7: Compound 5-((S)-1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopropylmethoxy)-4-((tetrahydrofuran-3-yl)oxy )Synthesis of phenyl)oxazole-4-carboxylic acid

Compound 5-((S)-1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopropylmethoxy)-4-((tetrahydrofuran-3-yl)oxy)benzene Base) methyl oxazole-4-carboxylate (1.39g, 2.77mmol) and lithium hydroxide monohydrate (0.59g, 13.80mmol) were dissolved in a mixed solvent of tetrahydrofuran (30mL) and water (15mL), at 40°C After reacting for 3 hours, remove THF, add hydrochloric acid (1M) to adjust the pH value to 1, add ethyl acetate for extraction (30mL×3), combine the organic phases and dry with Na ₂ SO ₄ , remove the solvent to obtain 1.35g of white solid, product Rate: 96%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.64–7.61 (m, 2H), 6.91 (d, J=8.2Hz, 1H), 5.46–5.44 (m, 1H), 5.06–5.03 (m, 1H), 4.10–4.00(m,3H),3.99–3.90(m,1H),3.89(d,J=6.8Hz,2H),2.32–2.15(m,2H),1.58(d,J=7.0Hz,3H) ,1.44(s,9H),1.34–1.32(m,1H),0.67–0.64(m,2H),0.40–0.37(m,2H);

MS-ESI: m/z 487.3 [MH] ^- .

Step 8: Compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-((tetrahydrofuran-3-yl)oxy)phenyl)-4-((2,4 Synthesis of tert-butyl-difluorobenzyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

Compound 5-((S)-1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopropylmethoxy)-4-((tetrahydrofuran-3-yl)oxy)benzene Base) oxazole-4-carboxylic acid (0.32g, 0.65mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.19g, 0.99mmol) and N- Hydroxy-7-azabenzotriazole (0.14g, 1.02mmol) was dissolved in dichloromethane (15mL), stirred at room temperature for 0.5h, and 2,4-difluorobenzylamine (0.10mL, 0.90mmol) and N,N-diisopropylethylamine (0.40mL, 2.25mmol), stirred at room temperature for 12h, added water (15mL), extracted with dichloromethane (20mL×3), combined the organic phases with Na ₂ SO ₄ was dried, the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=3/1) to obtain 302 mg of white solid, yield: 75%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.57 (d, J=8.4Hz, 1H), 7.51 (s, 1H), 7.46–7.40 (m, 1H), 7.01–6.77 (m, 3H), 5.30– 5.28(m,1H),5.06–5.02(m,1H),4.72–4.58(m,2H),4.10–4.00(m,3H),3.98–3.92(m,1H),3.89(d,J＝6.8 Hz,2H),2.25–2.20(m,2H),1.54(d,J＝7.0Hz,3H),1.44(s,9H),0.93–0.82(m,1H),0.70–0.60(m,2H) ,0.41–0.37(m,2H);

MS-ESI: m/z 614.3 [M+H] ⁺ .

Step 9: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-((tetrahydrofuran-3-yl)oxy)phenyl)-N Synthesis of -(2,4-difluorobenzyl)oxazole-4-carboxamide hydrochloride

To compound ((1S)-1-(2-(3-(cyclopropylmethoxy)-4-((tetrahydrofuran-3-yl)oxy)phenyl)-4-((2,4-di To a solution of tert-butyl fluorobenzyl)carbamoyl)oxazol-5-yl)ethyl)carbamate (302 mg, 0.49 mmol) in dichloromethane (1 mL) was added HCl in ethyl acetate (4M, 3 mL) , stirred at room temperature for 0.5 h, and after removing the solvent, recrystallized from methanol/ethyl acetate (v/v=1/20) to obtain 235 mg of white solid, yield: 87%.

Compound 104: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.82–7.59(m, 2H), 7.51–7.46(m, 1H), 7.10(d, J=8.4Hz, 1H), 7.00–6.94(m ,2H),5.20–5.12(m,2H),4.64(s,2H),4.08–3.81(m,6H),2.38–2.09(m,2H),1.78(d,J＝7.0Hz,3H), 1.34–1.28(m,1H),0.72–0.51(m,2H),0.41–0.36(m,2H);

MS-ESI: m/z 514.3 [M+H-HCl] ⁺ .

Example 117: Compound 5-((S)-1-aminoethyl)-N-(2,4-difluorobenzyl)-2-(4-(difluoromethoxy)- Synthesis of 3-(4-((2-oxotetrahydrofuran-3-yl)amino)butoxy)phenyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound (S)-4-(5-(5-(1-(tert-butoxycarbonylamino)ethyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazole- Synthesis of 2-yl)-2-(difluoromethoxy)phenoxy)butyl acetate

Compound (S)-(1-(4-((2,4-difluorobenzyl)carbamoyl)-2-(4-(difluoromethoxy)-3-hydroxyphenyl)oxazole- 5-yl) ethyl) tert-butyl carbamate (1.30g, 2.4mmol), potassium carbonate (0.65g, 4.7mmol) and 4-bromobutyl acetate (0.40mL, 3.0mmol) were dissolved in N,N -Dimethylformamide (20mL), react at 60°C for 4.5h, add water (30mL), extract with ethyl acetate (50mL×3), combine the organic phases and dry with anhydrous Na ₂ SO ₄ , remove the solvent , the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=5/1) to obtain 1.50 g of white solid, yield: 95%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.59–7.56(m,2H),7.45–7.39(m,1H),7.23(d,J=8.1Hz,1H),6.89–6.84(m,2H), 6.61(t,J _FH ＝74.5Hz,1H),5.34–5.29(m,1H),4.70–4.60(m,2H),4.18–4.13(m,6H),2.05(s,3H),1.96–1.93 (m,2H),1.89–1.83(m,2H),1.53(t,J=7.0Hz,3H),1.43(s,9H);

MS-ESI: 654.2[M+H] ⁺ .

Step 2: Compound (S)-(1-(4-((2,4-difluorobenzyl)carbamoyl)-2-(4-(difluoromethoxy)-3-(4-hydroxybutyl Synthesis of tert-butyl (oxy)phenyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-4-(5-(5-(1-(tert-butoxycarbonylamino)ethyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazole-2- base)-2-(difluoromethoxy)phenoxy)butyl acetate (1.50g, 2.29mmol) and lithium hydroxide monohydrate (0.6g, 14.29mmol) were dissolved in tetrahydrofuran (40mL) and water (20mL ) in a mixed solvent at 40°C for 6 h, remove tetrahydrofuran, add ethyl acetate for extraction (30mL×3), combine the organic phases and dry with Na ₂ SO ₄ , remove the solvent, and conduct column separation of the concentrate (petroleum ether/acetic acid Ethyl ester (v/v)=2/1), to obtain 1.34g of white solid, yield: 95%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.60–7.57(m,2H),7.46–7.40(m,1H),7.24(d,J=8.8Hz,1H),6.90–6.86(m,2H), 6.63(t, J _FH ＝74.5Hz, 1H), 5.33–5.31(m, 1H), 4.71–4.62(m, 2H), 4.18(t, J＝6.2Hz, 2H), 3.77(t, J＝6.3 Hz, 2H), 2.02–1.95(m, 2H), 1.87–1.77(m, 2H), 1.55(d, J=7.0Hz, 3H), 1.44(s, 9H);

MS-ESI: 610.1[MH] ^- .

Step 3: Compound (S)-4-(5-(5-(1-(tert-butoxycarbonylamino)ethyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazole- Synthesis of 2-yl)-2-(difluoromethoxy)phenoxy)butyl 4-methylbenzenesulfonate

Compound (S)-(1-(4-((2,4-difluorobenzyl)carbamoyl)-2-(4-(difluoromethoxy)-3-(4-hydroxybutoxy ) phenyl) oxazol-5-yl) ethyl) tert-butyl carbamate (1.32g, 2.16mmol) and 4-methylbenzenesulfonyl chloride (1.20g, 6.29mmol) were dissolved in dichloromethane (40mL) , add triethylamine (0.9mL, 6.5mmol) dropwise at 0°C, react at 0°C for 6h, add dichloromethane for extraction (30mL×3), combine the organic phases and dry with Na ₂ SO ₄ , remove the solvent, and concentrate The liquid was subjected to column separation (petroleum ether/ethyl acetate (v/v)=2/1) to obtain 1.60 g of white solid, yield: 96%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.80 (d, J = 8.3Hz, 2H), 7.59 (dd, J ₁ = 8.3Hz, J ₂ = 1.9Hz, 1H), 7.56 (d, J = 1.8Hz ,1H),7.46–7.40(m,1H),7.35(d,J＝8.0Hz,2H),7.23(d,J＝8.3Hz,1H),6.90–6.84(m,2H),6.56(t, J _FH ＝74.3Hz,1H),5.34–5.30(m,1H),4.71–4.61(m,2H),4.17–4.10(m,4H),2.45(s,3H),1.95–1.89(m,4H ), 1.55(d, J=7.0Hz, 3H), 1.44(s, 9H);

MS-ESI: 766.2[M+H] ⁺ .

Step 4: Compound (S)-(1-(2-(3-(4-azidobutoxy)-4-(difluoromethoxy)phenyl)-4-((2,4-difluoro Synthesis of tert-butyl benzyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-4-(5-(5-(1-(tert-butoxycarbonylamino)ethyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazole-2- Base)-2-(difluoromethoxy)phenoxy)butyl 4-methylbenzenesulfonate (1.60g, 2.09mmol) and sodium azide (0.7g, 10.0mmol) were dissolved in acetone (30mL) In a mixed solvent of water (10mL), react at 80°C for 6h, remove acetone, add ethyl acetate for extraction (30mL×3), combine the organic phases and dry with Na ₂ SO ₄ , remove the solvent, and conduct column separation of the concentrate (petroleum ether/ethyl acetate (v/v)=5/1), 1.30 g of white solid was obtained, yield: 97%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.60 (dd, J ₁ = 8.3Hz, J ₂ = 1.8Hz, 1H), 7.58 (d, J = 1.7Hz, 1H), 7.47–7.41 (m, 1H) ,7.25(d,J＝8.2Hz,1H),6.92–6.84(m,2H),6.61(t,J _FH ＝74.4Hz,1H),5.33–5.28(m,1H),4.72–4.62(m, 2H), 4.17(t, J=6.0Hz, 2H), 3.43(t, J=6.6Hz, 2H), 2.02–1.95(m, 2H), 1.89–1.82(m, 2H), 1.56(d,J =7.0Hz, 3H), 1.45(s, 9H);

MS-ESI: 637.3 [M+H] ⁺ .

Step 5: Compound (S)-(1-(2-(3-(4-aminobutoxy)-4-(difluoromethoxy)phenyl)-4-((2,4-difluorobenzyl Synthesis of base) carbamoyl) oxazol-5-yl) ethyl) tert-butyl carbamate

Compound (S)-(1-(2-(3-(4-azidobutoxy)-4-(difluoromethoxy)phenyl)-4-((2,4-difluorobenzyl )carbamoyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (1.298g, 2.039mmol) and triphenylphosphine (0.85g, 3.2mmol) were dissolved in ethyl acetate (25mL) and water ( 5mL) in a mixed solvent, reacted at room temperature for 6h, added ethyl acetate for extraction (30mL×3), combined the organic phases with Na ₂ SO ₄ dried, removed the solvent, and the concentrated solution was subjected to column separation (methanol/dichloromethane (v /v)=10/1), 1.177g white solid was obtained, yield: 94%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.58–7.53 (m, 2H), 7.44–7.39 (m, 1H), 7.20 (d, J=8.3Hz, 1H), 6.88–6.83 (m, 2H), 6.67(t,J＝74.1Hz,1H),5.31–5.22(m,1H),4.66–4.64(m,2H),4.17–4.12(m,2H), 3.11–3.06(m,2H),1.98– 1.89(m,4H),1.55(d,J=7.0Hz,3H),1.43(s,9H);

MS-ESI: 611.3[M+H] ⁺ .

Step 6: Compound ((1S)-1-(4-((2,4-difluorobenzyl)carbamoyl)-2-(4-(difluoromethoxy)-3-(4-(( Synthesis of tert-butyl 2-oxotetrahydrofuran-3-yl)amino)butoxy)phenyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-(1-(2-(3-(4-aminobutoxy)-4-(difluoromethoxy)phenyl)-4-((2,4-difluorobenzyl) Carbamoyl) oxazol-5-yl) ethyl) tert-butyl carbamate (500mg, 0.82mmol), 2-bromo-γ-butyrolactone (201.6mg, 1.23mmol) and potassium carbonate (250mg, 1.81mmol) ) into anhydrous N,N-dimethylformamide (10mL), react at 90°C for 1h, add water (20mL), extract with ethyl acetate (30mL×3), combine the organic phases with Na ₂ SO ₄ was dried, the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=1/2) to obtain 216 mg of white solid, yield: 38%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.59–7.57(m,2H),7.46–7.41(m,1H),7.25–7.22(m,1H),6.89–6.84(m,2H),6.64(t ,J _FH ＝74.6Hz,1H),5.39–5.25(m,1H),4.71–4.63(m,2H),4.50–4.46(m,1H),4.29–4.23(m,1H),4.18–4.10( m,2H),3.84–3.76(m,1H),3.13–3.05(m,1H),2.98–2.86(m,1H),2.66–2.58(m,1H),2.42–2.35(m,1H), 2.00–1.89(m,4H),1.56(d,J=7.0Hz,3H),1.44(s,9H);

MS-ESI: 695.9 [M+H] ⁺ .

Step 7: Compound 5-((S)-1-aminoethyl)-N-(2,4-difluorobenzyl)-2-(4-(difluoromethoxy)-3-(4-( Synthesis of (2-oxotetrahydrofuran-3-yl)amino)butoxy)phenyl)oxazole-4-carboxamide hydrochloride

To the compound ((1S)-1-(4-((2,4-difluorobenzyl)carbamoyl)-2-(4-(difluoromethoxy)-3-(4-((2- To a solution of tert-butyl oxytetrahydrofuran-3-yl)amino)butoxy)phenyl)oxazol-5-yl)ethyl)carbamate (206 mg, 0.29 mmol) in dichloromethane (2 mL) was added HCl Ethyl acetate solution (4M, 4mL), stirred at room temperature for 0.5h, after removing the solvent, recrystallized with methanol/ethyl acetate (v/v=1/20) to obtain 116mg of white solid, yield: 62%.

Compound 105: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.58–7.55(m,2H),7.46–7.41(m,1H),7.25–7.22(m,1H),6.89–6.84(m,2H) ,6.64(t,J _FH ＝74.6Hz,1H),5.42–5.22(m,1H),4.75–4.58(m,2H),4.50–4.46(m,1H),4.33–4.08(m,3H), 3.84–3.76(m,1H),3.15–3.00(m,1H),2.92–2.86(m,1H),2.66–2.58(m,1H),2.42–2.35(m,1H),2.01–1.83(m ,4H),1.56(d,J=7.0Hz,3H);

MS-ESI: 595.1 [M+H-HCl] ⁺ .

Example 118: Compound (S)-5-(5-(5-(1-aminoethyl)-4-((2,4-difluorobenzyl)carbamoyl)oxa Synthesis of Azol-2-yl)-2-(difluoromethoxy)phenoxy)valeric acid hydrochloride

To compound (S)-5-(5-(5-(1-(tert-butoxycarbonylamino)ethyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazole-2- Add HCl in ethyl acetate (4M, 3mL) to a solution of -2-(difluoromethoxy)phenoxy)pentanoic acid (194mg, 0.30mmol) in dichloromethane (1mL) and stir at room temperature for 0.5h , after removing the solvent, recrystallized from methanol/ethyl acetate (v/v=1/20) to obtain 70 mg of white solid, yield: 92%.

Compound 113: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.82 (d, J = 1.8Hz, 1H), 7.74 (dd, J ₁ = 8.4Hz, J ₂ = 1.9Hz, 1H), 7.50-7.47 ( m,1H),7.33(d,J＝8.3Hz,1H),7.00–6.96(m,2H),6.88(t,J _FH ＝74.4Hz,1H),5.20–5.17(m,1H),4.65( s, 2H), 4.20(t, J＝6.1Hz, 2H), 2.43(t, J＝7.2Hz, 2H), 1.94–1.90(m, 2H), 1.87–1.83(m, 2H), 1.78(d ,J=7.0Hz,3H);

MS-ESI: m/z 540.9 [M+H-HCl] ⁺ .

Example 119: Compound (S)-5-(1-aminoethyl)-N-(2,4-difluorobenzyl)-2-(4-(difluoromethoxy)- Synthesis of 3-((5-(methylamino)-5-oxopentyl)oxy)phenyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound (S)-(1-(4-((2,4-difluorobenzyl)carbamoyl)-2-(4-(difluoromethoxy)-3-((5-( Synthesis of tert-butyl methylamino)-5-oxopentyl)oxy)phenyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(5-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazole- 2-yl)-2-(difluoromethoxy)phenoxy)valeric acid (300mg, 0.496mmol), methylamine hydrochloride (38mg, 0.563mmol), 1-ethyl-3-(3-di Methaminopropyl) carbodiimide hydrochloride (134mg, 0.704mmol) and N-hydroxy-7-azabenzotriazole (96mg, 0.704mmol) were dissolved in dichloromethane (20mL), stirred at room temperature 30min, N,N-diisopropylethylamine (0.33mL, 1.876mmol) was added dropwise to the solution at 0°C, stirred at room temperature for 10h, after adding water (25mL), extracted with dichloromethane (25mL×3 ). The organic phases were combined, and the organic phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=1/2) to obtain 255 mg of white solid, yield: 83.3 %.

¹ H NMR (600MHz, CDCl ₃ ): δppm 7.58-7.60(m, 2H), 7.42-7.46(m, 1H), 7.24(d, J=8.4Hz, 1H), 6.85-6.91(m, 2H), 6.63(t,J _FH ＝74.4Hz,1H),5.65(br.s,1H),5.31-5.32(m,1H),4.66-4.69(m,2H),4.12-4.17(m,2H),2.83 (s,3H),2.30-2.35(m,2H),1.86-1.99(m,4H),1.56(d,J=6.8Hz,3H),1.45(s,9H);

MS-ESI: m/z 653.20 [M+H] ⁺ .

Step 2: Compound (S)-5-(1-aminoethyl)-N-(2,4-difluorobenzyl)-2-(4-(difluoromethoxy)-3-((5- Synthesis of (methylamino)-5-oxopentyl)oxy)phenyl)oxazole-4-carboxamide hydrochloride

To compound (S)-(1-(4-((2,4-difluorobenzyl)carbamoyl)-2-(4-(difluoromethoxy)-3-((5-(methylamino )-5-oxopentyl)oxy)phenyl)oxazol-5-yl)ethyl)carbamate (250mg, 0.383mmol) in dichloromethane (2mL) solution in dichloromethane (2mL) was added HCl in ethyl acetate The ester solution (4M, 2mL) was stirred at room temperature for 30min, and the solvent was removed to obtain 225.6mg of white solid, yield: 100%.

Compound 162: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.82(s, 1H), 7.72(d, J=7.8Hz, 1H), 7.47-7.49(m, 1H), 7.31(d, J=7.8 Hz,1H),6.95-7.0(m,2H),6.87(t,J _FH ＝74.4Hz,1H),5.15-5.19(m,1H),4.63(s,2H),4.19(m,2H), 2.77(s,3H),2.37(m,2H),1.86-1.99(m,4H),1.78(d,J=7.0Hz,3H);

MS-ESI: m/z 553.20 [M+H-HCl] ⁺ .

Example 120: Compound (S)-5-(1-aminoethyl)-N-(2,4-difluorobenzyl)-2-(4-(difluoromethoxy)- Synthesis of 3-((5-(dimethylamino)-5-oxopentyl)oxy)phenyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound (S)-(1-(4-((2,4-difluorobenzyl)carbamoyl)-2-(4-(difluoromethoxy)-3-((5-( Synthesis of tert-butyl dimethylamino)-5-oxopentyl)oxy)phenyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(5-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazole- 2-yl)-2-(difluoromethoxy)phenoxy)valeric acid (334mg, 0.5222mmol), dimethylamine hydrochloride (52mg, 0.6266mmol), 1-ethyl-3-(3- Dimethylaminopropyl) carbodiimide hydrochloride (151mg, 0.7833mmol) and N-hydroxy-7-azabenzotriazole (107mg, 0.7833mmol) were dissolved in dichloromethane (20mL), room temperature Stir for 30min, add N,N-diisopropylethylamine (0.36mL, 2.089mmol) dropwise to the solution at 0°C, stir at room temperature for 10h, add water (25mL), extract with dichloromethane (25mL×3 ), and combine the organic phases. The organic phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v)=1/2) to obtain 252 mg of white solid, yield: 72.38%.

¹ H NMR (600MHz, CDCl ₃ ): δppm 7.58-7.59(m, 2H), 7.42-7.46(m, 1H), 7.24(d, J=8.7Hz, 1H), 6.85-6.91(m, 2H), 6.64(t,J _FH ＝74.6Hz,1H),5.29-5.34(m,1H),4.67-4.69(m,2H),4.15-4.18(m,2H),3.04(s,3H),2.97(s ,3H),2.44-2.47(m,2H),1.93-1.98(m,2H),1.86-1.91(m,2H),1.56(d,J=7.0Hz,3H),1.45(s,9H);

MS-ESI: m/z 667.2 [M+H] ⁺ .

Step 2: Compound (S)-5-(1-aminoethyl)-N-(2,4-difluorobenzyl)-2-(4-(difluoromethoxy)-3-((5- Synthesis of (Dimethylamino)-5-oxopentyl)oxy)phenyl)oxazole-4-carboxamide hydrochloride

To compound (S)-(1-(4-((2,4-difluorobenzyl)carbamoyl)-2-(4-(difluoromethoxy)-3-((5-(dimethyl To a solution of tert-butyl amino)-5-oxopentyl)oxy)phenyl)oxazol-5-yl)ethyl)carbamate (252 mg, 0.378 mmol) in dichloromethane (2 mL) was added HCl in acetic acid Ethyl ester solution (4M, 3mL), stirred at room temperature for 40min, and the solvent was removed to obtain 233mg of white solid, yield: 102.2%.

Compound 176: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.81 (d, J = 1.8Hz, 1H), 7.72 (dd, J ₁ = 8.3Hz, J ₂ = 1.8Hz, 1H), 7.46-7.50 ( m,1H),7.33(d,J=8.3Hz,1H),6.95-7.0(m,2H),6.89(t,J _FH =74.4Hz,1H),5.15-5.19(m,1H),4.65( s,2H),4.19-4.21(m,1H),3.01(s,3H),2.94(s,3H),2.51-2.53(m,1H),1.91-1.96(m,2H),1.81-1.86( m,2H),1.77(d,J=7.0Hz,3H);

MS-ESI: m/z 567.20 [M+H-HCl] ⁺ .

Example 121: Compound (S)-5-(1-aminoethyl)-2-(3-((5-((cyclopropylmethyl)amino)-5-oxopentyl Synthesis of yl)oxy)-4-(difluoromethoxy)phenyl)-N-(2,4-difluorobenzyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound (S)-(1-(2-(3-((5-((cyclopropylmethyl)amino)-5-oxopentyl)oxy)-4-(difluoromethoxy Synthesis of tert-butyl)phenyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(5-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazole- 2-yl)-2-(difluoromethoxy)phenoxy)valeric acid (300mg, 0.469mmol), cyclopropylmethylamine (40mg, 0.563mmol), 1-ethyl-3-(3-di Methaminopropyl) carbodiimide hydrochloride (135mg, 0.7036mmol) and N-hydroxy-7-azabenzotriazole (96mg, 0.7036mmol) were dissolved in dichloromethane (20mL), stirred at room temperature 30min, N,N-diisopropylethylamine (0.25mL, 1.407mmol) was added dropwise to the solution at 0°C, stirred at room temperature for 10h, after adding water (25mL), extracted with dichloromethane (25mL×3 ), and combine the organic phases. The organic phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v)=1/2) to obtain 322 mg of white solid, yield: 99.11%.

¹ H NMR (600MHz, CDCl ₃ ): δppm 7.58-7.60(m, 2H), 7.43-7.46(m, 1H), 7.25(d, J=6.0Hz, 1H), 6.85-6.91(m, 2H), 6.64(t,J _FH ＝74.4Hz,1H),5.67(br.s,1H),5.28-5.32(m,1H),4.64-4.71(m,2H),4.13-4.18(m,2H),3.13 -3.15(m,2H),2.33(t,J=6.6Hz,2H),1.90-1.96(m,4H),1.56(d,J=7.0Hz,3H),1.45(s,9H),0.94- 0.99(m,1H),0.51-0.54(m,2H),0.20-0.23(m,2H);

MS-ESI: m/z 693.2 [M+H] ⁺ .

Step 2: Compound (S)-5-(1-aminoethyl)-2-(3-((5-((cyclopropylmethyl)amino)-5-oxopentyl)oxy)-4 Synthesis of -(difluoromethoxy)phenyl)-N-(2,4-difluorobenzyl)oxazole-4-carboxamide hydrochloride

To compound (S)-(1-(2-(3-((5-((cyclopropylmethyl)amino)-5-oxopentyl)oxy)-4-(difluoromethoxy) A solution of tert-butyl phenyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazol-5-yl)ethyl)carbamate (322 mg, 0.4648 mmol) in dichloromethane (2 mL) Add HCl in ethyl acetate solution (4M, 3mL), stir at room temperature for 40min, remove the solvent to obtain 285mg of white solid, yield: 97.47%.

Compound 177: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.82 (d, J = 1.8Hz, 1H), 7.72 (dd, J ₁ = 1.8Hz, J ₂ = 8.4Hz, 1H), 7.46-7.52 ( m,1H),7.33(d,J=8.4Hz,1H),6.94-7.01(m,2H),6.88(t,J _FH =74.5Hz,1H),5.15-5.20(m,1H),4.65( s,2H),4.19-4.22(m,2H),3.06(d,J=7.0Hz,2H),2.33-2.36(m,2H),1.86-1.92(m,4H),1.78(d,J= 7.2Hz, 3H), 0.94-1.02(m, 1H), 0.47-0.52(m, 2H), 0.19-0.23(m, 2H);

MS-ESI: m/z 593.20 [M+H-HCl] ⁺ .

Example 122: Compound (S)-5-(1-aminoethyl)-N-(2,4-difluorobenzyl)-2-(4-(difluoromethoxy)- Synthesis of 3-((5-oxo-5-(4-(pyrimidin-2-yl)piperazin-1-yl)pentyl)oxy)phenyl)oxazole-4-carboxamide dihydrochloride to make

Step 1: Compound (S)-(1-(4-((2,4-difluorobenzyl)carbamoyl)-2-(4-(difluoromethoxy)-3-((5-oxo Synthesis of tert-butyl substituted-5-(4-(pyrimidin-2-yl)piperazin-1-yl)pentyl)oxy)phenyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(5-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazole- 2-yl)-2-(difluoromethoxy)phenoxy)valeric acid (300mg, 0.469mmol), 1-(2-pyrimidinyl)piperazine (93mg, 0.469mmol), 1-ethyl-3 -(3-Dimethylaminopropyl)carbodiimide hydrochloride (135mg, 0.7036mmol) and N-hydroxy-7-azabenzotriazole (96mg, 0.7036mmol) were dissolved in dichloromethane (20mL ), stirred at room temperature for 30min, added N,N-diisopropylethylamine (0.25mL, 1.407mmol) dropwise to the solution at 0°C, stirred at room temperature for 10h, added water (25mL), and dichloromethane Extract (25 mL×3), and combine the organic phases. The organic phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v)=1/2) to obtain 284 mg of white solid, yield: 77.05%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.35(d, J=4.8Hz, 2H), 7.58-7.60(m, 2H), 7.41-7.45(m, 1H), 7.24(d, J=8.8Hz, 1H), 6.84-6.92(m, 2H), 6.64(t, J _FH ＝74.8Hz, 1H), 6.56(t, J＝4.8Hz, 1H), 5.30-5.35(m, 1H), 4.66-4.69( m,2H),4.17-4.20(m,2H),3.83-3.89(m,4H),3.71-3.74(m,2H),3.57-3.60(m,2H),2.51-2.55(m,2H), 1.90-1.98(m,4H),1.56(d,J=7.2Hz,3H),1.45(s,9H);

MS-ESI: m/z 786.20 [M+H] ⁺ .

Step 2: Compound (S)-5-(1-aminoethyl)-N-(2,4-difluorobenzyl)-2-(4-(difluoromethoxy)-3-((5- Synthesis of oxo-5-(4-(pyrimidin-2-yl)piperazin-1-yl)pentyl)oxy)phenyl)oxazole-4-carboxamide dihydrochloride

To compound (S)-(1-(4-((2,4-difluorobenzyl)carbamoyl)-2-(4-(difluoromethoxy)-3-((5-oxo- 5-(4-(pyrimidin-2-yl)piperazin-1-yl)pentyl)oxy)phenyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (284mg, 0.3614mmol) Add HCl ethyl acetate solution (4M, 3mL) to dichloromethane (2mL) solution, stir at room temperature for 40min, remove the solvent to obtain 271.1mg of white solid, yield: 99%.

Compound 178: ¹ H NMR (400MHz, CD ₃ OD): δppm 8.65 (d, J = 5.2Hz, 2H), 7.84 (d, J = 2.0Hz, 1H), 7.73 (dd, J ₁ = 8.4Hz, J ₂ =1.9Hz,1H),7.46-7.52(m,1H),7.33(d,J=8.4Hz,1H),7.05(t,J=5.2Hz,1H),6.94-7.01(m,2H), 6.90(t,J _FH ＝74.4Hz,1H),5.15-5.21(m,1H),4.65(s,2H),4.22-4.25(m,2H),4.02-4.05(m,2H),3.93-3.96 (m,2H),3.81-3.86(m,4H),2.61-2.64(m,2H),1.87-1.99(m,4H),1.78(d,J=7.2Hz,3H);

MS-ESI: m/z 343.70 [M+2H-2HCl] ²⁺ .

Example 123: Compound (S)-5-(1-aminoethyl)-2-(3-((5-(4-(cyclopropylformyl)piperazin-1-yl)- Synthesis of 5-oxopentyl)oxy)-4-(difluoromethoxy)phenyl)-N-(2,4-difluorobenzyl)oxazole-4-carboxamide hydrochloride to make

Step 1: Compound (S)-(1-(2-(3-((5-(4-(cyclopropylformyl)piperazin-1-yl)-5-oxopentyl)oxy)-4 Synthesis of tert-butyl -(difluoromethoxy)phenyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(5-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazole- 2-yl)-2-(difluoromethoxy)phenoxy)pentanoic acid (300mg, 0.469mmol), N-cyclopropylcarbonylpiperazine hydrochloride (107mg, 0.5690mmol), 1-ethyl- 3-(3-Dimethylaminopropyl) carbodiimide hydrochloride (135mg, 0.7036mmol) and N-hydroxy-7-azabenzotriazole (96mg, 0.7036mmol) were dissolved in dichloromethane ( 20mL), stirred at room temperature for 30min, added dropwise N,N-diisopropylethylamine (0.25mL, 1.407mmol) to this solution at 0°C, stirred at room temperature for 10h, added water (25mL), separated, water The phase was extracted with dichloromethane (25 mL×3), and the organic phases were combined. The organic phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v)=1/2) to obtain 251 mg of white solid, yield: 69.0%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.59-7.61(m, 2H), 7.42-7.47(m, 1H), 7.24(d, J=8.0Hz, 1H), 6.84-6.92(m, 2H), 6.63(t, J _FH ＝74.8Hz, 1H), 5.28-5.33(m, 1H), 4.66-4.69(m, 2H), 4.18(t, J＝6.0Hz, 2H), 3.51-3.70(m, 8H ), 2.50(t, J=6.4Hz, 2H), 1.91-1.97(m, 4H), 1.56(d, J=7.2Hz, 3H), 1.45(s, 9H), 1.30-1.35(m, 1H) ,1.02-1.05(m,2H),0.80-0.85(m,2H);

MS-ESI: m/z 776.25 [M+H] ⁺ .

Step 2: Compound (S)-5-(1-aminoethyl)-2-(3-((5-(4-(cyclopropylformyl)piperazin-1-yl)-5-oxopentyl Synthesis of )oxy)-4-(difluoromethoxy)phenyl)-N-(2,4-difluorobenzyl)oxazole-4-carboxamide hydrochloride

To compound (S)-(1-(2-(3-((5-(4-(cyclopropylformyl)piperazin-1-yl)-5-oxopentyl)oxy)-4-( Difluoromethoxy)phenyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazol-5-yl)ethyl)carbamate (251mg, 0.3235mmol) HCl ethyl acetate solution (4M, 3mL) was added to the methyl chloride (2mL) solution, stirred at room temperature for 40min, and the solvent was removed to obtain 225mg of white solid, yield: 97.66%.

Compound 179: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.83 (d, J = 2.0Hz, 1H), 7.73 (dd, J ₁ = 8.4Hz, J ₂ = 2.0Hz, 1H), 7.46-7.52 ( m,1H),7.33(d,J=8.4Hz,1H),6.94-7.02(m,2H),6.90(t,J _FH =74.4Hz,1H),5.15-5.20(m,1H),4.65( s,2H),4.22(t,J=6.0Hz,2H),3.59-3.83(m,8H),2.58(t,J=7.2Hz,2H),1.92-2.04(m,2H),1.85-1.90 (m,2H),1.78(d,J=6.8Hz,3H),1.34-1.36(m,1H),0.89-0.92(m,2H),0.84-0.88(m,2H);

MS-ESI: m/z 676.20 [M+H-HCl] ⁺ .

Example 124: Compound 5-((S)-1-aminoethyl)-2-(3-((5-(4-(cyclopropylformyl)piperazin-1-yl)- 5-oxopentyl)oxy)-4-(difluoromethoxy)phenyl)-N-(2-((cyclopropylmethyl)amino)-1-(2,4-difluorobenzene Synthesis of yl)-2-oxoethyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound ((1S)-1-(2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-4-((cyano(2,4-difluorobenzene Synthesis of base) methyl) carbamoyl) oxazol-5-yl) ethyl) tert-butyl carbamate

Compound (S)-2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-5-(1-((tert-butoxycarbonyl)amino)ethyl)oxazole- 4-Formic acid (940mg, 1.9mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (540mg, 2.8mmol) and N-hydroxy-7-azabenzo Triazole (380mg, 2.8mmol) was dissolved in dichloromethane (20mL), stirred at room temperature for 30min, and 2-amino-2-(2,4-difluorophenyl)acetonitrile hydrochloride (460mg, 2.2mmol) was added Finally, N,N-diisopropylethylamine (1.3mL, 7.5mmol) was added dropwise to the solution at 0°C, stirred at room temperature for 10h, washed with water (25mL×3), and the aqueous phase was reversed with dichloromethane Extract (15mL×3), combine the organic phases, dry the organic phases with anhydrous Na ₂ SO ₄ , remove the solvent, and conduct column separation (petroleum ether/ethyl acetate (v/v)=7/1) to obtain 645mg White solid, yield: 53%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.69-7.70 (m, 1H), 7.66-7.68 (m, 1H), 7.62 (dd, J ₁ =8.4Hz, J ₂ =1.5Hz, 1H), 7.38- 7.51(m,5H),7.29(d,J=7.6Hz,1H),6.96-7.03(m,2H),6.66(t,J _FH =74.4Hz,1H),6.39(d,J=8.8Hz, 1H), 5.30-5.34(m, 1H), 5.25-5.37(d, J=2.0Hz, 1H), 1.54-1.58(m, 3H), 1.46(s, 9H);

MS-ESI: m/z 677.15 [M+Na] ⁺ .

Step 2: Compound 2-(2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-5-((S)-1-((tert-butoxycarbonyl)amino)ethyl Synthesis of oxazole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid

The compound ((1S)-1-(2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-4-((cyano(2,4-difluorophenyl) Methyl)carbamoyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (0.645g, 0.985mmol) and sodium hydroxide (2.244g, 56.1mmol) were dissolved in water (10mL) and ethanol (10mL ), stirred at 75°C for 4h, spin-dried ethanol, added hydrochloric acid (1M) to adjust the pH value to 1, extracted with ethyl acetate (20mL×3), combined the organic phases, dried the organic phases with anhydrous Na ₂ SO ₄ , and removed the solvent , to obtain 0.452 g of light red solid, yield: 68.1%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.71(d, J=2.0Hz, 1H), 7.62-7.66(m, 1H), 7.35-7.52(m, 6H), 7.27(d, J=7.6Hz, 1H),6.88-6.96(m,2H),6.66(t,J _FH ＝74.4Hz,1H),5.98-6.01(m,1H),5.32-5.37(m,1H),5.25(s,2H), 1.47-1.53(m,3H),1.39-1.40(m,9H);

MS-ESI: m/z 696.15 [M+Na] ⁺ .

Step 3: Compound ((1S)-1-(2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-4-((2-((cyclopropylmethyl) Synthesis of tert-butyl amino)-1-(2,4-difluorophenyl)-2-oxoethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

2-(2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)oxa Azole-4-carboxamido)-2-(2,4-difluorophenyl)acetic acid (452mg, 0.671mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide salt Salt (193mg, 1.01mmol) and N-hydroxy-7-azabenzotriazole (137mg, 1.01mmol) were dissolved in dichloromethane (20mL), stirred at room temperature for 30min, cyclopropylmethylamine (71.6 mg, 1.01mmol), N,N-diisopropylethylamine (0.47mL, 2.68mmol) was added dropwise to the solution at 0°C, stirred at room temperature for 10h, washed with water (25mL×3), and the aqueous phase Extract with dichloromethane (25mL× ₃ ), combine the organic phases, dry the organic phases with anhydrous _Na2SO4 , remove the solvent, and carry out column separation of the concentrate (petroleum ether/ethyl acetate (v/v)=1/1 ), to obtain 287 mg of white solid, yield: 58.9%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.76 (d, J=2.0Hz, 1H), 7.65-7.67 (m, 1H), 7.52-7.54 (m, 3H), 7.43-7.47 (m, 2H), 7.38-7.74(m,1H),7.29(d,J＝7.6Hz,1H),6.90-6.94(m,2H),6.67(t,J _FH ＝74.8Hz,1H),5.86-5.89(m,1H ),5.30-5.32(m,1H),5.28(s,2H),3.15-3.20(m,2H),1.47-1.53(m,3H),1.39-1.40(m,9H),1.33-1.34(m ,1H),0.52-0.54(m,2H),0.18-0.23(m,2H);

MS-ESI: m/z 727.25 [M+H] ⁺ .

Step 4: Compound ((1S)-1-(4-((2-((cyclopropylmethyl)amino)-1-(2,4-difluorophenyl)-2-oxoethyl)amino Synthesis of tert-butyl formyl)-2-(4-(difluoromethoxy)-3-hydroxyphenyl)oxazol-5-yl)ethyl)carbamate

The compound ((1S)-1-(2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-4-((2-((cyclopropylmethyl)amino) -1-(2,4-difluorophenyl)-2-oxoethyl)carbamoyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (287mg, 0.395mmol) and nickel chloride (51.2mg, 0.395mmol) was dissolved in ethanol (10mL), stirred at room temperature, slowly added dropwise sodium borohydride (75mg, 1.97mmol) in ethanol (20mL) solution in an ice bath, stirred at room temperature for 1.5h, added hydrochloric acid (1M) Adjust the pH value to 1, stir at room temperature until the reaction solution is clear, add sodium hydroxide solution (1M) to adjust the pH value to 14, extract with ethyl acetate (25mL×3), combine the organic phases, dry over anhydrous Na ₂ SO ₄ , remove solvent to obtain 0.246 g of reddish-brown solid, yield: 97.8%.

MS-ESI: m/z 637.30 [M+H] ⁺ .

Step 5: Compound 5-(5-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-4-((2-((cyclopropylmethyl)amino)-1 Synthesis of -(2,4-difluorophenyl)-2-oxoethyl)carbamoyl)oxazol-2-yl)-2-(difluoromethoxy)phenoxy)pentanoic acid methyl ester

The compound ((1S)-1-(4-((2-((cyclopropylmethyl)amino)-1-(2,4-difluorophenyl)-2-oxoethyl)carbamoyl )-2-(4-(Difluoromethoxy)-3-hydroxyphenyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (246mg, 0.386mmol), methyl 5-bromopentanoate (113mg, 0.58mmol) and potassium carbonate (107mg, 0.773mmol) were added to DMF (15mL), reacted at 60°C for 5 hours, then suction filtered to remove potassium carbonate, concentrated the filtrate, and carried out column separation (petroleum ether/ethyl acetate (v/v)=1/1), to obtain 232mg of white solid, yield: 80%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.63-7.65(m, 2H), 7.48-7.55(m, 1H), 7.26(d, J=8.8Hz, 1H), 6.84-6.95(m, 2H), 6.65(t,J _FH ＝74.8Hz,1H),5.86-5.89(m,1H),5.28-5.36(m,1H),4.18-4.21(m,2H),3.70(s,3H),3.13-3.23 (m,2H),2.45-2.49(m,2H),1.89-1.97(m,4H),1.47-1.48(m,3H),1.40-1.44(m,9H),1.30-1.31(m,1H) ,0.51-0.53(m,2H),0.18-0.22(m,2H);

MS-ESI: m/z 751.20 [M+H] ⁺ .

Step 6: Compound 5-(5-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-4-((2-((cyclopropylmethyl)amino)-1 Synthesis of -(2,4-difluorophenyl)-2-oxoethyl)carbamoyl)oxazol-2-yl)-2-(difluoromethoxy)phenoxy)pentanoic acid

Compound 5-(5-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-4-((2-((cyclopropylmethyl)amino)-1-( 2,4-Difluorophenyl)-2-oxoethyl)carbamoyl)oxazol-2-yl)-2-(difluoromethoxy)phenoxy)pentanoic acid methyl ester (232mg, 0.309 mmol) and solid sodium hydroxide (61mg, 1.55mmol) were dissolved in a mixed solvent of water (10mL) and ethanol (20mL), reacted at 60°C for 2h, removed ethanol by rotary evaporation, and adjusted the pH value to 1 by adding hydrochloric acid (1M). Extracted with ethyl acetate (25 mL×3), combined the organic phases, dried over anhydrous Na ₂ SO ₄ , and removed the solvent to obtain 210 mg of light yellow oil, yield: 92.2%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.82-7.85(m, 1H), 7.50-7.59(m, 2H), 7.26(d, J=8.0Hz, 1H), 6.87-6.95(m, 2H), 6.64(t,J _FH ＝74.7Hz,1H),5.86(m,1H),5.35-5.37(m,1H),4.26-4.29(m,2H),3.13-3.21(m,2H),2.49(m ,2H),1.81-1.90(m,4H),1.49-1.54(m,3H),1.39-1.49(m,9H),1.31-1.36(m,1H),0.51-0.53(m,2H),0.20 -0.22(m,2H);

MS-ESI: m/z 737.20 [M+H] ⁺ .

Step 7: Compound ((1S)-1-(2-(3-((5-(4-(cyclopropylformyl)piperazin-1-yl)-5-oxopentyl)oxy)-4 -(Difluoromethoxy)phenyl)-4-((2-((cyclopropylmethyl)amino)-1-(2,4-difluorophenyl)-2-oxoethyl)amino Synthesis of tert-butyl formyl)oxazol-5-yl)ethyl)carbamate

Compound 5-(5-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-4-((2-((cyclopropylmethyl)amino)-1-( 2,4-Difluorophenyl)-2-oxoethyl)carbamoyl)oxazol-2-yl)-2-(difluoromethoxy)phenoxy)pentanoic acid (210mg, 0.28mmol) , 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (80mg, 0.42mmol) and N-hydroxyl-7-azabenzotriazole (57mg, 0.42mmol) Dissolve in dichloromethane (20mL), stir at room temperature for 30min, add N-cyclopropylcarbonyl piperazine salt (80mg, 0.42mmol), add N,N-diisopropyl Ethylamine (0.20mL, 1.12mmol), stirred at room temperature for 10h, washed with water (25mL×3), extracted the aqueous phase with dichloromethane (15mL×3), combined the organic phase, and dried the organic phase with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=1/2) to obtain 211 mg of white solid, yield: 86.4%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.63-7.65(m, 2H), 7.48-7.53(m, 1H), 7.24(d, J=8.4Hz, 1H), 6.89-6.95(m, 2H), 6.64(t, J _FH ＝74.8Hz, 1H), 5.86-5.87(m, 1H), 5.28-5.34(m, 1H), 4.22(t, J＝5.6Hz, 2H), 3.53-3.70(m, 8H ),3.13-3.24(m,2H),2.52(t,J＝6.8Hz,2H),1.93-2.01(m,4H),1.48-1.53(m,3H),1.40-1.43(m,9H), 1.32-1.35(m,1H),1.27-1.30(m,1H),1.02-1.05(m,2H),0.80-0.85(m,2H),0.51-0.55(m,2H),0.19-0.20(m ,2H);

MS-ESI: m/z 873.30 [M+H] ⁺ .

Step 8: Compound 5-((S)-1-aminoethyl)-2-(3-((5-(4-(cyclopropylformyl)piperazin-1-yl)-5-oxopentyl )Oxygen)-4-(difluoromethoxy)phenyl)-N-(2-((cyclopropylmethyl)amino)-1-(2,4-difluorophenyl)-2-oxo Synthesis of ethyl)oxazole-4-carboxamide hydrochloride

To the compound ((1S)-1-(2-(3-((5-(4-(cyclopropylformyl)piperazin-1-yl)-5-oxopentyl)oxy)-4-( Difluoromethoxy)phenyl)-4-((2-((cyclopropylmethyl)amino)-1-(2,4-difluorophenyl)-2-oxoethyl)carbamoyl ) Oxazol-5-yl) ethyl) tert-butyl carbamate (211mg, 0.242mmol) in dichloromethane (2mL) was added HCl in ethyl acetate (4M, 2mL), stirred at room temperature for 30min, and the solvent was removed , to obtain 195 mg of white solid, yield: 99.7%.

Compound 196: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.83(s, 1H), 7.73(d, J=8.4Hz, 1H), 7.58(m, 1H), 7.34(d, J=8.4Hz, 1H), 7.04-7.09(m, 2H), 6.90(t, J _FH ＝74.4Hz, 1H), 5.92(d, J＝1.4Hz, 1H), 5.16-5.20(m, 1H), 4.23(t, J＝6.0Hz, 2H), 3.59-3.84(m, 8H), 3.01-3.18(m, 2H), 2.57-2.60(t, J＝7.2Hz, 2H), 1.87-2.01(m, 4H), 1.76 (d, J=6.8Hz, 3H), 1.30-1.35(m, 2H), 0.83-0.93(m, 4H), 0.45-0.50(m, 2H), 0.19-0.22(m, 2H);

MS-ESI: m/z 773.25 [M+H-HCl] ⁺ .

Example 125: Compound (S)-5-(1-aminoethyl)-N-(2,4-difluorobenzyl)-2-(4-(difluoromethoxy)- Synthesis of 3-((5-(methylsulfonylamino)-5-oxopentyl)oxy)phenyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound (S)-(1-(4-((2,4-difluorobenzyl)carbamoyl)-2-(4-(difluoromethoxy)-3-((5-( Synthesis of tert-butyl methanesulfonylamino)-5-oxopentyl)oxy)phenyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(5-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazole- 2-yl)-2-(difluoromethoxy)phenoxy)pentanoic acid (200 mg, 0.313 mmol) and N,N'-carbonyldiimidazole (152 mg, 0.938 mmol) were dissolved in anhydrous THF (20 mL) , stirred at 60°C for 20min, cooled to room temperature, added methylsulfonamide (119mg, 1.25mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (71.4mg, 0.469mmol) , stirred at 60°C for 3.5h, washed with saturated ammonium chloride solution (25mL×3), extracted the aqueous phase with ethyl acetate (25mL), combined the organic phases, dried the organic phases with anhydrous Na ₂ SO ₄ , removed the solvent, and concentrated The liquid was subjected to column separation (petroleum ether/ethyl acetate (v/v)=1/2) to obtain 112 mg of white solid, yield: 50%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.58-7.62(m, 2H), 7.40-7.46(m, 1H), 7.24(d, J=8.4Hz, 1H), 6.83-6.91(m, 2H), 6.64(t,J _FH ＝74.0Hz,1H),5.31-5.33(m,1H),4.66-4.68(m,2H),4.12-4.17(m,2H),3.31(s,3H),2.51-2.54 (m,2H),1.94-1.96(m,4H),1.56(d,J=6.8Hz,2H),1.45-1.47(m,9H);

MS-ESI: m/z 717.30 [M+H] ⁺ .

Step 2: Compound (S)-5-(1-aminoethyl)-N-(2,4-difluorobenzyl)-2-(4-(difluoromethoxy)-3-((5- Synthesis of (methylsulfonylamino)-5-oxopentyl)oxy)phenyl)oxazole-4-carboxamide hydrochloride

To compound (S)-(1-(4-((2,4-difluorobenzyl)carbamoyl)-2-(4-(difluoromethoxy)-3-((5-(methylsulfonyl) To a solution of tert-butyl (amido)-5-oxopentyl)oxy)phenyl)oxazol-5-yl)ethyl)carbamate (133 mg, 0.188 mmol) in dichloromethane (1 mL) was added HCl Isopropanol solution (7M, 2 mL), stirred at room temperature for 40 min, and the solvent was removed to obtain 121 mg of white solid, yield: 100%.

Compound 228: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.82(s, 1H), 7.73(d, J=8.4Hz, 1H), 7.47-7.51(m, 1H), 7.33(d, J=8.4 Hz,1H),6.97-7.01(m,2H),6.89(t,J _FH ＝74.4Hz,1H),5.16-5.19(m,1H),4.65(s,2H),4.19-4.21(m,2H ),3.24(s,3H),2.45-2.47(m,2H),1.87-1.95(m,4H),1.78(d,J=7.2Hz,3H);

MS-ESI: m/z 617.15 [M+H-HCl] ⁺ .

Example 126: Compound (S)-5-(1-aminoethyl)-N-(2,4-difluorobenzyl)-2-(4-(difluoromethoxy)- Synthesis of 3-((5-morpholinyl-5-oxopentyl)oxy)phenyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound (S)-(1-(4-((2,4-difluorobenzyl)carbamoyl)-2-(4-(difluoromethoxy)-3-((5-carbamoyl) Synthesis of tert-Butyl (Linyl-5-oxopentyl)oxy)phenyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(5-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazole- 2-yl)-2-(difluoromethoxy)phenoxy)valeric acid (150mg, 0.235mmol), morpholine (31mg, 0.352mmol), 1-ethyl-3-(3-dimethylaminopropyl Base) carbodiimide hydrochloride (67mg, 0.352mmol) and N-hydroxy-7-azabenzotriazole (48mg, 0.352mmol) were dissolved in dichloromethane (20mL), stirred at room temperature for 30min, in Add N,N-diisopropylethylamine (0.12mL, 0.704mmol) dropwise to this solution at 0°C, stir at room temperature for 10h, wash with water (25mL×3), and extract the aqueous phase with dichloromethane (25mL× 3), the organic phases were combined, and the organic phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=1/2) to obtain 133 mg of a white solid. Rate: 80%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.58-7.61(m, 2H), 7.41-7.47(m, 1H), 7.23(d, J=8.0Hz, 1H), 6.84-6.92(m, 2H), 6.62(t, J _FH ＝74.8Hz, 1H), 5.31-5.33(m, 1H), 4.66-4.71(m, 2H), 4.18(d, J＝6.0Hz, 1H), 3.68-3.71(m, 4H ),3.63-3.65(m,2H),3.49-3.52(m,2H),2.46(t,J＝6.8Hz,2H),1.88-2.01(m,4H),1.56(d,J＝6.8Hz, 2H), 1.45(s, 9H);

MS-ESI: m/z 709.30 [M+H] ⁺ .

Step 2: Compound (S)-5-(1-aminoethyl)-N-(2,4-difluorobenzyl)-2-(4-(difluoromethoxy)-3-((5- Synthesis of Morpholinyl-5-oxopentyl)oxy)phenyl)oxazole-4-carboxamide hydrochloride

To compound (S)-(1-(4-((2,4-difluorobenzyl)carbamoyl)-2-(4-(difluoromethoxy)-3-((5-morpholinyl A solution of tert-butyl-5-oxopentyl)oxy)phenyl)oxazol-5-yl)ethyl)carbamate (133 mg, 0.188 mmol) in dichloromethane (1 mL) was added HCl in ethyl acetate The solution (7M, 2 mL) was stirred at room temperature for 40 min, and the solvent was removed to obtain 121 mg of white solid, yield: 100%.

Compound 235: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.83(s, 1H), 7.73(d, J=8.4Hz, 1H), 7.46-7.52(m, 1H), 7.33(d, J=8.4 Hz,1H),6.95-7.01(m,2H),6.90(t,J _FH ＝74.4Hz,1H),5.16-5.21(m,1H),4.65(s,2H),4.20-4.23(m,2H ),3.64-3.68(m,4H),3.57-3.59(m,4H),2.53(t,J＝6.8Hz,2H),1.83-1.99(m,4H),1.78(d,J＝6.8Hz, 3H);

MS-ESI: m/z 609.25 [M+H-HCl] ⁺ .

Example 127: Compound (S)-5-(1-aminoethyl)-N-(2,4-difluorobenzyl)-2-(4-(difluoromethoxy)- Synthesis of 3-((5-oxo-5-ureidopentyl)oxy)phenyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound (S)-(1-(4-((2,4-difluorobenzyl)carbamoyl)-2-(4-(difluoromethoxy)-3-((5-oxo Synthesis of tert-butyl (substituent-5-ureidopentyl)oxy)phenyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(5-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazole- 2-yl)-2-(difluoromethoxy)phenoxy)pentanoic acid (300 mg, 0.469 mmol) and N,N'-carbonyldiimidazole (228 mg, 1.41 mmol) were dissolved in anhydrous THF (20 mL) , stirred at 60°C for 20min, cooled to room temperature, added urea (214mg, 3.563mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.305mL, 0.315mmol), 80°C Stir for 18h, wash with saturated ammonium chloride solution (25mL×3), extract the aqueous phase with ethyl acetate (25mL), combine the organic phases, dry the organic phases with anhydrous Na ₂ SO ₄ , remove the solvent, and conduct column separation of the concentrate (petroleum ether/ethyl acetate (v/v)=1/1), 100 mg of white solid was obtained, yield: 31.3%.

¹ H NMR (400MHz, CD ₃ OD): δppm 7.72-7.77(m, 1H), 7.66-7.67(m, 1H), 7.45-7.51(m, 1H), 7.29(d, J=8.4Hz, 1H) ,6.94-6.99(m,2H),6.86(t,J _FH ＝74.8Hz,1H),5.41-5.45(m,1H),4.62(s,2H),4.18-4.20(m,2H),2.45- 2.49(m,2H),1.86-1.92(m,4H),1.53(d,J=7.2Hz,3H),1.42(s,9H);

MS-ESI: m/z 682.20 [M+H] ⁺ .

Step 2: Compound (S)-5-(1-aminoethyl)-N-(2,4-difluorobenzyl)-2-(4-(difluoromethoxy)-3-((5- Synthesis of oxo-5-ureidopentyl)oxy)phenyl)oxazole-4-carboxamide hydrochloride

To compound (S)-(1-(4-((2,4-difluorobenzyl)carbamoyl)-2-(4-(difluoromethoxy)-3-((5-oxo- To a solution of tert-butyl 5-ureidopentyl)oxy)phenyl)oxazol-5-yl)ethyl)carbamate (100 mg, 0.147 mmol) in dichloromethane (1 mL) was added HCl in isopropanol (7M, 2 mL), stirred at room temperature for 40 min, and removed the solvent to obtain 91 mg of white solid, yield: 100%.

Compound 240: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.82(s, 1H), 7.72-7.76(m, 2H), 7.62-7.65(m, 1H), 7.47-7.51(m, 1H), 7.33 (d,J=8.4Hz,1H),6.95-7.01(m,2H),6.89(t,J _FH =74.4Hz,1H),5.16-5.19(m,1H),4.65(s,2H),4.19 -4.21(m,2H),2.46-2.48(m,2H),1.87-1.94(m,4H),1.78(d,J=6.6Hz,3H);

MS-ESI: m/z 582.30 [M+H-HCl] ⁺ .

Example 128: Compound N-(2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)-5-((S)-1-aminoethyl Base)-2-(4-(difluoromethoxy)-3-((5-morpholinyl-5-oxopentyl)oxy)phenyl)oxazole-4-carboxamide hydrochloride synthesis

Step 1: Compound ((1S)-1-(4-((2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)carbamoyl)-2-(3- Synthesis of tert-butyl (benzyloxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-5-(1-((tert-butoxycarbonyl)amino)ethyl)oxazole- 4-Formic acid (0.30g, 0.595mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.170g, 0.892mmol) and N-hydroxyl-7-aza Benzotriazole (0.125g, 0.892mmol) was dissolved in dichloromethane (20mL), stirred at room temperature for 30min, and 2-amino-2-(2,4-difluorophenyl)acetamide (0.159g, 0.714 mmol), N,N-diisopropylethylamine (0.45mL, 2.38mmol) was added dropwise to the solution at 0°C, stirred at room temperature for 10h, washed with water (25mL×3), and the aqueous phase was washed with dichloro Extracted with methane (25mL×3), combined the organic phases, dried the organic phases with anhydrous Na ₂ SO ₄ , removed the solvent, and subjected the concentrated solution to column separation (petroleum ether/ethyl acetate (v/v)=2/1) to obtain 0.333g white solid, yield: 81.9%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.75(s, 1H), 7.65(d, J=8.4Hz, 1H), 7.36-7.55(m, 6H), 7.29(d, J=8.4Hz, 1H) ,6.90-6.96(m,2H),6.67(t,J _FH ＝74.4Hz,1H),5.94(d,J＝7.2Hz,1H),5.31-5.35(m,1H),5.27(s,2H) ,1.48-1.53(m,3H),1.41-1.48(m,9H);

MS-ESI: m/z 673.20 [M+H] ⁺ .

Step 2: Compound ((1S)-1-(4-((2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)carbamoyl)-2-(4 Synthesis of tert-butyl -(difluoromethoxy)-3-hydroxyphenyl)oxazol-5-yl)ethyl)carbamate

The compound ((1S)-1-(4-((2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)carbamoyl)-2-(3-(benzyl Oxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate (0.333g, 0.495mmol) and nickel chloride (0.068g, 0.495mmol) were dissolved In ethanol (5mL), add sodium borohydride (0.098g, 2.48mmol) in ethanol (20mL) dropwise to this solution at 0°C, stir at room temperature for 10h, add hydrochloric acid (1M) to adjust pH=1, stir To clarification, add sodium hydroxide solution (1M) to adjust pH=14, extract with ethyl acetate (25mL×3), combine the organic phases, dry the organic phases with anhydrous Na ₂ SO ₄ , remove the solvent, and the concentrated solution is subjected to column separation ( Petroleum ether/ethyl acetate (v/v)=2/1) to obtain 221 mg of white solid, yield: 76.6%.

¹ H NMR (400MHz, CD ₃ OD): δppm 7.63 (d, J = 2.0Hz, 1H), 7.48 (dd, J ₁ = 8.4Hz, J ₂ = 2.0Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.00-7.06(m, 2H), 6.89(t, J _FH ＝74.8Hz, 1H), 5.88(d, J＝12.4Hz, 1H), 5.35-5.40(m, 1H), 1.50( d,J=7.2Hz,3H),1.39(s,9H);

MS-ESI: m/z 583.20 [M+H] ⁺ .

Step 3: Compound 5-(5-(4-((2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)carbamoyl)-5-((S)- Synthesis of 1-((tert-butoxycarbonyl)amino)ethyl)oxazol-2-yl)-2-(difluoromethoxy)phenoxy)pentanoic acid methyl ester

Compound ((1S)-1-(4-((2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)aminocarboxamido)-2-(4-( Difluoromethoxy)-3-hydroxyphenyl)oxazol-5-yl)ethyl)carbamate (442mg, 0.818mmol), methyl 5-bromovalerate (239mg, 1.23mmol) and carbonic acid Potassium (226mg, 1.64mmol) was dissolved in DMF (15mL), sealed at 60°C for 4 hours, filtered to remove potassium carbonate, concentrated the filtrate, and separated by column (petroleum ether/ethyl acetate (v/v)=1/1 ), to obtain 454mg of colorless oily substance, yield: 84.8%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.63-7.65(m, 2H), 7.50-7.56(m, 1H), 7.26(d, J=8.4Hz, 1H), 6.90-6.96(m, 2H), 6.65(t, J _FH ＝74.4Hz, 1H), 5.94(d, J＝6.8Hz, 1H), 5.29-5.37(m, 1H), 4.17-4.20(m, 2H), 3.71(s, 3H), 2.45-2.49(m,2H),1.89-1.97(m,4H),1.48-1.53(m,3H),1.40-1.45(m,9H);

MS-ESI: m/z 697.25 [M+H] ⁺ .

Step 4: Compound 5-(5-(4-((2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)carbamoyl)-5-((S)- Synthesis of 1-((tert-butoxycarbonyl)amino)ethyl)oxazol-2-yl)-2-(difluoromethoxy)phenoxy)pentanoic acid

The compound 5-(5-(4-((2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)carbamoyl)-5-((S)-1- ((tert-butoxycarbonyl)amino)ethyl)oxazol-2-yl)-2-(difluoromethoxy)phenoxy)methyl valerate (220mg, 0.316mmol) and sodium hydroxide (64mg, 1.58mmol) was dissolved in a mixed solvent of water (10mL) and ethanol (20mL), reacted at 60°C for 90min, removed ethanol by rotary evaporation, added hydrochloric acid (1M) to adjust the pH value to 1, extracted with ethyl acetate (25mL×3), The organic phases were combined, dried over anhydrous Na ₂ SO ₄ , and the solvent was removed to obtain 179 mg of light yellow oil, yield: 83.0%.

¹ H NMR (400MHz, CD ₃ OD): δppm 7.44-7.77 (m, 1H), 7.67 (dd, J ₁ = 8.0Hz, J ₂ = 2.0Hz, 1H), 7.57-7.61 (m, 1H), 7.29 (d, J＝8.0Hz, 1H), 6.99-7.05(m, 2H), 6.86(t, J _FH ＝74.4Hz, 1H), 5.89-5.91(m, 1H), 5.41-5.44(m, 1H) ,4.17-4.20(m,2H),2.41-2.45(m,2H),1.82-1.94(m,4H),1.51(d,J=7.2Hz,3H),1.40(s,9H);

MS-ESI: m/z 683.20 [M+H] ⁺ .

Step 5: Compound ((1S)-1-(4-((2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)carbamoyl)-2-(4- Synthesis of tert-butyl (difluoromethoxy)-3-((5-morpholinyl-5-oxopentyl)oxy)phenyl)oxazol-5-yl)ethyl)carbamate

The compound 5-(5-(4-((2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)carbamoyl)-5-((S)-1- ((tert-butoxycarbonyl)amino)ethyl)oxazol-2-yl)-2-(difluoromethoxy)phenoxy)pentanoic acid (0.179g, 0.262mmol), 1-ethyl-3- (3-Dimethylaminopropyl) carbodiimide hydrochloride (0.076g, 0.393mmol) and N-hydroxyl-7-azabenzotriazole (0.054g, 0.393mmol) were dissolved in dichloromethane ( 20mL), stirred at room temperature for 30min, added morpholine (0.027g, 0.315mmol), added N,N-diisopropylethylamine (0.15mL, 0.787mmol) dropwise to the solution at 0°C, and stirred at room temperature After 10h, wash with water (25mL×3), extract the aqueous phase with dichloromethane (25mL×3), combine the organic phases, dry the organic phases with anhydrous Na ₂ SO ₄ , remove the solvent, and conduct column separation of the concentrate (methanol/di Chloromethane (v/v)=1/20), preliminary purification, preparation of silica gel plate separation (developing solvent: methanol/dichloromethane (v/v)=1/10), to obtain 81 mg of white solid, yield: 41% .

¹ H NMR (400MHz, CD ₃ OD): δppm 7.77(s, 1H), 7.66(d, J=8.4Hz, 1H), 7.55-7.58(m, 1H), 7.29(d, J=8.4Hz, 1H ),6.98-7.04(m,2H),6.87(t,J _FH ＝74.4Hz,1H),5.90(d,J＝11.6Hz,1H),5.41-5.44(m,1H),4.16-4.20(m ,2H),3.64-3.69(m,4H),3.56-3.60(m,4H),2.51-2.54(m,2H),1.88-1.93(m,2H),1.92-1.86(m,2H),1.52 (d,J=6.8Hz,3H),1.40(s,9H);

MS-ESI: m/z 752.10 [M+H] ⁺ .

Step 6: Compound N-(2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)-5-((S)-1-aminoethyl)-2-(4 Synthesis of -(difluoromethoxy)-3-((5-morpholinyl-5-oxopentyl)oxy)phenyl)oxazole-4-carboxamide hydrochloride

To compound ((1S)-1-(4-((2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)carbamoyl)-2-(4-(di Fluoromethoxy)-3-((5-morpholinyl-5-oxopentyl)oxy)phenyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (81mg, 0.108mmol) Add HCl in ethyl acetate (4M, 3mL) to a solution of dichloromethane (2mL), stir at room temperature for 40min, and remove the solvent to obtain 74mg of white solid, yield: 100%.

Compound 256: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.82(s, 1H), 7.73(d, J=7.8Hz, 1H), 7.58-7.62(m, 1H), 7.34(d, J=8.4 Hz,1H),7.02-7.07(m,2H),6.90(t,J _FH ＝74.4Hz,1H),5.92(s,1H),5.16-5.19(m,1H),4.21-4.23(m,2H ),3.65-3.70(m,4H),3.59(m,4H),2.53-2.55(m,2H),1.92-1.97(m,2H),1.83-1.88(m,2H),1.77(d,J =7.2Hz,3H);

MS-ESI: m/z 652.20 [M+H-HCl] ⁺ .

Example 129: Compound (S)-2-(4-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethane Synthesis of ethyl (oxy)phenyl)oxazole-4-carboxamide)phenyl)acetate hydrochloride

Step 1: Synthesis of ethyl p-aminophenylacetic acid

Add Pd/C (64mg) to a methanol (10mL) solution of ethyl p-nitrophenylacetate (500mg, 2.39mmol), reduce with hydrogen, stir at room temperature for 1.5h, filter with diatomaceous earth, and spin the filtrate to give p- Ethyl aminophenylacetate: light red liquid 420mg, yield: 97%.

¹ H NMR (400MHz, CD ₃ OD): δppm 7.03 (d, J = 8.4Hz, 2H), 6.71 (d, J = 8.4Hz, 2H), 4.13 (q, J = 7.1Hz, 1H), 3.49 ( s,2H),1.24(t,J=7.1Hz,3H);

MS-ESI: m/z 180.2 [M+H] ⁺ .

Step 2: Compound (S)-2-(4-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(di Synthesis of ethyl fluoromethoxy)phenyl)oxazole-4-carboxamide)phenyl)acetate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) oxazole-4-carboxylic acid (250mg, 0.53mmol), ethyl p-aminophenylacetate (115mg, 0.64mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (154mg, 0.80mmol) and N-hydroxy-7-azabenzotriazole (182mg, 1.33mmol) were dissolved in dichloromethane (15mL), and N,N- Diisopropylethylamine (0.37mL, 2.14mmol), stirred at room temperature for 2.5h, added water to wash (10mL×2), the organic phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ Ethyl acetate (v/v)=5/1), to obtain 256 mg of white solid, yield: 76%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.68 (d, J = 8.4Hz, 2H), 7.63 (dd, J ₁ = 8.3Hz, J ₂ = 1.9Hz, 1H), 7.59 (s, 1H), 7.32 (d,J=8.4Hz,2H),7.27(d,J=6.2Hz,1H),6.72(t,J _FH =75.0Hz,1H),5.35–5.30(m,1H),4.16(q,J ＝7.1Hz, 2H), 4.01(d, J=6.9Hz, 2H), 3.61(s, 2H), 1.57(d, J=7.0Hz, 3H), 1.43(s, 9H), 1.37–1.33(m ,1H),1.26(t,J=7.1Hz,3H),0.73–0.68(m,2H),0.44–0.41(m,2H);

MS-ESI: m/z 574.2 [M-55] ⁺ .

Step 3: Compound (S)-2-(4-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) Synthesis of ethyl oxazole-4-carboxamide)phenyl)acetate hydrochloride

To compound (S)-2-(4-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethane Add HCl in ethyl acetate (4M, 5mL) to a solution of oxy)phenyl)oxazole-4-carboxamide)phenyl)ethyl acetate (249mg, 0.40mmol) in dichloromethane (4mL), and stir at room temperature After 1.5 h, the solvent was removed to obtain 220 mg of white solid, yield: 98%.

Compound 370: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.86(s, 1H), 7.77(d, J=8.8Hz, 1H), 7.75(d, J=8.5Hz, 2H), 7.34(d, J＝8.3Hz, 1H), 7.32(d, J＝8.1Hz, 2H), 6.93(t, J _FH ＝74.7Hz, 1H), 5.28–5.25(m, 1H), 4.16(q, J＝7.1Hz ,2H),4.07(d,J=6.9Hz,2H),3.65(s,2H),1.82(d,J=6.9Hz,3H),1.38–1.35(m,1H),1.26(t,J= 7.1Hz, 3H), 0.71–0.68(m, 2H), 0.46–0.44(m, 2H);

MS-ESI: m/z 530.8 [M+H-HCl] ⁺ .

Example 130: Compound (S)-N-(4-(2-amino-2-oxoethyl)phenyl)-5-(1-aminoethyl)-2-(3- Synthesis of (cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride

Step 1: Synthesis of p-aminophenylacetamide

Add ethyl p-nitrophenylacetate (500mg, 2.39mmol) and methanol solution of ammonia (7M, 12mL) into the sealed tube, react at 75°C for 24h, remove the solvent after stopping the reaction, add dichloromethane (10mL) to wash, filter To obtain p-nitrophenylacetamide: 340 mg of light red solid, yield: 78%.

¹ H NMR (400MHz, CD ₃ OD): δppm 8.22(d, J=8.7Hz, 2H), 7.58(d, J=8.7Hz, 2H), 3.69(s, 2H);

MS-ESI: m/z 181.0 [M+H] ⁺ .

Pd/C (34mg) was added to a solution of p-nitrophenylacetamide (340mg, 1.89mmol) in methanol (10mL), reduced by hydrogen gas, stirred at room temperature for 3h, filtered with diatomaceous earth, and the filtrate was spin-dried to obtain p-aminobenzene Acetamide: 280 mg of light red solid, yield: 98%.

¹ H NMR (400MHz, CD ₃ OD): δppm 7.06(d, J=8.3Hz, 2H), 6.71(d, J=8.4Hz, 2H), 3.38(s, 2H);

MS-ESI: m/z 151.2 [M+H] ⁺ .

Step 2: Compound (S)-(1-(4-((4-(2-amino-2-oxoethyl)phenyl)carbamoyl)-2-(3-(cyclopropylmethoxy Synthesis of )-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate tert-butyl

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) oxazole-4-carboxylic acid (250mg, 0.53mmol), p-aminophenylacetamide (96mg, 0.64mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride ( 154mg, 0.80mmol) and N-hydroxy-7-azabenzotriazole (182mg, 1.33mmol) were dissolved in dichloromethane (15mL), and N,N-di Isopropylethylamine (0.37mL, 2.14mmol), stirred at room temperature for 3h, added water to wash (10mL×2), the organic phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrate was subjected to column separation (dichloromethane/methanol (v/v)=40/1), to obtain 220 mg of white solid, yield: 68%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.72(d, J=8.2Hz, 2H), 7.63(d, J=8.3Hz, 1H), 7.59(s, 1H), 7.31(d, J=8.2Hz ,2H),7.26(d,J=8.2Hz,1H),6.72(t,JFH= _75.0Hz ,1H),5.52–5.44(m,2H),5.37–5.33(m,1H),4.00(d ,J=6.9Hz,2H),3.59(s,2H),1.57(d,J=7.0Hz,3H),1.43(s,9H),1.37–1.33(m,1H),0.72–0.68(m, 2H),0.43–0.41(m,2H);

MS-ESI: m/z 545.7[M-55] ⁺ .

Step 3: Compound (S)-N-(4-(2-amino-2-oxoethyl)phenyl)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy Synthesis of yl)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide hydrochloride

To compound (S)-(1-(4-((4-(2-amino-2-oxoethyl)phenyl)carbamoyl)-2-(3-(cyclopropylmethoxy)- To a solution of tert-butyl 4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate (220 mg, 0.37 mmol) in dichloromethane (4 mL) was added HCl in ethyl acetate ( 4M, 4mL), stirred at room temperature for 1.5h, and removed the solvent to obtain 196mg of white solid, yield: 99%.

Compound 361: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.86(s, 1H), 7.77(d, J=9.8Hz, 1H), 7.75(d, J=8.4Hz, 2H), 7.37(s, 1H), 7.34(d, J=7.9Hz, 2H), 6.93(t, J _FH ＝74.7Hz, 1H), 5.27–5.24(m, 1H), 4.07(d, J=6.9Hz, 2H), 3.55 (s,2H),1.81(d,J＝6.9Hz,3H),1.38–1.36(m,1H),0.71–0.68(m,2H),0.46–0.44(m,2H);

MS-ESI: m/z 501.3 [M+H-HCl] ⁺ .

Example 131: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-(1H-pyrazol-4-yl)oxazole-4-carboxamide dihydrochloride

Step 1: Compound (S)-(1-(4-((1H-pyrazol-4-yl)carbamoyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethane Synthesis of tert-butyl (oxy)phenyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) oxazole-4-carboxylic acid (250mg, 0.53mmol), 4-aminopyrazole (53mg, 0.64mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride ( 153mg, 0.80mmol) and N-hydroxy-7-azabenzotriazole (182mg, 1.33mmol) were dissolved in dichloromethane (15mL), and N,N-di Isopropylethylamine (0.37mL, 2.14mmol), stirred at room temperature for 10h, added water to wash (10mL×2), the organic phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate Ester (v/v)=1/1), to obtain 138 mg of white solid, yield: 47%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.96(s, 2H), 7.62–7.59(m, 1H), 7.58(s, 1H), 7.24(d, J=8.4Hz, 1H), 6.70(t, J _FH ＝75.0Hz, 1H), 5.36–5.32(m, 1H), 3.98(d, J＝6.9Hz, 2H), 1.56(d, J＝7.0Hz, 3H), 1.43(s, 9H), 1.35 –1.32(m,1H),0.71–0.66(m,2H),0.43–0.39(m,2H);

MS-ESI: m/z 478.8[M-55] ⁺ .

Step 2: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1H- Synthesis of pyrazol-4-yl)oxazole-4-carboxamide dihydrochloride

To compound (S)-(1-(4-((1H-pyrazol-4-yl)carbamoyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy ) phenyl) oxazol-5-yl) ethyl) tert-butyl carbamate (117mg, 0.22mmol) in dichloromethane (4mL) solution was added HCl ethyl acetate solution (4M, 4mL), stirred at room temperature for 1.5 h, the solvent was removed to obtain 87 mg of white solid, yield: 78%.

Compound 380: ¹ H NMR (600MHz, CD ₃ OD): δppm 8.30 (s, 2H), 7.85 (d, J = 1.6Hz, 1H), 7.78 (dd, J ₁ = 8.3Hz, J ₂ = 1.6Hz, 1H), 7.35(d, J=8.3Hz, 1H), 6.93(t, J _FH ＝74.7Hz, 1H), 5.29–5.26(m, 1H), 4.07(d, J=6.9Hz, 2H), 1.82 (d,J=7.0Hz,3H),1.39–1.35(m,1H),0.72–0.69(m,2H),0.44–0.42(m,2H);

MS-ESI: m/z 434.9 [M+H-2HCl] ⁺ .

Example 132: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-(pyridin-4-ylmethyl)oxazole-4-carboxamide dihydrochloride

Step 1: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((pyridin-4-ylmethyl ) carbamoyl) oxazol-5-yl) ethyl) synthesis of tert-butyl carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) oxazole-4-carboxylic acid (250mg, 0.53mmol), 4-picolylamine hydrochloride (93mg, 0.64mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide salt Salt (153mg, 0.80mmol) and N-hydroxy-7-azabenzotriazole (182mg, 1.33mmol) were dissolved in dichloromethane (15mL), and N was added dropwise to the solution at 0°C, N-Diisopropylethylamine (0.37mL, 2.14mmol), stirred at room temperature for 3.5h, added water to wash (10mL×2), the organic phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum Ether/ethyl acetate (v/v)=1/2) to obtain 194 mg of white solid, yield: 65%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.55 (d, J = 4.7Hz, 2H), 7.53 (dd, J ₁ = 8.3Hz, J ₂ = 1.8Hz, 1H), 7.49 (d, J = 1.7Hz ,1H),7.25(d,J＝5.6Hz,2H),7.19(d,J＝8.3Hz,1H),6.66(t,J _FH ＝75.0Hz,1H),5.29–5.25(m,1H), 4.63(d, J=6.3Hz, 2H), 3.92(d, J=6.9Hz, 2H), 1.50(d, J=7.0Hz, 3H), 1.38(s, 9H), 1.30–1.26(m, 1H ),0.66–0.62(m,2H),0.37–0.33(m,2H);

MS-ESI: m/z 559.3 [M+H] ⁺ .

Step 2: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(pyridine- Synthesis of 4-ylmethyl)oxazole-4-carboxamide dihydrochloride

To compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((pyridin-4-ylmethyl)amino Formyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (188mg, 0.34mmol) in dichloromethane (6mL) solution was added HCl in ethyl acetate solution (4M, 4mL), stirred at room temperature for 1h, The solvent was removed to obtain 178 mg of white solid, yield: 99%.

Compound 383: ¹ H NMR (600MHz, CD ₃ OD): δppm 8.86(d, J=6.1Hz, 2H), 8.13(d, J=6.1Hz, 2H), 7.84(d, J=1.4Hz, 1H) ,7.76(dd,J ₁ ＝8.3Hz,J ₂ ＝1.4Hz,1H),7.34(d,J＝8.3Hz,1H),6.93(t,J _FH ＝74.7Hz,1H),5.23–5.20(m ,1H),4.95(s,2H),4.05(d,J＝6.9Hz,2H),1.80(d,J＝6.9Hz,3H),1.38–1.35(m,1H),0.70–0.67(m, 2H),0.45–0.42(m,2H);

MS-ESI: m/z 457.8 [MH-2HCl] ^- .

Example 133: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-(pyridin-2-ylmethyl)oxazole-4-carboxamide dihydrochloride

Step 1: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((pyridin-2-ylmethyl ) carbamoyl) oxazol-5-yl) ethyl) synthesis of tert-butyl carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) oxazole-4-carboxylic acid (250mg, 0.53mmol), 2-aminomethylpyridine (69mg, 0.64mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (153 mg, 0.80 mmol) and N-hydroxy-7-azabenzotriazole (182 mg, 1.33 mmol) were dissolved in dichloromethane (15 mL), and N, N -Diisopropylethylamine (0.37mL, 2.14mmol), stirred at room temperature for 12h, added water to wash (10mL×2), the organic phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ Ethyl acetate (v/v)=1/1), to obtain 223 mg of white solid, yield: 74%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.61 (d, J = 4.4Hz, 1H), 8.11 (br.s, 1H), 7.70 (td, J ₁ = 7.7Hz, J ₂ = 1.7Hz, 1H) ,7.60(dd,J ₁ =8.3Hz,J ₂ =1.8Hz,1H),7.57(s,1H),7.36(d,J=7.8Hz,1H),7.25–7.23(m,2H),6.70( t, J _FH = 75.1Hz, 1H), 5.31–5.28 (m, 1H), 4.76 (d, J = 5.5Hz, 2H), 3.98 (d, J = 7.0Hz, 2H), 1.53 (d, J = 7.0Hz,3H),1.43(s,9H),1.35–1.30(m,1H),0.71–0.66(m,2H),0.43–0.39(m,2H);

MS-ESI: m/z 559.8 [M+H] ⁺ .

Step 2: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(pyridine- Synthesis of 2-ylmethyl)oxazole-4-carboxamide dihydrochloride

To compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((pyridin-2-ylmethyl)amino To a solution of formyl)oxazol-5-yl)ethyl)carbamate (216mg, 0.39mmol) in dichloromethane (6mL) was added HCl in ethyl acetate (4M, 4mL), stirred at room temperature for 1h, The solvent was removed to obtain 205 mg of white solid, yield: 99%.

Compound 384: ¹ H NMR (600MHz, CD ₃ OD): δppm 8.85(d, J=5.6Hz, 1H), 8.65(t, J=7.7Hz, 1H), 8.15(d, J=8.0Hz, 1H) ,8.05(t,J=6.6Hz,1H),7.84(s,1H),7.76(d,J=8.3Hz,1H),7.34(d,J=8.3Hz,1H),6.93(t,J _FH =74.7Hz,1H),5.24–5.20(m,1H),5.03(s,2H),4.05(d,J=6.8Hz,2H),1.79(d,J=6.9Hz,3H),1.37–1.34 (m,1H),0.70–0.66(m,2H),0.45–0.42(m,2H);

MS-ESI: m/z 459.9 [M+H-2HCl] ⁺ .

Example 134: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-((5-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide dihydrochloride

Step 1: Synthesis of the compound (5-fluoropyridin-2-yl)methanamine

Add hydroxylamine hydrochloride (333mg, 4.80mmol) to a solution of 5-fluoropyridine-2-aldehyde (300mg, 2.40mmol) in acetonitrile (15mL), stir at room temperature, add triethylamine (1.33mL, 9.60mmol) dropwise, 80°C Reacted for 3h, removed the solvent, added ethyl acetate (15mL), washed with water (10mL×2), dried the organic phase with anhydrous Na ₂ SO ₄ , concentrated to obtain 5-fluoropyridine-2-carbaldehyde oxime: white solid 336mg, yield : 98%.

¹ H NMR (400MHz, CD ₃ OD): δppm 8.38(s,1H), 8.14(s,1H), 7.82–7.75(m,1H), 7.48–7.36(m,1H);

MS-ESI: m/z 141.1 [M+H] ⁺ .

Add sodium borohydride (476mg, 11.88mmol) to a solution of 5-fluoropyridine-2-carbaldehyde oxime (333mg, 2.38mmol) and nickel chloride (308mg, 2.38mmol) in absolute ethanol (18mL) under ice-bath conditions, Excessive heat release, continue to react in ice bath for 40 minutes, stir at room temperature for 20 minutes, add hydrochloric acid solution to adjust the pH value to about 1, stir until the solution becomes clear, add sodium hydroxide to adjust the pH value to about 14, a white solid precipitates, and the upper layer After the clear liquid was sucked out, the solvent was removed, dichloromethane (25 mL) was added, and filtered. The filtrate was dried over Na ₂ SO ₄ , and the solvent was removed to obtain 150 mg of brown liquid, yield: 50%.

¹ H NMR (600MHz, CD ₃ OD): δppm 8.51 (d, J = 2.7Hz, 1H), 7.66 (td, J ₁ = 8.5Hz, J ₂ = 2.8Hz, 1H), 7.51 (dd, J ₁ = 8.6Hz, J ₂ =4.2Hz, 1H), 4.27(s, 2H);

MS-ESI: m/z 127.2 [M+H] ⁺ .

Step 2: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(((5-fluoropyridine-2 Synthesis of -yl)methyl)carbamoyl)oxazol-5-yl)ethyl)carbamate tert-butyl

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) Oxazole-4-carboxylic acid (250mg, 0.53mmol), (5-fluoropyridin-2-yl) methylamine (81mg, 0.64mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbon Diimine hydrochloride (153mg, 0.80mmol) and N-hydroxy-7-azabenzotriazole (182mg, 1.33mmol) were dissolved in dichloromethane (20mL), and added to the solution at 0°C Add N,N-diisopropylethylamine (0.37mL, 2.14mmol) dropwise, stir at room temperature for 7.5h, add water to wash (10mL×2), dry the organic phase with anhydrous Na ₂ SO ₄ , remove the solvent, and concentrate the solution for Column separation (petroleum ether/ethyl acetate (v/v)=3/1) gave 130 mg of white solid, yield: 41%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.48 (d, J = 2.4Hz, 1H), 8.05 (br.s, 1H), 7.62 (dd, J ₁ = 8.3Hz, J ₂ = 1.8Hz, 1H) ,7.59(d,J=1.7Hz,1H),7.44–7.40(m,2H),7.26(d,J=8.3Hz,1H),6.72(t,J _FH ＝75.0Hz,1H),5.34–5.30 (m,1H),4.76(d,J=5.5Hz,2H),4.00(d,J=7.0Hz,2H),1.55(d,J=7.0Hz,3H),1.45(s,9H),1.36 –1.32(m,1H),0.74–0.69(m,2H),0.45–0.42(m,2H);

MS-ESI: m/z 577.3 [M+H] ⁺ .

Step 3: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((5 Synthesis of -fluoropyridin-2-yl)methyl)oxazole-4-carboxamide dihydrochloride

To compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(((5-fluoropyridin-2-yl ) methyl) carbamoyl) oxazol-5-yl) ethyl) tert-butyl carbamate (128 mg, 0.22 mmol) in dichloromethane (4 mL) was added HCl in ethyl acetate (4M, 4 mL) , stirred at room temperature for 1.5h, and removed the solvent to obtain 118 mg of white solid, yield: 96%.

Compound 385: ¹ H NMR (600MHz, CD ₃ OD): δppm 8.83(br.s, 1H), 8.27(t, J=8.1Hz, 1H), 8.00–7.99(m, 1H), 7.82(s, 1H ),7.75(d,J＝8.2Hz,1H),7.35–7.33(m,1H),7.05–6.80(m,1H),5.21–5.20(m,1H),4.93(s,2H),4.05– 4.04(m,2H),1.80–1.79(m,3H),1.37–1.34(m,1H),0.69–0.68(m,2H),0.44–0.42(m,2H);

MS-ESI: m/z 477.8 [M+H-2HCl] ⁺ .

Example 135: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-(pyridin-3-ylmethyl)oxazole-4-carboxamide dihydrochloride

Step 1: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((pyridin-3-ylmethyl ) carbamoyl) oxazol-5-yl) ethyl) synthesis of tert-butyl carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) oxazole-4-carboxylic acid (250mg, 0.53mmol), 3-aminomethylpyridine (69mg, 0.64mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (153 mg, 0.80 mmol) and N-hydroxy-7-azabenzotriazole (182 mg, 1.33 mmol) were dissolved in dichloromethane (15 mL), and N, N -Diisopropylethylamine (0.37mL, 2.14mmol), stirred at room temperature for 5h, added water to wash (10mL×2), the organic phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum ether/ Ethyl acetate (v/v)=1/2), to obtain 254 mg of white solid, yield: 85%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.65 (br.s, 1H), 8.56 (d, J=4.3Hz, 1H), 7.73 (d, J=7.8Hz, 1H), 7.57–7.55 (m, 1H),7.52(s,1H),7.32–7.29(m,1H),7.22(d,J＝8.3Hz,1H),6.69(t,J _FH ＝75.0Hz,1H),5.32–5.30(m, 1H), 4.68–4.65(m, 2H), 3.96(d, J=6.9Hz, 2H), 1.54(d, J=7.0Hz, 3H), 1.43(s, 9H), 1.34–1.30(m, 1H ),0.70–0.65(m,2H),0.41–0.37(m,2H);

MS-ESI: m/z 559.3 [M+H] ⁺ .

Step 2: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(pyridine- Synthesis of 3-ylmethyl)oxazole-4-carboxamide dihydrochloride

To compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((pyridin-3-ylmethyl)amino Formyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (250mg, 0.45mmol) in dichloromethane (4mL) was added HCl in ethyl acetate (4M, 4mL), stirred at room temperature for 2h, The solvent was removed to obtain 220 mg of white solid, yield: 92%.

Compound 406: ¹ H NMR (600MHz, CD ₃ OD): δppm 8.97(s, 1H), 8.84(d, J=5.5Hz, 1H), 8.72(d, J=8.1Hz, 1H), 8.15-8.13( m, 1H), 7.81 (d, J = 1.7Hz, 1H), 7.74 (dd, J ₁ = 8.4Hz, J ₂ = 1.7Hz, 1H), 7.33 (d, J = 8.3Hz, 1H), 6.92 ( t,J _FH ＝74.7Hz,1H),5.23–5.19(m,1H),4.86–4.85(m,2H),4.04(d,J＝6.9Hz,2H),1.78(d,J＝7.0Hz, 3H),1.37–1.34(m,1H),0.70–0.67(m,2H),0.45–0.42(m,2H);

MS-ESI: m/z 459.3 [M+H-2HCl] ⁺ .

Example 136: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-(1-methyl-1H-pyrazol-3-yl)oxazole-4-carboxamide hydrochloride

Step 1: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-methyl-1H- Synthesis of tert-butyl pyrazol-3-yl)carbamoyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) oxazole-4-carboxylic acid (250mg, 0.53mmol), N-methyl-3-aminopyrazole (62mg, 0.64mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiethylene Amine hydrochloride (153mg, 0.80mmol) and N-hydroxy-7-azabenzotriazole (182mg, 1.33mmol) were dissolved in dichloromethane (15mL), and added dropwise to the solution at 0°C N,N-Diisopropylethylamine (0.37mL, 2.14mmol), stirred at room temperature for 3.5h, added water to wash (10mL×2), dried the organic phase with anhydrous Na ₂ SO ₄ , removed the solvent, and the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v)=2/1), 260 mg of white solid was obtained, yield: 85%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.59(s, 1H), 7.58–7.55(m, 1H), 7.31(d, J=2.1Hz, 1H), 7.25(d, J=8.8Hz, 1H) ,6.79(d,J=2.2Hz,1H),6.71(t,J _FH ＝75.1Hz,1H),5.36–5.32(m,1H),4.00(d,J=7.0Hz,2H),3.86(s ,3H),1.56(d,J＝7.0Hz,3H),1.43(s,9H),1.37–1.32(m,1H),0.73–0.68(m,2H),0.46–0.42(m,2H);

MS-ESI: m/z 548.8 [M+H] ⁺ .

Step 2: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1- Synthesis of methyl-1H-pyrazol-3-yl)oxazole-4-carboxamide hydrochloride

To compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-methyl-1H-pyrazole -3-yl)carbamoyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (265mg, 0.48mmol) in dichloromethane (4mL) was added HCl in ethyl acetate (4M, 4mL ), stirred at room temperature for 1 h, and removed the solvent to obtain 231 mg of white solid, yield: 98%.

Compound 411: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.84 (d, J = 1.6Hz, 1H), 7.77 (dd, J ₁ = 8.4Hz, J ₂ = 1.6Hz, 1H), 7.73 (s, 1H), 7.35(d, J＝8.3Hz, 1H), 6.93(t, J＝ _FH ＝74.7Hz, 1H), 6.66(d, J＝2.2Hz, 1H), 5.31–5.28(m, 1H), 4.07 (d,J=6.9Hz,2H),3.94(s,3H),1.83(d,J=6.9Hz,3H),1.39–1.34(m,1H),0.72–0.68(m,2H),0.47– 0.43(m,2H);

MS-ESI: m/z 448.3 [M+H-HCl] ⁺ .

Example 137: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-(pyrimidin-2-ylmethyl)oxazole-4-carboxamide dihydrochloride

Step 1: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((pyrimidin-2-ylmethyl ) carbamoyl) oxazol-5-yl) ethyl) synthesis of tert-butyl carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) oxazole-4-carboxylic acid (250mg, 0.53mmol), 2-aminomethylpyrimidine hydrochloride (93mg, 0.64mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide Hydrochloride (153mg, 0.80mmol) and N-hydroxy-7-azabenzotriazole (182mg, 1.33mmol) were dissolved in dichloromethane (15mL), and N was added dropwise to the solution at 0°C , N-diisopropylethylamine (0.37mL, 2.14mmol), stirred at room temperature for 17h, added water to wash (10mL×2), the organic phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column separation (petroleum Ether/ethyl acetate (v/v)=1/1) to obtain 225 mg of white solid, yield: 73%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.77 (d, J = 4.9Hz, 2H), 8.24 (br.s, 1H), 7.64 (dd, J ₁ = 8.3Hz, J ₂ = 1.9Hz, 1H) ,7.59(d,J=1.7Hz,1H),7.25–7.24(m,1H),6.71(t,J _FH =75.0Hz,1H),5.32–5.28(m,1H),4.91(d,J= 5.2Hz, 2H), 3.99(d, J＝6.9Hz, 2H), 1.54(d, J＝7.0Hz, 3H), 1.43(s, 9H), 1.36–1.31(m, 1H), 0.72–0.67( m,2H),0.43–0.39(m,2H);

MS-ESI: m/z 560.8 [M+H] ⁺ .

Step 2: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(pyrimidine- Synthesis of 2-ylmethyl)oxazole-4-carboxamide dihydrochloride

To compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((pyrimidin-2-ylmethyl)amino To a solution of formyl)oxazol-5-yl)ethyl)carbamate (218mg, 0.39mmol) in dichloromethane (4mL) was added HCl in ethyl acetate (4M, 4mL), stirred at room temperature for 1h, The solvent was removed to obtain 207 mg of white solid, yield: 99%.

Compound 412: ¹ H NMR (600MHz, CD ₃ OD): δppm 9.01 (d, J = 4.9Hz, 2H), 7.82 (s, 1H), 7.76 (d, J = 8.3Hz, 1H), 7.71-7.69 ( m,1H),7.34(d,J＝8.3Hz,1H),6.93(t,J _FH ＝74.7Hz,1H),5.20–5.17(m,1H),4.96–4.95(m,2H),4.04( d,J=6.8Hz,2H),1.79(d,J=6.7Hz,3H),1.37–1.35(m,1H),0.70–0.67(m,2H),0.45–0.42(m,2H);

MS-ESI: m/z 460.2 [M+H-2HCl] ⁺ .

Example 138: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-((5-methylpyridin-2-yl)methyl)oxazole-4-carboxamide dihydrochloride

Step 1: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(((5-methylpyridine- Synthesis of tert-butyl 2-yl)methyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) oxazole-4-carboxylic acid (220mg, 0.47mmol), 2-methylamino-5-picoline (69mg, 0.56mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbon di Imine hydrochloride (135mg, 0.70mmol) and N-hydroxy-7-azabenzotriazole (160mg, 1.17mmol) were dissolved in dichloromethane (16mL), and dropped into this solution at 0°C Add N,N-diisopropylethylamine (0.33mL, 1.88mmol), stir at room temperature for 14h, add water for washing (10mL×2), dry the organic phase with anhydrous Na ₂ SO ₄ , remove the solvent, and conduct column separation of the concentrate (petroleum ether/ethyl acetate (v/v)=2/1), 202 mg of white solid was obtained, yield: 75%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.44(s, 1H), 8.06(br.s, 1H), 7.62(dd, J ₁ =8.3Hz, J ₂ =1.8Hz, 1H), 7.59(d, J＝1.7Hz, 1H), 7.52(dd, J ₁ ＝7.9Hz, J ₂ ＝1.7Hz, 1H), 7.27(s, 1H), 7.23(d, J＝8.7Hz, 1H), 6.70(t, JFH＝ _75.0Hz , 1H), 5.31–5.27(m, 1H), 4.72(d, J＝5.5Hz, 2H), 3.98(d, J＝6.9Hz, 2H), 2.34(s, 3H), 1.53 (d,J=7.0Hz,3H),1.43(s,9H),1.35–1.31(m,1H),0.71–0.67(m,2H),0.44–0.40(m,2H);

MS-ESI: m/z 573.3 [M+H] ⁺ .

Step 2: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((5 Synthesis of -methylpyridin-2-yl)methyl)oxazole-4-carboxamide dihydrochloride

To compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(((5-methylpyridine-2- To a solution of tert-butyl)methyl)carbamoyl)oxazol-5-yl)ethyl)carbamate (200mg, 0.35mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M, 4mL ), stirred at room temperature for 2 h, and removed the solvent to obtain 190 mg of white solid, yield: 99%.

Compound 429: ¹ H NMR (600MHz, CD ₃ OD): δppm 8.69(s, 1H), 8.46(d, J=5.5Hz, 1H), 7.99(d, J=5.5Hz, 1H), 7.82(d, J＝1.8Hz, 1H), 7.75(dd, J1 _＝ 8.4Hz, J2＝1.9Hz, 1H), 7.35(d, J＝8.3Hz, 1H), 6.93(t, _JFH ＝ _74.7Hz , 1H ),5.23–5.19(m,1H),4.95(d,J=6.4Hz,2H),4.04(d,J=7.0Hz,2H),2.58(s,3H),1.77(d,J=7.0Hz ,3H),1.37–1.34(m,1H),0.71–0.68(m,2H),0.45–0.42(m,2H);

MS-ESI: m/z 473.3 [M+H-2HCl] ⁺ .

Example 139: Compound (S)-5-(1-aminoethyl)-N-((5-chloropyridin-2-yl)methyl)-2-(3-(cyclopropyl) Synthesis of methoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamide dihydrochloride

Step 1: Compound (S)-(1-(4-(((5-chloropyridin-2-yl)methyl)carbamoyl)-2-(3-(cyclopropylmethoxy)-4- Synthesis of tert-butyl (difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) oxazole-4-carboxylic acid (220mg, 0.47mmol), 2-aminomethyl-5-chloropyridine hydrochloride (101mg, 0.56mmol), 1-ethyl-3-(3-dimethylaminopropyl) Carbodiimide hydrochloride (135mg, 0.70mmol) and N-hydroxy-7-azabenzotriazole (160mg, 1.17mmol) were dissolved in dichloromethane (16mL), and the solution was added to the solution at 0°C Add N,N-diisopropylethylamine (0.33mL, 1.88mmol) dropwise, stir at room temperature for 10h, add water to wash (10mL×2), dry the organic phase with anhydrous Na ₂ SO ₄ , remove the solvent, and concentrate the solution for Column separation (petroleum ether/ethyl acetate (v/v)=3/1) gave 223 mg of white solid, yield: 80%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.56 (d, J = 2.3Hz, 1H), 8.01 (br.s, 1H), 7.67 (dd, J ₁ = 8.3Hz, J ₂ = 2.4Hz, 1H) , 7.60 (dd, J ₁ =8.3Hz, J ₂ =1.8Hz, 1H), 7.56 (d, J = 1.7Hz, 1H), 7.33 (d, J = 8.3Hz, 1H), 7.24 (d, J = 8.4Hz, 1H), 6.70(t, J _FH ＝75.0Hz, 1H), 5.32–5.27(m, 1H), 4.74–4.73(m, 2H), 3.98(d, J＝7.0Hz, 2H), 1.53 (d,J=7.0Hz,3H),1.43(s,9H),1.34–1.31(m,1H),0.72–0.67(m,2H),0.43–0.40(m,2H);

MS-ESI: m/z 594.3 [M+H] ⁺ .

Step 2: Compound (S)-5-(1-aminoethyl)-N-((5-chloropyridin-2-yl)methyl)-2-(3-(cyclopropylmethoxy)-4 Synthesis of -(difluoromethoxy)phenyl)oxazole-4-carboxamide dihydrochloride

To compound (S)-(1-(4-(((5-chloropyridin-2-yl)methyl)carbamoyl)-2-(3-(cyclopropylmethoxy)-4-(di To a solution of tert-butyl fluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate (219mg, 0.37mmol) in dichloromethane (4mL) was added HCl in ethyl acetate (4M, 4mL) , stirred at room temperature for 3 h, and removed the solvent to obtain 207 mg of white solid, yield: 99%.

Compound 436: ¹ H NMR (600MHz, CD ₃ OD): δppm 8.82(s, 1H), 8.32(d, J=8.4Hz, 1H), 7.83(d, J=8.6 Hz, 1H), 7.82(s, 1H), 7.75(d, J＝8.3Hz, 1H), 7.34(d, J＝8.3Hz, 1H), 6.93(t, J _FH ＝74.7Hz, 1H), 5.22–5.18(m, 1H), 4.87 (s,2H),4.04(d,J=6.9Hz,2H),1.78(d,J=6.9Hz,3H),1.36–1.34(m,1H),0.70–0.68(m,2H),0.45– 0.42(m,2H);

MS-ESI: m/z 493.3 [M+H-2HCl] ⁺ .

Example 140: Compound 2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-N-(2,4-difluorobenzyl)-5- Synthesis of phenylthiazole-4-carboxamide

Step 1: Synthesis of the compound ethyl thiobenzoate

Concentrated hydrochloric acid (3 mL) was added to a solution of benzoic acid (5.73 g, 46.97 mmol) in ethanol (60 mL), stirred at 86° C. for 3 h, concentrated to obtain a crude product, and saturated NaHCO ₃ solution was added to adjust the pH to 7, and extracted with DCM ( 100 mL×3), the combined organic phases were washed with water (50 mL×2), dried over Na ₂ SO ₄ , concentrated to obtain 5.2 g of colorless oil (ethyl benzoate), yield: 74%.

Add Lawson's reagent (8.08g, 20mmol) to a solution of ethyl benzoate (3g, 20mmol) in anhydrous xylene (25mL), stir at 140°C for 10h, add Et ₂ O (25mL), filter, and the filtrate After concentration, the concentrate was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=20/1) to obtain 2.85 g of light yellow oil, yield: 86%.

Step 2: Synthesis of the compound 2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-5-phenylthiazole-4-carboxylic acid methyl ester

The compound 2-(((3-(cyclopropylmethoxy)-4-methoxyphenyl)(methylthio)methylene)amino)acetic acid methyl ester (1.183g, 3.663mmol) was dissolved in Add ethyl thiobenzoate (2.8g, 16.87mmol) and DBU (2.784g, 18.32mmol) to water tetrahydrofuran (40mL), stir at 80°C for 15.5h, add water (40mL), extract with ethyl acetate (20mL× 3), the combined organic phases were washed with saturated brine (40mL×3), dried over Na ₂ SO ₄ , concentrated, and the concentrate was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=5/1 ), to obtain 347 mg of yellow solid, yield: 24%.

MS-ESI (pos. ion) m/z: 396.1 [M+H] ⁺ .

Step 3: Synthesis of compound 2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-5-phenylthiazole-4-carboxylic acid

The compound 2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-5-phenylthiazole-4-carboxylic acid methyl ester (160 mg, 0.4046 mmol) was dissolved in THF/H ₂ O ( v/v=2/1, 6mL), add LiOH (48.4mg, 2.023mmol) in water (0.5mL) solution, stir at 40°C for 3h, add hydrochloric acid (1.2M, 2mL) to adjust pH=1-2, Extracted with ethyl acetate (10 mL×3), combined organic phases and washed with saturated brine (10 mL×3), dried over Na ₂ SO ₄ , concentrated to obtain 120 mg of yellow solid, yield: 78%.

MS-ESI (pos.ion) m/z: 382.0 [M+H] ⁺ .

Step 4: Compound 2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-N-(2,4-difluorobenzyl)-5-phenylthiazole-4-carboxamide Synthesis

The compound 2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-5-phenylthiazole-4-carboxylic acid (90 mg, 0.2344 mmol) was dissolved in anhydrous DCM (15 mL), added EDCI (67.5mg, 0.3516mmol) and HOBT (47.5mg, 0.3516mmol), stirred at room temperature for 30min, then added compound 2,4-difluorobenzylamine (40.2mg, 0.2812mmol) and DIPEA (126μL, 0.7032mmol), Stir at 25°C for 16h, add water (15mL), extract with DCM (10mL×3), combine the organic phases and wash with saturated brine (15mL×3), dry over Na ₂ SO ₄ , concentrate, and the concentrated solution is separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=5/1), 92 mg of light yellow solid was obtained, yield: 77.5%.

Compound 44: ¹ HNMR (400MHz, CDCl ₃ ): δ (ppm) 7.97 (br.s, 1H), 7.68-7.60 (m, 2H), 7.51-7.35 (m, 6H), 6.93 (d, J=8.8 Hz,1H),6.87-6.77(m,2H),4.62(d,J＝5.6Hz,2H),3.98-3.91(m,5H),1.43-1.31(m,1H),0.72-0.65(m, 2H),0.43-0.37(m,2H);

MS-ESI (pos. ion) m/z: 507.1 [M+H] ⁺ .

Example 141: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-N- Synthesis of (2,4-difluorobenzyl)thiazole-4-carboxamide hydrochloride

Step 1: Synthesis of compound (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propionic acid

Na ₂ CO ₃ (29.8 g, 280.9 mmol) and 9-fluorenylmethyl-N-succinimidyl carbonate (28.4 g, 84.27 mmol) were added to L-alanine (5 g, 56.18 mmol) in water /dioxane (v/v=1/1, 400mL) solution, stirred at room temperature for 18h, filtered, extracted with Et ₂ O (100mL×3), the aqueous phase was acidified with concentrated hydrochloric acid, extracted with ethyl acetate (150mL×3 ), the combined organic phases were dried with Na ₂ SO ₄ and concentrated to obtain 17.3 g of white solid, yield: 99%.

MS-ESI (pos.ion) m/z: 334.2 [M+Na] ⁺ .

Step 2: Synthesis of compound (S)-(9H-fluoren-9-yl)methyl(1-fluoro-1-oxopropan-2-yl)carbamate

Compound (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanoic acid (5 g, 14.38 mmol) was dissolved in anhydrous DCM (100 mL) and triethylamine was added (2.2mL, 15.82mmol) and cyanuric fluoride (2.4mL, 28.76mmol), stirred at -40°C for 2h, washed with ice water (50mL×5), dried the organic phase with Na ₂ SO ₄ and concentrated to obtain 4.2g white Solid, yield: 93%.

MS-ESI (pos.ion) m/z: 326.2 [M-F+OCH ₃ ] ⁺ .

Step 3: Synthesis of compound (4S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-amino-3-oxopentanoic acid ethyl ester hydrochloride

At -78°C, KHMDS (1M, 13.7mL) was added into dibenzylidene glycine ethyl ester (3.67g, 13.72mmol) in anhydrous THF (80mL), stirred at -78°C for 1h, and then the compound ( S)-(9H-fluoren-9-yl)methyl(1-fluoro-1-oxopropan-2-yl)carbamate (4.3g, 13.72mmol) in anhydrous THF (20mL), -78 After stirring for 1 h at -78 °C, hydrochloric acid (3M, 34.3 mL) was added at -78 °C, stirred at 25 °C for 20 min, concentrated, washed with Et ₂ O (100 mL×2), and co-evaporated with toluene below 40 °C to obtain White solid 4.75g, yield: 79%.

MS-ESI (pos. ion) m/z: 397.3 [M+H] ⁺ .

Step 4: Synthesis of compound 3-(cyclopropylmethoxy)-4-methoxybenzoyl chloride

At 0°C, oxalyl chloride (1.41 mL, 14.85 mmol) and DMF (104 μL, 1.35 mmol) were added to compound 3-(cyclopropylmethoxy)-4-methoxybenzoic acid (3 g, 13.50 mmol) Anhydrous DCM (100 mL), stirred at 25°C for 15.5 h, concentrated, and distilled under reduced pressure to obtain 3.25 g of white solid (crude product), yield: 100.3%.

MS-ESI (pos.ion) m/z: 237.2 [M-Cl+OCH ₃ ] ⁺ .

Step 5: Compound (4S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-(3-(cyclopropylmethoxy)-4-methoxy Synthesis of ethyl benzamido)-3-oxopentanoate

Compound 3-(cyclopropylmethoxy)-4-methoxybenzoyl chloride (3.17g, 13.17mmol) was dissolved in anhydrous THF (100mL), and compound (4S)-4- ((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-amino-3-oxopentanoic acid ethyl ester hydrochloride (4.75 g, 10.97 mmol) in anhydrous DMF (50 mL) solution and triethylamine (3.04mL, 21.94mmol), stirred at 25°C for 3.5h, concentrated, the residue was dissolved in EtOAc/Et ₂ O (v/v=1/1, 100mL), washed with hydrochloric acid (1M), NaHCO ₃ washing with solution (10%, 70mL×2) and saturated brine (70mL×2), drying over Na ₂ SO ₄ , concentrating, and separating and purifying the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =2/1), to obtain 3.4 g of white powder, yield: 43%.

¹ HNMR (400MHz, CDCl ₃ ): δ (ppm) 7.79-7.72 (m, 2H), 7.64-7.56 (m, 2H), 7.45-7.35 (m, 3H), 7.35-7.27 (m, 2H), 7.19 (d,J=6.0Hz,1H),6.93(d,J=8.4Hz,1H),5.89(d,J=7.6Hz,1H),5.66-5.57(m,1H),5.02-4.90(m, 1H), 4.48-4.18(m, 4H), 3.97-3.86(m, 5H), 1.56(d, J=7.6Hz, 3H), 1.37-1.23(m, 4H), 0.70-0.60(m, 2H) ,0.40-0.30(m,2H);

MS (ESI, pos.ion) m/z: 601.2 [M+H] ⁺ .

Step 6: Compound (S)-5-(1-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy) Synthesis of ethyl 4-methoxyphenyl)thiazole-4-carboxylate

Compound (4S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-(3-(cyclopropylmethoxy)-4-methoxybenzyl Amino)-3-oxopentanoic acid ethyl ester (2.7g, 4.5mmol) was dissolved in anhydrous THF (100mL), added Lawson's reagent (3.64g, 9mmol), stirred at 80°C for 10.5h, added water (100mL ), extracted with ethyl acetate (100mL×3), combined the organic phases and washed with saturated brine (100mL), dried over Na ₂ SO ₄ , concentrated, and the concentrated solution was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate ( v/v)=1.5/1), 2.6 g of light yellow solid was obtained.

MS-ESI (pos. ion) m/z: 599.2 [M+H] ⁺ .

Step 7: Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)thiazole- Synthesis of 4-Formic Acid

Compound (S)-5-(1-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4 -Methoxyphenyl)thiazole-4-carboxylic acid ethyl ester (2.1g, 3.5mmol) was dissolved in THF/H ₂ O (v/v=1/1, 210mL), and sodium hydroxide solution (1M, 15.4mL) was added ), stirred at 80°C for 3.5h, then added di-tert-butyl dicarbonate (916.7mg, 4.2mmol), stirred at 33°C for 4h, added hydrochloric acid (1M) to adjust pH=2-3, extracted with ethyl acetate (150mL× 3), the combined organic phases were washed with saturated brine (30mL×2), dried over Na ₂ SO ₄ , concentrated, and the concentrate was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1 ), to obtain 1.08g of yellow solid, yield: 68%.

MS-ESI (pos. ion) m/z: 449.3 [M+H] ⁺ .

Step 8: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-4-((2,4-difluorobenzyl)aminomethyl Synthesis of tert-butyl Acyl)thiazol-5-yl)ethyl)carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)thiazole-4- Dissolve formic acid (200mg, 0.4464mmol) in DCM (15mL), add EDCI (128mg, 0.6696mmol) and HOBT (90.4mg, 0.6696mmol), stir at 25°C for 0.5h, then add 2,4-difluorobenzylamine (76.6mg, 0.5357mmol) and DIPEA (240μL, 1.339mmol), stirred at 25°C for 15h, added water (20mL), extracted with DCM (15mL×2), combined organic phases and washed with saturated Na ₂ CO ₃ solution ( 30mL×2) and saturated brine (30mL×2), dried over Na ₂ SO ₄ , concentrated, and the concentrate was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=5/1) to obtain 131 mg of white solid, yield: 43.6%.

MS-ESI (pos.ion) m/z: 574.2 [M+H] ⁺ .

Step 9: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-N-(2,4-difluoro Synthesis of benzyl)thiazole-4-carboxamide hydrochloride

To compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-4-((2,4-difluorobenzyl)carbamoyl) Add HCl in ethyl acetate (4M, 3mL) to a solution of tert-butyl thiazol-5-yl)ethyl)carbamate (131mg, 0.1947mmol) in dichloromethane (1mL), stir at room temperature for 30min, filter, and filter cake It was washed with ethyl acetate (0.5 mL×6), dissolved in methanol (5 mL), and concentrated to obtain 83 mg of white solid, yield: 74%.

Compound 63: ¹ HNMR (400MHz, CD ₃ OD): δ (ppm) 7.65 (d, J = 2.4Hz, 1H), 7.56 (dd, J = 8.4Hz, 1H), 7.50-7.42 (m, 1H), 7.05(d,J=8.4Hz,1H),7.00-6.90(m,2H),5.35-5.27(m,1H),4.66(s,2H),3.93(d,J=6.8Hz,2H),3.90 (s,3H),1.75(d,J=6.4Hz,3H),1.35-1.24(m,1H),0.66-0.60(m,2H),0.39-0.33(m,2H);

MS-ESI (pos.ion) m/z: 474.1 [M+H-HCl] ⁺ .

Example 142: Compound (S)-6-((5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-methoxybenzene Synthesis of (yl)thiazole-4-carboxamido)methyl)pyridinecarboxylic acid dihydrochloride

Step 1: Compound (S)-6-((5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-methoxybenzene Synthesis of ethyl)thiazole-4-carboxamido)methyl)pyridinecarboxylate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)thiazole-4- Formic acid (250mg, 0.5580mmol) was dissolved in DCM (20mL), EDCI (214mg, 1.117mmol) and HOBT (151mg, 1.117mmol) were added, stirred at 25°C for 0.5h, and then 6-aminomethyl-2- Ethyl pyridinecarboxylate (121mg, 0.6696mmol) and DIPEA (300μL, 1.675mmol) were stirred at 25°C for 18h, after adding water (30mL), extracted with DCM (20mL×2). Combined organic phases were washed with saturated _Na2CO3 solution (30mL× ₂ ) and saturated brine (30mL× ₂ ), dried over _Na2SO4 , concentrated, and the concentrate was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate Ester (v/v)=1/1), to obtain 200 mg of white foamy solid, yield: 58.7%.

¹ HNMR (400MHz, CDCl ₃ ): δ (ppm) 8.46 (br.s, 1H), 8.04 (d, J = 7.2Hz, 1H), 7.87-7.80 (m, 1H), 7.65 (d, J = 7.6 Hz,1H),7.44-7.39(m,2H),6.89(d,J＝8.8Hz,1H),6.27(br.s,1H),5.65-5.40(m,1H),4.91-4.83(m, 2H), 4.54-4.42(m, 2H), 3.98(d, J=7.6Hz, 2H), 3.92(s, 3H), 1.98-1.76(m, 3H), 1.58(d, J=6.8Hz, 3H ),1.37-1.32(m,1H),0.70-0.62(m,2H),0.43-0.38(m,2H),0.06(s,9H);

MS-ESI (pos.ion) m/z: 611.2 [M+H] ⁺ .

Step 2: Compound (S)-6-((5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-methoxybenzene Synthesis of (yl)thiazole-4-carboxamido)methyl)picolinic acid

Compound (S)-6-((5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl) Thiazole-4-carboxamido) methyl) ethyl picolinate (200mg, 0.3275mmol) was dissolved in THF/H ₂ O (v/v=2/1, 9mL), and lithium hydroxide monohydrate (69mg, 1.637 mmol), stirred at 40°C for 3.5h, added hydrochloric acid (1.2M) to adjust pH=2-3, extracted with ethyl acetate (15mL×3), combined the organic phases and washed with saturated brine (15mL×2), Na ₂ SO ₄ was dried and concentrated to obtain 174 mg of white solid, yield: 91.2%.

¹ HNMR (400MHz, CDCl ₃ ): δ (ppm) 8.44 (br.s, 1H), 8.15 (d, J = 7.6Hz, 1H), 7.98-7.91 (m, 1H), 7.68 (d, J = 7.2 Hz,1H),7.46-7.38(m,2H),6.90(d,J＝8.4Hz,1H),6.07(br.s,1H),5.65-5.50(m,1H),4.89-4.83(m, 2H),3.98-3.87(m,5H),1.58(d,J＝7.2Hz,3H),1.37-1.30(m,1H),0.70-0.63(m,2H),0.43-0.36(m,2H) ,0.07(s,9H);

MS-ESI (pos. ion) m/z: 583.2 [M+H] ⁺ .

Step 3: Compound (S)-6-((5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)thiazole-4-carboxamide Synthesis of base) methyl) picolinic acid dihydrochloride

To compound (S)-6-((5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl) Add HCl in ethyl acetate (4M, 3mL) to a solution of thiazole-4-carboxamido)methyl)picolinic acid (174mg, 0.2918mmol) in dichloromethane (1mL), stir at room temperature for 40min, filter, and use the filter cake Washed with ethyl acetate (0.5 mL×6), dissolved in methanol (5 mL), and concentrated to obtain 128 mg of a yellow solid, yield: 91%.

Compound 64: ¹ HNMR (400MHz, CD ₃ OD): δ (ppm) 8.47–8.42 (m, 1H), 8.35 (d, J = 7.6Hz, 1H), 8.07 (d, J = 7.6Hz, 1H), 7.67(d,J=2.0Hz,1H),7.59(dd,J=4.4Hz,1H),7.07(d,J=8.4Hz,1H),5.43-5.35(m,1H),5.00(d,J =3.2Hz, 2H), 3.94(d, J=6.8Hz, 2H), 3.91(s, 3H), 1.77(d, J=7.6Hz, 3H), 1.35-1.24(m, 1H), 0.66-059 (m,2H),0.40-0.34(m,2H);

MS-ESI (pos. ion) m/z: 483.2 [M+H-2HCl] ⁺ .

Example 143: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-ethoxyphenyl)-N- Synthesis of (2,4-difluorobenzyl)oxazole-4-carboxamide hydrochloride

Step 1: Synthesis of compound 3-(cyclopropylmethoxy)-4-ethoxybenzoic acid methyl ester

Compound 3-(cyclopropylmethoxy)-4-hydroxybenzoic acid methyl ester (5g, 22.50mmol) was dissolved in DMF (100mL), K ₂ CO ₃ (7.77g, 56.25mmol) and bromoethane were added (2.02mL, 27mmol), stirred at 60°C for 10.5h, filtered, concentrated the filtrate, added water (50mL), extracted with DCM (100mL×3), combined the organic phases and washed with saturated brine (100mL×2), Na ₂ SO ₄ was dried and concentrated to obtain 5.5 g of light red liquid, yield: 97.7%.

MS-ESI (pos. ion) m/z: 251.2 [M+H] ⁺ .

Step 2: Synthesis of compound 3-(cyclopropylmethoxy)-4-ethoxybenzoic acid

The compound 3-(cyclopropylmethoxy)-4-ethoxybenzoic acid methyl ester (5.5 g, 21.97 mmol) was dissolved in THF/H ₂ O (v/v=2/1, 150 mL), and hydrogen was added Sodium oxide (2.2g, 54.93mmol) in water (15mL) solution, stirred at 60°C for 2h, concentrated, added concentrated hydrochloric acid to adjust pH=2-3, extracted with DCM (100mL×3), combined the organic phases with saturated salt Washed with water (100 mL×2), dried over Na ₂ SO ₄ , concentrated to obtain 5.02 g of white solid, yield: 96.3%.

¹ HNMR (400MHz, CDCl ₃ ): δ (ppm) 7.78-7.70 (m, 1H), 7.60 (d, J = 2.0Hz, 1H), 6.90 (d, J = 8.4Hz, 1H), 4.22-4.14 ( m,2H),3.91(d,J＝6.8Hz,2H),1.53-1.45(m,3H),1.39-1.28(m,1H),0.69-0.61(m,2H), 0.41-0.34(m, 2H);

MS-ESI (pos. ion) m/z: 237.3 [M+H] ⁺ .

Step 3: Synthesis of the compound 2-(3-(cyclopropylmethoxy)-4-ethoxyphenylamido)acetic acid methyl ester

Compound 3-(cyclopropylmethoxy)-4-ethoxybenzoic acid (5g, 21.16mmol) was dissolved in anhydrous DCM (150mL), EDCI (6.094g, 31.74mmol) and HOBT (4.285g, 31.74mmol), continue to stir at room temperature for 30min, then add glycine methyl ester hydrochloride (3.188g, 25.40mmol), under ice bath, slowly drop DIPEA (11.4mL, 63.48mmol), continue at room temperature for 16.5 h, after adding water (100mL), extract with CH ₂ Cl ₂ (100mL×2), combine the organic phases, wash with saturated brine (100mL×2), dry over Na ₂ SO ₄ , remove the solvent, and concentrate the solution on a silica gel column Chromatography (dichloromethane/methanol (v/v)=20/1) gave 3.93 g of white solid, yield: 61.6%.

¹ HNMR (400MHz, CDCl ₃ ): δ (ppm) 7.41 (d, J = 2.0Hz, 1H), 7.33 (dd, J = 8.2Hz, 1H), 6.85 (d, J = 8.4Hz, 1H), 6.61 (br.s,1H),4.22(d,J=5.2Hz,2H),4.17–4.09(m,2H),3.89(d,J=6.8Hz,2H),3.79(s,3H),1.50- 1.43(m,3H),1.36-1.26(m,1H),0.65-0.58(m,2H),0.38-0.31(m,2H);

MS-ESI (pos. ion) m/z: 308.1 [M+H] ⁺ .

Step 4: Synthesis of the compound 2-(3-(cyclopropylmethoxy)-4-ethoxyphenylthioamido)acetic acid methyl ester

The compound 2-(3-(cyclopropylmethoxy)-4-ethoxyphenylamido)acetic acid methyl ester (3.93g, 12.8mmol) was dissolved in anhydrous tetrahydrofuran (130mL), and Lawson's reagent was added (5.18g, 12.8mmol), reacted at 75°C for 2h, added water (100mL), extracted with ethyl acetate (100mL×3), combined the organic phases and washed them with saturated Na ₂ CO ₃ solution (100mL×3) and saturated Washed with brine (100mL×2), dried over anhydrous sodium sulfate, and the concentrated solution was subjected to silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain 3.704g of a yellow solid, yield: 89.5% .

¹ HNMR (400MHz, CDCl ₃ ): δ (ppm) 8.03 (br.s, 1H), 7.54 (d, J = 2.0Hz, 1H), 7.35 (dd, J = 8.4Hz, 1H), 6.84 (d, J＝8.4Hz, 1H), 4.57(d, J＝4.4Hz, 2H), 4.18–4.10(m, 2H), 3.91(d, J＝6.8Hz, 2H), 3.84(s, 3H), 1.50- 1.43(m,3H),1.38-1.23(m,1H),0.66-0.60(m,2H),0.39-0.33(m,2H);

MS-ESI (pos.ion) m/z: 324.2 [M+H] ⁺ .

Step 5: Synthesis of the compound 2-(((3-(cyclopropylmethoxy)-4-ethoxyphenyl)(methylthio)methylene)amino)acetate methyl ester

At -78°C, compound 2-(3-(cyclopropylmethoxy) was added dropwise to a suspension of trimethyloxonium tetrafluoroboric acid (3.39g, 22.90mmol) in anhydrous dichloromethane (50mL) -4-Ethoxyphenylthioamido)methyl acetate (3.704g, 11.45mmol) in anhydrous dichloromethane (100mL) solution, stirred at 0°C for 2h, then added saturated sodium bicarbonate solution (100mL), Extracted with DCM (100 mL×2), combined the organic phases and washed with ice water (100 mL×3), dried over Na ₂ SO ₄ , and removed the solvent to obtain 3.86 g of light red liquid, yield: 100%.

MS-ESI (pos.ion) m/z: 338.2 [M+H] ⁺ .

Step 6: Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-ethoxyphenyl)oxazole -Synthesis of methyl 4-carboxylate

At -78°C, the compound 2-(((3-(cyclopropylmethoxy)-4-ethoxyphenyl)(methylthio)methylene)amino)acetic acid methyl ester (3.86g, 11.45mmol) in anhydrous tetrahydrofuran (50mL) and potassium hexamethyldisilazide in tetrahydrofuran (1M, 45.8mL) were added to compound (S)-(1-fluoro-1-oxopropane-2- base) tert-butyl carbamate (4.38g, 22.9mmol) in anhydrous tetrahydrofuran (50mL), react at -78°C for 1.5h, add water (70mL), stir at 25°C for 10min, then extract with ethyl acetate (100mL × 3), the organic phases were combined and washed with brine (10%, 100mL × 2), Na ₂ SO ₄ dried, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (petroleum ether/ethyl acetate (v/v)= 2/1), to obtain 2.69g light yellow solid, yield: 51%.

¹ HNMR (400MHz, CDCl ₃ ): δ (ppm) 7.57 (dd, J = 8.4Hz, 1H), 7.51 (d, J = 2.0Hz, 1H), 6.87 (d, J = 8.4Hz, 1H), 5.75 -5.57(m,1H),4.14-4.07(m,2H),3.92(s,3H),3.88(d,J=7.2Hz,2H),1.55(d,J=6.8Hz,3H),1.52- 1.49(m,3H),1.28-1.22(m,1H),0.67-0.60(m,2H),0.40-0.34(m,2H),0.06(s,9H);

MS-ESI (pos. ion) m/z: 461.2 [M+H] ⁺ .

Step 7: Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-ethoxyphenyl)oxa Synthesis of azole-4-carboxylic acid

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-ethoxyphenyl)oxazole-4 -Methyl formate (1.344g, 2.918mmol) was dissolved in THF/H ₂ O (v/v=2/1, 60mL), lithium hydroxide monohydrate (0.613g, 14.59mmol) was added, and reacted at 40°C for 4.5h, Add hydrochloric acid (1M) to adjust the pH=2-3, add ethyl acetate to extract (100mL×3), combine the organic phases and wash with saturated brine (100mL×2), dry over Na ₂ SO ₄ , remove the solvent to obtain 1.1g white Solid, yield: 84.5%.

¹ HNMR (400MHz, CDCl ₃ ): δ (ppm) 7.61 (dd, J = 8.4Hz, 1H), 7.56 (s, 1H), 6.91 (d, J = 8.4Hz, 1H), 5.50-5.35 (m, 1H), 4.19-4.09(m, 2H), 3.92(d, J=7.2Hz, 2H), 1.55(d, J=6.8Hz, 3H), 1.52-1.49(m, 3H), 1.28-1.22(m ,1H),0.67-0.60(m,2H),0.40-0.34(m,2H),0.06(s,9H);

MS-ESI (pos. ion) m/z: 447.1 [M+H] ⁺ .

Step 8: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-ethoxyphenyl)-4-((2,4-difluorobenzyl)aminomethyl Synthesis of tert-butyl Acyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-ethoxyphenyl)oxazole- 4-Formic acid (300mg, 0.6721mmol) was dissolved in DCM (20mL), EDCI (193.6mg, 1.008mmol) and HOBT (136.1mg, 1.117mmol) were added, stirred at 25°C for 0.5h, and then 2,4-di Fluorobenzylamine (115.3mg, 0.8065mmol) and DIPEA (361μL, 2.016mmol), stirred at 25°C for 3h, added water (20mL), extracted with DCM (20mL×2), combined the organic phases and washed with saturated brine (30mL×2 ), dried over Na ₂ SO ₄ , concentrated, and the concentrated solution was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=6/1) to obtain 144 mg of a colorless colloidal liquid, yield: 37.5% .

¹ HNMR (400MHz, CDCl ₃ ): δ (ppm) 7.68 (br.s, 1H), 7.58 (d, J = 8.4Hz, 1H), 7.51 (s, 1H), 7.46-7.37 (m, 1H), 6.92(d,J＝8.0Hz,1H),6.90-6.82(m,2H),5.22-5.04(m,1H),4.67-4.62(m,2H),4.20-4.12(m,2H),3.94( d, J＝6.8Hz, 2H), 1.53(d, J＝6.8Hz, 3H), 1.51-1.46(m, 3H), 1.36-1.32(m, 1H), 0.69-0.62(m, 2H), 0.42 -0.37(m,2H),0.07(s,9H).

Step 9: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-ethoxyphenyl)-N-(2,4-difluoro Synthesis of benzyl)oxazole-4-carboxamide hydrochloride

To compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-ethoxyphenyl)-4-((2,4-difluorobenzyl)carbamoyl) Add HCl in ethyl acetate (4M, 3mL) to a solution of tert-butyl oxazol-5-yl)ethyl)carbamate (140mg, 0.2449mmol) in dichloromethane (1mL), stir at room temperature for 40min, concentrate, and leave Ethyl acetate was added to the mixture and filtered, the filter cake was washed with ethyl acetate (20 mL×5), dissolved in methanol (5 mL), and concentrated to obtain 100 mg of white solid, yield: 80.4%.

Compound 76: ¹ HNMR (400MHz, CD ₃ OD): δ (ppm) 7.67 (dd, J = 8.4Hz, 1H), 7.62 (d, J = 2.4Hz, 1H), 7.49-7.41 (m, 1H), 7.08(d,J＝8.8Hz,1H),7.00-6.90(m,2H),5.15-5.07(m,1H),4.61(s,2H),4.19-4.11(m,2H),3.92(d, J＝6.8Hz, 2H), 1.73(d, J＝6.4Hz, 3H), 1.58(d, J＝7.2Hz, 3H), 1.47-1.41(m, 3H), 1.35-1.25(m, 1H), 0.66-0.60(m,2H),0.39-0.33(m,2H);

MS-ESI (pos.ion) m/z: 472.2 [M+H-HCl] ⁺ .

Example 144: Compound (S)-6-((5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-ethoxybenzene Synthesis of oxazole-4-carboxamido)methyl)picolinic acid dihydrochloride

Step 1: Compound (S)-6-((5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-ethoxybenzene Synthesis of ethyl) oxazole-4-carboxamido) methyl) picolinate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-ethoxyphenyl)oxazole- 4-Formic acid (560mg, 1.255mmol) was dissolved in DCM (30mL), EDCI (361mg, 1.883mmol) and HOBT (256mg, 1.883mmol) were added, stirred at 25°C for 0.5h, and then 6-aminomethyl-2 -Ethyl pyridinecarboxylate (271mg, 1.506mmol) and DIPEA (675μL, 3.765mmol), stirred at 25°C for 3h, added water (30mL), extracted with DCM (30mL×2), combined the organic phases and washed with saturated brine (30mL ×2), dried over Na ₂ SO ₄ , concentrated, and the concentrate was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=3/1) to obtain 319 mg of white solid, yield: 99%.

¹ HNMR (400MHz, CDCl ₃ ): δ (ppm) 8.50 (br.s, 1H), 8.17 (d, J = 6.4Hz, 1H), 8.11–8.03 (m, 1H), 7.94-7.84 (m, 1H ),7.60(d,J=8.4Hz,1H),7.55(s,1H),6.92(d,J=8.4Hz,1H),5.35-5.25(m,1H),5.15-5.08(m,2H) ,4.60-4.50(m,2H),4.20-4.13(m,2H),3.96(d,J＝6.8Hz,2H),1.60(d,J＝7.2Hz,3H),1.52-1.43(m,6H ),1.39-1.33(m,1H),0.69-0.61(m,2H),0.45-0.37(m,2H),0.07(s,9H);

MS-ESI (pos.ion) m/z: 609.4 [M+H] ⁺ .

Step 2: Compound (S)-6-((5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-ethoxybenzene Synthesis of oxazole-4-carboxamido)methyl)picolinic acid

Compound (S)-6-((5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-ethoxyphenyl) Oxazole-4-carboxamido)methyl) ethyl picolinate (319mg, 0.5241mmol) was dissolved in THF/H ₂ O (v/v=2/1, 9mL), and lithium hydroxide monohydrate (110mg, 2.620mmol), stirred at 40°C for 4.5h, added hydrochloric acid (1M) to adjust pH=2-3, extracted with ethyl acetate (15mL×3), combined the organic phases and washed with saturated brine (20mL×2), Na ₂ SO ₄ was dried and concentrated, and the concentrate was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=20/1) to obtain 102 mg of white solid, yield: 33.5%.

¹ HNMR (400MHz, CDCl ₃ ): δ (ppm) 8.30 (br.s, 1H), 8.18 (d, J = 6.8Hz, 1H), 8.02–7.93 (m, 1H), 7.72-7.65 (m, 1H ),7.62(d,J=7.6Hz,1H),7.56(s,1H),6.94(d,J=8.0Hz,1H),6.66(br.s,1H),5.40-5.25(m,1H) ,4.97-4.75(m,2H),4.22-4.12(m,2H),4.00-3.90(m,2H),1.54(d,J＝6.8Hz,3H),1.52-1.46(m,3H),1.39 -1.30(m,1H),0.70-0.60(m,2H),0.45-0.36(m,2H),0.07(s,9H);

MS-ESI (pos.ion) m/z: 581.1 [M+H] ⁺ .

Step 3: Compound (S)-6-((5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-ethoxyphenyl)oxazole-4-methan Synthesis of amido)methyl)picolinic acid dihydrochloride

To compound (S)-6-((5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-ethoxyphenyl) Add HCl in ethyl acetate (4M, 3mL) to a solution of oxazole-4-carboxamido)methyl)picolinic acid (102mg, 0.1756mmol) in dichloromethane (1mL), stir at room temperature for 40min, concentrate, the residue Ethyl acetate was added to the mixture, filtered, and the filter cake was washed with ethyl acetate (2 mL×5), dissolved in methanol (5 mL), and concentrated to obtain 59 mg of a yellow solid, yield: 65%.

Compound 82: ¹ HNMR (400MHz, CD ₃ OD): δ (ppm) 8.22-8.07 (m, 2H), 7.85-7.75 (m, 1H), 7.69 (dd, J = 8.0Hz, 1H), 7.65 (d ,J=2.0Hz,1H),7.10(d,J=8.4Hz,1H),5.18-5.09(m,1H),4.94-4.85(m,2H),4.20-4.12(m,2H),3.93( d,J=6.8Hz,2H),1.74(d,J=6.8Hz,3H),1.49-1.41(m,3H),1.39-1.23(m,1H),0.67-0.60(m,2H),0.40 -0.34(m,2H);

MS-ESI (pos.ion) m/z: 481.1 [M+H-2HCl] ⁺ .

Example 145: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-(2,4-difluorobenzyl)thiazole-4-carboxamide hydrochloride

Step 1: Synthesis of compound 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoyl chloride

At 0°C, oxalyl chloride (1.55mL, 16.27mmol) and DMF (114μL, 1.48mmol) were added to compound 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid (3.82g , 14.79mmol) in anhydrous DCM (100mL), stirred at 25°C for 3h, and distilled under reduced pressure to obtain 4.09g of white solid, yield: 100%.

MS-ESI (pos.ion) m/z: 273.1 [M-Cl+OCH ₃ ] ⁺ .

Step 2: Compound (4S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-(3-(cyclopropylmethoxy)-4-(difluoro Synthesis of Ethyl Methoxy)benzamido)-3-oxopentanoate

Compound 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoyl chloride (4.09g, 14.79mmol) was dissolved in anhydrous THF (100mL), and compound (4S )-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-amino-3-oxopentanoic acid ethyl ester hydrochloride (5.31g, 13.40mmol) anhydrous DMF (50mL) and triethylamine (3.72mL, 26.80mmol) solution, stirred at 25°C for 3h, concentrated, the residue was dissolved in EtOAc/Et ₂ O (v/v=1/1, 100mL), washed with hydrochloric acid (1M) washing, NaHCO ₃ solution washing (10%, 70mL×2) and saturated brine washing (70mL×2), Na ₂ SO ₄ drying, concentrating, and the concentrated solution was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v /v)=2/1), 3.24 g of white solid was obtained, yield: 38%.

¹ HNMR (400MHz, CDCl ₃ ): δ (ppm) 7.79-7.73 (m, 2H), 7.63-7.52 (m, 2H), 7.48 (s, 1H), 7.44-7.34 (m, 3H), 7.34-7.27 (m,2H),7.22(d,J=8.4Hz,1H),6.88-6.51(m,1H),5.74(d,J=8.4Hz,1H),5.61(d,J=6.4Hz,1H) ,5.02-4.90(m,1H),4.49-4.16(m,4H),3.96-3.85(m,2H),1.55(d,J=7.2Hz,3H),1.36-1.24(m,4H),0.69 -0.56(m,2H),0.38-0.28(m,2H).

Step 3: Compound (S)-5-(1-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy) Synthesis of ethyl 4-(difluoromethoxy)phenyl)thiazole-4-carboxylate

Compound (4S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Base) benzamido)-3-oxopentanoic acid ethyl ester (2.6g, 4.084mmol) was dissolved in anhydrous THF (100mL), added Lawson's reagent (3.3g, 8.168mmol), stirred at 80°C for 21h , after adding water (100mL), extracted with ethyl acetate (100mL×3), combined the organic phases and washed with saturated brine (100mL), dried over Na ₂ SO ₄ , concentrated, and the concentrated solution was separated and purified by silica gel column chromatography (petroleum ether/ Ethyl acetate (v/v)=2/1) to obtain 1.86 g of light blue solid.

¹ HNMR (400MHz, CD ₃ OD): δ (ppm) 7.79-7.53 (m, 5H), 7.40-7.15 (m, 5H), 7.13-6.97 (m, 1H), 6.96-6.50 (m, 1H), 5.70-5.55(m,1H),4.52-4.37(m,2H),4.37-4.24(m,1H),4.23-4.12(m,1H),3.98(d,J＝6.8Hz,2H),3.88- 3.76(m,2H),1.55(d,J＝6.0Hz,2H),1.47-1.36(m,3H),1.36-1.24(m,4H),0.70-0.56(m,2H),0.45-0.30( m,2H).

Step 4: Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene base) synthesis of thiazole-4-carboxylic acid

Compound (S)-5-(1-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4 -(Difluoromethoxy)phenyl)thiazole-4-carboxylic acid ethyl ester (1.86g, 2.931mmol) was dissolved in THF/H ₂ O (v/v=1/1, 210mL), and sodium hydroxide solution ( 1M, 12.89mL), stirred at 80°C for 3h, then added di-tert-butyl dicarbonate (768mg, 3.517mmol), stirred at 33°C for 4h, added hydrochloric acid (1M) to adjust pH=2-3, extracted with ethyl acetate ( 150mL×3), the combined organic phases were washed with saturated brine (30mL×2), dried over Na ₂ SO ₄ , concentrated, and the concentrate was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2 /1), to obtain 1.145 g of white solid, yield: 80.6%.

¹ HNMR (400MHz, CDCl ₃ ): δ (ppm) 7.50 (s, 1H), 7.39 (d, J = 8.0Hz, 1H), 7.22 (d, J = 8.4Hz, 1H), 6.90-6.49 (m, 1H), 5.65-5.55(m, 1H), 3.97(d, J=6.8Hz, 2H), 1.60(d, J=6.4Hz, 3H), 1.36-1.28(m, 1H), 0.72-0.65(m ,2H),0.43-0.36(m,2H),0.07(s,9H);

MS-ESI (pos. ion) m/z: 485.1 [M+H] ⁺ .

Step 5: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((2,4-difluorobenzyl Synthesis of base) carbamoyl) thiazol-5-yl) ethyl) tert-butyl carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) Thiazole-4-carboxylic acid (300mg, 0.6192mmol) was dissolved in DCM (20mL), EDCI (178mg, 0.9288mmol) and HOBT (126mg, 0.9288mmol) were added, stirred at 25°C for 0.5h, and then 2,4-di Fluorobenzylamine (106mg, 0.7430mmol) and DIPEA (333μL, 1.858mmol), stirred at 25°C for 3h, added water (20mL), extracted with DCM (15mL×2), combined the organic phases with saturated Na ₂ CO ₃ solution Wash (30mL×2) and saturated brine (30mL×2), dry over Na ₂ SO ₄ , concentrate, the concentrated solution is separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=5/1) , to obtain 285 mg of white solid, yield: 75.5%.

¹ HNMR (400MHz, CDCl ₃ ): δ (ppm) 8.56 (br.s, 1H), 8.06 (d, J = 7.6Hz, 1H), 7.90-7.83 (m, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.53(d, J=2Hz, 1H), 7.41(dd, J=8.4Hz, 1H), 7.20(d, J=8.8Hz, 1H), 6.89-6.49(m, 1H), 6.16 (br.s,1H),5.65-5.45(m,1H),4.55-4.45(m,2H),4.01(d,J=6.8Hz,2H),1.59(d,J=6.8Hz,3H), 1.35-1.27(m,1H),0.71-0.62(m,2H),0.46-0.39(m,2H),0.07(s,9H).

Step 6: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2, Synthesis of 4-difluorobenzyl)thiazole-4-carboxamide hydrochloride

To compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((2,4-difluorobenzyl) Carbamoyl) thiazol-5-yl) ethyl) tert-butyl carbamate (285 mg, 0.4680 mmol) in dichloromethane (1 mL) was added HCl in ethyl acetate (4M, 3 mL), stirred at room temperature for 40 min, Concentrate, add ethyl acetate to the residue, filter, wash the filter cake with ethyl acetate (1 mL×6), dissolve in methanol (5 mL), and concentrate to obtain 230 mg of white solid, yield: 90%.

Compound 83: ¹ HNMR (400MHz, CD ₃ OD): δ (ppm) 7.81 (d, J = 1.6Hz, 1H), 7.59 (dd, J = 8.4Hz, 1H), 7.51-7.43 (m, 1H), 7.25(d,J＝8.4Hz,1H),7.07-6.67(m,1H),7.00-6.90(m,1H),5.38-5.30(m,1H),4.72-4.62(m,2H),4.02( d,J=6.8Hz,2H),1.77(d,J=6.8Hz,3H),1.38-1.26(m,1H),0.69-0.62(m,2H),0.43-0.37(m,2H);

MS-ESI (pos.ion) m/z: 510.1 [M+H-HCl] ⁺ .

Example 146: Compound (S)-6-((5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Synthesis of yl)phenyl)thiazole-4-carboxamido)methyl)pyridinecarboxylic acid dihydrochloride

Step 1: Compound (S)-6-((5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethane Synthesis of ethyl oxy)phenyl)thiazole-4-carboxamido)methyl)picolinate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) Thiazole-4-carboxylic acid (300mg, 0.6192mmol) was dissolved in DCM (20mL), EDCI (178mg, 0.9288mmol) and HOBT (126mg, 0.9288mmol) were added, stirred at 25°C for 0.5h, and then 6-aminomethyl -Ethyl 2-pyridinecarboxylate (134mg, 0.7430mmol) and DIPEA (333μL, 1.858mmol), stirred at 25°C for 3h, added water (20mL), extracted with DCM (15mL×2), combined the organic phases with saturated Wash with Na ₂ CO ₃ solution (30mL×2) and saturated brine (30mL×2), dry over Na ₂ SO ₄ , concentrate, and the concentrated solution is separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =3/1), 332 mg of white solid was obtained, yield: 82.9%.

¹ HNMR (400MHz, CDCl ₃ ): δ (ppm) 8.59 (br.s, 1H), 8.08 (d, J = 7.6Hz, 1H), 7.93-7.85 (m, 1H), 7.70 (d, J = 8.0 Hz,1H),7.56(d,J=2.4Hz,1H),7.43(dd,J=8.6Hz,1H),7.22(d,J=8.4Hz,1H),6.87-6.50(m,1H), 6.18(br.s,1H),5.66-5.50(m,1H),4.98-4.84(m,2H),4.56-4.46(m,2H),4.04(d,J=7.2Hz,2H),1.61( d,J＝7.2Hz,3H),1.49-1.43(m,3H),1.38-1.30(m,1H),0.75-0.66(m,2H),0.48-0.42(m,2H),0.09(s, 9H);

MS-ESI (pos.ion) m/z: 647.3 [M+H] ⁺ .

Step 2: Compound (S)-6-((5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethane Synthesis of oxy)phenyl)thiazole-4-carboxamido)methyl)picolinic acid

Compound (S)-6-((5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy ) phenyl) thiazole-4-carboxamido) methyl) ethyl picolinate (320 mg, 0.4949 mmol) was dissolved in THF/H ₂ O (v/v=2/1, 9 mL), and lithium hydroxide monohydrate was added (104mg, 2.474mmol), stirred at 40°C for 4.5h, added hydrochloric acid (1M) to adjust pH=2-3, extracted with ethyl acetate (15mL×3), combined organic phases and washed with saturated brine (15mL×2), Na ₂ SO ₄ was dried, concentrated, and the concentrate was separated and purified by silica gel column chromatography (petroleum ether) to obtain 230 mg of white solid, yield: 75%.

¹ HNMR (400MHz, CDCl ₃ ): δ (ppm) 8.55 (br.s, 1H), 8.19 (d, J = 6.4Hz, 1H), 8.07-8.00 (m, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.53(s, 1H), 7.42(dd, J=8.2Hz, 1H), 7.23(d, J=8.4Hz, 1H), 6.92-6.50(m, 1H), 5.97(br.s ,1H),5.70-5.55(m,1H),4.94(d,J=5.2Hz,2H),4.01(d,J=7.2Hz,2H),1.61(d,J=6.4Hz,3H),1.38 -1.30(m,1H),0.72-0.64(m,2H),0.47-0.39(m,2H),0.09(s,9H);

MS-ESI (pos. ion) m/z: 619.3 [M+H] ⁺ .

Step 3: Compound (S)-6-((5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)thiazole- Synthesis of 4-formamido)methyl)picolinic acid dihydrochloride

To compound (S)-6-((5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)thiazole-4-carboxamido)methyl)picolinic acid (220mg, 0.3557mmol) in dichloromethane (1mL) was added HCl in ethyl acetate (4M, 3mL), stirred at room temperature for 40min, added Ethyl acetate was filtered, and the filter cake was washed with ethyl acetate (1 mL×6), dissolved in methanol (5 mL), and concentrated to obtain 150 mg of light yellow solid, yield: 87.8%.

Compound 85: ¹ HNMR (400MHz, CD ₃ OD): δ (ppm) 8.36-8.25 (m, 2H), 8.03-7.92 (m, 1H), 7.86 (d, J=2.4Hz, 1H), 7.63 (dd ,J=8.4Hz,1H),7.30(d,J=8.4Hz,1H),7.09-6.70(m,1H),5.45-5.38(m,1H),4.97(s,2H),4.06(d, J＝7.2Hz, 2H), 1.81(d, J＝5.6Hz, 3H), 1.41-1.30(m, 1H), 0.72-0.65(m, 2H), 0.46-0.42(m, 2H);

MS-ESI (pos.ion) m/z: 519.3 [M+H-2HCl] ⁺ .

Example 147: Compound (S)-5-(1-aminoethyl)-N-(benzofuran-3-ylmethyl)-2-(3-(cyclopropylmethyl) Synthesis of oxy)-4-(difluoromethoxy)phenyl)thiazole-4-carboxamide hydrochloride

Step 1: Compound (S)-(1-(4-((benzofuran-3-ylmethyl)carbamoyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Synthesis of tert-butyl methoxy)phenyl)thiazol-5-yl)ethyl)carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) Thiazole-4-carboxylic acid (200mg, 0.4129mmol) was dissolved in DCM (20mL), added EDCI (119mg, 0.6194mmol) and HOBT (85mg, 0.6194mmol), stirred at 25°C for 0.5h, then added benzofuran-3 -Methylamine hydrochloride (91mg, 0.4953mmol) and DIPEA (259μL, 1.445mmol), stirred at 25°C for 3h, added water (20mL), and extracted with DCM (15mL×2). Combined organic phases were washed with saturated _Na2CO3 solution (30mL× ₂ ) and saturated brine (30mL× ₂ ), dried over _Na2SO4 , concentrated, and the concentrate was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate Ester (v/v)=5/1), 147 mg of white solid was obtained, yield: 58%.

¹ HNMR (400MHz, CDCl ₃ ): δ (ppm) 7.72-7.66 (m, 2H), 7.50 (d, J = 8.4Hz, 1H), 7.42 (s, 1H), 7.38-7.30 (m, 2H), 7.29-7.23(m,1H),7.18(d,J=8.4Hz,1H),6.86-6.46(m,1H),5.67-5.47(m,1H),4.78(d,J=6.0Hz,2H) ,3.91(d,J=6.4Hz,2H),1.63(d,J=7.2Hz,3H),1.33-1.27(m,1H),0.68-0.62(m,2H),0.39-0.33(m,2H ),0.07(s,9H);

MS-ESI (pos. ion) m/z: 614.3 [M+H] ⁺ .

Step 2: Compound (S)-5-(1-aminoethyl)-N-(benzofuran-3-ylmethyl)-2-(3-(cyclopropylmethoxy)-4-(di Synthesis of fluoromethoxy)phenyl)thiazole-4-carboxamide hydrochloride

To compound (S)-(1-(4-((benzofuran-3-ylmethyl)carbamoyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Base) phenyl) thiazol-5-yl) ethyl) tert-butyl carbamate (147mg, 0.2395mmol) in dichloromethane (1mL) solution was added HCl in ethyl acetate solution (4M, 3mL), stirred at room temperature for 40min , added ethyl acetate, filtered, the filter cake was washed with ethyl acetate (1 mL×6), dissolved in methanol (5 mL), and concentrated to obtain 125 mg of white solid, yield: 95%.

Compound 86: ¹ HNMR (400MHz, CD ₃ OD): δ (ppm) 7.83-7.77 (m, 3H), 7.58 (dd, J = 8.4Hz, 1H), 7.49 (d, J = 8.4Hz, 1H), 7.35-7.23(m,3H),7.08-6.69(m,1H),5.43-5.35(m,1H),4.81-4.77(m,2H),4.02(d,J＝6.8Hz,2H),1.82( d,J＝7.2Hz,3H),1.38-1.28(m,1H),0.71-0.63(m,2H),0.45-0.38(m,2H);

MS-ESI (pos. ion) m/z: 514.3 [M+H-HCl] ⁺ .

Example 148: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Base)-N-((S)-1-(2,4-difluorophenyl)-2-oxo-2-(4-(pyridin-4-ylmethyl)piperazin-1-yl)ethyl base) oxazole-4- Formamide trihydrochloride and 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N- ((R)-1-(2,4-difluorophenyl)-2-oxo-2-(4-(pyridin-4-ylmethyl)piperazin-1-yl)ethyl)oxazole- 4-formamide Synthesis of trihydrochloride

Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-( 1-(2,4-difluorophenyl)-2-oxo-2-(4-(pyridin-4-ylmethyl)piperazin-1-yl)ethyl)oxazole-4-carboxamide tri The hydrochloride was resolved to obtain the compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N -((S)-1-(2,4-difluorophenyl)-2-oxo-2-(4-(pyridin-4-ylmethyl)piperazin-1-yl)ethyl)oxazole -4-Carboxamide trihydrochloride (white solid) and 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )phenyl)-N-((R)-1-(2,4-difluorophenyl)-2-oxo-2-(4-(pyridin-4-ylmethyl)piperazin-1-yl ) ethyl) oxazole-4-carboxamide trihydrochloride (white solid).

Example 149: Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Base)-N-((S)-(2,4-difluorophenyl)(2H-tetrazol-5-yl)methyl)oxazole-4-carboxamide dihydrochloride and 5-((S )-1- Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((R)-(2,4-difluorophenyl)( 2h-four Synthesis of oxazol-5-yl)methyl)oxazole-4-carboxamide dihydrochloride

Compound 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-( (2,4-difluorophenyl) (2H-tetrazol-5-yl) methyl) oxazole-4-carboxamide dihydrochloride resolution to obtain compound 5-((S)-1-aminoethyl Base)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((S)-(2,4-difluorophenyl)(2H- Tetrazol-5-yl)methyl)oxazole-4-carboxamide dihydrochloride (white solid) and 5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethyl) Oxy)-4-(difluoromethoxy)phenyl)-N-((R)-(2,4-difluorophenyl)(2H-tetrazol-5-yl)methyl)oxazole- 4-Formamide dihydrochloride (white solid).

Example 150: Compound (S)-5-(1-aminoethyl)-2-(3-((5-(cyclopentylamino)-5-oxopentyl)oxy Synthesis of yl)-4-(difluoromethoxy)phenyl)-N-(2,4-difluorobenzyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound (S)-(1-(2-(3-((5-(cyclopentylamino)-5-oxopentyl)oxy)-4-(difluoromethoxy)phenyl) Synthesis of tert-butyl 4-((2,4-difluorobenzyl)carbamoyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(5-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-4-((2,4-difluorobenzyl)carbamoyl)oxazole- 2-yl)-2-(difluoromethoxy)phenoxy)valeric acid (0.25g, 0.39mmol), cyclopropylamine (40mg, 0.47mmol), 1-ethyl-3-(3-dimethylamine Propyl) carbodiimide hydrochloride (112mg, 0.59mmol) and N-hydroxy-7-azabenzotriazole (80mg, 0.59mmol) were dissolved in dichloromethane (15mL), at 0°C Add N,N-diisopropylethylamine (0.27mL, 1.56mmol) dropwise to this solution, stir at room temperature for 5h, add water (10mL×3), dry the organic phase with anhydrous Na ₂ SO ₄ , remove the solvent, The concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v)=1/1) to obtain 240 mg of white solid, yield: 86%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.60–7.58(m,2H),7.47–7.41(m,1H),7.24(d,J=8.0Hz,1H),6.91–6.86(m,2H), 6.63(t,J _FH ＝74.5Hz,1H),5.53–5.51(m,1H),5.32–5.30(m,1H),4.68–4.67(m,2H),4.25–4.19(m,1H),4.17 –4.14(m,2H),2.28(t,J＝7.0Hz,2H),2.03–1.96(m,2H),1.92–1.86(m,4H),1.68–1.58(m,4H),1.56(d ,J＝7.0Hz,3H),1.45(s,9H),1.38–1.35(m,1H);

MS-ESI: m/z 707.2 [M+H] ⁺ .

Step 2: Compound (S)-5-(1-aminoethyl)-2-(3-((5-(cyclopentylamino)-5-oxopentyl)oxy)-4-(difluoromethane Synthesis of oxy)phenyl)-N-(2,4-difluorobenzyl)oxazole-4-carboxamide hydrochloride

To compound (S)-(1-(2-(3-((5-(cyclopentylamino)-5-oxopentyl)oxy)-4-(difluoromethoxy)phenyl)-4 -((2,4-Difluorobenzyl)carbamoyl)oxazol-5-yl)ethyl)carbamate (0.23 g, 0.33 mmol) in dichloromethane (3 mL) was added with HCl Ethyl acetate solution (4M, 2mL), stirred at room temperature for 1.5h, and the solvent was removed to obtain 209mg of white solid, yield: 99%.

Compound 193: ¹ H NMR (400MHz, CD ₃ OD): δppm 7.82(s, 1H), 7.73(d, J=8.4Hz, 1H), 7.52-7.46(m, 1H), 7.33(d, J=8.3 Hz,1H),7.01–6.94(m,2H),6.88(t,J _FH ＝74.5Hz,1H),5.18–5.17(m,1H),4.65(s,2H),4.19(t,J＝5.6 Hz, 2H), 4.13–4.09(m, 1H), 2.31(t, J=6.8Hz, 2H), 1.95–1.84(m, 6H), 1.78(d, J=6.9Hz, 3H), 1.74–1.68 (m,2H),1.64–1.59(m,2H),1.50–1.40(m,2H);

MS-ESI: m/z 607.2 [M+H-HCl] ⁺ .

Example 151: Compound (S)-2-(3-(4-aminobutoxy)-4-(difluoromethoxy)phenyl)-5-(1-aminoethyl Synthesis of -N-(2,4-difluorobenzyl)oxazole-4-carboxamide dihydrochloride

To compound (S)-(1-(2-(3-(4-aminobutoxy)-4-(difluoromethoxy)phenyl)-4-((2,4-difluorobenzyl) Add HCl in ethyl acetate (4M, 3mL) to a solution of tert-butyl carbamate (160mg, 0.26mmol) in dichloromethane (2mL) and stir at room temperature for 1h , and the solvent was removed to obtain 140 mg of white solid, which was processed after preparation to obtain 53 mg of white solid, yield: 36%.

Compound 128: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.86 (d, J = 1.8Hz, 1H), 7.76 (dd, J ₁ = 8.4Hz, J ₂ = 1.8Hz, 1H), 7.52-7.48 ( m,1H),7.35(d,J＝8.4Hz,1H),7.01–6.85(m,2H),6.91(t,J _FH ＝74.1Hz,1H),5.20–5.16(m,1H),4.65( s, 2H), 4.25(t, J=5.7Hz, 2H), 3.09(t, J=7.5Hz, 2H), 2.03–1.93(m, 4H), 1.78(d, J=7.0Hz, 3H);

MS-ESI: 511.0 [M+H-2HCl] ⁺ .

Example 152: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Synthesis of -N-(1-methyl-1H-pyrazol-4-yl)oxazole-4-carboxamide dihydrochloride

Step 1: Synthesis of 1-methyl-1H-pyrazol-4-amine

Add 1-methyl-4-nitro-1H-pyrazole (500mg, 3.93mmol) and Pd/C (10%, 50mg) into methanol (10mL), reduce it with hydrogen at room temperature, and stop the reaction after 6h React, filter with suction, and concentrate the filtrate to obtain 305 mg of red liquid, yield: 80%.

¹ H NMR (600MHz, CDCl ₃ ): δppm 7.18(s,1H), 7.14(s,1H), 3.78(s,3H);

MS-ESI: m/z 98.20 [M+H] ⁺ .

Step 2: Compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-methyl-1H- Synthesis of tert-butyl pyrazol-4-yl)carbamoyl)oxazol-5-yl)ethyl)carbamate

Compound (S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) oxazole-4-carboxylic acid (300mg, 0.64mmol), 1-methyl-1H-pyrazol-4-amine (75mg, 0.77mmol), 1-ethyl-3-(3-dimethylaminopropyl) Carbodiimide hydrochloride (245mg, 1.28mmol) and N-hydroxy-7-azabenzotriazole (130mg, 0.96mmol) were dissolved in dichloromethane (10mL), and the solution was added to the solution at 0°C Add N,N-diisopropylethylamine (0.33mL, 1.92mmol) dropwise, stir at room temperature for 5h, wash with water (10mL×3), dry the organic phase with anhydrous Na ₂ SO ₄ , remove the solvent, and carry out the concentrated solution Column separation (petroleum ether/ethyl acetate (v/v)=2/1) gave 232 mg of light yellow solid, yield: 66%.

¹ H NMR (600MHz, CDCl ₃ ): δppm 7.89(br.s, 1H), 8.05(s, 1H), 7.61(dd, J ₁ =8.3Hz, J ₂ =1.8Hz, 1H), 7.57(d, J＝12.2Hz, 2H), 7.25(d, J＝8.3Hz, 1H), 6.71(t, J＝ _75.1Hz , 1H), 5.32–5.35(m, 1H), 3.99(d, J＝6.9Hz ,2H),3.91(s,3H),1.56(d,J＝7.0Hz,3H),1.44(s,9H),1.31–1.36(m,1H),0.68–0.71(m,2H),0.40– 0.43(m,2H);

MS-ESI: m/z 546.70 [MH] ^- .

Step 3: Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1- Synthesis of methyl-1H-pyrazol-4-yl)oxazole-4-carboxamide dihydrochloride

To compound (S)-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((1-methyl-1H-pyrazole -4-yl)carbamoyl)oxazol-5-yl)ethyl)carbamate tert-butyl ester (225mg, 0.41mmol) in dichloromethane (4mL) was added HCl in ethyl acetate (4M, 4mL ), stirred at room temperature for 30 min, and removed the solvent to obtain 212 mg of white solid, yield: 97%.

Compound 402: ¹ H NMR (600MHz, CD ₃ OD): δppm 8.20–8.23 (m, 1H), 7.95–7.99 (m, 1H), 7.81 (s, 1H), 7.73 (dd, J ₁ =8.3Hz, J ₂ ＝1.7Hz, 1H), 7.31(d, J＝8.3Hz, 1H), 6.89(t, J _FH ＝75.1Hz, 1H), 5.20–5.24(m, 1H), 4.03(d, J＝6.9 Hz,2H),3.97(s,3H),1.78(d,J＝7.0Hz,3H),1.31–1.37(m,1H),0.65–0.68(m,2H),0.40–0.43(m,2H) ;

MS-ESI: m/z 448.10 [M+H-2HCl] ⁺ .

Example 153: Compound (S)-5-(1-(4-(aminomethyl)-1H-1,2,3-triazol-1-yl)ethyl)-2-(3- Synthesis of (cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2,4-difluorobenzyl)oxazole-4-carboxamide hydrochloride

Step 1: Compound (S)-5-(1-azidoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2 , Synthesis of 4-difluorobenzyl)oxazole-4-carboxamide

Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2,4- Difluorobenzyl)oxazole-4-carboxamide hydrochloride (312.4mg, 0.59mmol), copper sulfate pentahydrate (1.476mg, 0.059mmol) and potassium carbonate (244.5mg, 1.77mmol) were added to methanol (25mL) , a solution of 1H-imidazole-1-sulfonyl azide (204.3mg, 1.18mmol) in methanol (5mL) was slowly added dropwise to the solution, the reaction was continued at room temperature for 12h, methanol was removed, and saturated NH ₄ Cl solution (20mL ), extracted with ethyl acetate (25mL×3), combined the organic phases, dried with anhydrous Na ₂ SO ₄ for 1 h, removed the solvent, and the concentrated solution was subjected to column separation (Petroleum ether/EtOAc(v/v)=3/1) , to obtain 274 mg of white solid, yield: 89.4%.

Step 2: Compound (S)-((1-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((2,4 Synthesis of tert-butyl -difluorobenzyl)carbamoyl)oxazol-5-yl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)carbamate

The compound N-Boc-aminopropyne (98.2mg, 0.633mmol), anhydrous copper sulfate (13mg, 0.05mmol) and sodium ascorbate (20.9mg, 0.105mmol) were added to a 25mL double-necked round bottom flask, and pumped Vacuum, nitrogen protection, then add compound (S)-5-(1-azidoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)- N-(2,4-difluorobenzyl)oxazole-4-carboxamide (274mg, 0.528mmol) in THF (16mL) solution, add distilled water (4mL), react at 60°C for 1h, remove THF, then add saturated NH ₄ Cl solution (25mL), extracted with dichloroethane (25mL×3), combined the organic phases, dried with anhydrous Na ₂ SO ₄ , removed the solvent, and the concentrated solution was subjected to column separation (Petroleum ether/EtOAc (v/ v)=1/1), 320 mg of white solid was obtained, yield: 89.9%.

Step 3: Compound (S)-5-(1-(4-(aminomethyl)-1H-1,2,3-triazol-1-yl)ethyl)-2-(3-(cyclopropane Synthesis of methoxy)-4-(difluoromethoxy)phenyl)-N-(2,4-difluorobenzyl)oxazole-4-carboxamide hydrochloride

Compound (S)-((1-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((2,4-di Fluorobenzyl)carbamoyl)oxazol-5-yl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)carbamate tert-butyl ester (385mg, 0.571mmol) To CH ₂ Cl ₂ (2 mL), HCl ^. EtOAc (4M, 5 mL) was added, stirred overnight at room temperature, and then the solvent was removed to obtain 328.4 mg of white solid, yield: 94.2%.

Compound 72: ¹ H NMR (400MHz, CD ₃ OD): δppm 8.93–8.96 (m, 1H), 8.32 (s, 1H), 7.77 (d, J=1.6Hz, 1H), 7.69 (dd, J ₁ = 8.4Hz, J ₂ ＝1.7Hz, 1H), 7.43–7.49(m, 1H), 7.32(d, J＝8.1Hz, 1H), 6.94–7.01(m, 2H), 6.91(t, J _FH ＝74.8 Hz,1H),6.82–6.87(m,1H),4.60–4.63(m,2H),4.27(s,2H),4.03(d,J＝6.9Hz,2H),2.12(d,J＝7.2Hz ,3H),1.31–1.37(m,1H),0.67–0.71(m,2H),0.41–0.45(m,2H);

MS-ESI: m/z 575.45 [M+H-HCl] ⁺ .

Example 154: Compound (S)-4-((1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4- Synthesis of ((2,4-difluorobenzyl)carbamoyl)oxazol-5-yl)ethyl)amino)-4-oxobutanoic acid

Step 1: Compound (S)-4-((1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((2,4- Synthesis of methyl difluorobenzyl)carbamoyl)oxazol-5-yl)ethyl)amino)-4-oxobutanoate

Compound (S)-5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2,4- Difluorobenzyl)oxazole-4-carboxamide hydrochloride (250mg, 0.47mmol), monomethyl succinate (74mg, 0.56mmol), 1-ethyl-3-(3-dimethylaminopropyl ) carbodiimide hydrochloride (135mg, 0.71mmol) and N-hydroxy-7-azabenzotriazole (96mg, 0.71mmol) were added in dichloromethane (15mL), stirred at room temperature for 30min, at 0°C Add N,N-diisopropylethylamine (0.33mL, 1.88mmol) dropwise to the solution under the conditions, stir at room temperature for 15h, remove the solvent, and the concentrated solution is subjected to column separation (petroleum ether/ethyl acetate (v/v) = 1/1), to obtain 204 mg of white solid, yield: 71%.

¹ H NMR (400MHz, CDCl ₃ ): δppm 7.59(dd, J ₁ =8.4Hz, J ₂ =2.0Hz, 1H), 7.54(s, 1H), 7.41-7.46(m, 1H), 7.25(d, J＝8.3Hz, 1H), 6.85-6.93(m, 2H), 6.72(t, J _FH ＝74.9Hz, 1H), 5.57-5.61(m, 1H), 4.67(d, J＝6.2Hz, 2H) ,3.99(d,J=7.0Hz,2H),3.69(s,3H),2.66-2.70(m,2H),2.52-2.63(m,2H),1.54(d,J=7.0Hz,3H), 1.31-1.37(m,1H),0.68-0.73(m,2H),0.40-0.44(m,2H);

MS-ESI: m/z 608.2 [M+H] ⁺ .

Step 2: Compound (S)-4-((1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((2,4- Synthesis of Difluorobenzyl)carbamoyl)oxazol-5-yl)ethyl)amino)-4-oxobutanoic acid

Compound (S)-4-((1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-((2,4-difluoro Benzyl)carbamoyl)oxazol-5-yl)ethyl)amino)-4-oxobutanoic acid methyl ester (150mg, 10.63mmol) and sodium hydroxide (50mg, 1.23mmol) were dissolved in ethanol (20mL) In a mixed solvent of water (10mL), react at 60°C for 2h, remove ethanol, add hydrochloric acid (1M) to adjust the pH value to about 1, add ethyl acetate for extraction (10mL×3), combine the organic phases and wash with anhydrous Na ₂ Drying over SO ₄ and removal of solvent gave 146 mg of white solid, yield: 99%.

Compound 437: ¹ H NMR (600MHz, CD ₃ OD): δppm 7.69 (s, 1H), 7.61 (dd, J ₁ =8.3Hz, J ₂ =1.7Hz, 1H), 7.42-7.46 (m, 1H), 7.25(d, J＝8.3Hz, 1H), 6.90-6.93(m, 2H), 6.87(t, J _FH ＝74.9Hz, 1H), 5.68-5.71(m, 1H), 4.55-4.63(m, 2H ),3.95(d,J=7.0Hz,2H),2.58-2.61(m,2H),2.51-2.55(m,2H),1.56(d,J=7.0Hz,3H),1.29-1.35(m, 1H),0.63-0.66(m,2H),0.37-0.39(m,2H);

MS-ESI: m/z 594.1 [M+H] ⁺ .

The compound numbers in Table 2-20 correspond one-to-one to the compound numbers in the specific structure of the compounds of the present invention in the detailed description of the invention.

Using suitable raw materials, through the similar synthesis method of Example 102, the compounds shown in Table 2 can be obtained:

Table 2 Compounds and their characterization data

Using suitable raw materials, the compounds shown in Table 3 can be obtained by the similar synthesis method of Example 108:

Table 3 Compounds and their characterization data

Adopt suitable raw material, by the analogous synthetic method of embodiment 1, can obtain the compound shown in table 4:

Table 4 Compounds and their characterization data

Using suitable raw materials, the compounds shown in Table 5 can be obtained by the similar synthesis method of Example 124:

Table 5 Compounds and their characterization data

Using suitable raw materials, the compounds shown in Table 6 can be obtained by the similar synthesis method of Example 125:

Table 6 Compounds and their characterization data

Using suitable raw materials, the compounds shown in Table 7 can be obtained through the similar synthesis method of Example 39:

Table 7 Compounds and their characterization data

Example Compound number characterizing data 175 120 Compound 120: MS-ESI: m/z 587.15[M+H-2HCl]⁺. 176 121 Compound 121: MS-ESI: m/z 587.15[M+H-2HCl]⁺. 177 122 Compound 122: MS-ESI: m/z 587.15[M+H-2HCl]⁺.

Using suitable raw materials, through the similar synthesis method of Example 40, the compounds shown in Table 8 can be obtained:

Table 8 Compounds and their characterization data

Example Compound number characterizing data 178 108 Compound 108: MS-ESI: m/z 484.20[M+H-HCl]⁺.

Using suitable raw materials, the compounds shown in Table 9 can be obtained by the similar synthesis method of Example 65:

Table 9 Compounds and their characterization data

Example Compound number characterizing data 179 169 Compound 169: MS-ESI: m/z 552.18[M+H-2HCl]⁺.

Using suitable raw materials, the compounds shown in Table 10 can be obtained by the similar synthesis method of Example 74:

Table 10 Compounds and their characterization data

Example Compound number characterizing data 180 189 Compound 189: MS-ESI: m/z 619.25[M+H-HCl]⁺. 181 190 Compound 190: MS-ESI: m/z 619.25[M+H-HCl]⁺.

Using suitable raw materials, the compounds shown in Table 11 can be obtained through the similar synthesis method of Example 76:

Table 11 Compounds and their characterization data

Example Compound number characterizing data

Example Compound number characterizing data 182 200 Compound 200: MS-ESI: m/z 608.21[M+H-HCl]⁺.

Using suitable raw materials, the compounds shown in Table 12 can be obtained by the similar synthesis method of Example 79:

Table 12 Compounds and their characterization data

Example Compound number characterizing data 183 197 Compound 197: MS-ESI: m/z 580.20[M+H-HCl]⁺.

Using suitable raw materials, the compounds shown in Table 13 can be obtained by the similar synthesis method of Example 99:

Table 13 Compounds and their characterization data

Example Compound number characterizing data 184 40 Compound 40: MS-ESI: m/z 513.08[M+H-2HCl]⁺. 185 84 Compound 84: MS-ESI: m/z 508.18[M+H-HCl]⁺. 186 111 Compound 111: MS-ESI: m/z 536.17[M+H-HCl]⁺. 187 124 Compound 124: MS-ESI: m/z 508.18[M+H-HCl]⁺. 188 126 Compound 126: MS-ESI: m/z 512.15[M+H-HCl]⁺. 189 127 Compound 127: MS-ESI: m/z 510.16[M+H-HCl]⁺. 190 130 Compound 130: MS-ESI: m/z 511.15[M+H-HCl]⁺. 191 131 Compound 131: MS-ESI: m/z 519.16[M+H-HCl]⁺. 192 142 Compound 142: MS-ESI: m/z 523.19[M+H-2HCl]⁺. 193 143 Compound 143: MS-ESI: m/z 523.19[M+H-2HCl]⁺. 194 362 Compound 362: MS-ESI: m/z 487.17[M+H-HCl]⁺. 195 363 Compound 363: MS-ESI: m/z 519.18[M+H-HCl]⁺. 196 381 Compound 381: MS-ESI: m/z 474.19[M+H-HCl]⁺. 197 397 Compound 397: MS-ESI: m/z 459.18[M+H-2HCl]⁺.

Using suitable raw materials, the compounds shown in Table 14 can be obtained by the similar synthesis method of Example 119:

Table 14 Compounds and their characterization data

Example Compound number characterizing data 198 118 Compound 118: MS-ESI: m/z 653.25[M+H-HCl]⁺. 199 119 Compound 119: MS-ESI: m/z 652.27[M+H-2HCl]⁺. 200 259 Compound 259: MS-ESI: m/z 628.29[M+H-HCl]⁺.

Using suitable raw materials, the compounds shown in Table 15 can be obtained by the similar synthesis method of Example 120:

Table 15 Compounds and their characterization data

Example Compound number characterizing data 201 191 Compound 191: MS-ESI: m/z 539.18[M+H-HCl]⁺. 202 204 Compound 204: MS-ESI: m/z 554.19[M+H-2HCl]⁺. 203 205 Compound 205: MS-ESI: m/z 610.22[M+H-HCl]⁺.

Adopt suitable starting material, by the similar synthetic method of embodiment 59, can obtain the compound shown in table 16:

Table 16 Compounds and their characterization data

Example Compound number characterizing data 204 163 Compound 163: MS-ESI: m/z 563.17[M+H-3HCl]⁺.

Adopt suitable raw material, through the route of synthetic method sixteen, can obtain the compound shown in table 17:

Table 17 Compounds and their characterization data

Example Compound number characterizing data 205 18 Compound 18: MS-ESI: m/z 474.18[M+H-HCl]⁺. 206 116 Compound 116: MS-ESI: m/z 510.16[M+H-HCl]⁺.

Adopt suitable raw material, through the route of synthetic method 17, can obtain the compound shown in table 18:

Table 18 Compounds and their characterization data

Example Compound number characterizing data 207 117 Compound 117: MS-ESI: m/z 495.15[M+H]⁺. 208 125 Compound 125: MS-ESI: m/z 493.13[M+H]⁺.

Adopt suitable raw material, through the route of synthetic method 18, can obtain the compound shown in table 19:

Table 19 Compounds and their characterization data

Example Compound number characterizing data 209 123 Compound 123: MS-ESI: m/z 493.18[M+H-HCl]⁺.

Adopt suitable raw material, through the route of synthetic method nineteenth, can obtain the compound shown in table 20:

Table 20 Compounds and their characterization data

Example Compound number characterizing data 210 129 Compound 129: MS-ESI: m/z 677.25[M+H-2HCl]⁺.

biological test

The present invention adopts following method to carry out biological test to the compound shown in formula (I), formula (I ') or formula (II):

1. Using the BPS production kit (BPS, 603343), according to the instructions provided by the manufacturer, the fluorescence polarization method was used to detect the inhibitory effect of the compound on the PDE4B2 enzyme.

2. The PDE4B2 enzyme concentration was prepared to be 83.33pg/μL, and the final concentration was 27.78pg/μL; the substrate FAM-Cyclic-3', 5'-AMP concentration was prepared to be 300nM, and the final concentration of the reaction was 100nM, and the enzyme and substrate were diluted All solutions use the PDE Assay buffer that comes with the kit; the Binding Agent is diluted 100 times with the Binding Agent Diluent that comes with the kit, and set aside. The reaction system is shown in Table 21.

Table 21 IC ₅₀ Detection System of Compounds on PDE4B2 Enzyme

3. A 384-well plate is used for detection, and the experiment is set to test sample wells, positive control wells, negative control wells, and blank wells. Each sample uses double-duplex wells to detect the inhibitory effect on the PDE4B2 enzyme concentration at 10 concentrations. Using PDE4B2 Enzyme and FAM-Cyclic-3', 5'-AMP substrate reaction wells were used as positive controls, FAM-Cyclic-3', 5'-AMP substrate wells were used as negative controls, and buffer wells were used as blank controls. After adding the corresponding samples, enzymes, substrates, and buffers to each well in the order shown in Table 21, incubate in a 25°C incubator for 1 hour, then add 15 μL of the prepared Binding Agent to each well, and shake at a 25°C constant temperature shaker for 1 hour. Detection was performed at FP485/525 wavelengths using a PHER Astar FS multifunctional microplate reader (BMG). Graph PadPrism 5 software was used to plot the inhibitory effect of the compound on PDE4B2 enzyme at different concentrations, and calculate the IC ₅₀ .

According to the method described above, the compounds provided in the examples of the present invention were tested for their inhibitory effects on PDE4B2 enzymes. See Table 22 for the results. The compound numbers in Table 22 correspond one-to-one to the compound numbers in the description part of the compound of the present invention in the detailed description of the invention.

Table 22 The assay result of compound of the present invention to PDE4B2 enzyme inhibitory effect

Compound number IC₅₀(nM) Compound number IC₅₀(nM) Compound number IC₅₀(nM) Roflumilast 0.60 Compound 2 0.50 Compound 3 2.40 Compound 4 1.58 Compound 5 4.70 Compound 6 19.50 Compound 7 6.50 Compound 9 101.68 Compound 10 29.74 Compound 13 4.25 Compound 15 39.50 Compound 16 33.89 Compound 17 3.31 Compound 21 19.87 Compound 22 3.51 Compound 23 1.86 Compound 24 0.64 Compound 28 101.88 Compound 29 0.40 Compound 30 3.41 Compound 31 2.66

Compound number IC₅₀(nM) Compound number IC₅₀(nM) Compound number IC₅₀(nM) Compound 32 38.12 Compound 33 15.42 Compound 34 3.22 Compound 35 7.20 Compound 36 5.66 Compound 37 1.68 Compound 38 3.78 Compound 39 18.28 Compound 41 7.30 Compound 43 146.85 Compound 46 70.74 Compound 49 36.66 Compound 51 3.05 Compound 52 28.83 Compound 54 3.25 Compound 57 4.26 Compound 70 1.75 Compound 73 13.85 Compound 74 4.28 Compound 75 1.60 Compound 76 0.69 Compound 77 0.57 Compound 78 4.01 Compound 79 3.03 Compound 80 6.90 Compound 81 1.39 Compound 82 104.90 Compound 84 6.70 Compound 87 1.66 Compound 88 9.59 Compound 89 0.86 Compound 92 5.00 Compound 95 5.54 Compound 96 34.10 Compound 97 5.52 Compound 98 28.99 Compound 99 4.54 Compound 100 3.55 Compound 101 0.16 Compound 102 1.50 Compound 106 0.29 Compound 113 8.04 Compound 114 10.05 Compound 132 2.98 Compound 133 2.28 Compound 134 8.02 Compound 135 0.32 Compound 137 1.09 Compound 138 2.20 Compound 139 2.51 Compound 140 1.49 Compound 141 4.53 Compound 144 6.21 Compound 146 14.44 Compound 147 52.22 Compound 148 0.36 Compound 150 3.49 Compound 151 12.66 Compound 152 3.47 Compound 154 1.09 Compound 155 0.34 Compound 156 3.75 Compound 158 1.54 Compound 159 5.40 Compound 160 2.24 Compound 161 15.6 Compound 162 3.51 Compound 164 15.97 Compound 165 15.9 Compound 166 1.57 Compound 167 9.59 Compound 168 13.68 Compound 170 31.48 Compound 171 4.09 Compound 172 4.98 Compound 173 15.22 Compound 174 15.41 Compound 176 10.72 Compound 177 6.71 Compound 178 3.15 Compound 179 1.21 Compound 180 5.45 Compound 182 6.10 Compound 183 7.13 Compound 184 17.47 Compound 187 1.77 Compound 188 11.35 Compound 193 34.29 Compound 194 24.64 Compound 196 7.39 Compound 198 8.03 Compound 199 25.74 Compound 200 1.84 Compound 201 11.82 Compound 202 0.60 Compound 207 13.32 Compound 208 1.38 Compound 209 6.16 Compound 211 5.83

Compound number IC₅₀(nM) Compound number IC₅₀(nM) Compound number IC₅₀(nM) Compound 212 7.32 Compound 214 0.48 Compound 217 29.81 Compound 219 0.51 Compound 220 0.53 Compound 221 2.29 Compound 222 17.54 Compound 223 6.71 Compound 224 10.48 Compound 225 18.82 Compound 226 0.51 Compound 227 1.32 Compound 228 15.00 Compound 229 5.39 Compound 231 88.73 Compound 232 4.65 Compound 233 33.45 Compound 234 12.37 Compound 235 6.78 Compound 236 26.88 Compound 238 15.41 Compound 239 35.50 Compound 240 73.84 Compound 244 6.61 Compound 256 23.92 Compound 257 13.29 Compound 271 27.13 Compound 313 14.97 Compound 325 8.91 Compound 380 5.32 Compound 383 3.28 Compound 384 0.81 Compound 385 1.73 Compound 402 54.32 Compound 406 0.76 Compound 411 30.56 Compound 412 0.22 Compound 429 0.65 Compound 436 1.39

The data in Table 22 shows that the compounds of the present invention generally exhibit higher inhibitory activity in the in vitro screening experiments for PDE4B2 enzyme inhibition.

It will be apparent to those skilled in the art that the present invention is not limited to the foregoing illustrative embodiments, but may be embodied in other specific forms without departing from its essential characteristics. It is therefore intended that the embodiments be considered in all respects as illustrative and non-restrictive, and that reference should be made to the appended claims, rather than to the foregoing embodiments, within the meaning and range of equivalents of the appended claims All changes within are included in the present invention.

In the description of this specification, descriptions referring to the terms "one embodiment", "some embodiments", "example", "specific examples" or "some examples" mean specific features described in connection with the embodiment or example, A structure, material or characteristic is included in at least one embodiment or example of the invention. In this specification, schematic representations of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.

Finally, it should be noted that there are other ways to implement the invention. Accordingly, the embodiments of the present invention will be described as illustrations, but are not limited to the content described in the present invention, and may be modified within the scope of the present invention or equivalent content added in the claims. All publications or patents cited in the present invention shall be regarded as reference documents of the present invention.

Claims (19)

1. A compound, which is a compound represented by formula (I') or a stereoisomer of a compound represented by formula (I') or a pharmaceutically acceptable salt: in: p is 0 or 1; X is -O- or -S-; R ¹ is C _1-4 alkyl or halogenated C _1-4 alkyl; Each R ² is independently H, D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , HOC(=O)-C _1-4 alkoxy-, C _1-4 alkoxy -(CH ₂ ) _e -C(=O)-C _1-4 alkoxy-, C _3-6 cycloalkyl-(CH ₂ ) _e -NH-C(=O)-C _1-4 alkoxy Base-, C _1-4 alkyl-NH-C (=O)-C _1-4 alkoxy-, R ^e R ^f NC (= O)-C _1-4 alkoxy-, C _1-5 Heteroaryl-C _2-6 heterocyclyl-C(=O)-C _1-4 alkoxy-, C _3-6 cycloalkyl-C(=O)-C _2-6 heterocyclyl-C (=O)-C _1-4 alkoxy-, NH ₂ -C(=O)-C _1-4 alkoxy-, C _1-4 alkyl-OC(=O)-(CR ^c R ^d ) _f -NH-C(=O)-C _1-4 alkoxy-, NH ₂ -C(=O)-(CR ^c R ^d ) _f -NH-C(=O)-C _1-4 alkane Oxygen-, C _1-4 alkyl-S(=O) ₂ -NH-C(=O)-C _1-4 alkoxy-, C _1-4 alkyl-OC(=O)-C _{1 -4} alkoxy-, NH ₂ -S(=O) ₂ -NH-C(=O)-C _1-4 alkoxy-, C _2-6 heterocyclyl-C(=O)-C _{1 -4} alkoxy-, C _1-4 alkoxy, amino-substituted C _1-4 alkoxy, halogenated C _1-4 alkoxy, C _2-6 heterocyclyloxy, C _6-10 Aryl C _1-4 alkoxyl, C _3-6 cycloalkyloxy or C _3-6 cycloalkyl C _1-4 alkoxy, the aryl is phenyl or naphthyl, the heterocycle The base is pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, 1,3-dioxolyl, dithiocyclopentyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, Morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl or thiaxyl, the heteroaryl is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl ^Azolyl , oxazolyl, oxadiazolyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl ^; each R is independently optionally substituted by one or more R; each e is independently 0, 1 or 2; each f is independently 0, 1 or 2; Each of R ⁵ and R ⁶ is independently H, D, F, Cl, Br, I, CN, NO ₂ , NH ₂ , OH, COOH or C _1-4 alkyl; R ⁴ is C _6-10 aryl, C _6-10 aryl-S(=O) ₂ -, C _1-9 heteroaryl or C _6-10 aryl C _1-4 alkyl, said aryl is phenyl or naphthyl, and the heteroaryl is thiazolyl, thienyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, oxadiazolyl, pyridyl, N -Oxypyridin-2-yl, N-oxypyridin-4-yl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl, furo[3 ,2-c]pyridyl, Furo[3,2-b]pyridyl, Furo[2,3-b]pyridyl, Furo[2,3-c]pyridyl, Benzoxadiazolyl , indolyl, isoindolyl, indazolyl, benzimidazolyl, benzopyrazinyl, benzofuryl, pyridopyrazinyl, 3,4-dihydro-pyridinyl [3,2-b ][1,4]oxazinyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuryl, thieno[3,2-b]pyridyl, thieno[2, 3-c]pyridyl, thieno[2,3-b]pyridyl, 1,4-benzodioxanyl or 1,2,3,4-tetrahydroquinolin-2-yl; R ⁴ any optionally substituted by one or more R ¹⁴ ; Each R ⁷ is independently H, D or C _1-4 alkyl; Each of R ^a and R ^b is independently H, D, F, Cl, Br, I, CN, OH, NO ₂ , NH ₂ , -COOR ^9c , C _1-4 alkyl, -C(=O)-NR ⁹ R ^9a , -C _1-4 alkyl-C(=O)-NR ⁹ R ^9a , -C(=S)-NH ₂ , amino-substituted C _1-4 alkyl, -NH-C(=O )-R ^9b , -C _1-4 alkyl-NH-C(=O)-R ^9b ,-NH-S(=O) ₂ -C _1-4 alkyl,-C _1-4 alkyl-NH -S(=O) ₂ -C _1-4 alkyl, -NH-S(=O) ₂ -C _3-6 cycloalkyl, -C _1-4 alkyl-NH-S(=O) ₂ - C _3-6 cycloalkyl, -S(=O) ₂ -C _1-4 alkyl, -C _1-4 alkyl-S(=O) ₂ -C _1-4 alkyl, C _6-10 aryl Base or C _1-5 heteroaryl, said aryl is phenyl or naphthyl, said heteroaryl is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxa Diazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl; each R and R ^is independently H, OH, CN, F, Cl, Br, I or ^C _1-4 alkyl; Each R ^e and R ^f is independently H, OH or C _1-4 alkyl; Each of R ⁹ , R ^9a and R ^9b is independently H, D, OH, NH ₂ , -S(=O) ₂ -NH ₂ , -C(=O)-NH ₂ , -C _1-4 alkyl- C(=O)-NH ₂ , -C _1-4 alkyl-C(=O)OC _1-4 alkyl, -C _1-4 alkyl-OC(=O)-C _1-4 alkyl, C _1-4 alkyl, -S(=O) ₂ -C _1-4 alkyl, -S(=O) ₂ -C _3-6 cycloalkyl, C _1-4 alkoxy, C _1-4 Alkylamino, C _3-6 cycloalkyl, C _3-6 cycloalkylC _1-4 alkylamino, C _3-6 cycloalkylC _1-4 alkyl, C _3-6 cycloalkyloxy Or C _3-6 cycloalkylamino; or R ⁹ , R ^9a and the nitrogen atom connected to it together form a ring composed of 3-6 atoms; the ring composed of 3-6 atoms, R ⁹ , R ^9a and R ^9b are each independently optionally substituted by one or more R ¹⁵ ; Each R ^9c is independently H, D, -C _1-4 alkyl-C (=O)OC _1-4 alkyl, -C _1-4 alkyl-OC (=O)-C _1-4 alkyl , C _1-4 alkyl or C _6-10 aryl C _1-4 alkyl, the aryl is phenyl or naphthyl; Each R ¹² is independently D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH, C _1-4 alkyl or C _1-4 alkoxy; each R ¹⁴ is independently D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH or C _1-4 alkyl; Each R ¹⁵ is independently D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH, C _1-4 alkyl, C _6-10 aryl, C _1-5 heteroaryl, C _1-5 heteroaryl C _1-4 alkyl or C _3-6 cycloalkylcarbonyl, the aryl is phenyl or naphthyl, the heteroaryl is pyrrolyl, imidazolyl, pyrazolyl, Triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl; and R ¹¹ is H or C _1-4 alkyl. 2. The compound according to claim 1, which is a compound represented by formula (II) or a stereoisomer or a pharmaceutically acceptable salt of the compound represented by formula (II): in: m is 0; R ¹⁰ is H, HOC(=O)-C _1-4 alkyl-, C _1-4 alkoxy-(CH ₂ ) _e -C(=O)-C _1-4 alkyl-, C _{3- 6} Cycloalkyl-(CH ₂ ) _e -NH-C(=O)-C _1-4 Alkyl-, C _1-4 Alkyl-NH-C(=O)-C _1-4 Alkyl-, R ^e R ^f NC(=O)-C _1-4 alkyl-, C _1-5 heteroaryl-C _2-6 heterocyclyl-C(=O)-C _1-4 alkyl-, C _{3 -6} Cycloalkyl-C(=O)-C _2-6 Heterocyclyl-C(=O)-C _1-4 Alkyl-, NH ₂ -C(=O)-C _1-4 Alkyl- , C _1-4 alkyl-OC(=O)-(CR ^c R ^d ) _f -NH-C(=O)-C _1-4 alkyl-, NH ₂ -C(=O)-(CR ^c R ^d ) _f -NH-C(=O)-C _1-4 alkyl-, C _1-4 alkyl-S(=O) ₂ -NH-C(=O)-C _1-4 alkyl- , C _1-4 alkyl-OC(=O)-C _1-4 alkyl-, NH ₂ -S(=O) ₂ -NH-C(=O)-C _1-4 alkyl-, C _{2 -6} heterocyclyl-C(=O)-C _1-4 alkyl-, amino-substituted C _1-4 alkyl, halogenated C _1-4 alkyl, C _1-4 alkyl, C _2-6 Heterocyclyl, C _6-10 aryl C _1-4 alkyl, C _3-6 cycloalkyl or C _3-6 cycloalkyl C _1-4 alkyl, the aryl is phenyl or naphthyl, The heterocyclic group is pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothiophenyl, 1,3-dioxolyl, dithiocyclopentyl, tetrahydropyranyl, tetrahydrothiopyranyl, Piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl or thiaxyl, the heteroaryl is pyrrolyl, imidazolyl, pyrazolyl, tri ^Azolyl , tetrazolyl, oxazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl; R is optionally substituted by ^one or more R; and R ¹¹ is H or C _1-4 alkyl. 3. The compound according to claim 1 or 2, wherein the pharmaceutically acceptable salt is hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, maleate, succinic acid Salt, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, pyruvate, oxalate, glycolate, salicylate, glucuronate, Galacturonate, citrate, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, mesylate, Esylate, triflate, or a combination thereof. 4. The compound according to claim ¹ or 2, wherein R is methyl, ethyl, propyl, isopropyl, halomethyl, haloethyl or halopropyl. 5. The compound according to claim ¹ , wherein each R is independently H, D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , methoxy, ethoxy, propoxy radical, isopropoxy, butoxy, isobutyloxy, tert-butyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethyl Oxygen, Cyclopropylethoxy, Cyclobutylmethoxy, Cyclobutylethoxy, Cyclopentylmethoxy, Cyclopentylethoxy, Cyclohexylmethoxy, Cyclohexylethoxy, Oxa Cyclobutyloxy, tetrahydrofuranyloxy, benzyloxy, phenylethoxy, HOC(=O)-C _1-4 alkoxy-, C _1-3 alkoxy-(CH ₂ ) _e - C(=O)-C _1-4 alkoxy-, C _1-4 alkyl-OC(=O)-C _1-4 alkoxy-, C _2-4 heterocyclyl-C(=O) -C _1-4 alkoxy-, C _1-4 heteroaryl-C _2-4 heterocyclyl-C(=O)-C _1-4 alkoxy-, C _3-6 cycloalkyl-C (=O)-C _2-4 heterocyclyl-C(=O)-C _1-4 alkoxy-, NH ₂ -C(=O)-C _1-4 alkoxy-, NH ₂ -C (=O)-(CR ^c R ^d ) _f -NH-C(=O)-C _1-4 alkoxy-, R ^e R ^f NC(=O)-C _1-4 alkoxy-, C _1-4 Alkyl-OC(=O)-(CR ^c R ^d ) _f -NH-C(=O)-C _1-4 Alkoxy-, NH ₂ -S(=O) ₂ -NH-C (=O)-C _1-4 alkoxy-, C _1-3 alkyl-S(=O) ₂ -NH-C(=O)-C _1-4 alkoxy-, C _3-6 ring Alkyl-(CH ₂ ) _e -NH-C(=O)-C _1-4 alkoxy- or amino-substituted C _1-4 alkoxy, the heterocyclic group is pyrrolidinyl, imidazolidinyl , tetrahydrofuryl, tetrahydrothienyl, 1,3-dioxolyl, dithiocyclopentyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl or thiazolinyl Oxaalkyl, the heteroaryl is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl ; Each R ² is independently optionally substituted by one or more R ¹² ; each R and R ^is independently H, OH, CN, F, Cl, Br, I or ^C _1-3 alkyl; each R ^e and R ^f is independently H, OH or C _1-3 alkyl; and Each ^R12 is independently D, F, Cl, Br, I, CN, NO2, OH, _NH2 , COOH, methyl, ethyl, _propyl , methoxy, ethoxy or propoxy. ^6. The compound according to claim 1 or ² , wherein each R and R are independently H, D, F, Cl, Br, I, NH ₂ , methyl, ethyl, propyl or isopropyl . 7. The compound according to claim ¹ , wherein R is phenyl, naphthyl, thiazolyl, thienyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, oxazolyl Diazolyl, pyridyl, N-pyridin-2-oxide, pyridin-4-yl N-oxide, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl, Furo[3,2-c]pyridyl, Furo[3,2-b]pyridyl, Furo[2,3-b]pyridyl, Furo[2,3-c]pyridyl, Benzo Oxadiazolyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzopyrazinyl, benzofuranyl, pyridopyrazinyl, 3,4-dihydro-pyridinyl[3 ,2-b][1,4]oxazinyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuryl, thieno[3,2-b]pyridyl, thiophene A[2,3-c]pyridyl, Thieno[2,3-b]pyridyl, 1,4-benzodioxanyl, 1,2,3,4-tetrahydroquinolin-2-yl or benzenesulfonyl; R ⁴ is optionally substituted by one or more R ¹⁴ ; and Each ^R14 is independently D, F, Cl, Br, I, CN, NO2, OH, _NH2 , COOH methyl, ethyl, _propyl or isopropyl. 8. The compound according to claim 1 or 2, wherein each R ^a and R ^b are independently H, D, F, Cl, Br, I, CN, OH, NO ₂ , NH ₂ , -COOR ^9c , formazan Base, ethyl, propyl, isopropyl, -C(=O)-NR ⁹ R ^9a , -C(=S)-NH ₂ , aminomethyl, aminoethyl, -C _1-3 alkyl- NH-C(=O)-R ^9b , -C _1-3 alkyl-NH-S(=O) ₂ -C _3-6 cycloalkyl, -C _1-3 alkyl-S(=O) ₂ -C _1-3 alkyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, phenyl, pyridyl or pyrimidinyl; Each of R ⁹ , R ^9a and R ^9b is independently H, D, OH, NH ₂ , -S(=O) ₂ -NH ₂ , -C(=O)-NH ₂ , -C _1-3 alkyl- C(=O)-NH ₂ , -C _1-4 alkyl-C(=O)OC _1-4 alkyl, -C _1-3 alkyl-OC(=O)-C _1-3 alkyl, Methyl, ethyl, propyl, isopropyl, -S(=O) ₂ -C _1-3 alkyl, -S(=O) ₂ -cyclopropyl, -S(=O) ₂ -cyclobutyl radical, -S(=O) ₂ -cyclopentyl, -S(=O) ₂ -cyclohexyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, Ethylamino, Propylamino, Isopropylamino, Cyclopropylmethyl, Cyclobutylmethyl, Cyclopentylmethyl, Cyclopropylmethylamino, Cyclobutylmethylamino, Cyclopentylmethylamino, Cyclopropyloxy radical, cyclobutyloxy, cyclopentyloxy, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or R ⁹ , R ^9a Form a ring composed of 3-6 atoms together with the nitrogen atom connected to it, and the ring composed of 3-6 atoms is azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorph morpholine, 1-oxo-thiomorpholine or 1,1-dioxo-thiomorpholine; the ring consisting of 3-6 atoms, R ⁹ , R ^9a and R ^9b are each independently and optionally One or more R ¹⁵ substitutions; Each R ^9c is independently H, D, -C _1-3 alkyl-C(=O)OC _1-3 alkyl, -C _1-3 alkyl-OC(=O)-C _1-4 alkyl , methyl, ethyl, propyl, isopropyl, benzyl, phenethyl; and Each R ¹⁵ is independently D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH, methyl, ethyl, propyl, phenyl, pyridyl, pyrimidinyl, thiazolyl, thiophene base, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, oxadiazolyl, pyridylmethyl, pyrimidinylmethyl, pyridylethyl, pyrimidinylethyl, benzene Formyl, cyclopropylcarbonyl, cyclobutylcarbonyl or cyclopentylcarbonyl. 9. The compound according to claim 2, wherein R ¹⁰ is H, HOC(=O)-C _1-4 alkyl-, C _1-4 alkoxy-(CH ₂ ) _e -C(=O) -C _1-4 alkyl-, C _3-6 cycloalkyl-(CH ₂ ) _e -NH-C(=O)-C _1-4 alkyl-, C _1-4 alkyl-NH-C( =O)-C _1-4 alkyl-, R ^e R ^f NC (=O)-C _1-4 alkyl-, C _1-5 heteroaryl-C _2-6 heterocyclyl-C(=O )-C _1-4 alkyl-, C _3-6 cycloalkyl-C (=O)-C _2-6 heterocyclyl-C (=O)-C _1-4 alkyl-, NH ₂ -C (=O)-C _1-4 alkyl-, C _1-4 alkyl-OC(=O)-(CR ^c R ^d ) _f -NH-C(=O)-C _1-4 alkyl-, NH ₂ -C(=O)-(CR ^c R ^d ) _f -NH-C(=O)-C _1-4 alkyl-, C _1-4 alkyl-S(=O) ₂ -NH-C (=O)-C _1-4 alkyl-, C _1-4 alkyl-OC(=O)-C _1-4 alkyl-, NH ₂ -S(=O) ₂ -NH-C(=O )-C _1-4 alkyl-, C _2-6 heterocyclyl-C(=O)-C _1-4 alkyl-, amino-substituted C _1-4 alkyl, halogenated C _1-4 alkyl , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, C _2-6 heterocyclyl, C _6-10 aryl C _1-4 alkyl, C _{3 -6} cycloalkyl or C _3-6 cycloalkyl C _1-4 alkyl, the aryl is phenyl or naphthyl, the heterocyclyl is pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydro Thienyl, 1,3-dioxolyl, dithiocyclopentyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, di Oxyalkyl, dithianyl or thiaxyl, the heteroaryl is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, pyridyl, Pyrimidinyl, pyrazinyl or pyridazinyl; R ¹⁰ is optionally substituted by one or more R ¹² ; each R and R ^is independently H, OH, CN, F, Cl, Br, I or ^C _1-3 alkyl; each R ^e and R ^f is independently H, OH or C _1-3 alkyl; and Each R ¹² is independently D, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH, C _1-3 alkyl or C _1-3 alkoxy. 10. The compound according to claim ⁹ , wherein R is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl , Cyclopentyl, Cyclohexyl, Cyclopropylmethyl, Cyclopropylethyl, Cyclobutylmethyl, Cyclobutylethyl, Cyclopentylmethyl, Cyclopentylethyl, Cyclohexylmethyl, Cyclohexylethyl Base, oxetanyl, tetrahydrofuryl, benzyl, phenethyl, HOC(=O)-C _1-4 alkyl-, C _1-3 alkoxy-(CH ₂ ) _e -C(=O )-C _1-4 alkyl-, C _1-4 alkyl-OC (=O)-C _1-4 alkyl-, C _2-4 heterocyclyl-C (=O)-C _1-4 alkane Base-, C _1-4 Heteroaryl-C _2-4 Heterocyclyl-C(=O)-C _1-4 Alkyl-, C _3-6 Cycloalkyl-C(=O)-C _{2- 4} heterocyclyl-C(=O)-C _1-4 alkyl-, NH ₂ -C(=O)-C _1-4 alkyl-, NH ₂ -C(=O)-(CR ^c R ^d ) _f -NH-C(=O)-C _1-4 alkyl-, R ^e R ^f NC(=O)-C _1-4 alkyl-, C _1-4 alkyl-OC(=O)- (CR ^c R ^d ) _f -NH-C(=O)-C _1-4 alkyl-, NH ₂ -S(=O) ₂ -NH-C(=O)-C _1-4 alkyl-, C _1-3 alkyl-S(=O) ₂ -NH-C(=O)-C _1-4 alkyl-, C _3-6 cycloalkyl-(CH ₂ ) _e -NH-C(=O )-C _1-4 alkyl- or amino-substituted C _1-4 alkyl, the heterocyclic group is pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothiophenyl, 1,3-dioxolane Base, dithiocyclopentyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl or thiaxyl, the heteroaryl is pyrrolyl, imidazolyl, pyrrolyl Azolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl; R ¹⁰ is optionally substituted by one or more R ¹² ; each ^R and R ^is independently H, OH, CN, F, Cl, Br, I, methyl, ethyl or propyl; each ^R and R ^is independently H, OH, methyl, ethyl or propyl; and Each ^R12 is independently D, F, Cl, Br, I, CN, NO2, OH, _NH2 , COOH, methyl, ethyl, _propyl , methoxy, ethoxy or propoxy. 11. A compound, which is a compound having one of the following structures or a stereoisomer or a pharmaceutically acceptable salt of a compound having one of the following structures: 12. A pharmaceutical composition comprising the compound of any one of claims 1-11. 13. The pharmaceutical composition according to claim 12, further comprising at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant or vehicle. 14. Use of the compound of any one of claims 1-11 or the pharmaceutical composition of any one of claims 12-13 in the preparation of medicines, wherein the medicines are used for prevention, treatment, treatment or alleviation Diseases associated with phosphodiesterase type 4 PDE4. 15. The use according to claim 14, wherein the disease related to phosphodiesterase type 4 PDE4 is respiratory disease, allergy and inflammation, central nervous system CNS disease, pulmonary fibrosis or non-insulin dependent diabetes. 16. The use according to claim 15, wherein said respiratory disease is: chronic respiratory obstruction COPD, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchiectasis, pulmonary tuberculosis fibrosis, pulmonary cystic fibrosis , acute respiratory distress syndrome ARDS or airway inflammation. 17. The use according to claim 16, wherein the airway inflammation is bronchitis. 18. The use according to claim 17, wherein the bronchitis is chronic bronchitis, allergic bronchitis, diffuse panbronchiolitis or bronchiolitis obliterans. 19. The use according to claim 15, wherein said inflammation is: allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, allergic rhinitis, ulcer colitis, ankylosing spondylitis, rheumatoid arthritis, or psoriatic arthritis.