CN119798282A - Myt1 inhibitors based on fused pyridine rings - Google Patents

Abstract

The present invention provides a compound of formula (I): wherein ring A, ring B, ring C, Y, R _A、R_B、R_C, m, n, p, and q are as disclosed in the specification. The invention also provides pharmaceutical compositions comprising compounds of formula (I) as inhibitors of Myt1 and methods of use thereof.

Description

Fused pyridine ring-based Myt1 inhibitors

Technical Field

The present invention relates to methods of using inhibitors of membrane-associated tyrosine and threonine-specific cdc2 inhibitory kinases (Myt 1) (gene name PKMYT) e.g., for the treatment of diseases or disorders such as cancer, in particular, diseases or disorders dependent on Myt1 activity (e.g., cancers with CCNE1 amplification/overexpression or FBXW7 mutations). In particular, the present invention relates to fused pyridine ring based Myt1 inhibitors, pharmaceutical compositions comprising the compounds and methods of use thereof.

Background

DNA is continually damaged either internally (e.g., stagnant replication forks, reactive oxygen species) or externally (uv, ionizing radiation, chemicals) which may cause DNA damage. To address these potential hazards, cells evolve complex mechanisms to counteract these adverse events to prevent them from compromising genome integrity and thereby causing genome-unstable diseases, such as cancer. These mechanisms are collectively known as the DNA Damage Response (DDR).

One component of the entire DDR is the activation of various checkpoint pathways that regulate specific DNA repair mechanisms at various stages of the cell cycle, including G1, S, G and mitotic checkpoints. Most cancer cells have lost the G1 checkpoint due to p53 mutations, and therefore rely on the G2 checkpoint for necessary DNA damage correction before entering mitosis and dividing into 2 sub-cells.

PKMYT1 inhibit the progression of the cell cycle and drive the progression of various tumors by inhibiting the activity of cyclin-related proteins such as cyclin A, CDK1 and CDK 2.

Inhibitory phosphorylation of cdc2 is important for the time to entry into mitosis. Phosphorylation of cdc2 at Tyr-15 and Thr-14 inhibits premature entry into mitosis during the intervals (G1, S and G2). Upon G2-M transition, cdc2 dephosphorylates at Tyr-15 and Thr-14, allowing mitosis to proceed.

Studies have shown that premature activation of cdc2 can lead to mitotic disasters and cell death. Myt1 is an important cell cycle regulator, especially in the G2/M phase. Inhibition of Myt1 is expected to lead to premature activation of cdc2, killing rapidly proliferating cells. Furthermore, myt1 inhibition is expected to reduce resistance to traditional chemotherapeutics, as the mechanism by which cells avoid death involves arrest in the G2 phase of the cell cycle, as well as pre-division repair or DNA damage. This arrest is prevented by blocking Myt 1-inhibitory phosphorylation of cdc2, forcing the cells to enter mitosis prematurely. Myt1 provides an intervention point to inhibit the development of chemotherapy drug resistance by tumor cells through this mechanism. Summarizing, inhibition of Myt1 may itself have therapeutic benefit in reducing tumor proliferation, and furthermore, may be used in combination with conventional chemotherapy to overcome resistance.

Thus, there is a need to develop an effective Myt1 kinase inhibitor for the treatment of cancer, in particular therapies that allow for targeted cancer treatment.

Disclosure of Invention

One aspect of the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate, hydrate or isotopically-labeled compound thereof:

Wherein ring A, ring B, ring C, Y, R _A、R_B、R_C, m, n, p, and q are as defined in the specification.

Another aspect of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate or hydrate thereof, and one or more pharmaceutically acceptable carriers or excipients thereof. The pharmaceutical composition of the invention is useful as an inhibitor of Myt 1.

Another aspect of the invention is to provide the use of a compound of formula (I) or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate or hydrate thereof in the manufacture of a medicament for use as a Myt1 inhibitor.

Another aspect of the invention is to provide a method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate, or hydrate thereof, to inhibit the growth of cancer in the subject. The compounds of formula (I) may be used alone or in combination with another therapeutic agent and/or therapy.

Detailed Description

The invention may be understood more readily by reference to the following detailed description of various embodiments, examples and tables having associated descriptions of the invention. Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition, it will be understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

Definition of the definition

The definitions set forth in this section are intended to clarify the terminology used throughout the present application. The term "herein" means the entire application.

It must be noted that, as used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Accordingly, unless otherwise required herein, singular terms shall include the plural and plural terms shall include the singular.

Generally, ranges are expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, one embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment. In addition, it is understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. As used herein, the term "about" refers to ± 20%, preferably ± 10% and even more preferably ± 5%.

As used herein, the term "optionally substituted" means that the substitution is optional. Where substitution is desired, such substitution means that any number of hydrogens on the designated atom are replaced with an option from the designated group, with the proviso that the normal valency of the designated atom is not exceeded, and the substitution results in a stable compound. For example, when the substituent is a keto group (i.e., =o), then 2 hydrogens on the atom are replaced. Examples of substituents for a "substituted" group are those present in the exemplary compounds and embodiments disclosed herein and may include, for example, halo, cyano, alkyl, alkoxy, haloalkyl, alkylamino, aminoalkyl, dialkylamino, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, alkylaminoalkoxy, alkylaminoalkyl, and the like.

As used herein, the term "halo" includes fluoro, chloro, bromo and iodo. "halo" as a prefix of a group means that one or more hydrogens on the group are replaced with one or more halogens.

The term "alkyl" as used herein refers to a monovalent, saturated, straight or branched hydrocarbon radical containing from 1 to 12 carbon atoms. Preferably, the alkyl is a C ₁-C₈ alkyl. More preferably, the alkyl is a C ₁-C₆ alkyl. Alkyl groups may be unsubstituted or substituted with one or more substituents. Examples of C ₁-C₆ alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms), heptyl (including all isomeric forms), octyl (including all isomeric forms), and the like.

The term "alkoxy" used alone or as a suffix or prefix, refers to a group of the general formula-O- (alkyl), wherein alkyl is defined above. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.

As used herein, the term "alkenyl" refers to an acyclic monovalent straight or branched hydrocarbon radical containing one, two, or three carbon-carbon double bonds. Non-limiting examples of alkenyl groups include vinyl, prop-1-enyl, prop-2-enyl, 1-methylvinyl, but-1-enyl, but-2-enyl, but-3-enyl, 1-methylprop-1-enyl, 2-methylprop-1-enyl and 1-methylprop-2-enyl. Alkenyl groups may be optionally substituted as defined herein for alkyl groups.

"Amine groups" used as a prefix or suffix to a group means that one or more hydrogens on the group are replaced with one or more amine groups.

As used herein, the term "alkylamino" refers to a group having the formula-N (RN 1) 2 or-NHRN 1, wherein RN1 is alkyl as defined herein. The alkyl portion of the alkylamino group may be optionally substituted as defined for the alkyl group. Each optional substituent on the substituted alkylamino group may be unsubstituted per se or, if the valency permits, substituted with an unsubstituted substituent as defined herein for each corresponding group.

As used herein, the term "fused" refers to rings that share a covalent bond. Fused bicyclic compounds refer to two rings sharing two adjacent atoms. Examples of fused bicyclic rings include, for example, fused bicyclic aryl, heterocyclyl or heteroaryl

The term "cycloalkyl" as used herein, unless otherwise indicated for the number of rings, refers to saturated monovalent hydrocarbon radicals having a cyclic configuration, including monocyclic, bicyclic, tricyclic, and higher polycyclic alkyl radicals (and fused and bridged bicyclic and spiro moieties when polycyclic), wherein each cyclic moiety has from 3 to 12 carbon atoms. Preferably, cycloalkyl groups have 3 to 8 carbon atoms. More preferably, cycloalkyl groups have 3 to 6 carbon atoms. When cycloalkyl contains more than one ring, the rings may be fused or unfused and include bicyclic groups. Fused rings generally refer to at least two rings sharing two atoms therebetween. Such cycloalkyl groups include, for example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, or bicyclic, polycyclic, or bridged ring structures such as adamantyl and the like.

Unless otherwise indicated for the number of rings, the term "aryl" means a monovalent 6 to 14 membered mono-or bi-carbocyclic ring, wherein the monocyclic ring is an aromatic ring and at least one of the rings in the bicyclic ring is an aromatic ring. Representative examples include, but are not limited to, phenyl, biphenyl, naphthyl, indenyl, and the like.

Unless otherwise indicated by the number of rings, "heteroaryl" means a monovalent group of 5 to 14 ring atoms of a single ring, a fused double ring, or a fused triple ring containing one or more, for example, one, two, three, or four ring heteroatoms independently selected from the group consisting of: -O-, -S (O) _n - (N is 0,1 or 2), -N-, -N (R ^x) -, and the remaining ring atoms are carbon, wherein the ring comprising the monocyclic group is an aromatic ring and wherein at least one of the fused rings comprising the bicyclic or tricyclic group is an aromatic ring. One or both ring carbon atoms of any non-aromatic ring comprising a bi-or tri-cyclic group may be replaced by a-C (O) -, -C (S) -or-C (=nh) -group. R ^x is hydrogen, alkyl, hydroxy, alkoxy, acyl or alkylsulfonyl. Fused bicyclic groups include bridged ring systems. Unless otherwise indicated, the valences may be located on any atom of any ring of the heteroaryl group, as allowed by the valency rules. In particular, R ^x is absent when the valence position is on the nitrogen. More specifically, the term "heteroaryl" includes, but is not limited to, benzocyclopentylalkyl, 2, 3-dihydrobenzofuranyl, 2, 3-dihydrofuro [3,2-b ] pyridine, 2, 3-dihydrofuro [3,2-c ] pyridine, 6, 7-dihydro-5H-cyclopenta [ b ] pyridine, chromanyl, isochromanyl, 3, 4-dihydro-2H-pyrano [2,3-b ] pyridine, 5, 8-dihydro-6H-pyrano [3,4-b ] pyridine, 1,3,4, 5-tetrahydrobenzo [ c ] oxacil, indanyl, phthalyl, indolinyl, 1,2, 4-triazolyl, oxa1, 3, 5-triazolyl, Phthalimidyl, pyridyl, pyrrolyl, imidazolyl, thienyl, furyl, indolyl, 2, 3-dihydro-1H-indolyl (including, for example, 2, 3-dihydro-1H-indol-2-yl or 2, 3-dihydro-1H-indol-5-yl and the like), isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, benzodioxol-4-yl, benzofuranyl, cinnolinyl, indolizinyl, naphthyridin-3-yl, phthalazin-4-yl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, tetrazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, Isoxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl (including, for example, tetrahydroisoquinolin-4-yl or tetrahydroisoquinolin-6-yl, etc.), pyrrolo [3,2-c ] pyridinyl (including, for example, pyrrolo [3,2-c ] pyridin-2-yl or pyrrolo [3,2-c ] pyridin-7-yl, etc.), benzopyranyl, thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl, benzothienyl, and derivatives, or N-oxides or protected derivatives thereof.

Unless otherwise indicated for the number of rings, "heterocyclyl" means a saturated or partially unsaturated monovalent monocyclic group of 3 to 9 ring atoms or a saturated or partially unsaturated monovalent fused bicyclic group of 5 to 12 ring atoms in which one or more, e.g., one, two, three or four, ring heteroatoms are independently selected from the group consisting of-O-, -S (O) _x - (x is 0,1 or 2), -n=, -N (R ^y) - (wherein R ^y is hydrogen, alkyl, hydroxy, alkoxy, acyl or alkylsulfonyl) and the remaining ring atoms are carbon. One or both ring carbon atoms may be replaced by a-C (O) -, -C (S) -or-C (=nh) -group. As used herein, the term "heterocyclyl" means a monocyclic, bicyclic, tricyclic or tetracyclic ring system having fused, bridged and/or spiro 3-, 4-, 5-, 6-, 7-or 8-members, unless otherwise indicated, a ring containing one, two, three or four heteroatoms independently selected from nitrogen, oxygen and sulfur. Fused bicyclic groups include bridged ring systems. Unless otherwise indicated, the valences of a group may be located on any atom of any ring within the group, as allowed by the valency rules. In particular, R ^y is absent when the valence position is on a nitrogen atom. More specifically, the term "heterocyclyl" includes, but is not limited to, piperidinyl, pyrimidinyl, morpholinyl, piperazinyl, azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 2, 5-dihydro-1H-pyrrolyl, 4-piperidonyl, 2-oxopiperazinyl, tetrahydropyranyl, 2-oxopiperidinyl, thiomorpholinyl, perhydro azepinyl, pyrazolidinyl, dihydroimidazolyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidine, quinuclidinyl, isothiazolidinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, tetrahydrofuranyl, and tetrahydropyranyl, and derivatives thereof, as well as N-oxides or protected derivatives thereof.

As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of the disclosed compounds wherein the parent compound is modified by preparing a pharmaceutically acceptable acid or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues (e.g., amines), alkali metal or organic salts of acidic residues (e.g., carboxylic acids), and the like. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts formed from the parent compound with, for example, a non-toxic inorganic or organic acid. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. Non-limiting examples of salts of the compounds of the present invention include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethanesulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, butyrate, camphoric acid salt, camphorsulfonate, citrate, digluconate, glycerophosphate, hemisulfate, heptanoate, caproate, formate, succinate, malonate, fumarate, maleate, methanesulfonate, mesitylene sulfonate, naphthalenesulfonate, nicotinate, oxalate, pamoate, pectate, persulfate, 3-phenylpropionate, bittering, trimethylacetate, propionate, trichloroacetate, trifluoroacetate, glutamate, bicarbonate, undecanoate, lactate, citrate, tartrate, gluconate, benzenesulfonate, and p-toluenesulfonate.

As used herein, the term "geometric isomers" includes, but is not limited to, cis and trans, E-and Z-formulas, c-, t-and R-formulas, internal and external formulas, R-, S-and meso formulas, boat, chair, twist, envelope, and half chair formulas, and combinations thereof.

As used herein, the term "enantiomer" refers to a pair of stereoisomers that are non-overlapping mirror images of each other. The 1:1 mixture of a pair of enantiomers is a racemic mixture. The term "enantiomer" is used to refer to a racemic mixture where appropriate. "diastereoisomers" are stereoisomers having at least two atoms that are not mirror images of each other. Absolute stereochemistry may be specified according to the Cahn-Ingold-PrelogR-S system. When the compound is a pure enantiomer, the stereochemistry at each chiral carbon may be specified by R or S. The resolved compound may be represented as (+) or (-) depending on the direction in which it rotates the plane polarization (right-hand or left-hand) at the wavelength of the sodium D-line. Certain compounds described herein may contain one or more asymmetric centers or axes, and may thus produce enantiomers, diastereomers, and other stereoisomeric forms, which may be defined as (R) -or (S) -, in terms of absolute stereochemistry. The present invention is intended to include all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R) -and (S) -isomers can be prepared using chiral synthetic components 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 cycloalkyl substituent may have a cis or trans configuration.

As used herein, the term "tautomer" refers to the fact that compounds may exist at different points of hydrogen attachment. Examples are ketones and their enol forms, known as keto-enol tautomers. Individual tautomers and mixtures thereof are encompassed by the present invention.

As used herein, "prodrug" is intended to include any covalently bound carrier that releases the active parent drug according to formula I via in vivo physiological effects (e.g., hydrolysis, metabolism, etc.) upon administration of such prodrug to a subject. The suitability and techniques for use in preparing and using prodrugs are well known to those of ordinary skill in the art. Prodrugs of compounds of formula (I) (parent compounds) may be prepared by modifying functional groups present in the compounds in such a way that the variants cleave into the parent compounds in conventional procedures or in vivo. "prodrugs" include compounds of formula (I) wherein a hydroxy, amine, or sulfhydryl group is bonded to any group that, when the prodrug is administered to a subject, cleaves to form a free hydroxy, free amine, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, derivatives and metabolites of compounds of formula (I) including biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. In particular embodiments, the prodrugs of compounds of formula (I) having a carboxy functional group are lower alkyl (e.g., C1-C6) esters of carboxylic acids. The carboxylic acid esters are preferably formed by esterifying any carboxylic acid moiety present on the molecule.

As used herein, the term "solvate" means a compound or a pharmaceutically acceptable salt thereof that further includes a stoichiometric or non-stoichiometric combination of solvents by non-covalent intermolecular forces. If the solvent is water, the solvate may be advantageously referred to as a "hydrate," such as a hemihydrate, a monohydrate, a sesquihydrate, a dihydrate, a trihydrate, and the like.

As used herein, the term "Myt1 inhibitor" refers to a compound that reduces Myt1 activity after exposure to the enzyme Myt1 (whether in vitro, in cell culture, or in an animal) such that the measured Myt1 IC50 is 10mM or less (e.g., 5mM or less or 1mM or less).

For certain Myt1 inhibitors, the Myt1 IC50 may be 100nM or less (e.g., 10nM or less, or 3nM or less) and may be as low as 100pM or 10pM. Preferably, the Myt1 IC50 is 1nM to 1mM (e.g., 1nM to 750nM, 1nM to 500nM, or 1nM to 250 nM).

Even more preferably, myt1 IC50 is less than 20nM (e.g., 1nM to 20 nM)

As used herein, "treatment" refers to the medical management of a subject for the purpose of ameliorating, improving, stabilizing, preventing, or curing a disease or disorder.

The term includes active treatment (treatment intended to ameliorate a disease or condition), causal treatment (treatment for a cause of a related disease or condition), palliative treatment (treatment intended to alleviate symptoms of a disease or condition), prophylactic treatment (treatment intended to reduce or partially or fully inhibit the development of a related disease or condition), and supportive treatment (treatment for supplementing another treatment).

Compounds of formula (I)

1. The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate, hydrate or isotopically labeled compound thereof,

Wherein:

Ring a is a 5-7 membered monocyclic aryl, heterocyclyl or heteroaryl group or an 8-11 membered fused bicyclic aryl, heterocyclyl or heteroaryl group;

Ring B is a 5-6 membered monocyclic aryl, heterocyclyl or heteroaryl group;

ring C is a 5-7 membered monocyclic aryl, heterocyclyl or heteroaryl group or an 8-11 membered fused bicyclic aryl, heterocyclyl or heteroaryl group;

R _A is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, halogen, hydroxy, oxo, cyano or amino;

R _B is hydrogen, C1-C6 alkyl, halogen, hydroxy, oxo, cyano or amino;

R _C is L-Q-R ₁, hydrogen, halogen, hydroxy, oxo, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH (C1-C6 alkyl), -N (C1-C6 alkyl), C3-C6 cycloalkyl, C1-C6 haloalkyl, -O- (C1-C6 haloalkyl), -NH- (C1-C6 haloalkyl), -N (C1-C6 haloalkyl), sulfur pentafluoride, C1-C6 haloalkoxy or halocycloalkyl, -NH-S (O) ₂ - (C1-C6 alkyl), -NHP (=O) - (C1-C6 alkyl), -NHC (O) - (C1-C6 alkyl), -NH- (C1-C6 alkyl), -S (O) ₂ - (C1-C6 alkyl), -P (=34-C6 alkyl);

l is a direct bond, O or NH;

q is absent, a direct bond or C1-C6 alkyl;

R ₁ is C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclyl containing one or two heteroatoms selected from N, O, S, wherein alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or two substituents R ₂;

R ₂ is C1-C6 alkyl, halogen, hydroxy, oxo, cyano, amino, - (C=O) (C1-C6 alkyl) or-N (C1-C6 alkyl);

Y is O, CR ₃、CR₃R₄, N or NH;

R ₃ and R ₄ are independently hydrogen, C1-C6 alkyl, halogen, hydroxy, oxo, cyano or amino, or R ₃ and R ₄ attached to the same carbon atom together with the carbon atom to which they are attached form a C3-C7 cycloalkyl group, or R ₃ and R ₄ attached to different carbon atoms together with the carbon atom to which they are attached form a C3-C7 cycloalkyl group;

m is 1, 2, 3 or 4;

n is 0 or 1;

p is 1, 2 or 3;

q is 1 or 2.

2. In some embodiments, wherein q is 1 and y is CR ₃R₄;R₃、R₄ as defined in 1.

3. In some embodiments, wherein q is 1 and y is NH.

4. In some embodiments, wherein q is 2, Y is CR ₃ or N, and R ₃ is as defined in 1.

5. In some embodiments, wherein q is 2 and y is CR ₃R₄;R₃、R₄ as defined in claim 1.

6. In some embodiments, wherein ring B is a 5-6 membered heteroaryl containing at least one N atom.

7. In some embodiments, wherein ring B is thiazole or pyridine.

8. In some embodiments, wherein ring a is selected from phenyl, a 5-6 membered heteroaryl containing at least one N atom, or an 8-11 membered fused bicyclic heteroaryl containing at least two N atoms.

9. In some embodiments, wherein ring a is selected from phenyl, a 6 membered heteroaryl containing at least one N atom, or a 9 membered fused bicyclic heteroaryl containing at least two N atoms.

10. In some embodiments, wherein ring a is selected from R _A, m are as defined in 1.

11. In some embodiments, wherein ring a is selected from R _A1、R_A2、R_A3、R_A4、R_A5 and R _A6 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, halogen, hydroxy, oxo, cyano or amino.

12. In some embodiments, wherein ring a isR _A1 and R _A2 are methyl.

13. In some embodiments, wherein ring a isR _A1、R_A2 is methyl, and R _A3 is halogen.

14. In some embodiments, wherein ring a isR _A5 is methyl.

15. In some embodiments, wherein ring a is selected from

16. In some embodiments, wherein ring C is a 5-7 membered monocyclic heteroaryl or an 8-11 membered fused bicyclic heteroaryl containing at least two N atoms.

17. In some embodiments, wherein ring C is a 9-membered fused bicyclic heteroaryl containing at least two N atoms.

18. In some embodiments, wherein ring C is selected from

R _C, p are as defined in 1.

19. In some embodiments, wherein R _C is selected from the group consisting of-CH ₃、-CH₂CH₃、-CH₂CF₃,

20. In some embodiments, wherein the compound of formula (I) is selected from:

pharmaceutical compositions, uses and methods

The compounds of the invention may be administered therapeutically as pure chemicals, but may be suitable for administration of the compounds as pharmaceutical compositions or formulations. Accordingly, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, prodrug or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients.

In some embodiments, the use of a compound of formula (I), or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, prodrug, or solvate thereof, is for the manufacture of a medicament for treating cancer in a subject in need thereof.

In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, prodrug, or solvate thereof, is administered to the subject in combination with a second anticancer agent, surgical therapy, ionizing radiation, or combination thereof.

The pharmaceutical composition may be administered in a variety of dosage forms including, but not limited to, solid or liquid dosage forms, oral dosage forms, parenteral dosage forms, intranasal dosage forms, suppositories, buccal tablets, dragees, buccal, controlled release dosage forms, pulsatile release dosage forms, immediate release dosage forms, intravenous solutions, suspensions, or combinations thereof. The compounds may be administered, for example, by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, respiratory (aerosol), rectal, vaginal and topical (including buccal and sublingual) administration.

In one embodiment of the invention, the compound of formula (I) is administered orally. For oral administration, the compounds will typically be provided in unit dosage forms suitable for ingestion by an individual as tablets, pills, dragees, lozenges or capsules, as powders or granules, or as aqueous solutions, suspensions, liquids, gels, syrups, slurries and the like. The dosage form may be a controlled release dosage form formulated as a tablet or a tablet. Tablets for oral use may include the active ingredient in admixture with one or more pharmaceutically acceptable excipients.

"Excipient" generally refers to a substance, typically an inert substance, added to a pharmacological composition or otherwise used as a vehicle to further aid in the administration of a compound. Examples of excipients include, but are not limited to, inert diluents, disintegrants, binders, lubricants, sweeteners, flavoring agents, coloring agents, preservatives, foaming mixtures and adsorbents. Suitable inert diluents include, but are not limited to, sodium and calcium carbonate, sodium and calcium phosphate, lactose, and the like. Suitable disintegrants include, but are not limited to, starches (e.g., corn starch), cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof (e.g., sodium alginate), and the like. The binder may include, but is not limited to, magnesium aluminum silicate, starch (e.g., corn, wheat, or rice starch), gelatin, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, and the like. The lubricant, if present, is typically magnesium stearate and calcium stearate, stearic acid, talc or hydrogenated vegetable oil. If desired, the tablets may be overcoated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract. The compositions may also be formulated into chewable tablets, for example, by using a substance such as mannitol in the formulation.

Pharmaceutical compositions for oral use can be obtained by combining a compound of formula (I) with a solid excipient, optionally grinding the resulting mixture, and processing the mixture particles after adding suitable other compounds (if desired) to obtain tablets or dragee cores. Suitable solid excipients include, in addition to those previously mentioned, carbohydrate or protein fillers including, but not limited to, sugars including lactose, sucrose, mannitol or sorbitol, starches from corn, wheat, rice, potato or other plants, celluloses such as methylcellulose, hydroxypropyl methylcellulose or sodium carboxymethyl cellulose, and gums including acacia and tragacanth, and proteins such as gelatin and collagen.

Capsules for oral use include hard gelatin capsules wherein the active ingredient is mixed with a solid diluent and soft gelatin capsules wherein the active ingredient is mixed with water or an oil, such as peanut oil, liquid paraffin or olive oil.

Dragee cores have a suitable coating. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol Mo Ningjiao (carbopolgel), polyethylene glycol and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings to identify or characterize different combinations of active compound doses.

The pharmaceutical composition may also comprise a suitable solid or gel phase carrier. Examples of such carriers include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

Compounds and pharmaceutical compositions suitable for use in the present invention include compounds and pharmaceutical compositions in which the active ingredient is administered in an amount effective to achieve its intended purpose. The term "therapeutically effective amount" refers to the case in which the amount of a compound of formula (I), or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, prodrug or solvate thereof, alone or in combination with ionizing radiation or an anticancer agent, provides the desired effect in the subject being treated when administered in single or multiple doses to the subject. Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., determining the IC ₅₀ value. As used herein, "IC ₅₀" refers to the concentration of an agent at which the agent may produce 50% of the maximum inhibition response.

The actual amount of the compound of formula (I) administered will be determined by the physician under relevant conditions, including the condition to be treated, the size and type of neoplasia, the route of administration selected, the actual compound of the invention administered, the hedgehog pathway modulator, the timing of administration relative to other therapies, the type, species, age, weight, sex and medical condition of the individual, the renal and hepatic function of the individual, and the severity of the symptoms of the individual. Achieving optimal accuracy in producing drug concentrations within the efficacy range requires a regimen based on the kinetics of drug availability to the target site. This involves taking into account the distribution, equilibration and elimination of the drug. In some cases, dosage levels below the lower limit of the aforementioned range may be in excess of a sufficient amount, while in other cases still larger dosages may be employed.

By "individual" to be treated by the methods of the invention is meant a human or non-human animal, such as primates, mammals, and vertebrates.

By "in vivo" is meant within a living individual, such as within an animal or human. In this context, the agent may be used therapeutically in vivo to delay or eliminate proliferation of abnormally replicating cells. The agent may also be used in vivo as a prophylactic agent to prevent abnormal cell proliferation or manifestation of symptoms associated therewith.

By "in vitro" is meant outside of a living individual. Examples of in vitro cell populations include cell cultures and biological samples, such as fluid or tissue samples from humans or animals. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine and saliva. Exemplary tissue samples include tumors and biopsies thereof. In this context, the compounds of the present invention may find application in a variety of therapeutic and experimental applications.

The invention also relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, prodrug or solvate thereof for the manufacture of a medicament for modulating the hedgehog pathway.

Furthermore, the present invention relates to a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, prodrug or solvate thereof.

"Cancer" refers to a cell proliferative disease state including, but not limited to, heart cancers such as sarcomas (e.g., hemangiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas, and teratomas, lung cancers such as bronchogenic cancers (e.g., squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, and adenocarcinoma), alveolar cancers (e.g., bronchiolar carcinoma), bronchogenic adenomas, sarcomas, lymphomas, chondromiso-and mesotheliomas, gastrointestinal cancers such as esophageal cancers (e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma), gastric cancers (e.g., lymphoma and leiomyosarcoma), gastric cancers (e.g., lymphomas and leiomyosarcoma), bronchogenic cancers, Pancreatic cancer (e.g., ductal adenocarcinoma, insulinoma, glyconoma, gastrinoma, carcinoid and vasoactive intestinal peptide tumor), small intestine cancer (e.g., adenocarcinoma, lymphoma, carcinoid, karposi's sarcoma, smooth myoma, hemangioma, lipoma, neurofibroma and fibroma), large intestine cancer (e.g., adenocarcinoma, tubular adenoma, villous adenoma, hamartoma and smooth myoma), genitourinary tract cancer such as kidney cancer (e.g., adenocarcinoma, wilms ' stumor) [ Wilm ' stumor ] kidney cell tumor, lymphoma and leukemia), bladder and urinary tract cancer (e.g., squamous cell carcinoma, Transitional cell carcinoma and adenocarcinoma), prostate cancer (e.g., adenocarcinoma and sarcoma), testicular cancer (e.g., sperm cell carcinoma, teratoma, embryonal tumor, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors and lipoma), liver cancer such as liver cancer (e.g., hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatoblastoma and hemangioma, bone cancer such as osteogenic sarcoma (e.g., osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, ewing's sarcoma), malignant lymphoma (e.g., reticulosarcoma), hepatoma, Multiple myeloma, malignant giant cell tumor chordoma, osteochondral tumor (e.g., osteochondral exogenesis warts), benign chondria, chondroblastoma, cartilage myxofibroma, osteoid tumor and giant cell tumor, cancers of the nervous system such as craniocerebral cancers (e.g., osteoma, hemangioma, granuloma, xanthoma and osteomyelitis deformity), meningioma (e.g., meningioma and gliosis), brain cancers (e.g., astrocytoma, medulloblastoma, neuroglioma, ependymoma, blastoma (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma and congenital tumor), meningioma, and the like, Spinal neurofibromas, meningiomas, neurogliomas, and sarcomas, gynaecological cancers such as uterine cancers (e.g., endometrial cancers), cervical cancers (e.g., cervical cancers and pre-neoplastic cervical dysplasias), ovarian cancers (e.g., ovarian cancers [ e.g., serous cystic adenocarcinoma, bursal adenocarcinoma, and categorical unknown cancers ], granulosa cell tumors, shi Tuoli-lediglobular tumors (seltoli-LEYDIG CELL tumor), asexual cell tumors, and malignant teratomas), vulvar cancers (e.g., squamous cell carcinoma, intraepithelial cancers, adenocarcinoma, fibrosarcoma, and melanoma), vaginal cancers (e.g., clear cell carcinoma, vaginal cancer, Squamous cell carcinoma, botryoid sarcoma [ e.g., embryonal rhabdomyosarcoma ] and fallopian tube carcinoma), hematological cancers such as hematological cancers (myeloleukemia [ acute and chronic ], acute lymphoblastic leukemia, chronic lymphoblastic leukemia, myeloproliferative diseases, multiple myeloma and myelodysplasia), hodgkin's disease, non-Hodgkin's lymphoma [ malignant lymphoma ], skin cancers such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, cutaneous fibromas, keloids, psoriasis, adrenal gland cancers such as neuroblastoma, or breast cancer.

The compounds of formula (I) may be administered as the sole active agent or in combination with other known cancer therapies.

The term "concurrently" means that the compounds of formula (I) may be administered shortly before, shortly after, simultaneously with or any combination of the immediately before, shortly after or simultaneously with one or more other anti-tumor therapies. Thus, the compound of formula (I) and the second anticancer agent may be administered as a single composition or simultaneously as two separate compositions or sequentially as two separate compositions. Likewise, the compound of formula (I) may be administered simultaneously, separately or sequentially with chemotherapy or ionizing radiation. Those skilled in the art will appreciate that the amount of the compound of formula (I) administered with an anti-cancer therapy is preferably an amount sufficient to enhance the effect of the anti-cancer therapy or an amount sufficient to induce apoptosis or cell death with the anti-cancer therapy to maintain anti-angiogenic effect.

The term "second anticancer agent" as used herein refers to an agent capable of inhibiting or preventing the growth of a tumor or detecting the maturation and proliferation of malignant (cancerous) cells, unless otherwise specified. Second anticancer agents suitable for use in combination with the compounds of formula (I) include, but are not limited to, targeted cancer drugs such as trastuzumab, ramucizumab (ramucirumab), bevacizumab, everolimus (everolimus), tamoxifen (tamoxifen), toremifene (toremifene), fulvestrant (fulvestrant), anastrozole (anastrozole), exemestane, lapatinib (lapatinib), and combinations thereof, Letrozole (letrozole), pertuzumab (pertuzumab), adotrastuzumab Shan Kangen tamoxifen (ado-trastuzumabemtansine), parpoxib (palbociclib), cetuximab (cetuximab), panitumumab (panitumumab), zafirabi (ziv-aflibept), regorafenib (regorafenib), imatinib mesylate (lmatinibmesylate), lanreotide acetate (lanreotideacetate), Sunitinib, regorafenib (regorafenib), denoniab, aliskiric acid (alitretinoin), sorafenib (sorafenib), pazopanib (pazopanib), temsirolimus (temsirolimus), everolimus (everolimus), tretinoin (tretinoin), dasatinib (dasatinib), nilotinib (nilotinib), bosutinib (bosutinib), Rituximab, alemtuzumab, ofatumumab, obatumumab (obinutuxumab), ibrutinib (ibrutinib), ai Dexi cloth (idelalisib), brinzumab (blinatumomab), su Lani cloth (soragenib), crizotinib (crizotinib), erlotinib (erlotinib), gefitinib (gefitinib), afatinib dimaleate (afatinibdimaleate), and, Christinib (ceritnib), ramucirumab (ramucirumab), nivolumab, pembrolizumab (pembrolizumab), octeninib (osimertinib) and Leishmaniab (necitumumab), alkylating agents such as busulfan (busulfan), chlorambucil, cyclophosphamide, ifosfamide, melphalan (melphalan), nitrogen mustard, streptozotocin, thiotepa (thiotepa), uracil nitrogen mustard, triethylmelamine, temozolomide (temozolomide) and 2-chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU), antibiotics or plant bases such as actinomycin-D, Bleomycin, candidiasis, daunomycin (daunorubicin), rubus parcels (doxorubicin), idamycin (idarubicin), irinotecan (irinotecan), L-asparaginase (L-ASPARAGINASE), mitomycin-C (mitomycin-C), mithramycin (mitramycin), noveltine (navlbine), paclitaxel (paclitaxel), docetaxel (docetaxel), topotecan (topotecan), Vinblastine (vinblastine), vincristine (vincristine), teniposide (teniposide) (VM-26) and etoposide (etoposide) (VP-16), hormones or steroids such as 5α -reductase inhibitors, aminoglutethimide (aminoglutethimide), anastrozole (anastrozole), bicalutamide (bicalutamide), chlorotriarene, diethylstilbestrol (diethylstilbestrol) (DES), drotaandrosterone (dromostanolone), Estramustine (estramustine), ethinyl estradiol, flutamide (flutamide), fluoxymesterone (fluoxymesterone), goserelin (goserelin), hydroxyprogesterone, letrozole, leuprolide (leuprolide), medroxyprogesterone acetate (medroxyprogesterone acetate), megestrol acetate (megestrol acetate), methylprednisolone (methylprednisolone), and pharmaceutical compositions, methyltestosterone (methyltestosterone), mitotane (mitotane), nilamide (nilutamide), prednisolone (prednisolone), arzoxifene (SERM-3), tamoxifen (tamoxifen), testosterone (testolactone), testosterone (testosterone), triamcinolone (triamicnolone) and norrad (zoladex), synthetic formulations such as all-trans retinoic acid, carmustine (carmustine) (BCNU), Carboplatin (CBDCA), lomustine (lomustine) (CCNU), cis-diamminedichloroplatine (cisplatin), dacarbazine (dacarbazine), golidel (gliadel), altretamine (hexamethylmelamine), hydroxyurea, levamisole, mitoxantrone (mitoxantrone), o, p '-dichloro-diphenyl-dichloroethane (o, p' -DDD) (also known as lycra (lysodren) or mitotane (mitotane)), oxaliplatin (oxaliplatin), Porphin sodium (porfimersodium), procarbazine and imatinib mesylate (imatinib mesylate)Antimetabolites such as chlorodeoxyadenosine, cytosine arabinoside, 2' -deoxy Ke Fumei (2 ' -deoxycoformycin), fludarabine phosphate (fludarabine phosphate), 5-fluorouracil (5-FU), 5-fluoro-2 ' -deoxyuridine (5-FUdR), gemcitabine (gemcitabine), camptothecins, 6-mercaptopurine, methotrexate, 4-methyl amphetamine (4-MTA) and thioguanine, and biologicals such as interferon-alpha, BCG (Bacillus Calmette-Guerin, BCG), granulocyte colony stimulating factor (granulocyte colony stimulating factor, G-CSF), granulocyte-macrophage colony stimulating factor (granulocyte-macrophage colony-stimulating factor, GM-CSF), interleukin-2 and herceptin.

The term "treating" as used herein means reversing, alleviating, inhibiting the development of, or preventing the disorder or condition to which the term applies, or one or more symptoms of the disorder or condition, unless otherwise specified. The term "treatment" as used herein refers to the therapeutic behavior of "treatment" as defined above, unless otherwise specified.

As used herein, the following abbreviations refer to post-colon:

DCM: dichloromethane;

DMF;

DMSO, dimethyl sulfoxide;

ESI, electrospray ionization;

HPLC, high performance liquid chromatography;

LCMS/LC-MS liquid chromatography mass spectrometry;

NMI, N-methylimidazole;

TCFH N, N, N ', N' -tetramethyl chloroformidine hexafluorophosphate;

TFA, trifluoroacetic acid;

TLC, thin layer chromatography;

Y, yield.

Examples

Example 1:

Synthesis of Compound 0031

Step 1 Synthesis of Compound I31-8

To a mixture of Compound I31-7 (3 g,19.41 mmol), potassium iodide (0.32 g,1.94 mmol), triethylamine (8.07 mL,58.23 mmol) and DMF (20 mL) was added bromoethane (1.74 mL,23.29 mmol) at room temperature, and the mixture was stirred at room temperature for 18 hours. LCMS monitored completion of the reaction. Water (20 mL) was added for dilution, ethyl acetate (60 mL. Times.3) was used for extraction, the organic phases were combined, washed with saturated ammonium chloride solution (20 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (ethyl acetate/petroleum ether (1/100 to 1/4) eluting silica gel) to give compound I31-8 (0.45 g,2.46mmol, y=12.71%) as a white solid.

LC-MS(ESI):m/z=183.0[M+H]⁺

Step 2 Synthesis of Compound I31-9

Compound I31-8 (300 mg,1.64 mmol) was dissolved in ammonia (8 mL), warmed to 80℃and stirred for 2 hours. LCMS monitored completion of the reaction. The reaction solution was concentrated to dryness to give compound I31-9 (260 mg,1.59mmol, y=96.99%) as a white solid.

LC-MS(ESI):m/z=164.2[M+H]⁺

Step 3 Synthesis of Compound I31-2

To a mixed solution of compound I31-1 (4 g,15.99 mmol), azobisisobutyronitrile (0.26 g,1.60 mmol) and tetrachloromethane (40 mL) was added N-bromosuccinimide (2.85 g,15.99 mmol) under ice bath, and the mixture was stirred at 80℃for 16 hours. LCMS monitored completion of the reaction. Filtration, rinsing with dichloromethane (30 mL) and concentration of the filtrate to dryness afforded compound I31-2 (5 g,15.20mmol, y=95.06%) as a yellow solid.

LC-MS(ESI):m/z=327.9/329.8[M+H]⁺

Step 4 Synthesis of Compound I31-4

To a mixed solution of compound I31-2 (3.5 g,10.64 mmol), compound I31-3 (1.93 g,12.77 mmol) and N, N-dimethylformamide (30 mL) was added potassium carbonate (3.68 g,26.59 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hours. LCMS monitored completion of the reaction. Water (30 mL) was added for dilution, ethyl acetate (80 mL. Times.3) was used for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (ethyl acetate/petroleum ether (1/100 to 1/20) eluting silica gel) to give compound I31-4 (2.9 g,7.26mmol, y= 68.24%) as a yellow solid.

LC-MS(ESI):m/z=399.1/401.1[M+H]⁺

Step 5 Synthesis of Compound I31-5

To a mixed solution of tetrahydrofuran (14 mL) and water (14 mL) was dissolved compound I31-4 (2.8 g,7.01 mmol) at room temperature, sodium hydroxide (0.84 g,21.04 mmol) was added, and the mixture was stirred at room temperature for 18 hours. LCMS monitored completion of the reaction. Concentrating, adding saturated ammonium chloride solution to adjust pH to 6-7, extracting with ethyl acetate (40 mL. Times.3), mixing organic phases, drying over anhydrous sodium sulfate, filtering, and concentrating. The residue was purified by column chromatography (methanol/dichloromethane (1/100 to 1/10) eluting with silica gel) to give compound I31-5 (1.8 g,4.85mmol, y= 69.14%) as a yellow solid.

LC-MS(ESI):m/z=370.8/372.8[M+H]⁺

Step 6 Synthesis of Compound I31-6

To a mixed solution of compound I31-5 (1.1 g,2.96 mmol) and acetonitrile (10 mL) was added [ chloro (dimethylamino) methylene ] dimethylammonium hexafluoro-. Lamda.5-phosphoramide (1.00 g,3.56 mmol) and 1-methylimidazole (0.83 mL,10.37 mmol), respectively, at room temperature, and the mixture was stirred at room temperature for 18 hours. LCMS monitored completion of the reaction. Concentrated, diluted with water (10 mL), extracted with ethyl acetate (30 mL x 3), the organic phases combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (ethyl acetate/petroleum ether (1/100 to 1/4) eluting silica gel) to give compound I31-6 (700 mg,1.98mmol, y=66.88%) as a white solid.

LC-MS(ESI):m/z=351.0/353.0[M+H]⁺

1H NMR(400MHz,DMSO)δ:7.14(d,J＝8.4Hz,1H),6.97(d,J＝8.4Hz,1H),4.81(d,J＝5.4Hz,2H),3.79(s,3H),2.07(s,2H),1.95(s,3H)

Step 7 Synthesis of Compound I31-10

To a mixed solution of compound I31-6 (200 mg,0.57 mmol), cesium carbonate (461.20 mg,1.42 mmol), 1-ethylpyrazolo [3,4-d ] pyrimidin-4-amine (101.63 mg,0.62 mmol) and dioxane (6 ml) were added tris (dibenzylideneacetone) palladium (51.85 mg,0.06 mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (65.52 mg,0.11 mmol), respectively, purged 3 times with nitrogen, and heated to 80 ℃ under nitrogen atmosphere and stirred for 2.5 hours. LCMS monitored completion of the reaction. Water (5 mL) was added for dilution, ethyl acetate (20 mL. Times.3) was used for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (ethyl acetate/petroleum ether (1/100 to 7/3) eluting silica gel) to give compound I31-10 (200 mg,0.46mmol, y= 81.11%) as a yellow solid.

LC-MS(ESI):m/z=436.2[M+H]⁺

Step 8 Synthesis of Compound 0031

To a mixed solution of compound I31-10 (0.37 g,0.85 mmol) and methylene chloride (5 mL) was added dropwise boron tribromide (4.72mL,8.50mmol,17%in DCM) under ice-bath cooling, and the temperature was raised to 40℃for reaction for 1 hour. LCMS monitored completion of the reaction. Quenched with methanol, concentrated to dryness, and the crude product was prepared by high performance liquid phase (Waters-sunfire-10 um-19 x 250mm (eluent = 5% to 40% (v/v) acetonitrile and water with 0.1% nh ₄HCO₃)) to give compound 0031 (16 mg,0.04mmol, y = 4.47%) as a white solid.

LC-MS(ESI):m/z=422.1[M+H]⁺

1H NMR(400MHz,DMSO)δ:13.19(s,1H),9.32(s,1H),8.77(s,1H),8.55(s,1H),6.95(d,J＝8.2Hz,1H),6.78(d,J＝8.2Hz,1H),4.67(d,J＝2.8Hz,3H),4.46(q,J＝7.1Hz,3H),2.04(s,4H),1.95(s,4H),1.43(t,J＝7.2Hz,4H)

Example 2:

Synthesis of Compound 0032

Step 1 Synthesis of Compound I32-2

Boron tribromide (0.91 mL,0.91 mmol) was added over 30 minutes to a solution of compound I32-1 (220 mg,0.460 mmol) in dichloromethane (4 mL) at-78℃followed by stirring the reaction at 25℃for 3 hours. LCMS detected consumption of starting material and product formation. The reaction was concentrated, the residue quenched with saturated aqueous sodium bicarbonate (5 mL) and extracted with dichloromethane (15 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered, and the crude product obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (eluent=dichloromethane: methanol=0 to 10%) to give compound I32-2 (130 mg,0.28 mmol) as a yellow solid.

LC-MS(ESI):m/z=468.2[M+H]⁺

Step 2 Synthesis of Compound I32-3

To a solution of compound I32-2 (280 mg,0.60 mmol) in methylene chloride was added Dess-martin oxidant (508 mg,1.20 mmol), followed by stirring the reaction at 25℃for 3 hours. LCMS detected consumption of starting material and product formation. The reaction was adjusted to pH7 with saturated aqueous sodium bicarbonate and extracted with dichloromethane (5 ml x 3). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate and filtered, and the crude product obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (eluent=dichloromethane: methanol=0 to 5%) to give compound I32-3 (200 mg,0.36mmol, y=59.70%) as a yellow solid.

LC-MS(ESI):m/z=448.1[M+H]⁺

Step 3 Synthesis of Compound 0032

To a solution of compound I32-3 (120 mg,0.270 mmol) in dichloromethane (2 mL) was added boron tribromide (1.34 mL,1.34 mmol), followed by stirring the reaction at 25℃for 3 hours. LCMS showed starting material had been consumed and product was formed. The reaction was quenched with saturated aqueous sodium bicarbonate (10 mL) and extracted with dichloromethane (15 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered, and the crude filtrate was concentrated under reduced pressure and purified by prep-HPLC (gilson_306_1741waters-SunFire-C18-10 μm-19 x 250mm (eluent = 10% to 60% (v/v) acetonitrile and water with 0.1% nh ₄HCO₃) to afford compound 0032 (13.86 mg,0.03 mmol) as a pale yellow solid.

LC-MS(ESI):m/z=434.1[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:13.22(s,1H),9.51(s,1H),8.77(s,1H),8.55(s,1H),7.44(d,J＝7.2Hz,1H),7.03(d,J＝8.2Hz,1H),6.85(d,J＝7.4Hz,2H),4.46(q,J＝7.2Hz,2H),1.90(s,3H),1.81(s,3H),1.43(t,J＝7.2Hz,3H)

Example 3:

synthesis of Compound 0034

Step 1 Synthesis of Compound I34-2

To a solution of compound I34-1 (10 g,52.08mmol, pickle) in MeOH (200 mL) was added potassium tert-butoxide (29.22 g,260.42 mmol) and the resulting mixture was stirred at 80℃for 16 h. LCMS detected the desired product. The reaction was added water (400 mL) and the mixture was adjusted to ph=3 with HCl (1M), the mixture was filtered and the filter cake was washed with H ₂ O (50 mL x 3), and the filtrate was concentrated to dryness under reduced pressure to give the crude compound I34-2 (10 g,49.85mmol, y= 95.70%) as a white solid. The solid was used directly in the next step without purification.

LC-MS(ESI):m/z=188.0[M+H]⁺

Step 2 Synthesis of Compound I34-4

A mixture of compound I34-2 (1.5 g,8.00 mmol), compound I34-3 (1.45 g,9.60mmol, bi), TCFH (6.73 g,23.99 mmol) and NMI (2.55 mL,31.99 mmol) in acetonitrile (30 mL) was stirred at 25℃for 16 hours. LCMS detected the desired product. The mixture was concentrated to dryness under reduced pressure to give the crude product. The residue was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 15% (V/V)) as yellow solid compound I34-4 (1070 mg,3.34mmol, y = 41.47%).

LC-MS(ESI):m/z=321.2[M+H]⁺

Step 3 Synthesis of Compound I34-6

To a solution of compound I34-4 (1.07 g,3.34 mmol) in dioxane (16 mL) and H ₂ O (4 mL) was added compound I34-5 (0.85 mL,5.00mmol, pichia), dichloro [1,1' -bis (diphenylphosphine) ferrocene ] palladium (79.84 mg,0.11 mmol) and Cs ₂CO₃ (3.26 g,10.01 mmol). The mixture was replaced 3 times with N ₂ and warmed to 100 ℃ under N ₂ and stirred for 4 hours. LCMS showed complete consumption of starting material and formation of the desired product. The mixture was poured into water (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (20 ml x 3), dried over anhydrous Na ₂SO₄, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 20%) to give compound I34-6 (800 mg,2.56mmol, y = 76.78%) as a yellow solid.

LC-MS(ESI):m/z=313.2[M+H]⁺

Step 4 Synthesis of Compound I34-7

To a solution of compound I34-6 (630 mg,2.63 mmol) in DMF (15 mL) was added potassium tert-butoxide (0.10 mL,0.79 mmol), the mixture was replaced 3 times with N ₂, and the mixture was stirred at 120℃under N ₂ for 16 hours. A black solution was formed. HPLC showed complete consumption of starting material and formation of the desired product. The mixture was poured into water (15 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (10 ml x 3), dried over anhydrous Na ₂SO₄, filtered and concentrated to dryness under reduced pressure to give the crude compound I34-7 (200 mg,0.64mmol, y=24.39%) as a yellow solid. The solid was used directly in the next step without purification.

LC-MS(ESI):m/z=313.2[M+H]⁺

Step 5 Synthesis of Compound I34-8

POCl ₃ (0.12 mL,1.28 mmol) was added to a solution of compound I34-7 (200 mg,0.64 mmol) in DMF (2 mL) at 0deg.C and the resulting mixture was stirred at 80deg.C for 2 hours. LCMS showed complete consumption of starting material and formation of the desired product, and the mixture was concentrated to dryness under reduced pressure to give the crude product. The residue was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 50% -50%) to give compound I34-8 (143 mg,0.45mmol, y = 70%) as a brown oil.

LC-MS(ESI):m/z=317.2[M+H]⁺

Step 6 Synthesis of Compound I34-9

To compound I34-8 (175 mg,0.55 mmol), compound I31-9 (108.17 mg,0.66mmol, after), tris (dibenzylideneacetone) palladium (50.59 mg,0.06 mmol), K ₂CO₃ (229.03 mg,1.66 mmol) and Xantphos (63.93 mg,0.11 mmol) formed a black solution LCMS showed complete consumption of starting material and formation of the desired product, the mixture was poured into water (10 mL) and extracted with ethyl acetate (30 mL x 3), the combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂SO₄, filtered and concentrated to dryness under reduced pressure to give the crude product, the residue was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 50% -50%) to give compound I34-9 (200 mg,0.45mmol, y = 81.63%) as a yellow solid.

LC-MS(ESI):m/z=444.4[M+H]⁺

Step 7 Synthesis of Compound 0034

To a solution of compound I34-9 (150 mg,0.34 mmol) in DCM (3 mL) at 0deg.C was added BBr ₃ (1.69 mL,1.69 mmol) and the resulting mixture was stirred at 25deg.C for 1 hour. LCMS showed complete consumption of starting material and formation of the desired product. The reaction mixture was concentrated to dryness under reduced pressure to give the crude product, which was quenched with saturated NH ₃/MeOH (5 mL). The crude product was purified by preparative HPLC (eluent=25% to 55% (v/v) CH ₃ CN and H ₂ O with 10mmol/LNH ₄HCO₃) to give compound 0034 (88.22 mg,0.20mmol, y=60.13%) as a white solid.

LC-MS(ESI):m/z=430.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:11.22(s,1H),9.29(s,1H),8.66–8.64(m,1H),8.61(s,1H),8.58–8.54(m,1H),8.30–8.26(m,1H),6.94(d,1H),6.73(d,J＝8.2Hz,1H),4.45–4.39(m,2H),3.79–3.75(m,2H),3.29–3.26(m,2H),2.08(s,3H),2.00(s,3H),1.42(t,3H)

Example 4:

synthesis of Compound 0035

Step 1 Synthesis of Compound I35-2

To a solution of compound I35-1 (4 g,23.31mmol, pickle) in MeOH (50 mL) was added thionyl chloride (8.46 mL,116.56mmol, pickle) and the resulting mixture was stirred at 60℃for 18 hours. TLC (petroleum ether: ethyl acetate=20/1) showed the formation of new spots. The mixture was concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 100:1 to 20:1) to give compound I35-2 (2.5 g,13.47mmol, y = 57.7%) as a white solid.

LC-MS(ESI):m/z=186.0[M+H]⁺

Step 2 Synthesis of Compound I35-3

To a solution of compound I35-2 (1.97 g,10.61 mmol) and azobisisobutyronitrile (0.17 g,1.06 mmol) in CCl ₄ (25 mL) was added N-bromosuccinimide (2.08 g,11.68 mmol) and the resulting mixture was stirred at 80℃for 18 hours to give a yellow solution. TLC (petroleum ether: ethyl acetate=10:1) showed new spot formation. The mixture was concentrated to dryness under reduced pressure to give the crude product. The crude product was then purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 100:1 to 10:1) to give crude compound I35-3 (2.0 g,3.78mmol, y = 35.6%) as a yellow solid.

LC-MS(ESI):m/z=264.0/266.0[M+H]⁺

Step 3 Synthesis of Compound I35-5

To a mixture of compound I35-3 (700 mg,2.65 mmol) and compound I35-4 (480.21 mg,3.18 mmol) in DMF (15 mL) was added potassium carbonate (914.37 mg,6.62mmol, bi), and the resulting mixture was stirred at 80℃for 18 hours. LCMS detected the desired mass. The mixture was poured into water (20 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic phases were concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 100:1 to 4:1) to give compound I35-5 (0.35 g,1.05mmol, y = 39.5%) as a yellow solid.

LC-MS(ESI):m/z=335.0[M+H]⁺

Step 4 Synthesis of Compound I35-6

Compound I35-5 (300 mg,0.90 mmol) and acetic acid (2 mL) were added to a 5mL microwave tube, and the resulting mixture was stirred by microwave at 120℃for 2 hours and then cooled to room temperature. TLC (petroleum ether/ethyl acetate=5/1) showed starting material consumed and new spots detected. The reaction mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was then purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 50:1 to 5:1) to give compound I35-6 (160 mg,0.53mmol, y = 58.9%) as a yellow solid.

LC-MS(ESI):m/z=303.2[M+H]⁺

Step 5 Synthesis of Compound I35-8

To a mixture of compound I35-6 (160 mg,0.53 mmol), compound I35-7 (86.24 mg,0.53 mmol), xantphos (61.16 mg,0.11 mmol) and cesium carbonate (516.56 mg,1.59 mmol) in DMF (1 mL) was added tris (dibenzylideneacetone) palladium (48.39 mg,0.05 mmol), the mixture was displaced 3 times with N ₂ and stirred for 18 hours at elevated temperature to 80℃under N ₂. A black solution was formed. LCMS showed complete consumption of starting material and formation of the desired product. The reaction mixture was poured into water (3 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 20:1 to 1:1) to give compound I35-8 (100 mg,0.22mmol, y = 41.8%) as a yellow solid.

LC-MS(ESI):m/z=430.2[M+H]⁺

Step 6 Synthesis of Compound 0035

To a solution of compound I35-8 (100 mg,0.23 mmol) in DCM (4 mL) was added BBr ₃ (0.11 mL,1.16 mmol) at 0 ℃ and then stirred at 25 ℃ for 3 hours. The mixture was concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by preparation (eluent = 30% to 60% (v/v) CH ₃ CN and H ₂ O with 0.025% nh ₄HCO₃) to give compound 0035 (38.19 mg,0.09mmol, y = 39.5%) as a white solid.

LC-MS(ESI):m/z=416.2[M+H]⁺

1H NMR(400MHz,DMSO-d₆)δ:11.36(s,1H),9.36(s,1H),8.71(d,J＝8.6Hz,1H),8.63(d,J＝3.6Hz,2H),8.23(d,J＝8.6Hz,1H),6.97(d,J＝8.3Hz,1H),6.80(d,J＝13.2Hz,1H),4.70(d,J＝1.9Hz,2H),4.42(q,J＝7.2Hz,2H),2.03(s,3H),1.94(s,3H),1.42(t,J＝7.2Hz,3H)

Example 5:

Synthesis of Compound 0044

Step 1 Synthesis of Compound I44-2

To a solution of compound I44-1 (235 mg,1.29mmol, after completion), p-methoxybenzylamine (0.17 mL,1.32 mmol), xantphos (127.44 mg,0.22 mmol) and cesium carbonate (1076.38 mg,3.30 mmol) in DMF (5 mL) was added tris (dibenzylideneacetone) palladium (100.84 mg,0.11mmol. Lcms detection afforded product MS. the mixture was poured into water (10 mL) and extracted with ethyl acetate (30 mL x 3), the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous Na ₂SO₄, filtered and concentrated to dryness under reduced pressure to afford the crude product.

LC-MS(ESI):m/z=283.3[M+H]⁺

Step 2 Synthesis of Compound I44-3

To a solution of compound I44-2 (360 mg,1.28 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL,13.42 mmol) at 0deg.C. The reaction was stirred at 60 ℃ for 3 hours. Product MS was obtained by LCMS and the mixture was concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by HPLC (eluent = 25% to 40% (v/v) acetonitrile and water with 0.01% tfa) to give compound I44-3 (220 mg,1.22 mmol) as a white solid.

LC-MS(ESI):m/z=163.2[M+H]⁺

Step 3 Synthesis of Compound I44-5

To a solution of 2-bromo-5- (3-methoxy-2, 6-dimethylphenyl) -4, 5-dihydro-6-pyrrolo [3,4-d ] thiazol-6-one (200 mg,0.57 mmol), compound I44-3 (101.02 mg,0.62 mmol), xantphos (65.52 mg,0.11 mmol) and cesium carbonate (553.44 mg,1.70 mmol) in DMF (6 mL) was added tris (dibenzylideneacetone) palladium (51.85 mg,0.06 mmol), the mixture was sparged 3 times with nitrogen and stirred under nitrogen for 2 hours at 90 ℃. LCMS detected the desired mass MS. The mixture was poured into water (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous Na ₂SO₄, filtered and concentrated to dryness under reduced pressure to give the crude product. The residue was purified by HPLC (eluent = 40% to 40% (v/v) acetonitrile and water with 0.01% tfa) to give compound I44-5 (40 mg,0.09 mmol) as a yellow solid.

LC-MS(ESI):m/z=435.3[M+H]⁺

Step 4 Synthesis of Compound 0044

A solution of compound I44-5 (40 mg,0.09 mmol) and boron tribromide (0.46 mL,0.46 mmol) in DCM (1 mL) was stirred at 25℃for 1h to give a yellow solution. LCMS detected the desired mass MS. The mixture was concentrated to dryness under reduced pressure to give the crude product. The reaction mixture was quenched with ammonia in methanol (1M). The crude product was purified by HPLC (eluent = 27% to 57% (v/v) acetonitrile and water with 10mmol NH ₄HCO₃) to give compound 0044 (8.56 mg,0.02 mmol) as a white solid.

LC-MS(ESI):m/z=421.1[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:12.55(s,1H),9.32(s,1H),8.64(s,1H),8.24–8.06(m,1H),7.48–7.27(m,1H),7.00–6.89(m,1H),6.82–6.73(m,1H),4.69–4.56(m,2H),4.52–4.39(m,2H),2.05(s,3H),1.95(s,3H),1.41(t,J＝7.2Hz,3H).

Example 6:

synthesis of Compound 0045

Step 1 Synthesis of Compound I45-2

To a solution of compound I45-1 (2.00 g,13.02mmol, after completion of the reaction) in DMF (20 mL) was added sodium hydride (0.78 g,19.54mmol,60% purity) under nitrogen at 0deg.C, followed by iodoethane (1.15 mL,14.33 mmol). The reaction was stirred at 25 ℃ for 16 hours. LCMS showed formation of the desired MS. The mixture was poured into saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous Na ₂SO₄, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 100:0 to 95:5) to give compound I45-2 (1.95 g,10.74 mmol) as a colourless oil.

LC-MS(ESI):m/z=182.1[M+H]⁺

Step 2 Synthesis of Compound I45-3

Compound I45-2 (600 mg,3.30 mmol) was added to ammonium hydroxide (2 mL,15.58mmol,30% purity) and 1, 4-dioxane (2 mL). The reaction was stirred in a 110 ℃ microwave tube for 3 hours. LCMS showed formation of the desired MS. The mixture was concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by HPLC (Phenomenex Gemini 150mm*25mm*10um column (eluent = 10% to 900% (v/v) acetonitrile and water with 0.01% tfa) to give compound I45-3 (450 mg,2.77 mmol) as a white solid.

LC-MS(ESI):m/z=163.1[M+H]⁺

Step 3 Synthesis of Compound I45-4

To a solution of 2-bromo-5- (3-methoxy-2, 6-dimethylphenyl) -4, 5-dihydro-6-pyrrolo [3,4-d ] thiazol-6-one (150 mg,0.42 mmol), compound I45-3 (68.88 mg,0.42 mmol) in DMF (1.5 mL) was added tris (dibenzylideneacetone) palladium (38.89 mg,0.04 mmol), xantphos (49.14 mg,0.08 mmol) and cesium carbonate (138.36 mg,0.42 mmol). The reaction was stirred at 80 ℃ for 2.5 hours, LCMS showed the desired MS. The mixture was poured into water (5 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous Na ₂SO₄, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by HPLC (Phenomenex Gemini 150mm*25mm*10um column (eluent = 30% to 60% (v/v) acetonitrile and water with 0.025% tfa) to give compound I45-4 (50 mg,0.11 mmol) as a white solid.

LC-MS(ESI):m/z=435.2[M+H]⁺

Step 4 Synthesis of Compound 0045

To a solution of compound I45-4 (50 mg,0.12 mmol) in dichloromethane (2 mL) under nitrogen at-40℃was added boron tribromide (0.58 mL,0.58mmol, 1M) and the reaction was stirred at 25℃for 1 hour. LCMS showed formation of the desired MS. Methanol (2 mL) was added to quench and concentrate the reaction. The crude product was purified by HPLC (Phenomenex Gemini mm x 25mm x 10um column (eluent = 30% to 60% (v/v) acetonitrile and water with 0.025% nh ₄HCO₃) to give compound 0045 (11 mg,0.03 mmol) as a white solid.

LC-MS(ESI):m/z=421.3[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:12.57(s,1H),9.31(s,1H),8.61(s,1H),7.53(d,J＝3.5Hz,1H),7.06(d,J＝3.5Hz,1H),6.94(d,J＝8.2Hz,1H),6.77(d,J＝8.2Hz,1H),4.63(d,J＝3.0Hz,2H),4.33–4.25(m,2H),2.04(s,3H),1.95(s,3H),1.38(t,J＝7.2Hz,3H).

Example 7:

synthesis of Compound 0046

Step 1 Synthesis of Compound I46-1

To a solution of compound I31-7 (500 mg,3.23mmol, pichia), cyclopropylborodiol (555.77 mg,6.47 mmol), 2- (pyridin-2-yl) pyridine (431.86. Mu.L, 3.23 mol) and sodium carbonate (685.75 mg,6.43 mmol) in dichloroethane (15 mL) was added anhydrous copper acetate (587.57 mg,3.23 mmol) and the resulting mixture was stirred under an oxygen atmosphere at 60℃for 16 hours. LCMS detected the desired mass MS. The mixture was filtered and the filtrate was concentrated to dryness, then the residue was diluted with ethyl acetate (30 mL) and washed with 0.1M HCl (20 mL) and the organic phase was concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10:01 to 10:1) to give compound I46-1 (70 mg,0.36mmol, y = 11.1%) as a colourless oil.

LC-MS(ESI):m/z=195.0[M+H]⁺

Step 2 Synthesis of Compound I46-2

Compound I46-1 (70 mg,0.36 mmol) was dissolved in aqueous ammonia (3 mL) and stirred at 80℃for 2 hours. LCMS detected the desired mass MS. The reaction was concentrated to dryness under reduced pressure to give compound I46-2 (99.86 mg,0.57mmol, crude) as a white solid.

LC-MS(ESI):m/z=176.0[M+H]⁺

Step 3 Synthesis of Compound I46-3

To a solution of compound I31-8 (200 mg,0.57 mmol), compound I46-2 (99.86 mg,0.57 mmol) and cesium carbonate (464.29 mg,1.43 mmol) in DMF (6 mL) was added tris (dibenzylideneacetone) palladium (52.20 mg,0.06 mmol) and Xantphos (32.98 mg,0.06 mmol), the mixture was replaced 3 times with nitrogen and stirred at 80℃for 2 hours under nitrogen. LCMS detected the desired mass MS. The mixture was poured into water (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous Na ₂SO₄, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by Prep-HPLC ((eluent = 0% to 65% (v/v) acetonitrile and water with 0.01% tfa) to give compound I46-3 (90 mg,0.20mmol, y = 35.5%) as a white solid.

LC-MS(ESI):m/z=448.2[M+H]⁺

Step 4 Synthesis of Compound 0046

To a solution of compound I46-3 (50 mg,0.11 mmol) in dichloromethane (1 mL) under nitrogen was added boron tribromide (0.56 mL,0.56 mmol) and the resulting mixture was stirred at 25 ℃ for 2 hours to give a yellow solution. LCMS detected the desired mass MS. The reaction was quenched with MeOH (10 mL) and concentrated to dryness. The residue was then basified to ph=7-8 with 7m NH3 in methanol and dried by spin to give the crude product. The crude product was purified by HPLC (Waters-Xbridge-C18-10 μm-19 x 250mm (eluent = 10% to 95% (v/v) acetonitrile and water with 0.1% nh ₄HCO₃) to give compound 0046 (28.76 mg,0.09mmol, y = 41.3%) as a yellow solid.

LC-MS(ESI):m/z=434.1[M+H]⁺

1H NMR(400MHz,DMSO-d₆)δ:13.17(s,1H),9.32(s,1H),8.77(s,1H),8.49(s,1H),6.94(d,J＝8.3Hz,1H),6.77(d,J＝8.2Hz,1H),4.73-4.58(m,2H),3.97-3.91(m,1H),2.04(s,3H),1.94(s,3H),1.24–1.17(m,2H),1.16–1.10(m,2H).

Example 8:

synthesis of Compound 0047

Step 1 Synthesis of Compound I47-2

Compound I47-1 (2.00 g,13.11mmol, bide) was dissolved in N, N-dimethylformamide (20 mL), sodium hydride (0.47g,19.66mmol,60%in oil,Energy Chemical) was added under the protection of nitrogen at 0℃and reacted at 0℃for 0.5 hours, and after that, ethyl iodide (1.26 mL,15.73mmol, bide) was added dropwise to the reaction solution, and stirring was continued for 3 hours at 25 ℃. LCMS detected the target product, the mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na ₂SO₄, filtered and concentrated to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate=10:1-6:1) to give compound I47-2 (1.65 g,9.13 mmol) as a yellow oil.

LC-MS(ESI):m/z=181.0[M+H]⁺

Step 2 Synthesis of Compound I47-3

Compound I47-2 (500 mg,2.77 mmol) and tert-butyl carbamate (0.43mL,4.15mmol,Energy Chemical mmol) were dissolved in toluene (15 mL), tris (dibenzylideneacetone) dipalladium (126.74mg,0.14mmol,Energy Chemical), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (131.96mg,0.28mmol,Energy Chemical) and cesium carbonate (1803.80 mg,5.54 mmol) were added and stirred at 90℃for 16 hours. LCMS detected the target product, the mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na ₂SO₄, filtered and concentrated to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate=10:1-1:1, r _f =0.26) to give compound I47-3 (630 mg,2.41 mmol) as a yellow oil.

LC-MS(ESI):m/z=262.5[M+H]⁺

Step 3 Synthesis of Compound I47-4

Compound I47-3 (300 mg,1.15 mmol) was added to hydrochloric acid/dioxane (10mL,40.00mmol,Energy Chemical) and the reaction stirred at 25℃for 2 hours, LCMS detected the desired product, and the reaction concentrated to give compound I47-4 (200 mg,0.91mmol, crude) as a yellow oil

LC-MS(ESI):m/z=162.1[M+H]⁺

Step 4 preparation of Compound I47-5

Compound I47-4 (200 mg,0.57 mmol) and 2-bromo-5- (3-methoxy-2, 6-dimethylphenyl) -4, 5-dihydro-6H-pyrrolo [3,4-d ] thiazol-6-one (68.88 mg,0.42 mmol) were dissolved in N, N-dimethylformamide (4 mL), tris (dibenzylideneacetone) dipalladium (51.85mg,0.06mmol,Energy Chemical), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (65.52mg,0.11mmol,Energy Chemical) and cesium carbonate (553.44 mg,1.70 mmol) were added and stirred at 90℃for 3 hours. LCMS detected the target product, the mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na ₂SO₄, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Phenomenex Gemini 150mm*25mm*10um column (eluent = 30% to 60% (v/v) acetonitrile and water with 0.025% tfa) to give compound I47-5 (51 mg,0.12 mmol) as a white solid.

LC-MS(ESI):m/z=434.2[M+H]⁺

Step 5 Synthesis of Compound 0047

Compound I47-5 (50 mg,0.12 mmol) was dissolved in dichloromethane (2 mL), boron tribromide (0.69mL,0.69mmol,Energy Chemical) was added under nitrogen at 0deg.C, and reacted at 25deg.C for 2 hours. The target product was detected by LCMS, methanol (2 mL) was added to the reaction, and concentrated. The crude product was purified by Prep-HPLC (Phenomenex Gemini mm 25mm 10um column (eluent = 30% to 60% (v/v) acetonitrile and water with 0.025% nh ₄HCO₃) to give compound 0047 (14.48 mg,0.03 mmol) as a white solid.

LC-MS(ESI):m/z=420.3[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:11.07(s,1H),9.34(s,1H),8.25–8.09(m,2H),7.50(s,1H),6.97–6.91(m,1H),6.88–6.71(m,2H),4.74–4.56(m,2H),4.32–4.22(m,2H),2.04(s,3H),1.94(s,3H),1.43–1.33(m,3H).

Example 9:

synthesis of Compound 0049

Step 1 Synthesis of Compound I49-2

To a mixture of compound I49-1 (5 g,36.45mmol, pickle) was added dichloromethane (100 mL), N-bromosuccinimide (6.49 g,36.45 mmol), and the resulting mixture was stirred at 25℃for 3 hours. LCMS showed the starting material was consumed and the desired product formed. The mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0 to 9%) to give compound I49-2 (6.5 g,26 mmol) as a yellow oil.

LC-MS(ESI):m/z=216.0/218.0[M+H]⁺

Step 2 Synthesis of Compound I49-3

To a solution of compound I49-2 (6.46 g,29.90 mmol) in acetonitrile (60 mL) was added N-chlorosuccinimide (3.99 g,29.90mmol, bi), and the resulting mixture was stirred at 80℃for 3 hours. LCMS showed the starting material was consumed and the desired product formed. The mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0 to 15%) to give compound I49-3 (2.1 g,8.38 mmol) as a yellow solid.

LC-MS(ESI):m/z=250.0/252.0[M+H]⁺

Step 3 Synthesis of Compound I49-4

To a solution of compound I49-3 (2.1 g,8.38 mmol) in methanol (10 mL) was added palladium (0) (0.2 g,0.19mmol, an Naiji mmol) and acetic acid (0.02 mL,0.35 mmol), respectively, and the resulting mixture was stirred under hydrogen at 25 ℃ for 18 hours LCMS showed the starting material was consumed and the desired product formed.

LC-MS(ESI):m/z=172.0[M+H]⁺

Step 4 Synthesis of Compound I49-6

To a mixed solution of compound I49-5 (500 mg,1.14 mmol) and compound I49-4 (156.49 mg,0.91 mmol) were added N, N-dimethylformamide (5 mL) and potassium carbonate (393.80 mg,2.85 mmol), respectively, and the resulting mixture was stirred at 80℃for 4 hours. LCMS showed the starting material was consumed and the desired product formed. The mixture was poured into water (15 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0 to 5%) to give compound I49-6 (150 mg,0.36 mmol) as a white solid.

LC-MS(ESI):m/z=419.0/421.0[M+H]⁺

Step 5 Synthesis of Compound I49-7

Compound I49-6 (180 mg,0.43 mmol) was added to a mixed solution of water and methanol (1:1, 1.5 mL), sodium hydroxide (51.46 mg,1.29mmol, bide) was further added, and the resulting mixture was stirred at 50℃for 1 hour. LCMS showed the starting material was consumed and the desired product formed. The mixture was concentrated to dryness and ph=7 was adjusted with hydrochloric acid (1M). The mixture was then filtered, and the filtered solid was washed with water (10 mL) and dried under reduced pressure to give Compound I49-7 (150 mg,0.38 mmol) as a white solid.

LC-MS(ESI):m/z=391.1/393.1[M+H]⁺

Step 6 Synthesis of Compound I49-8

Compound I49-7 (150 mg,0.38 mmol) and [ chloro (dimethylamino) methylene ] dimethylhexafluoro-. Lamda.5-ammonium phosphide (214.92 mg,0.77mmol, bide) were added to acetonitrile (1.5 mL), and 1-methylimidazole (0.12 mL,1.53mmol, bi) was added thereto, and the resulting mixture was stirred at 25℃for 18 hours. LCMS showed the starting material was consumed and the desired product formed. The mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0 to 15%) to give compound I49-8 (110 mg,0.29 mmol) as a white solid.

LC-MS(ESI):m/z=373.0/375.0[M+H]⁺

Step 7 Synthesis of Compound I49-10

To a mixture of compound I49-8 (110 mg,0.29 mmol), compound I49-9 (57.65 mg,0.35 mmol), cesium carbonate (287.76 mg,0.88mmol, bi-obtained) and [5- (diphenylphosphino) -9, 9-dimethyl-9H-flavan-4-yl ] diphenylphosphine (34.07 mg,0.06mmol, bi-obtained) was added tris [ (1E, 4E) -1, 5-diphenylpenta-1, 4-dien-3-one ] bis [ palladium (0) ] (26.96 mg,0.03mmol, bi-obtained), and the reaction solution was stirred under nitrogen at 90℃for 3 hours. LCMS showed the starting material was consumed and the desired product formed. The mixture was poured into water (3 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0 to 50%) to give compound I49-10 (70 mg,0.15 mmol) as a yellow solid.

LC-MS(ESI):m/z=456.1[M+H]⁺

Step 8 Synthesis of Compound 0049

Compound I49-10 (70 mg,0.15 mmol) was added to dichloromethane (4 mL) and tribromoborane (0.77 mL,0.77mmol, bi.) was added and the resulting mixture stirred at 25℃for 2 hours to give a yellow solution. LCMS showed the starting material was consumed and the desired product formed. The reaction mixture was quenched with methanol (1 mL), concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by preparative HPLC (Phenomenex Gemini mm x 25mm x 10 umcolumn) (eluent = 10% to 75% (v/v) acetonitrile and water, 0.025% ammonium bicarbonate) to give compound 0049 (22.49 mg,0.05 mmol) as a white solid.

LC-MS(ESI):m/z=442.1[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:13.23(s,1H),10.17(s,1H),8.76(s,1H),8.54(s,1H),7.12(d,J＝8.6Hz,1H),6.97(d,J＝8.4Hz,1H),4.78-4.66(m,2H),4.46(q,J＝7.2Hz,2H),2.12(s,3H),1.43(t,J＝7.2Hz,3H).

Example 10:

synthesis of Compound 0050

Step 1 Synthesis of Compound I50-3

Compound I50-1 (1.85 mL,14.58mmol, after completion) was added to dichloromethane (10 mL) at 0deg.C, N-chlorosuccinimide (2.04 g,15.31mmol, after completion) was added and the reaction stirred at 0deg.C for 1 hour. TLC showed the starting material was consumed, giving a new spot. The mixture was poured into water (20 mL) and extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10:1 to 3:1) to give compound I50-3 (600 mg,3.50mmol, y = 23.9%) as a yellow solid.

LC-MS(ESI):m/z=172.1[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:7.03(d,J＝8.8Hz,1H),6.27(d,J＝8.8Hz,1H),4.97(s,2H),3.71(s,3H),1.98(s,3H).

Step 2 Synthesis of Compound I50-4

Compound I50-3 (417.30 mg,2.43 mmol) and compound I50-2 (800 mg,2.43 mmol) were added to N, N-dimethylformamide (5 mL), followed by potassium carbonate (840.10 mg,6.08 mmol), and heated to 80℃and stirred for 16 hours, LCMS showed complete consumption of starting material, mainly resulting in the product. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10:1 to 5:1) to give compound I50-4 (407 mg,0.97 mmol) as a white solid.

LC-MS(ESI):m/z=419.0/421.0[M+H]⁺

Step 3 Synthesis of Compound I50-5

Compound I50-4 (400 mg,0.95 mmol) was added to a mixed solution of tetrahydrofuran (5 mL) and water (5 mL), followed by sodium hydroxide (114.36 mg,2.86 mmol). The temperature was raised to 50 ℃ and stirred for 1 hour, LCMS showed complete consumption of starting material, mainly resulting in product. The mixture was poured into water (5 mL), ph=4 was adjusted with hydrochloric acid (1M), and extracted with ethyl acetate (30 mL x 1). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give compound I50-5 (270 mg,0.69 mmol) as a white solid.

LC-MS(ESI):m/z=390.8/392.8[M+H]⁺

Step 4 Synthesis of Compound I50-6

Compound I50-5 (260 mg,0.66 mmol) was added to acetonitrile (3 mL), TCFH (465.65 mg,1.66mmol, an Naiji) and methylimidazole (0.21 mL,2.64mmol, an Naiji) were added, respectively, and the reaction stirred at 25℃for 16 hours. LCMS showed complete consumption of starting material, with the product mainly formed. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10:1 to 7:1) to give compound I50-6 (200 mg,0.54 mmol) as a white solid.

LC-MS(ESI):m/z=372.8/374.8[M+H]⁺

Step 5 Synthesis of Compound I50-8

Compounds I50-6 (200 mg,0.57 mmol) and I50-7 (68.88 mg,0.42 mol) were added to dioxane (2 mL) under nitrogen, tris (dibenzylideneacetone) dipalladium (36.76 mg,0.04mmol, an Naiji), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (46.46 mg,0.08mmol, an Naiji) and cesium carbonate (392.40 mg,1.20 mmol) were added, respectively, and the mixture was stirred at 80℃for 2.5 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10/1-1/1) to give compound I50-8 (123 mg,0.27 mmol) as a yellow oil.

LC-MS(ESI):m/z=456.0[M+H]⁺

Step 6 Synthesis of Compound 0050

Compound I50-8 (123 mg,0.27 mmol) was added to dichloromethane (2 mL) under nitrogen and boron tribromide (1.35 mL,1.35mmol,1mOL/L, an Naiji) was added and stirred at 0deg.C for 2 hours. 2mL of methanol was added to the reaction, quenched and concentrated to dryness. The crude product was purified by preparative high performance liquid chromatography (Agilent-porous HPH-C18-2.7um-4.6 x 50mm (eluent = 20% to 80% (v/v) acetonitrile and water 0.025% ammonium bicarbonate) to give compound 0050 (57.72 mg,0.14 mmol) as a white solid.

LC-MS(ESI):m/z=442.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:13.24(s,1H),9.91(s,1H),8.78(s,1H),8.54(s,1H),7.24(d,J＝12Hz,1H),6.91(d,J＝8Hz,1H),4.78–4.64(m,2H),4.50–4.42(m,2H),2.02(s,3H),1.43(t,J＝7.2Hz,3H).

Example 11:

Synthesis of Compound 0051

Step 1 Synthesis of Compound I51-2

Compound I51-1 (1.0 g,4.91 mmol) and sodium tert-butoxide (0.48 g,4.96mmol, each) were added to isopropanol (15 mL) under nitrogen, and allyl [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene ] palladium (II) (0.07 g,0.12mmol, each) was added thereto, and the resulting mixture was stirred at 120℃for 1 hour to give a black solution. LCMS showed the starting material was consumed and the desired product formed. The mixture was filtered and the filtered solids were washed with ethyl acetate (10 ml x 3) and the filtrate concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0 to 5%) to give compound I51-2 (740 mg,4.37 mmol) as a yellow solid.

LC-MS(ESI):m/z=170.2[M+H]⁺

Step 2 Synthesis of Compound I51-4

Compound I51-3 (1.94 g,4.43 mmol) and compound I51-2 (0.60 g,3.55 mmol) were added separately to DMF (15 mL), followed by potassium carbonate (1.53 g,11.08mmol, after which time) and the resulting mixture was stirred at 80℃for 2 hours. LCMS showed the starting material was consumed and the desired product formed. The mixture was poured into water (30 mL) and extracted with ethyl acetate (75 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0 to 5%) to give compound I51-4 (1.0 g,2.40 mmol) as a yellow solid.

LC-MS(ESI):m/z=417.0/419.0[M+H]⁺

Step 3 Synthesis of Compound I51-5

Compound I51-4 (500 mg,1.20 mmol) was added to a mixed solution of tetrahydrofuran (2.5 mL) and water (2.5 mL), followed by sodium hydroxide (143.78 mg,3.59mmol, pichia) was added. The resulting mixture was stirred at 25 ℃ for 18 hours. LCMS showed the starting material was consumed and the desired product formed. The reaction mixture was adjusted to ph=7 with hydrochloric acid (1M), filtered, and the filter cake was washed with water (10 mL) and dried under reduced pressure to give compound I51-5 (320 mg,0.82 mmol) as a white solid.

LC-MS(ESI):m/z=389.0/391.0[M+H]⁺

Step 4 Synthesis of Compound I51-6

Compound I51-5 (440 mg,1.13 mmol) and [ chloro (dimethylamino) methylene ] dimethyl hexafluoro-. Lamda.5-ammonium phosphide (634.34 mg,2.26mmol, after completion) were added to acetonitrile (10 mL), and 1-methylimidazole (0.36 mL,4.52mmol, after completion) was added and the resulting mixture was stirred at 25℃for 18 hours. LCMS showed the starting material was consumed and the desired product formed. The mixture was poured into water (15 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0 to 5%) to give compound I51-6 (317 mg,0.85 mmol) as a white solid.

LC-MS(ESI):m/z=371.1/373.1[M+H]⁺

Step 5 Synthesis of Compound I51-8

Compound I51-6 (100 mg,0.27 mmol), compound I51-7 (48.35 mg,0.30 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (31.17 mg,0.05mmol, bi) and cesium carbonate (263.31 mg,0.81mmol, bide) were added to N, N-dimethylformamide (1.5 mL), respectively, tris (dibenzylideneacetone) dipalladium (24.67 mg,0.03mmol, bide) was added, the mixture was degassed and purged 3 times with nitrogen, and the temperature was raised to 90℃under N ₂ for stirring for 2.5 hours. LCMS showed the starting material was consumed and the desired product formed. The mixture was poured into water (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0 to 50%) to give compound I51-8 (100 mg,0.22 mmol) as a brown solid.

LC-MS(ESI):m/z=454.0[M+H]⁺

Step 6 Synthesis of Compound 0051

Compound I51-8 (110 mg,0.24 mmol) was added to dichloromethane (4 mL), and boron tribromide (1.21 mL,1.21mmol,1M, bi) was added and the resulting mixture stirred at 25℃for 2 hours. LCMS showed the starting material was consumed and the desired product formed. The mixture was quenched with methanol and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by preparative chromatography (Phenomenex Gemini mm x 25mm x 10um column (eluent = 10% to 75% (v/v) acetonitrile and water 0.025% ammonium bicarbonate) to give compound 0051 (58.44 mg,0.13 mmol) as a white solid.

LC-MS(ESI):m/z=440.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:13.22(s,1H),9.83(s,1H),8.76(s,1H),8.55(s,1H),6.68(d,J＝11.1Hz,1H),4.69(s,2H),4.46(q,J＝7.2Hz,2H),1.93(d,J＝11.1Hz,6H),1.43(t,J＝7.2Hz,3H).

Example 12:

Synthesis of Compound 0052

Step 1 Synthesis of Compound I52-3

Compound I52-2 (2 g,4.56 mmol) and compound I52-1 (0.62 g,3.65 mmol) were added separately to N, N-dimethylformamide (15 mL), followed by potassium carbonate (1.58 g,11.40 mmol). The resulting mixture was stirred at 80 ℃ for 2 hours to give a yellow solution. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The residue was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 3% to 30%) to give compound I52-3 (830 mg,1.99 mmol) as a yellow solid.

LC-MS(ESI):m/z=417.0/419.0[M+H]⁺

Step 2 Synthesis of Compound I52-4

Compound I52-3 (800 mg,1.92 mmol) and sodium hydroxide (230.06 mg,5.75 mmol) were added to tetrahydrofuran (4 mL) and water (4 mL), respectively, and the resulting mixture was stirred at 50℃for 1 hour to give a yellow solution. The mixture was concentrated, the pH of the mixture was adjusted with citric acid=6-7, extracted with ethyl acetate (20 mL x 3), the combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give compound I52-4 (800 mg,1.85 mmol) as a yellow oil.

LC-MS(ESI):m/z=389.1/391.1[M+H]⁺

Step 3 Synthesis of Compound I52-5

Compound I52-4 (750 mg,1.93 mmol) and N, N, N ', N' -tetramethyl chloroformyl amidine hexafluorophosphate (1081.26 mg,3.85 mmol) were added separately to acetonitrile (5 mL) and methylimidazole (0.61 mL,7.71 mmol) was added and the resulting mixture stirred at 25℃for 16 hours to give a yellow solution. The mixture was poured into water (15 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic phases were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 20% -20%) to give compound I52-5 (610 mg,1.64 mmol) as a yellow solid.

LC-MS(ESI):m/z=371.1/373.1[M+H]⁺

Step 4 Synthesis of Compound I52-7

Compound I52-5 (200 mg,0.54 mmol), compound I52-6 (96.71 mg,0.59 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (62.35 mg,0.11 mmol) and cesium carbonate (526.62 mg,1.62 mmol) were added to N, N-dimethylformamide (3 mL), respectively, followed by tris (dibenzylideneacetone) dipalladium (49.34 mg,0.05 mmol). The reaction was stirred at 90 ℃ for 2 hours to form a black solution. The mixture was poured into water (5 mL) and extracted with ethyl acetate (10 mL x 3) and the combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 50% to 50%) to give compound I52-7 (170 mg,0.37 mmol) as a brown solid.

LC-MS(ESI):m/z=454.3[M+H]⁺

Step 5 Synthesis of Compound 0052

Compound I52-7 (170 mg,0.37 mmol) was added to a solution of dichloromethane (2 mL) at 0deg.C, and boron tribromide (0.18 mL,1.87mmol,1M, an Naiji) was added and the resulting mixture stirred at 25deg.C for 1 hour to give a yellow solution. The mixture was concentrated to dryness under reduced pressure to give a crude product which was quenched with aminomethylol (2 m,2 ml). The mixture was purified by preparative HPLC (Waters-Xbridge-C18-10 um 19 x 250mm (eluent = 20% to 50% (v/v) acetonitrile and water with 10m% ammonium bicarbonate) to give compound 0052 (27.20 mg,0.06 mmol) as a white solid.

LC-MS(ESI):m/z=440.3[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:13.20(s,1H),9.42–9.37(m,1H),8.76(s,1H),8.55(s,1H),7.00(d,J＝11.4Hz,1H),4.73–4.63(m,2H),4.50–4.42(m,2H),2.06(s,3H),2.00(s,3H),1.43(t,J＝7.2Hz,3H).

Example 13:

synthesis of Compound 0053

Step 1 Synthesis of Compound I53-3

Compound I53-1 (0.36 mL,3.70mmol, pickle), compound I53-2 (1.20 mL,5.55mmol, pickle) and potassium carbonate (767.04 mg,5.55 mmol) were added separately to N, N-dimethylformamide (5 mL), and the resulting mixture was stirred at 25℃for 16 hours to give a yellow solution. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The residue was purified by silica gel chromatography (eluent=ethyl acetate) to give compound I53-3 (350 mg,1.19mmol, y=32.23%) as a yellow solid.

LC-MS(ESI):m/z=294.3[M+H]⁺

Step 2 Synthesis of Compound I53-4

Compound I31-8 (200 mg,0.57 mmol), compound I53-3 (182.77 mg,0.62 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (65.52 mg,0.11 mmol) and cesium carbonate (553.44 mg,1.70 mmol) were added to N, N-dimethylformamide (5 mL), followed by tris (dibenzylideneacetone) dipalladium (51.85 mg,0.06 mmol), respectively, under nitrogen. Stirring was carried out at 90℃for 2 hours, forming a black solution. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The residue was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0% to 70%) to give compound I53-4 (240 mg,0.42mmol, y = 74.92%) as a brown oil.

LC-MS(ESI):m/z=566.4[M+H]⁺

Step 3 Synthesis of Compound I53-5

Compound I53-4 (200 mg,0.35 mmol) was added to a solution of tetrahydrofuran (1 mL), followed by tetrabutylammonium fluoride (0.18 mL,0.18mmol, 1M). The resulting mixture was stirred at 25 ℃ for 1 hour to give a yellow solution. The reaction mixture was quenched with saturated ammonium chloride (5 mL). And extracted with ethyl acetate (10 mL x 3), the combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give compound I53-5 (140 mg,0.31mmol, y=87.71%) as a yellow solid.

LC-MS(ESI):m/z=452.3[M+H]⁺

Step 4 Synthesis of Compound 0053

Compound I53-5 (140 mg,0.31 mmol) was added to dichloromethane (2 mL) and boron tribromide (1.33 mmol,1.33mL,1M, an Naiji) was added and the resulting mixture stirred at 25℃for 1 hour to give a yellow solution. The mixture was concentrated to dryness under reduced pressure to give a crude product, and the reaction mixture was quenched with ammonia methanol (1M). The crude product was purified by preparative HPLC ((eluent=17% to 47% (v/v) acetonitrile and water with 0.1% fa) to give compound 0053 (67.11 mg,0.15mmol, y=57.72%) as a white solid.

LC-MS(ESI):m/z=438.3[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:13.14(s,1H),9.32(s,1H),8.72(s,1H),8.51(s,1H),6.94(d,J＝8.3Hz,1H),6.78(d,J＝8.2Hz,1H),4.87(s,1H),4.70–4.60(m,2H),4.45(t,J＝5.8Hz,2H),3.85(t,J＝6.0Hz,2H),2.04(s,3H),1.95(s,3H).

Example 14:

synthesis of Compound 0054

Step 1 Synthesis of Compound I54-2

Thionyl chloride (2 mL) was added dropwise to a mixed solution of dichloromethane (3 mL) and compound I54-1 (0.34 mL,3.37mmol, obtained) in an ice bath, and the reaction solution was stirred at 25℃for 18 hours. TLC showed the starting material spot disappeared and less polar spot formation was observed. The reaction solution was concentrated to dryness to give compound I54-2 (450 mg,3.12mmol, crude) as a white solid. Directly used in the next step without further treatment.

Step 2 Synthesis of Compound I54-3

To a mixed solution of compound I54-2 (450 mg,3.12mmol, crude product) and compound I53-1 (420 mg,3.11mmol, obtained) in N, N-dimethylformamide (10 mL) was added potassium carbonate (2061.80 mg,14.92 mmol), and the reaction solution was stirred at 60℃for 2 hours. The target molecular weight was detected by LCMS. The reaction solution was filtered and the filter cake was washed with N, N-dimethylformamide (5 ml x 2), the organic phases were combined and purified by preparative HPLC ((eluent = 0% to 8% (v/v) CH ₃ CN and H ₂ O with 0.01% nh ₄HCO₃) to give compound I54-3 (350 mg,1.70mmol, y = 54.60%) as a white solid.

LC-MS(ESI):m/z=207.1[M+H]⁺

Step 3 Synthesis of Compound I54-4

Compound I31-8 (120 mg,0.34 mmol), compound I54-3 (259.25 mg,1.26 mmol), cesium carbonate (276.72 mg,0.85 mmol) and N, N-dimethylformamide (6 mL) were added to a 10mL microwave tube, the resulting mixed solution was purged with nitrogen for 5 minutes, tris (dibenzylideneacetone) dipalladium (31.11 mg,0.03 mmol) and 4, 5-diphenylphosphine-9, 9-dimethylxanthene (39.31 mg,0.07 mmol) were added to the reaction solution, respectively, and the resulting mixture was then further purged with nitrogen for 5 minutes, and the reaction solution was subjected to microwave reaction at 90℃for 2.5 hours, and then cooled to room temperature. The target molecular weight was detected by LCMS. The reaction was then poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3), and the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC ((eluent=0% to 45% (v/v) CH ₃ CN and H ₂ O with 0.01% nh ₄HCO₃) to give compound I54-4 (150 mg,0.31mmol, y=92.0%) as a yellow solid.

LC-MS(ESI):m/z=479.2[M+H]⁺

Step 4 Synthesis of Compound 0054

To a solution of compound I54-4 (150 mg,0.31 mmol) in methylene chloride (15 mL) was added dropwise a solution of boron tribromide (3.13 mL, 1M/L) in methylene chloride at room temperature, and the reaction solution was stirred at 25℃for 18 hours. The target molecular weight was detected by LCMS. The reaction solution was quenched with methanol (5 ml). The reaction solution was then basified to ph=8-9 with 4mL of methanolic ammonia (7M/L). The reaction solution is concentrated to dryness to obtain crude compound. The crude product was purified by preparative HPLC (Phenomenex Gemini 150mm*25mm*10um column% (eluent=5% to 55% (v/v) CH ₃ CN and H ₂ O,0.1% hcooh) to give compound 0054 (2.75 mg,0.01mmol, y=1.85%) as a white solid.

LC-MS(ESI):m/z=465.0[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:8.72(s,1H),8.49(s,1H),8.19(s,1H),6.94(d,J＝8.4Hz,1H),6.77(d,J＝8.2Hz,1H),4.64(d,J＝2.8Hz,2H),4.50(t,J＝6.4Hz,2H),2.77(t,J＝6.4Hz,2H),2.17(s,6H),2.04(s,3H),1.95(s,3H)

Example 15:

Synthesis of Compound 0055

Step 1 Synthesis of Compound I55-2

To a solution of compound I55-1 (230 mg,0.65 mmol) in methylene chloride (2 mL) was added boron tribromide (3.26 mL,3.26mmol,1 mOL/L) under nitrogen at-40 ℃. The reaction was stirred at-40 ℃ for 2 hours. To the reaction solution was added methanol (2 mL) to quench, then concentrated, and the concentrated reaction solution was poured into water (20 mL) and extracted with dichloromethane (30 ml×2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give Compound I55-2 (180 mg,0.53 mmol) as a yellow solid.

LC-MS(ESI):m/z=338.9/340.9[M+H]⁺

Step 2 Synthesis of Compound I55-4

To a solution of compound I55-3 (0.72 mL,7.40mmol, obtained) in N, N-dimethylformamide (20 mL) was added 3-iodooxetane (0.76 mL,8.88mmol, obtained) and cesium carbonate (4.82 g,14.80 mmol), respectively, at room temperature, and the reaction solution was stirred at 80℃for 3.5 hours. The suspension was filtered through celite and the filter residue was washed with ethyl acetate (20 ml x 3) and the filtrate was concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by preparative HPLC (Phenomenex Gemini mm x 25mm x 10um column (eluent = 30% to 60% (v/v) CH ₃ CN and H ₂ O with 0.025% nh ₄HCO₃) to give compound I55-4 (150 mg,0.78 mmol) as a white solid.

LC-MS(ESI):m/z=192.0[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:8.23(s,1H),8.18(s,1H),7.77(d,J＝6.6Hz,2H),5.98–5.88(m,1H),5.06-5.00(m,2H),4.99–4.94(m,2H).

Step 3 Synthesis of Compound 0055

To a solution of compound I55-2 (172 mg,0.51 mmol) in N, N-dimethylformamide (5 mL) under nitrogen was added, in order, compound I55-4 (96.6 mg,0.51 mmol), tris (dibenzylideneacetone) dipalladium (46.43 mg,0.05mmol, pichia), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (58.68 mg,0.10mmol, pichia) and cesium carbonate (495.63 mg,1.52 mmol). The reaction was stirred at 90 ℃ for 2.5 hours. The reaction was quenched with dilute hydrochloric acid (1 m,10 ml) and extracted with ethyl acetate (30 ml x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by preparative high performance liquid chromatography (Waters-CORTECS-C18-2.7 μm-4.6 x 30mM (a: 10mM NH ₄HCO₃/H₂ O b: acetonitrile, b/a=5 to 95%)) to give compound 0055 (8.55 mg,0.02 mmol) as a yellow solid.

LC-MS(ESI):m/z=450.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:13.28(s,1H),9.32(s,1H),8.76(s,1H),8.65(s,1H),6.94(d,J＝8.1Hz,1H),6.78(d,J＝8.2Hz,1H),6.16–6.04(m,1H),5.12–4.96(m,4H),4.73–4.58(m,2H),2.04(s,3H),1.95(s,3H).

Example 16:

synthesis of Compound 0056

Step 1 Synthesis of Compound I56-2

Sodium hydride (62.49 mg,60% purity, 1.56 mmol) was added to a mixture of compound I56-1 (200 mg,1.04mmol, lev.) and N, N-2 methylformamide (2 mL) at 0℃and the mixture was nitrogen displaced 3 times, stirred for 30 minutes, then compound I31-2 (513.97 mg,1.56 mmol) was added and stirred at 25℃for 1 hour. A black solution was formed. The reaction mixture was quenched with aqueous ammonium chloride (5 mL). And extracted with ethyl acetate (15 ml x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0% to 5%) to give compound I56-2 (150 mg,0.34mmol, y = 32.72%) as a yellow solid.

LC-MS(ESI):m/z=441.0/443.0[M+H]⁺

Step 2 Synthesis of Compound I56-3

To a mixed solution of compound I56-2 (150 mg,0.34 mmol) in tetrahydrofuran (2 ml) and water (2 ml) was added sodium hydroxide (40.90 mg,1.02 mmol), and the resulting mixture was stirred at 50 ℃ for 4 hours to give a yellow solution. The reaction mixture was quenched with aqueous citric acid and extracted with ethyl acetate (10 ml x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound I56-3 (130 mg,0.32mmol, y= 92.57%) as a yellow solid.

LC-MS(ESI):m/z=413.0/415.0[M+H]⁺

Step 3 Synthesis of Compound I56-4

To a solution of compound I56-3 (170 mg,0.41 mmol) and N, N' -tetramethyl chloroformidine hexafluorophosphate (231.50 mg,0.83 mmol) was added N-methylimidazole (0.13 ml,1.65 mmol), and the resulting mixture was stirred at 25 ℃ for 16 hours to give a yellow solution. The mixture was poured into water (15 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0% -45%) to give compound I56-4 (150 mg,0.38mmol, y = 92.27%) as a yellow solid.

LC-MS(ESI):m/z=395.0/397.0[M+H]⁺

Step 4 Synthesis of Compound I56-5

To a solution of compound I56-4 (130 mg,0.33 mmol), compound I31-9 (59.22 mg,0.36 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (38.18 mg,0.07 mmol) and cesium carbonate (322.46 mg,0.99 mmol) in N, N-dimethylformamide (3 ml) was added tris (dibenzylideneacetone) dipalladium (30.21 mg,0.03 mmol), the mixture was replaced with nitrogen gas 3 times, and stirred at 90 ℃ for 2 hours. A black solution was formed. The mixture was poured into water (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0% -50%) to give compound I56-5 (164 mg,0.31mmol, y = 93.93%) as a brown solid.

LC-MS(ESI):m/z=476.2/478.2[M+H]⁺

Step 5 Synthesis of Compound 0056

Compound I56-5 (164 mg,0.31 mmol) was stirred in a mixed solution of hydrobromic acid in acetic acid (1 mL,33% by weight) at 65℃for 16 hours to give a yellow solution. The mixture was concentrated under reduced pressure to give the crude product, which was quenched with methanolic ammonia (1M) and concentrated. The crude product was purified by preparative HPLC (eluent=17% to 47% (v/v) acetonitrile and water with 0.1% ammonium bicarbonate) to give 0056 (3.36 mg,0.01mmol, y=2.04%) as a white solid.

LC-MS(ESI):m/z=462.0/464.0[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:13.28(s,1H),10.78(s,1H),8.76(s,1H),8.52(s,1H),7.43(d,J＝9.0Hz,1H),7.09(d,J＝8.8Hz,1H),4.72(s,2H),4.46(q,J＝7.2Hz,2H),1.43(t,J＝7.2Hz,3H)

Example 17:

Synthesis of Compound 0057

Step 1 Synthesis of Compound I57-3

To a solution of compound I57-1 (2 g,12.94mmol, b.i.) in N, N-dimethylformamide (20 mL) was added compound I57-2 (2.80 mL,19.41mmol, bide) and cesium carbonate (8.43 g,25.88 mmol) at room temperature. The reaction solution was stirred at 25 ℃ for 2 hours. The reaction was poured into water (200 mL) and extracted with ethyl acetate (100 mL x 3) and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel (eluent = petroleum ether: ethyl acetate = 10:1 to 8:1) to give compound I57-3 (650 mg,2.75 mmol) as a yellow oil.

LC-MS(ESI):m/z=237.0[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ8.98(s,1H),8.67(s,1H),5.49(q,J=9.0Hz,2H)。

Step 2 Synthesis of Compound I57-4

Compound I57-3 (640 mg,2.71 mmol) was mixed with ammonia (6 mL,45.18mmol,29%, complete) at room temperature. Stirred at 80 ℃ for 2 hours. The reaction solution was lyophilized to give Compound I57-4 (680 mg,3.13 mmol) as a yellow solid. It was used directly in the next step without further purification.

LC-MS(ESI):m/z=218.0[M+H]⁺

Step 3 Synthesis of Compound I57-6

To a solution of compound I57-4 (200 mg,0.57 mmol) in N, N-dimethylformamide (3 mL) was added, in order, compound I57-5 (68.88 mg,0.42 mmol), tris (dibenzylideneacetone) dipalladium (51.85 mg,0.06mmol, an Naiji), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (65.52 mg,0.11mmol, an Naiji) and cesium carbonate (553.44 mg,1.70 mmol) under nitrogen. The reaction was stirred at 90 ℃ for 2.5 hours. The reaction was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3) and the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (eluent = petroleum ether: ethyl acetate = 3:1 to 0:1) to give compound I57-6 (230 mg,0.47 mmol) as a yellow solid.

LC-MS(ESI):m/z=490.0[M+H]⁺

Step 4 Synthesis of Compound 0057

To a solution of compound I57-6 (225 mg,0.46 mmol) in methylene chloride (2 mL) was added dropwise a solution of boron tribromide (2.30 mL,2.30mmol,1mol/L, an Naiji) at-40℃under nitrogen. After the completion of the dropwise addition, the temperature was raised to 25℃and stirred for 2 hours. The reaction was quenched with methanol (2 mL) and concentrated to give the crude product. The crude product was purified by preparative high performance liquid chromatography (Agilent-Poroshell HPH-C18-2.7um-4.6 x 50mm (eluent = 20% to 80% (v/v) CH ₃ CN and H ₂O,0.025％NH₄HCO₃) to give compound 0057 (64.89 mg,0.14 mmol) as a white solid.

LC-MS(ESI):m/z=476.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:13.32(s,1H),9.33(s,1H),8.84(s,1H),8.67(s,1H),6.95(d,J＝8.3Hz,1H),6.78(d,J＝8.2Hz,1H),5.39(d,J＝9.0Hz,2H),4.68(d,J＝2.8Hz,2H),2.04(s,3H),1.95(s,3H).

Example 18:

Synthesis of Compound 0060

Step 1 Synthesis of Compound I31-10

To a mixed solution of compound I31-8 (200 mg,0.57 mmol) and compound I31-9 (93.01 mg,0.57 mmol) in ethylene glycol dimethyl ether (10 mL) under nitrogen atmosphere was added cesium carbonate (461.20 mg,1.42 mmol), tris (dibenzylideneacetone) dipalladium (51.85 mg,0.06 mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (65.52 mg,0.11 mmol) in this order, and the reaction solution was stirred at 100℃for 2 hours. The target molecular weight was detected by LCMS. The reaction was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3) and the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulphate, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (eluent = petroleum ether: ethyl acetate = 100:1 to 1:1) to give compound I31-10 (150 mg,0.21mmol, y = 37.7%) as a yellow solid.

LC-MS(ESI):m/z=436.1[M+H]⁺

Step 2 Synthesis of Compound I60-1

To a solution of compound I31-10 (50 mg,0.07 mmol) in tetrahydrofuran (1.5 mL) was added dropwise lithium bis (trimethylsilyl) amide (52.50 μl,0.05 mmol) (1M hexane solution) at-65 ℃ for 20 minutes after the addition was completed, then a solution of N- (dioxophenyl- λ6-thio) -N-fluorobenzenesulfonamide (13.24 mg,0.04 mmol) in tetrahydrofuran (0.5 mL) was added dropwise to the solution, and stirring was continued for 30 minutes at-65 ℃, and the temperature was raised to 25 ℃ for 30 minutes again. The reaction was then quenched with saturated ammonium chloride solution (3 mL) and extracted with ethyl acetate (30 mL x 3), and the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by preparative high performance liquid chromatography ((eluent=5% to 65% (v/v) CH ₃ CN and H ₂ O, containing 0.01% tfa) to give compound I60-1 (50 mg,0.04mmol, y=63.6%) as a yellow solid.

LC-MS(ESI):m/z=472.0[M+H]⁺

Step 3 Synthesis of Compound 0060

To a solution of compound I60-1 (50 mg,0.04 mmol) in methylene chloride (2 mL) was added dropwise a solution of boron tribromide (0.34 mL,0.34 mmol), and the resultant reaction solution was stirred at 25℃for 1 hour, and the reaction solution became yellow. The target molecular weight was detected by LCMS. The reaction was quenched with methanol (5 mL), and the reaction was basified with 7M methanolic ammonia (6 mL) to ph=8 to 9, then concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by preparative high performance liquid chromatography (Phenomenex Gemini mm x 25mm x 10um column (eluent = 5% to 60% (v/v) CH ₃ CN and H ₂O,0.01％NH₄HCO₃) to give compound 0060 (1.59 mg, y = 8.2%) as a yellow solid.

LC-MS(ESI):m/z=458.1[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:13.70(s,1H),9.54(s,1H),8.80(s,1H),8.52(s,1H),7.04(d,J＝8.3Hz,1H),6.88(d,J＝8.3Hz,1H),4.48(q,J＝7.2Hz,2H),2.08(s,3H),1.98(s,3H),1.44(t,J＝7.2Hz,3H).

Example 19:

Synthesis of Compound 0064

Step 1 Synthesis of Compound I64-2

Triethylamine (1.97 mL,14.19 mmol) was added dropwise to a solution of compound I64-1 (2 g,9.46mmol, pichia) and ethylenediazaoxalate (1.42 g,9.46mmol, BIDE) in ethanol (20 mL) at N ₂, 0℃and the reaction mixture was warmed to 25℃and stirred for 18 hours. LCMS showed the starting material was consumed and the desired product formed. The mixture was filtered and the solid was washed with ethyl acetate (20 ml x 3) and the filtrate concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 10% to 50%) to give compound I64-2 (1.26 g,5.81 mmol) as a white solid.

LC-MS(ESI):m/z=217.0/219.0[M+H]⁺

Step 2 Synthesis of Compound I64-3

To a mixed solution of compound I64-2 (1.26 g,5.81 mmol) and (4-methoxyphenyl) methylamine (758.42. Mu.L, 5.81mmol, BIDE) was added THF (20 mL), potassium carbonate (2005.67 mg,14.51mmol, BIDE), and the resulting mixture was stirred at 0℃for 4 hours. LCMS showed the starting material was consumed and the desired product formed. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 10% to 50%) to give compound I64-3 (1.57 g,4.94mmol, y = 85.33%) as a yellow oil.

LC-MS(ESI):m/z=318.1[M+H]⁺

Step 3 Synthesis of Compound I64-4

To a solution of compound I64-3 (1.57 g,4.94 mmol) in ethanol (15 mL) was added sodium thiomethoxide (0.69 g,9.88mmol, post), and the resulting mixture was stirred at 60℃for 18 hours to give a yellow solution. LCMS showed the starting material was consumed and the desired product formed. The mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 10% to 20%) to give compound I64-4 (1.16 g,3.52 mmol) as a yellow oil.

LC-MS(ESI):m/z=330.1[M+H]⁺

Step 4 Synthesis of Compound I64-5

A mixed solution of compound I64-4 (1.16 g,3.52 mmol) and DCM (12 mL) was added in portions over 0.5h at a temperature of no more than 0℃3-chlorobenzene-1-carboxylic acid (2.39 mL,7.75 mmol) and the resulting mixture was stirred at 25℃for 2 h. LCMS showed the starting material was consumed and the desired product formed. The mixture was poured into DCM (20 mL), washed with saturated brine (20 mL), and the organic phase was dried over anhydrous Na ₂SO₄, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 10% to 50%) to give compound I64-5 (830 mg,2.30 mmol) as a yellow oil.

LC-MS(ESI):m/z=362.0[M+H]⁺

Step 5 Synthesis of Compound I64-6

To a mixed solution of compound I64-5 (415 mg,1.15 mmol) and cyclopropyl alcohol (0.67 ml,11.48 mmol) was added cesium carbonate (1122.37 mg,3.44 mmol), and the resulting mixture was stirred at 50 ℃ for 18 hours to give a yellow solution. LCMS showed the starting material was consumed and the desired product formed. The mixture was filtered and the solid was washed with ethyl acetate (20 ml x 3) and the filtrate concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 10% to 50%) to give compound I64-6 (400 mg,1.17 mmol) as a yellow solid.

LC-MS(ESI):m/z=340.2[M+H]⁺

Step 6 Synthesis of Compound I64-7

A mixed solution of compound I64-6 (380 mg,1.12 mmol) and 2, 2-trifluoroacetic acid (5 mL) was stirred at 80℃for 18 hours. LCMS showed the starting material was consumed and the desired product formed. The mixture was concentrated to dryness under reduced pressure to give crude product. The crude product was adjusted to ph=7-8 with saturated NaHCO ₃ solution (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give compound I64-7 (210 mg,0.96 mmol) as a yellow solid.

LC-MS(ESI):m/z=220.2[M+H]⁺

Step 7 Synthesis of Compound I64-9

To a mixture of compound I64-8 (200 mg,0.57 mmol), compound I64-7 (124.14 mg,0.57 mmol), cesium carbonate (553.44 mg,1.70 mmol) and [5- (diphenylphosphino) -9, 9-dimethyl-9H-quinolin-4-yl ] diphenylphosphine (65.52 mg,0.11 mmol) dioxane (1 mL) was added tris [ (1 e,4 e) -1, 5-diphenylpenta-en-1, 4-dien-3-one ] bis [ palladium (0) ] (51.85 mg,0.06 mmol), the mixture was degassed and purged 3 times with N ₂ and stirred at N ₂ guard 90 ℃ for 18 hours. LCMS showed the starting material was consumed and the desired product formed. The mixture was filtered and the filter cake was washed with ethyl acetate (10 ml x 3) and the filtrate concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 10% to 50%) to give compound I64-9 (150 mg,0.31 mmol) as a brown solid.

LC-MS(ESI):m/z=492.2[M+H]⁺

Step 8 Synthesis of Compound 0064

To a mixture of compound I64-9 (120 mg,0.24 mmol) and DCM (8 mL) was added dropwise boron tribromide (1.22 mL,1.22mmol,1M in DCM), the reaction mixture was warmed to 25℃and stirred for 2 h. LCMS showed the starting material was consumed and the desired product formed. The reaction mixture was quenched with MeOH (2 mL) and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by Prep-HPLC (Phenomenex Gemini 150mm*25mm*10um column (eluent = 30% to 60% (v/v) CH ₃ CN and H ₂O,0.025％NH₄HCO₃) to give compound 0064 (34.81 mg,0.07 mmol) as a white solid.

LC-MS(ESI):m/z=478.2[M+H]⁺

1H NMR(400MHz,DMSO-d₆)δ:13.20(s,1H),9.35(s,1H),8.42(s,1H),6.94(d,J＝8.4Hz,1H),6.77(d,J＝8.3Hz,1H),4.67(d,J＝3.2Hz,2H),4.59-4.52(m,1H),4.30(q,J＝7.2Hz,2H),2.03(s,3H),1.94(s,3H),1.38(t,J＝7.2Hz,3H),0.92-0.81(m,4H).

Example 20:

synthesis of Compound 0065

Step 1 Synthesis of Compound I65-2

To a mixed solution of compound I31-8 (200 mg,0.57 mmol), compound I65-1 (84.45 mg,0.57mmol, after-coming), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (65.52 mg,0.11 mmol) and cesium carbonate (553.44 mg,1.70 mol) in N, N-dimethylformamide (4 ml) was added tris (dibenzylideneacetone) dipalladium (51.85 mg,0.06 mmol), the mixture was replaced with nitrogen gas 3 times, and the reaction was stirred at 90 ℃ for 2 hours. The mixture was poured into water (5 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by silica gel chromatography (eluent = tetrahydrofuran: petroleum ether: = 0% to 50%) to give compound I65-2 (300 mg,0.56mmol, y = 99.31%) as a yellow oil.

LC-MS(ESI):m/z=422.3[M+H]⁺

Step 2 Synthesis of Compound 0065

To a solution of compound I65-2 (240 mg,0.57 mmol) in dichloromethane (1 ml) was added boron tribromide (0.27 ml,2.85mmol, 1M) and stirred at 60℃for 2 hours. A black solution was formed. The mixture was concentrated under reduced pressure to give a crude product, and the reaction mixture was quenched with methanolic ammonia (1M). The crude product was purified by preparative HPLC (eluent = 17% to 47% (v/v) acetonitrile and water with 0.1% formic acid and ammonium bicarbonate twice) to give compound 0065 (13.86 mg,0.03mmol, y = 5.97%) as a white solid.

LC-MS(ESI):m/z=408.1[M+H]⁺

1H NMR(400MHz,DMSO-d₆)δ:13.18(s,1H),9.33(s,1H),8.77(s,1H),8.53(s,1H),6.95(d,J＝8.2Hz,1H),6.78(d,J＝8.2Hz,1H),4.67(d,J＝3.0Hz,2H),4.03(s,3H),2.04(s,3H),1.95(s,3H).

Example 21:

Synthesis of Compound 0067

Step 1 Synthesis of Compound I67-3

Compound I67-1 (250 mg,1.32 mmol) and compound I67-2 (522.30 mg,1.98 mmol) were added to methanol (3 mL), followed by AcOH (100. Mu.L, 1.75 mmol). The reaction was stirred at 25 ℃ for 0.5 hours, then sodium cyanoborohydride (165.71 mg,2.64mmol, an Naiji) was added. The reaction was stirred at 25 ℃ for 2.5 hours. LCMS showed the desired MS. The mixture was poured into water (10 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 100:1 to 95:5) to give compound I67-3 (245 mg,0.56mmol, y = 42.5%) as a yellow solid.

LC-MS(ESI):m/z=437.0/439.0[M+H]⁺

Step 2 Synthesis of Compound I67-4

Compound I67-3 (245 mg,0.64 mmol) was added to tetrahydrofuran (2 mL), methanol (2 mL), water (2 mL), and NaOH (65.80 mg,1.64 mmol) was added. Stirring was carried out at 50℃for 1 hour, LCMS showed the desired MS. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL). The combined aqueous phases were adjusted to ph=2, extracted with ethyl acetate (30 mL x 2), the organic phases combined and washed with brine (20 mL) and concentrated under reduced pressure to give compound I67-4 (230 mg,0.56mmol, crude) as a white solid.

LC-MS(ESI):m/z=409.0/411.0[M+H]⁺

Step 3 Synthesis of Compound I67-5

Compound I67-4 (230 mg,0.56 mmol) was added to acetonitrile (3 mL) followed by N, N, N ', N' -tetramethyl chloroformyl amidine hexafluorophosphate (393.83 mg,1.40mmol, an Naiji), methylimidazole (179.03. Mu.L, 2.25mmol, an Naiji). The reaction was stirred at 25 ℃ for 16 hours. LCMS showed to give the desired MS. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: sodium sulfate = 10:1 to 7:3) to give compound I67-5 (101 mg,0.26mmol, y = 45.9%) as a white solid.

LC-MS(ESI):m/z=391.0/393.0[M+H]⁺

Step 4 Synthesis of Compound I67-6

To a solution of compound I67-5 (100 mg,0.26 mmol) and compound I31-9 (50.00 mg,0.31 mmol) in N, N-dimethylformamide (1 mL) was added tris (dibenzylidene-BASE acetone) dipalladium (23.38 mg,0.03mmol, an Naiji), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (29.55 mg,0.05mmol, an Naiji) and cesium carbonate (249.58 mg,0.77 mmol). The reaction was stirred under nitrogen for 3h at 90 ℃. LCMS showed to give the desired MS. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: THF = 10:1 to 1:1) to give compound I67-6 (102 mg,0.22mmol, y = 84.9%) as a yellow solid.

LC-MS(ESI):m/z=474.2[M+H]⁺

Step 5 Synthesis of Compound 0067

Compound I67-6 (101 mg,0.22 mmol) was added to a solution of dichloromethane (2 mL) under nitrogen at-40℃followed by boron tribromide (1.08 mL,1.08mmol,1mol/L, an Naiji). The reaction was stirred at 25 ℃ for 2 hours, LCMS showed the desired Ms. To the reaction was added 2mL MeOH, quenched and concentrated. The crude product was purified by preparative high performance liquid chromatography (Agilent-pore shell HPH-C18-2.7um-4.6 x 50mm (eluent = 20% to 80% (v/v) acetonitrile and water, 0.025% ammonium bicarbonate) to give compound 0067 (18.07 mg,0.04mmol, 20.1%) as a white solid.

LC-MS(ESI):m/z=460.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:13.16(s,1H),10.43(s,1H),8.76(s,1H),8.53(s,1H),6.90(d,J＝10.7Hz,1H),4.79–4.65(m,2H),4.46(q,J＝7.3Hz,2H),2.00(s,3H),1.43(t,J＝7.2Hz,3H).

Example 22:

Synthesis of Compound 0068

Step 1 Synthesis of Compound I68-2

To a mixed solution of compound I68-1 (417.30 mg,2.43 mmol), compound I31-2 (1.5 g,4.56 mmol) and N, N-dimethylformamide (15 mL) was added potassium carbonate (1.58 g,11.40 mmol). The reaction solution was stirred at 80 ℃ for 16 hours. The mixture was poured into (50 mL) of water and extracted with ethyl acetate (60 ml×3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10:1 to 5:1) to give compound I68-2 (1.67 g,3.82mmol, y = 83.7%) as a white solid.

LC-MS(ESI):m/z=436.8/438.8[M+1]⁺

Step 2 Synthesis of Compound I68-3

To a solution of compound I68-2 (1.67 g,3.82mmol, 83.7%) in tetrahydrofuran (10 mL) was added water (10 mL), sodium hydroxide (0.46 g,11.45 mmol), respectively. The reaction was stirred at 50 ℃ for 1 hour. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 1). The combined aqueous phases were adjusted to ph=2 and extracted with ethyl acetate (30 ml×2), the combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give crude compound I68-3 (1.06 g,2.59mmol, y=67.8%) as a white solid.

LC-MS(ESI):m/z=409.1/411.1[M+H]⁺

Step 3 Synthesis of Compound I68-4

To a solution of compound I68-3 (1.06 g,2.59 mmol) in acetonitrile (10 mL) was added TCFH (1.82 g,6.47 mmol) NMI (825.11. Mu.L, 10.35 mmol). The reaction was stirred at 25 ℃ for 18 hours. Concentrating under reduced pressure to dryness to obtain crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10:1 to 7:3) to give compound I68-4 (800 mg,2.04mmol, y = 75.4%,) as a white solid.

LC-MS(ESI):m/z=390.9/392.9[M+H]⁺

Step 4 Synthesis of Compound I68-5

To compound I68-4 (200 mg,0.57 mmol) were added compound I31-9 (68.88 mg,0.42 mmol), DMF (2 mL), tris (dibenzylideneacetone) palladium (46.76 mg,0.05mmol, an Naiji), xantphos (59.10 mg,0.10mmol, an Naiji) and cesium carbonate (499.16 mg,1.53 mmol), respectively. The reaction was stirred at 90 ℃ for 3 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 ml×3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: THF = 10:1 to 1:1) to give compound I68-5 (120 mg,0.18mmol, y = 35.2%) as a yellow oil.

LC-MS(ESI):m/z=474.0[M+H]⁺

Step 5 Synthesis of Compound 0068

To a solution of compound I68-5 (100 mg,0.15 mmol) and methylene chloride (2 mL) was added BBr ₃ (0.75 mL,0.75mmol,1mmol/L, an Naiji) under nitrogen-40 ℃. The reaction was stirred at 25 ℃ for 2 hours. 2mL of methanol was added to the reaction, quenched, and concentrated to dryness. The crude product was purified by preparative HPLC (agilent HPH-C18-2.7um-4.6 x 50mmb (eluent = 20% to 80% (v/v) CH ₃ CN and H ₂O,0.025％NH₄HCO₃) to give 0068 (12.21 mg,0.14mmol, y = 18.1%) as a white solid.

LC-MS(ESI):m/z=460.1[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:13.33(s,1H),10.05(s,1H),8.76(s,1H),8.53(s,1H),7.51–7.37(m,1H),4.71(d,J＝13.0Hz,2H),4.46(d,J＝7.2Hz,2H),2.10–2.07(m,3H),1.43(t,J＝7.2Hz,3H)

Example 23:

synthesis of Compound 0072

Step 1 Synthesis of Compound I72-2

To a mixed solution of compound I72-1 (1.00 g,6.55mmol, obtained) and N, N-dimethylformamide (10 mL) was added sodium hydride (0.39 g,9.83mmol,60% oil solution), and reacted under nitrogen at 0℃followed by ethyl iodide (0.53 mL,6.62 mmol). The reaction was stirred at 25 ℃ for 16 hours. The desired molecular weight was detected by LCMS. The reaction mixture was quenched with aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The residue was purified by silica gel chromatography (eluent = tetrahydrofuran: petroleum ether = 0% to 50%) to give compound I72-2 (1.16 g,6.42mmol, y = 97.99%) as a white solid.

LC-MS(ESI):m/z=181.1[M+H]⁺

Step 2 Synthesis of Compound I72-3

To a solution of compound I72-2 (470 mg,2.60 mmol), p-methoxybenzylamine (0.41 mg,3.12mmol, after completion), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (301.12 mg,0.52 mmol) and cesium carbonate (2543.35 mg,7.81 mmol) in N, N-dimethylformamide (5 mL) was added tris (dibenzylidene-BASE acetone) dipalladium (238.27 mg,0.26 mmol), the mixture was replaced with nitrogen 3 times and stirred at 85 ℃ for 16 hours. A black solution was formed. The desired molecular weight was detected by LCMS. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The residue was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0% to 100%) to give compound I72-3 (220 mg,0.78mmol, y = 30.05%) as a yellow oil.

LC-MS(ESI):m/z=282.2[M+H]⁺

Step 3 Synthesis of Compound I72-4

Compound I72-3 (220 mg,0.78 mmol) was added to trifluoroacetic acid (1 mL) and stirred at 60℃for 16h to form a black solution. The desired molecular weight was detected by LCMS. The mixture was concentrated to dryness under reduced pressure to give crude product. The crude product was purified by Prep-HPLC ((eluent = 30% to 30% (v/v) acetonitrile and water with 0.1% ammonium bicarbonate) to give compound I72-4 (100 mg,0.62mmol, y = 79.33%) as a yellow solid.

LC-MS(ESI):m/z=162.1[M+H]⁺

Step 4 Synthesis of Compound I72-5

To a solution of compound I31-8 (197.81 mg,0.56 mmol), compound I72-4 (143.57 mg,0.25 mmol) and cesium carbonate (1212.65 mg,3.72 mmol) in N, N-dimethylformamide (4 mL) was added tris (dibenzylidene-BASE acetone) dipalladium (113.61 mg,0.12 mmol), the mixture was replaced 3 times with nitrogen and stirred at 90 ℃ for 2 hours to form a black solution. The desired molecular weight was detected by LCMS. The mixture was poured into water (15 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The residue was purified by silica gel chromatography (eluent = tetrahydrofuran: petroleum ether = 0% to 50%) to give compound I72-5 (250 mg,0.58mmol, y = 46.48%) as a yellow oil.

LC-MS(ESI):m/z=434.3[M+H]⁺

Step 5 Synthesis of Compound 0072

To a mixed solution of compound I72-5 (100 mg,0.23 mmol) and dichloromethane (2 mL) at 0 ℃ was added boron tribromide (1.15 mL,1.15 mmol), and the mixture was stirred at 25 ℃ for 16 hours to form a black solution. LCMS detected the desired molecular weight. The mixture was concentrated to dryness under reduced pressure to give the crude product, which was quenched with ammonia methanol (1M). The mixture was purified by Prep-HPLC (eluent = 35% to 65% (v/v) acetonitrile and water with 0.1% ammonium bicarbonate) to give compound 0072 (4.43 mg,0.01mmol, y = 4.58%) as a white solid.

LC-MS(ESI):m/z=420.1[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:12.06(s,1H),9.29(s,1H),8.02(d,J＝5.8Hz,1H),7.45(d,J＝3.2Hz,1H),7.26(d,J＝6.0Hz,1H),7.15(d,J＝3.2Hz,1H),6.94(d,J＝8.2Hz,1H),6.77(d,J＝8.2Hz,1H),4.59(d,J＝3.2Hz,2H),4.24(d,J＝7.2Hz,2H),2.04(s,3H),1.95(s,3H),1.36(t,J＝7.2Hz,3H)

Example 24:

Synthesis of Compound 0074

Step 1 Synthesis of Compound I74-2

To a mixed solution of compound I74-1 (200 mg,0.60 mmol), compound I45-2 (152.89 mg,0.72 mmol), cesium carbonate (485.69 mg,1.49 mmol) and DME (1.5 mL) were added tris (dibenzylideneacetone) palladium (54.60 mg,0.06 mmol) and Xantphos (69.00 mg,0.12 mmol), respectively, and the mixture was replaced 3 times with N ₂, and stirred at 100℃for 4 hours. The desired molecular weight was detected by LCMS. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na ₂SO₄, filtered and concentrated to dryness under reduced pressure to give the crude product. The residue was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10:1 to 2:3) to give compound I74-2 (180 mg,0.25mmol, y = 42.7%) as a yellow solid.

LC-MS(ESI):m/z=481.1[M+H]⁺

Step 2 Synthesis of Compound I74-3

To a solution of compound I74-2 (100 mg,0.17 mmol) in dichloromethane (1.5 mL) at-65 ℃ was added boron tribromide (499.39 μl,0.50 mmol) and the resulting mixture was stirred at-65 ℃ for 1 hour. The desired molecular weight was detected by LCMS. The reaction mixture was quenched with MeOH (5 mL) and concentrated to dryness, then the residue was basified with 3mL NH ₃ (7M in MeOH) and concentrated to dryness to give the crude product. The crude product was purified by silica gel chromatography (DCM: meoh=100:1 to 20:1) to give compound I74-3 (80 mg,0.15mmol, y=89.6%) as a yellow solid.

LC-MS(ESI):m/z=467.4[M+H]⁺

Step 3 Synthesis of Compound I74-4

To a solution of compound I74-3 (80 mg,0.12 mmol) in dichloromethane (4 mL) was added dessmartin reagent (101.82 mg,0.24 mmol) under ice-water cooling, and the resulting mixture was stirred at 20 ℃ for 18 hours to give a yellow solution. The desired molecular weight was detected by LCMS. The reaction mixture was adjusted to ph=7-8 with saturated sodium bicarbonate (10 mL), extracted with dichloromethane (30 mL x 3) and the combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by Prep-HPLC (eluent = 0% to 50% (v/v) CH ₃CN/H₂ O,0.1% hcooh) to give compound I74-4 (60 mg,0.11mmol, y = 89.5%) as a white solid.

LC-MS(ESI):m/z=447.2[M+H]⁺

Step 4 Synthesis of Compound 0074

To a solution of compound I74-4 (40 mg,0.09 mmol) in dichloromethane (3 mL) was added boron tribromide (0.45 mL,0.45 mmol) under ice-water cooling, and the resulting mixture was stirred at 20 ℃ for 2 hours to give a yellow solution. The desired molecular weight was detected by LCMS. The residue was quenched with methanol (5 mL) and concentrated to dryness, then the residue was basified with 6mL ammonia (7M in MeOH) to ph=8-9, then the residue was concentrated to dryness to give the crude product. The crude product was purified by Prep-HPLC (Phenomenex Gemini mm x 25mm x 10um column (eluent = 10% to 60% (v/v) CH ₃CN/H₂O,0.01NH₄HCO₃) to give compound 0074 (3.8 mg,0.01mmol, y = 12.9%) as a yellow solid.

LC-MS(ESI):m/z=433.0[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:12.63(s,1H),9.49(s,1H),8.62(s,1H),7.54(d,J＝3.4Hz,1H),7.41(d,J＝7.4Hz,1H),7.06(d,J＝3.4Hz,1H),7.02(d,J＝8.4Hz,1H),6.84(d,J＝8.4Hz,1H),6.80(d,J＝7.2Hz,1H),4.29(q,J＝7.4Hz,2H),1.89(s,3H),1.80(s,3H),1.38(t,J＝7.2Hz,3H)

Example 25:

synthesis of Compound 0075

Step 1 Synthesis of Compound I75-3

To a mixture of compound I75-1 (15 g,60.00mmol, pickle), compound I75-2 (10.15 mL,71.99mmol, pickle), cesium carbonate (39.10 g,119.99mmol, pickle), 1, 4-dioxane (100 mL) and water (25 mL) was added bis [5- (diphenylphosphino) cyclopentyl-1, 3-dienyl ] - λ2-iron (II) palladium chloride (2.19 g,3.00mmol, pickle) under nitrogen and stirred at 85℃for 18 hours under N ₂. TLC showed complete consumption of starting material and formation of new spots. The mixture was filtered and the filter cake was washed with ethyl acetate (20 ml x 3) and the filtrate was concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 50:1 to 10:1) to give compound I75-3 (10 g,54.01mmol, y = 90.02%) as a white solid.

¹H NMR(400MHz,DMSO-d₆)δ:7.80(d,J＝8.0Hz,1H),7.44(d,J＝12.0Hz,1H),3.92(s,3H),2.46(s,3H)

Step 2 Synthesis of Compound I75-4

To a mixture of Compound I75-3 (5.0 g,27.01 mmol), ammonium chloride (4.33 g,81.02mmol, pickle), ethanol (25 mL) and water (5 mL) was added iron powder (6.03 g,108.02mmol, pickle), and the mixture was stirred at 80℃for 2 hours. LCMS showed the starting material was consumed and the desired product formed. The mixture was filtered and washed with ethyl acetate (20 ml x 3) and the filtrate was concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 100:1 to 5:1) to give compound I75-4 (3.0 g,19.33mmol, y = 71.59%) as a grey solid.

LC-MS(ESI):m/z=156.0[M+H]⁺

Step 3 Synthesis of Compound I75-5

To a solution of compound I75-4 (0.3 g,1.93 mmol) in acetonitrile (6 mL) was added 1-chlorotetrahydropyrrole-2, 5-dione (0.36 g,2.71 mmol), and the reaction mixture was warmed to 90℃and stirred for 1.5 hours. LCMS showed the starting material was consumed and the desired product formed. The mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 100:1 to 10:1) to give compound I75-5 (50 mg,0.26mmol, y = 13.64%) as a yellow oil.

LC-MS(ESI):m/z=190.0[M+H]⁺

Step 4 Synthesis of Compound I75-6

A mixed solution of Compound I75-5 (70 mg,0.37 mmol), compound I67-2 (194.99 mg,0.74 mmol) and acetic acid (2 mL) was stirred for 1 hour, then sodium cyanoboroate (46.40 mg,0.74mmol, bi.) was added. The reaction mixture was stirred for an additional 1 hour. LCMS showed the starting material was consumed and the desired product formed. The reaction mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 100:1 to 5:1) to give compound I75-6 (140 mg,0.32mmol, y = 86.64%) as a yellow oil.

LC-MS(ESI):m/z=437.0/439.0[M+H]⁺

Step 5 Synthesis of Compound I75-7

To a solution of compound I75-6 (140 mg,0.32 mmol) in tetrahydrofuran (1 mL) was added sodium hydroxide (16.45 mg,0.41 mmol) dissolved in water (1 mL) and the resulting mixture was stirred at 50℃for 2 hours to give a yellow solution. LCMS showed the starting material was consumed and the desired product formed. The reaction mixture was adjusted to ph=3 with HCl (1M) and extracted with ethyl acetate (10 ml x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give crude compound I75-7 (150 mg,0.37mmol, crude) as a yellow solid.

LC-MS(ESI):m/z=409.0/411.0[M+H]⁺

Step 6 Synthesis of Compound I75-8

To a mixed solution of compound I75-7 (100 mg,0.24 mmol), [ chloro (dimethylamino) methylene ] dimethylammonium hexafluoro- λ5-phosphide (171.23 mg,0.61mmol, obtained) and acetonitrile (3.0 mL) was added 1-methylimidazole (77.84 μl,0.98 mmol), and the resulting mixture was stirred at 25 ℃ for 18 hours. LCMS showed the starting material was consumed and the desired product formed. The mixture was filtered and the filter cake was washed with ethyl acetate (20 ml x 3) and the filtrate was concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 50:1 to 5:1) to give compound I75-8 (100 mg,0.26mmol, crude) as a yellow solid.

LC-MS(ESI):m/z=390.8/392.8[M+H]⁺

Step 7 Synthesis of Compound I75-10

To a solution of compound I75-8 (110 mg,0.28 mmol), compound I31-9 (50.42 mg,0.31mmol, after obtaining), cesium carbonate (274.54 mg,0.84 mmol) and [5- (diphenylphosphino) -9, 9-dimethyl-9H-xanth-4-yl ] diphenylphosphine (32.50 mg,0.06 mmol) in 1, 4-dioxane was added tris [ (1 e,4 e) -1, 5-diphenylpenta-1, 4-dien-3-one ] bis [ palladium (0) ] (25.72 mg,0.03 mmol), and stirred under nitrogen at 110 ℃ for 18 hours. LCMS showed the starting material was consumed and the desired product formed. The mixture was filtered and the filter cake was washed with ethyl acetate (20 ml x 3) and the filtrate was concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10:1 to 1:1) to give compound I75-10 (110 mg,0.23mmol, y = 82.64%) as a brown solid.

LC-MS(ESI):m/z=474.2[M+H]⁺

Step 8 Synthesis of Compound 0075

Compound I75-10 (70 mg,0.15 mmol) was dissolved in hydrogen bromide (4 mL,33%, acOH) and the mixture was stirred at 90℃for 2.5 h. LCMS showed the starting material was consumed and the desired product formed. The mixture was concentrated to dryness under reduced pressure to give crude product. The crude product was purified by preparative HPLC (Phenomenex Gemini mm x 25mm x 10um column (eluent = 30% to 60% (v/v) CH ₃ CN and H ₂O,0.01％NH₄HCO₃) to give compound 0075 (19.47 mg,0.04mmol, y = 28.66%) as a white solid.

LC-MS(ESI):m/z=460.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:13.00(s,1H),10.38(s,1H),8.74(s,1H),8.56(s,1H),7.22(d,J＝11.4Hz,1H),4.77-4.59(m,2H),4.32(q,J＝7.4Hz,2H),2.14(s,3H),1.46(t,J＝7.3Hz,3H)

Example 26:

Synthesis of Compound 0076

Step 1 Synthesis of Compound I76-2

To a solution of lithium diisopropylamide (147.77 mL, 295.54mmol, 2mol/L, an Naiji) in tetrahydrofuran (100 mL) was added a solution of compound I76-1 (25 g,89.56mmol, obtained) in tetrahydrofuran (100 mL) under nitrogen at 0℃and the reaction mixture was stirred at 0℃for 0.5 hours. Diethyl pyrocarbonate (43.6 g,268.67mmol, obtained) was added at a temperature of 0℃and the reaction mixture was allowed to warm to 25℃and stirred for 16 hours. The reaction was quenched by pouring into ammonium chloride (aq, 250 mL) and extracted with ethyl acetate (500 mL x 3), the combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10:1 to 1:1) to give compound I76-2 (6 g,17.08mmol, y = 19.08%) as a yellow solid.

LC-MS(ESI):m/z=295.2/297.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:12.30(s,1H),4.33-4.16(m,2H),1.50(s,9H),1.28(t,J=7.1Hz,3H)

Step 2 Synthesis of Compound I76-3

Compound I76-2 (6 g,17.08 mmol) was added to water (30 mL), followed by tetrahydrofuran (30 mL), sodium hydroxide (2.05 g,51.25 mmol). The reaction was stirred at 50 ℃ for 2 hours. The reaction solution was concentrated under reduced pressure to a large portion of THF, the residue was poured into water (20 mL) and the aqueous phase was adjusted to ph=2 to 3 with hydrochloric acid (1M), extracted with ethyl acetate (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure by filtration to give compound I76-3 (3.7 g,11.45mmol, y=67.0%) as a yellow solid.

LC-MS(ESI):m/z=266.8/268.8[M+H]⁺

Step 3 Synthesis of Compound I76-4

Compound I76-3 (1.5 g,4.64 mmol) was added to acetonitrile (15 mL), followed by compound I76-3.1 (0.70 g,4.64 mmol), N, N, N ', N' -tetramethyl chloroformyl amidine hexafluorophosphate (3.26 g,11.60mmol, an Naiji) and methylimidazole (1.52 g,18.57mmol, an Naiji). The reaction solution was stirred at 25 ℃ for 16 hours. The system was concentrated directly under reduced pressure to give crude product, which was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10:1 to 1:1) to give compound I76-4 (180 mg,3.94mmol, y = 85.0%) as a yellow solid.

LC-MS(ESI):m/z=456.1/458.1[M+H]⁺

Step 4 Synthesis of Compound I76-5

Compound I76-4 (700 mg,1.53 mmol), cuprous iodide (23.2 mg,0.15 mmol), ditriphenylphospholpalladium dichloride (53.83 mg,0.08mmol, an Naiji), ethynyl trimethylsilane (262. Mu.L, 1.84mmol, an Naiji) were added to triethylamine (7 mL), and the nitrogen sparge system was warmed to 85℃after three times and stirred for 16 hours. The reaction was poured into water (10 mL) and extracted with ethyl acetate (30 mL x 3) and the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude compound I76-5 (700 mg,1.74mmol, crude) as a brown solid.

LC-MS(ESI):m/z=402.2[M+H]⁺

Step 5 Synthesis of Compound I76-6

Compound I76-5 (700 mg,1.74 mmol) was added to N, N-dimethylformamide (7 mL), followed by sodium tert-butoxide (335 mg,3.49mmol, an Naiji). The reaction was stirred at 100 ℃ for 16 hours, LCMS showed the desired MS. The mixture was poured into water (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10:1 to 4:1) to give compound I76-6 (418 mg,1.03mmol, y = 59.7%) as a white solid.

LC-MS(ESI):m/z=402.1[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:12.19(s,1H),7.42(d,J＝7.2Hz,1H),7.20(d,J＝8.4Hz,1H),7.02(d,J＝8.4Hz,1H),6.79(d,J＝7.2Hz,1H),3.83(s,3H),1.91(s,3H),1.80(s,3H),1.53(s,9H)

Step 6 Synthesis of Compound I76-7

Compound I76-6 (416 mg,1.04 mmol) was added to a solution of hydrogen chloride/ethyl acetate (6 mL,24.00mmol, ethyl acetate solution 4mol/L, an Naiji) and the system was warmed to 70℃and stirred at this temperature for 2 hours. The system was concentrated under reduced pressure to give compound I76-7 (280 mg,0.93mmol, y=89.7%) as a yellow solid.

LC-MS(ESI):m/z=302.3[M+H]⁺

Step 7 Synthesis of Compound I76-9

Compound I76-7 (150 mg,0.50 mmol), compound I76-8 (89.91 mg,0.50 mmol) was added to 1, 4-dioxane (3 mL), tris (dibenzylideneacetone) dipalladium (22.79 mg,0.02mmol, an Naiji), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (28.80 mg,0.05mmol, an Naiji) and cesium carbonate (486.52 mg,1.49 mmol) were further added, the nitrogen substitution system was warmed to 100℃and stirred for 16 hours. The reaction was poured into water (10 mL) and extracted with ethyl acetate (30 mL x 3), the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10:1 to 7:3) to give compound I76-9 (50 mg,0.11mmol, y = 19.8%) as a yellow solid.

LC-MS(ESI):m/z=446.2[M+H]⁺

Step 8 Synthesis of Compound 0076

Compound I76-9 (50 mg,0.11 mmol) was added to dichloromethane (2 mL) under nitrogen, boron tribromide (0.45 mL,0.45mmol, an Naiji) was slowly added dropwise at-40℃and the reaction was allowed to warm to 25℃after dropwise addition and stirred for 2 hours. The reaction was concentrated under reduced pressure to give crude product, which was purified by Prep-HPLC (Waters-Xbridge-C18-10 μm-19X 250mm, A:10mM ammonium bicarbonate/B: acetonitrile) to give 0076 (12.1 mg,0.03mmol, 31.5%) as a white solid.

LC-MS(ESI):m/z=432.1[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:12.13(br s,1H),9.54(br s,1H),8.03(d,J＝5.8Hz,1H),7.46(d,J＝3.2Hz,1H),7.37(d,J＝7.2Hz,1H),7.28(d,J＝5.8Hz,1H),7.16(d,J＝3.0Hz,1H),7.02(d,J＝8.2Hz,1H),6.84(d,J＝8.2Hz,1H),6.75(d,J＝7.2Hz,1H),4.24(q,J＝7.2Hz,2H),1.90(s,3H),1.80(s,3H),1.36(t,J＝7.2Hz,3H)

Example 27:

Synthesis of Compound 0077

Step 1 Synthesis of Compound I77-2

Sodium hydride (1.17 g, purity 60%,29.30 mmol) was added to N, N-dimethylformamide (30 mL) of Compound I77-1 (3 g,19.54mmol, obtained) under nitrogen atmosphere at 0℃and then ethyl iodide (1.58 mL,19.73mmol, obtained) was added to the reaction mixture. The reaction solution was stirred at 25 ℃ for 16 hours. LCMS showed complete consumption of starting material and formation of the target product. The reaction mixture was quenched with saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (40 mL x 3), and the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0% to 21%) to give compound I77-2 (1 g,5.51mmol, y = 28.19%) as a white solid.

LC-MS(ESI):m/z=182.0[M+H]⁺

Step 2 Synthesis of Compound I77-4

Compound I77-3 (300 mg,0.89 mmol) was added to 1, 4-dioxane (5 mL) under nitrogen followed by Xantphos (103.51 mg,0.18 mmol), compound I77-2 (162.44 mg,0.89 mmol), cesium carbonate (874.24 mg,2.68 mmol) and tris (dibenzylideneacetone) palladium (81.90 mg,0.09 mmol), and the mixture was degassed and purged 3 times with nitrogen and stirred at 100℃for 16 hours. LCMS indicated that starting material was consumed and the desired product formed. The reaction mixture was filtered and washed with methanol (20 mL) and dichloromethane (20 mL) and the filtrate was concentrated to dryness under reducing conditions to give the crude product. The crude product was purified by silica gel chromatography (eluent = methanol: dichloromethane = 0% -10%) to give compound I77-4 (370 mg,0.77mmol, y = 86.08%) as a white solid.

LC-MS(ESI):m/z=481.2[M+H]⁺

Step 3 Synthesis of Compound I77-5

To a solution of compound I77-4 (180 mg,0.37 mmol) in dichloromethane (3 mL) under nitrogen was added boron tribromide (561.81. Mu.L, 0.56mmol, pichia) at a temperature no greater than-65℃and the mixture was stirred at-65℃for 1 hour, then warmed to 25℃and stirred for a further 2 hours. A pale yellow solution formed. LCMS indicated complete reaction of the reactants and formation of the desired product. The reaction mixture was quenched with methanol (5 mL), adjusted to ph=7 with methanolic ammonia, and the mixture was concentrated to dryness to give the crude product. The crude product was purified by silica gel chromatography (eluent = methanol: dichloromethane = 0% to 6%) to give compound I77-5 (80 mg,0.14mmol, y = 68.67%) as a yellow solid.

LC-MS(ESI):m/z=467.2[M+H]⁺

Step 4 Synthesis of Compound I77-6

To a solution of compound I77-5 (120 mg,0.26 mmol) in dichloromethane (1 mL) at 0 ℃ was added dessmartin (218.18 mg,0.51mmol, after which the mixture was warmed to 25 ℃ and stirred for 24 hours. LCMS indicated complete reaction of starting material and formation of desired product. The reaction mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (eluent=methanol: dichloromethane=0% to 4%) to give compound I77-6 (40 mg,0.06mmol, yield: 34.83%) as a yellow solid.

LC-MS(ESI):m/z=447.2[M+H]⁺

Step 5 Synthesis of Compound 0077

To a solution of compound I77-6 (40 mg,0.09 mmol) in dichloromethane (0.7 mL) at 0 ℃ was added boron tribromide (450.00 μl,0.45mmol, after completion) and the mixture was warmed to 25 ℃ and stirred for 1 hour. A yellow solution formed. LCMS indicated complete reaction of starting material and formation of desired product. The reaction mixture was quenched with methanol (3 mL) and basified to ph=9 to 10 with methanolic ammonia solution and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by preparative high performance liquid chromatography (Phenomenex Gemini mM x 25mM x 10um column (eluent = water (10 mM ammonium bicarbonate solution): acetonitrile = 30% to 60%) to give 0077 (2.38 mg,0.01mmol, y = 6.14%) as a white solid.

LC-MS(ESI):m/z=433.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:12.59(s,1H),9.51(s,1H),8.64(s,1H),8.16(d,J＝4.4Hz,1H),7.39(d,J＝5.6Hz,2H),7.01(d,J＝7.6Hz,1H),6.90-6.74(m,2H),4.45(d,J＝6.4Hz,2H),1.89(s,3H),1.80(s,3H),1.40(t,J＝5.6Hz,3H)

Example 28:

Synthesis of Compound 0078

Step 1 Synthesis of Compound I78-2

To a solution of compound I78-1 (500 mg,1.15 mmol) in dioxane (5 mL) was added hydrochloric acid (2.30 mL,9.20 mmol), and the resulting mixture was stirred at 80℃for 4 hours. LCMS detected predominantly product. The reaction was concentrated to dryness and ph=7-8 was adjusted with aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (30 ml×3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give compound I78-2 (320 mg,0.95mmol, y=83.10%) as a yellow solid.

LC-MS(ESI):m/z=336.2[M+H]⁺

Step 2 Synthesis of Compound I78-4

To a solution of compound I78-2 (320 mg,0.95 mmol) and compound I78-3 (222.81 mg,1.14 mmol) in ethylene glycol dimethyl ether (12 mL) under nitrogen was added tris (dibenzylideneacetone) dipalladium (87.36 mg,0.10 mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (110.41 mg,0.19 mmol), respectively, and stirred under nitrogen at 100℃for 4 hours. The desired molecular weight was detected by LCMS. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by preparative HPLC (eluent = 0% to 50% (v/v) acetonitrile/water with 0.01% formic acid) to give compound I78-4 (400 mg,0.77mmol, y = 80.7%) as a white solid.

LC-MS(ESI):m/z=494.0[M+H]⁺

Step 3 Synthesis of Compound I78-5

To a solution of compound I78-4 (100 mg,0.20 mmol) in methylene chloride (2 mL) at-65℃was added boron tribromide (300.00. Mu.L, 0.30 mmol), the reaction was controlled at temperature for 1 hour, and then stirred at 25℃for 1 hour. The desired molecular weight was detected by LCMS, quenched with methanol (10 mL), ph=8-9 adjusted with ammonia (5 mL, meoh solution 7M), concentrated to dryness, and the crude product purified by silica gel chromatography (dichloromethane: methanol=100:1 to 10:1) to give compound I78-5 (280 mg,0.58mmol, y=72.0%) as a yellow solid.

LC-MS(ESI):m/z=480.2[M+H]⁺

Step 4 Synthesis of Compound I78-6

To a solution of compound I78-5 (340 mg,0.67 mmol) in dichloromethane (10 mL) was added 1, 1-triacetoxy-1, 3-dihydro-1λ5-benzo [ d ] [1,2] iodoxy-3-one (571.35 mg,1.35 mmol), and the resulting mixture was stirred at 25 ℃ for 18 hours. The desired molecular weight was detected by LCMS. Quench with sodium bicarbonate solution (20 mL) and extract with dichloromethane (30 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by preparative HPLC (eluent=5% to 45% (v/v) acetonitrile and water, containing 0.01% formic acid) to give compound I78-6 (180 mg,0.39mmol, y=58.4%) as a yellow solid.

LC-MS(ESI):m/z=460.2[M+H]⁺

Step 5 Synthesis of Compound 0078

To a solution of compound I78-6 (130 mg,0.28 mol) in methylene chloride (7 mL) was added boron tribromide (1.41 mL,1.41 mmol) under ice-bath, followed by stirring at 25℃for 1 hour. The desired molecular weight was detected by LCMS. Quench with MeOH (5 mL) and concentrate to dryness, then basify the residue with 4mL ammonia (7M/L) to ph=8-9 and concentrate to dryness to give crude product. The crude product was purified by preparative HPLC (Phenomenex Gemini mm x 25mm x 10um column (eluent = 5% to 55% (v/v) acetonitrile and water, 0.1% formic acid) to give compound 0078 (10.41 mg,0.02mmol, y = 8.26%) as a yellow solid.

LC-MS(ESI):m/z=446.0[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:13.21(s,1H),9.51(s,1H),8.77(s,1H),8.47(s,1H),7.43(d,J＝7.3Hz,1H),7.02(d,J＝8.4Hz,1H),6.88-6.80(m,2H),3.98-3.86(m,1H),1.89(s,3H),1.80(s,3H),1.23–1.18(m,2H),1.16–1.10(m,2H)

Example 29:

synthesis of Compound 0079

Step 1 Synthesis of Compound I79-3

Oxalyl chloride (170.18 μl,1.98 mmol) and N, N-dimethylformamide (12.86 μl,0.17 mmol) were added to a solution of compound I79-2 (500 mg,1.65 mmol) in dichloromethane (5 mL) under ice-bath, and the mixture was stirred at 25deg.C for 1.5 hr and concentrated to give the crude acid chloride. The crude acid chloride was dissolved in dichloromethane (5 mL) and then compound I79-1 (340.57 mg,1.98 mmol) and triethylamine (411.04. Mu.L, 2.48 mmol) were added and the reaction stirred at 25℃for 2 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10:1 to 1:1) to give compound I79-3 (390 mg,0.86mmol, y = 51.7%) as a white solid.

LC-MS(ESI):m/z=456.2[M+H]⁺

Step 2 Synthesis of Compound I79-4

To compound I79-3 (390 mg,0.86 mmol) was added hydrogen chloride (3 mL,12.00mmol,4mol/L dioxane hydrochloride solution An Naiji). The mixture was stirred at 85 ℃ for 4 hours. The reaction solution was concentrated to give Compound I79-4 (300 mg,0.84mmol, crude product) as a yellow solid.

LC-MS(ESI):m/z=356.2[M+H]⁺

Step 3 Synthesis of Compound I79-6

To a solution of compound I79-4 (180 mg,0.51 mmol), compound I79-5 (106.67 mg,0.59 mmol) and cesium carbonate (494.44 mg,1.52 mmol) in dioxane (3 mL) under nitrogen was added 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (29.27 mg,0.05mmol, an Naiji) and tris (dibenzylideneacetone) dipalladium (23.16 mg,0.03 mmol). The mixture was stirred at 100 ℃ for 16 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10:1 to 3:7) to give compound I79-6 (160 mg,0.30mmol, y = 5.8.9%) as a white solid.

LC-MS(ESI):m/z=502.2[M+H]⁺

Step 4 Synthesis of Compound I79-7

To a solution of Compound I79-6 (240 mg,0.48 mmol) in dichloromethane (2 mL) at-65℃was added dropwise boron tribromide (956.19. Mu.L, 0.96mmol,1 mol/L) and stirred at-60℃for 2 hours. 3mL of MeOH was added to the reaction quenched and concentrated to dryness. The crude product was purified by silica gel chromatography (eluent = petroleum ether: tetrahydrofuran = 10:1 to 1:1) to give compound I79-7 (130 mg,0.27mmol, y = 55.7%) as a yellow solid.

LC-MS(ESI):m/z=488.2[M+H]⁺

Step 5 Synthesis of Compound I79-8

To a solution of compound I79-7 (130 mg,0.27 mmol) in dichloromethane (3 mL) was added 1, 1-triacetoxy-1, 3-dihydro-1λ5-benzo [ d ] [1,2] iodooxy-3-one (0.17 mL,0.53mmol, an Naiji). The reaction was stirred at 25 ℃ for 16 hours. The mixture was poured into sodium thiosulfate (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium bicarbonate solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: tetrahydrofuran = 10:1 to 1:1) to give compound I79-8 (70 mg,0.10mmol, y = 39.1%) as a yellow oil.

LC-MS(ESI):m/z=468.2[M+H]⁺

Step 6 Synthesis of Compound 0079

To a solution of compound I79-8 (70 mg,0.10 mmol) in dichloromethane (2 mL) at-40℃was added boron tribromide (0.53 mL,0.53mmol,1mol/L in dichloromethane, an Naiji). The reaction was stirred at 25 ℃ for 2 hours. The reaction was quenched by adding 1mL of methanol and concentrated. The crude product was purified by high performance liquid chromatography (Agilent-Poroshell HPH-C18-2.7um-4.6 x 50mm (eluent = 20% to 80% (v/v) acetonitrile/water, 0.025% ammonium bicarbonate) to give compound 0079 (6.17 mg,0.01mmol, y = 12.78%) as a white solid.

LC-MS(ESI):m/z=454.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ13.26(s,1H),10.09(s,1H),8.77(s,1H),8.53(s,1H),7.49(d,J＝7.2Hz,1H),7.31(d,J＝8.8Hz,1H),6.97(d,J＝8.8Hz,1H),6.86(d,J＝7.4Hz,1H),4.46(q,J＝7.2Hz,2H),1.87(s,3H),1.43(t,J＝7.2Hz,3H)

Example 30:

Synthesis of Compound 0082

Step 1 Synthesis of Compound I82-2

To a solution of compound I31-8 (130.70 mg,0.37 mmol), compound I82-1 (50 mg,0.37mmol, after), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (43.14 mg,0.07 mmol) and cesium carbonate (364.34 mg,1.12 mmol) in N, N-dimethylformamide (4 mL) was added tris (dibenzylideneacetone) dipalladium (34.13 mg,0.04 mmol), the mixture was replaced with nitrogen 3 times and stirred at 90 ℃ for 2 hours. The mixture was poured into water (15 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by silica gel chromatography (eluent = tetrahydrofuran: petroleum ether = 0% to 70%) to give compound I82-2 (115 mg,0.28mmol, 75.90%) as a yellow oil.

LC-MS(ESI):m/z=407.2[M+H]⁺

Step 2 Synthesis of Compound 0082

To a solution of compound I82-2 (180 mg,0.44 mmol) in dichloromethane (1 ml) was added boron tribromide (2.20 ml,2.20 mmol) at 0 ℃ and stirred at 25 ℃ for 1 hour. The mixture was concentrated to dryness under reduced pressure to give the crude product, and the reaction mixture was quenched with methanolic ammonia (1M) and concentrated. The crude product was purified by preparative HPLC ((eluent = 18% to 48% (v/v) acetonitrile and water with 0.1% ammonium bicarbonate) to give compound 0082 (6.91 mg,0.02mmol, 3.98%) as a white solid.

LC-MS(ESI):m/z=393.1[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:12.57(s,1H),9.05(s,1H),8.52(s,1H),8.25(s,1H),8.06–7.95(m,1H),7.42–7.31(m,1H),6.94(d,J＝8.2Hz,1H),6.79(d,J＝8.2Hz,1H),4.62(s,2H),2.06(s,3H),1.98(s,3H)

Example 31:

Synthesis of Compound 0083

Step 1 Synthesis of Compound I83-3

To a solution of bis (propyl-2-yl) amine (0.99 mL,7.07mmol, bi-obtained) in tetrahydrofuran (10 mL) was added butyllithium (2.83 mL,7.07mmol,2.5mol/L, an Naiji) under nitrogen at-78 ℃. The reaction was stirred at-78℃for 0.5h, then a solution of Compound I83-1 (1 g,6.10mmol, obtained) in tetrahydrofuran (10 mL) was added. After 0.5h, compound I83-2 (0.72 mL,7.32mmol, obtained) was added and the reaction mixture was stirred at-78℃for 0.5 h. Saturated ammonium chloride solution (10 mL) was added to the reaction system at-60 ℃ and extracted with ethyl acetate (10 mL), the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude product, which was purified by silica gel chromatography (eluent=petroleum ether: ethyl acetate=100:1 to 95:5) to give compound I83-3 (1.12 g,4.74mmol, y=77.8%) as a white solid.

¹H NMR(400MHz,DMSO-d₆)δ:8.79(s,1H),4.37(q,J=7.1Hz,2H),1.39–1.29(m,3H)

Step 2 Synthesis of Compound I83-4

Compound I83-3 (780 mg,3.77 mmol) was added to a solution of dioxane (8 mL) at room temperature, followed by phenylmethylamine (824.46. Mu.L, 7.54 mmol), tris (dibenzylidene-BASE acetone) dipalladium (345.22 mg,0.38mmol, an Naiji) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (436.28 mg,0.75mmol, an Naiji), cesium carbonate (3684.93 mg,11.31 mmol). The nitrogen was replaced three times and the reaction was stirred for 16 hours at 100 ℃. The reaction was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3), the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product which was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10:1 to 5:1) to give compound I83-4 (230 mg,0.88mmol, y = 23.1%) as a yellow oil.

LC-MS(ESI):m/z=263.0[M+H]⁺

Step 3 Synthesis of Compound I83-5

Compound I83-4 (150 mg,0.57 mmol) was added to concentrated sulfuric acid (2 mL) at 0deg.C, and the reaction was warmed to 85deg.C and stirred for 1 hour. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3), the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product which was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10:1 to 1:1) to give compound I83-5 (70 mg,0.41mmol, y = 71.1%) as a yellow oil.

LC-MS(ESI):m/z=173.0[M+H]⁺

Step 4 Synthesis of Compound I83-6

Compound I83-5 (140 mg,0.81 mmol) was added to formamide (0.5 mL,4.57 mmol) at room temperature and the reaction stirred under microwaves at 180℃for 2 hours. The reaction was cooled and purified directly by preparative HPLC (Phenomenex Gemini 150mm*25mm*10um colume) (eluent = 10% to 60% (v/v) acetonitrile and water, 0.025% formic acid) to give compound I83-6 (120 mg,0.78mmol, y = 96.4%) as a yellow solid.

LC-MS(ESI):m/z=154.0[M+H]⁺

Step 5 Synthesis of Compound I83-7

Compound I83-6 (70 mg,0.46 mmol) was added to phosphorus oxychloride (2 mL) at room temperature, and the reaction was warmed to 110℃and stirred for 2h. The reaction was concentrated and poured into water (10 mL), extracted with ethyl acetate (10 mL x 3), the combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by preparative TLC (eluent = petroleum ether: ethyl acetate = 5:1) to give compound I83-7 (35 mg,0.20mmol, y = 44.6%) as a yellow solid.

LC-MS(ESI):m/z=172.0[M+H]⁺

Step 6 Synthesis of Compound I83-8

Compound I83-7 (35 mg,0.20 mmol) was added to ammonia (3 mL,23.37mmol, purity: 30%, an Naiji), and the reaction was warmed to 80℃and stirred for 2h. The reaction solution was concentrated to give compound I83-8 (20 mg,0.13mmol, y=64.6%) as a yellow solid, which was reacted directly.

LC-MS(ESI):m/z=153.0[M+H]⁺

Step 7 Synthesis of Compound I83-9

Compound I83-8 (17.23 mg,0.11 mmol), compound I31-8 (40 mg,0.11 mmol) were added to 1, 4-dioxane (0.5 mL), and then tris (dibenzylideneacetone) dipalladium (10.37 mg,0.01mmol, an Naiji), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (13.10 mg,0.02mmol, an Naiji) and cesium carbonate (110.69 mg,0.34 mmol) were added, respectively, the reaction system was replaced with nitrogen 3 times, and the temperature was raised to 85℃and stirred for 2.5 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3), the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude product, which was purified by preparative TLC (eluent = petroleum ether: ethyl acetate = 1:1) to give compound I83-9 (20 mg,0.05mmol, y = 43.0%) as a yellow solid.

LC-MS(ESI):m/z=425.1[M+H]⁺

Step 8 Synthesis of Compound 0083

Compound I83-9 (20 mg,0.05 mmol) was added to dichloromethane (1 mL) under nitrogen, followed by boron tribromide (0.24 mL,0.24mmol,1mol/L, an Naiji) and the reaction was warmed to 25℃and stirred for 1 hour. To the reaction system was added 1mL of methanol to quench the reaction, the system was concentrated under reduced pressure to give a crude product, and the crude product was purified by Pre-HPLC (Waters-CORTECS-C18-2.7 μm-4.6 x 30mm, a:10mm ammonium bicarbonate/water B: acetonitrile, 10-95) to give compound 0083 (1.01 mg,0.009mmol, y=5.7%) as a yellow solid.

LC-MS(ESI):m/z=411.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:9.09–9.04(m,1H),8.94–8.88(m,1H),7.00–6.96(m,1H),6.79–6.74(m,1H),4.68–4.62(m,2H),2.12(s,3H),2.06(s,3H)

Example 32:

Synthesis of Compound 0084

Step 1 Synthesis of Compound I84-3

To a solution of compound I84-1 (1.47 mL,10.89mmol, pickle) in tetrahydrofuran (30 mL) was added compound I84-2 (1.00 g,7.78mmol, pickle), and the resulting mixture was stirred at 50℃for 18 hours to give a yellow solution. LCMS detection found the target molecular weight. The reaction solution was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by column chromatography on silica gel (eluent = petroleum ether: ethyl acetate = 10:1 to 1:1) to give compound I84-3 (2.05 g,8.03mmol, crude) as a yellow solid.

LC-MS(ESI):m/z=256.0[M+H]⁺

Step 2 Synthesis of Compound I84-4

A solution of compound I84-3 (500 mg,1.96 mmol) in concentrated H ₂SO₄ (3 mL) was stirred at 110℃for 4H to give a brown solution. LCMS detection found the target molecular weight. The reaction solution was poured into water (20 mL) and adjusted to ph=7 with aqueous sodium hydroxide (1M). Then extracted with ethyl acetate (30 ml x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the crude product compound I84-4 (160 mg,1.06mmol, y= 54.03%) as a white solid.

LC-MS(ESI):m/z=152.0[M+H]⁺

Step 3 Synthesis of Compound I84-5

To a mixed solution of compound I84-4 (107.01 mg,0.71 mmol) and compound I31-8 (250 mg,0.71 mmol) in N, N-dimethylformamide (3 mL) was added 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (81.91 mg,0.14mmol, obtained), cesium carbonate (691.80 mg,2.12mmol, obtained) and tris (dibenzylideneacetone) dipalladium (64.81 mg,0.07mmol, obtained) in this order, and the reaction solution was degassed and purged 3 times with nitrogen and stirred under nitrogen at 80 ℃ for 2.5 hours. LCMS detection found the target molecular weight. The reaction was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel (eluent = petroleum ether: ethyl acetate = 50:1 to 1:1) to give compound I84-5 (120 mg,0.28mmol, y = 40.03%) as a yellow solid.

LC-MS(ESI):m/z=424.2[M+H]⁺

Step 4 Synthesis of Compound 0084

To a solution of compound I84-5 (85 mg,0.20 mmol) in dichloromethane (2 mL) was added dropwise a solution of boron tribromide (1.00 mL,1 m) in dichloromethane at 0 ℃, and after the addition was completed, the reaction solution was stirred at 25 ℃ for 1 hour to give a yellow solution. LCMS detection found the target molecular weight. The reaction was quenched with MeOH (1 mL) and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by preparative HPLC (Phenomenex Gemini 150mm*25mm*10um colume) (eluent = 30% to 60% (v/v) CH ₃ CN and H ₂ O with 0.025% nh ₄HCO₃) to give compound 0084 (7.66 mg,0.02mmol, y = 9.32%) as a yellow solid.

LC-MS(ESI):m/z=410.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:13.40(s,1H),9.35(s,1H),8.92(s,1H),8.39(d,J＝5.2Hz,1H),8.05(d,J＝5.2Hz,1H),6.95(d,J＝8.4Hz,1H),6.78(d,J＝8.2Hz,1H),4.73-4.58(m,2H),2.04(s,3H),1.94(s,3H)

Example 33:

Synthesis of Compound 0088

Step 1 Synthesis of Compound I88-3

Acetonitrile (15 ml), compound I88-2 (1.57 g,9.28 mmol), N, N, N ', N' -tetramethyl chloroformyl amidine hexafluorophosphate (6.51 g,23.21 mmol) and N-methylimidazole (2.96 ml,37.13 mmol) were added to compound I88-1 (3 g,9.28 mmol), respectively, and the reaction was stirred at 25℃for 16 hours. The reaction was concentrated and the crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0% -25%) to give compound I88-3 (2.58 g,5.44mmol, y = 58.59%) as a yellow oil.

LC-MS(ESI):m/z=474.2/476.2[M+H]⁺

Step 2 Synthesis of Compound I88-4

A mixed solution of compound I88-3 (2.58 g,5.44 mmol), cuprous iodide (0.06 mL,1.63 mmol), ethynyl trimethylsilane (1.94 mL,13.60 mmol) and ditolylphosphine palladium dichloride (0.38 g,0.54 mmol) in triethylamine (15 mL) was replaced 3 times with nitrogen and stirred at 80℃for 2 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0% -35%) to give compound I88-4 (1.68 g,4.01mmol, y = 73.64%) as a yellow solid.

LC-MS(ESI):m/z=420.2[M+H]⁺

Step 3 Synthesis of Compound I88-5

To a solution of compound I88-4 (1.68 g,4.01 mmol) in N, N-dimethylformamide (15 mL) was added sodium tert-butoxide (0.77 g,8.01 mmol). The reaction was stirred at 100 ℃ for 2 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude compound I88-5 (2 g,3.81mmol, y=95.24%) as a yellow solid.

LC-MS(ESI):m/z=420.2[M+H]⁺

Step 4 Synthesis of Compound I88-6

To compound I88-5 (2 g,4.77 mmol) was added a solution of hydrogen chloride-ethyl acetate (20 mL,4 mol/L). The reaction was stirred at 60 ℃ for 2 hours. The reaction mixture was adjusted to ph=7 with aqueous sodium bicarbonate and extracted with ethyl acetate (10 ml x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0% to 75%) to give compound I88-6 (600 mg,1.88mmol, y = 39.41%) as a yellow solid.

LC-MS(ESI):m/z=320.2[M+H]⁺

Step 5 Synthesis of Compound I88-8

To a mixed solution of compound I88-6 (150 mg,0.47 mmol), compound I88-7 (78.26 mg,0.47 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (54.36 mg,0.09 mmol) and cesium carbonate (459.12 mg,1.41 mmol) in N, N-dimethylformamide (3 ml) was added tris (dibenzylideneacetone) dipalladium (43.01 mg,0.05 mmol), the mixture was replaced with nitrogen gas 3 times, and stirred at 100 ℃ for 2 hours under microwave. The mixture was poured into water (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = tetrahydrofuran: petroleum ether = 0% -60%) to give compound I88-8 (50 mg,0.11mmol, y = 23.68%) as a yellow oil.

LC-MS(ESI):m/z=450.1[M+H]⁺

Step 6 Synthesis of Compound 0088

To a solution of compound I88-8 (50 mg,0.11 mmol) and methylene chloride (2 mL) was added boron tribromide (0.44 mL,0.44mmol, 1M), and the reaction was stirred at 20℃for 1 hour. The mixture was concentrated under reduced pressure to give crude product. The crude product was purified by preparative HPLC (eluent = 30% to 60% (v/v) acetonitrile and water, 0.025% ammonium bicarbonate) to give compound 0088 (7.36 mg,0.02mmol, y = 15.19%) as a white solid.

LC-MS(ESI):m/z=436.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:12.13(s,1H),9.55(s,1H),8.24–8.00(m,1H),7.47–7.35(m,2H),7.31–7.22(m,1H),7.20–7.13(m,1H),7.13–7.03(m,1H),6.85–6.73(m,1H),3.83(s,3H),2.05–1.84(m,6H)

Example 34:

synthesis of Compound 0097

Step 1 Synthesis of Compound I97-3

Compound I97-1 (100 mg,0.31 mmol), compound I97-2 (60.63 mg,0.31 mmol), xantphos (36.24 mg,0.06 mmol) and cesium carbonate (306.08 mg,0.94 mmol) were added separately to N, N-dimethylformamide (2 mL) under nitrogen, followed by addition of tris (dibenzylideneacetone) dipalladium (28.67 mg,0.03 mmol), displacement of the reaction solution with nitrogen three times, and then reaction at 90℃for 2 hours. A black solution was formed. Product formation was detected by LCMS. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (tetrahydrofuran: petroleum ether=0% -60%) to give compound I97-3 (80 mg,0.17mmol, y=53.0%) as a yellow oil.

LC-MS(ESI):m/z=477.2[M+H]⁺

Step 2 Synthesis of Compound 0097

Compound I97-3 (60 mg,0.13 mmol) was dissolved in dichloromethane (1 mL), boron tribromide (0.50 mL,0.50 mmol) was added and the mixture was stirred at 25℃for 1 hour. A black solution was formed. Product formation was detected by LCMS. The mixture was concentrated to dryness under reduced pressure to give crude product. The crude product was purified by high performance liquid chromatography (Phenomenex Gemini mm x 25mm x 10um column (eluent = acetonitrile: 0.025% sodium bicarbonate in water = 30% to 60%) to give compound 0097 (9.45 mg,0.02mmol, y = 16.0%) as a white solid.

LC-MS(ESI):m/z=463.1[M+H]⁺

1H NMR(400MHz,DMSO-d₆)δ:12.61(br s,1H),9.57(s,1H),8.71–8.60(m,1H),7.48–7.38(m,2H),7.13–6.99(m,2H),6.87–6.77(m,1H),3.66–3.60(m,1H),1.95–1.89(m,3H),1.89–1.83(m,3H),1.12–1.01(m,4H)

Example 35:

Synthesis of Compound 0099

Step 1 Synthesis of Compound I99-3

To a solution of compound I99-1 (100 mg,0.31 mmol), compound I99-2 (56.87 mg,0.31 mmol), xantphos (36.24 mg,0.06 mmol) and cesium carbonate (306.08 mg,0.94 mmol) in N, N-dimethylformamide (2 mL) under nitrogen protection was added tris (dibenzylideneacetone) dipalladium (28.67 mg,0.03 mmol), and the mixture was degassed and purged 3 times with nitrogen and the reaction stirred at 90 ℃ for 2 hours. A black solution was formed. Product formation was detected by LCMS. The mixture was poured into water (5 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = tetrahydrofuran: petroleum ether = 0% -60%) to give compound I99-3 (80 mg,0.17mmol, y = 55.00%) as a yellow oil.

LC-MS(ESI):m/z=465.2[M+H]⁺

Step 2 Synthesis of Compound 0099

Compound I99-3 (60 mg,0.13 mmol) was dissolved in dichloromethane (1 mL) followed by the addition of boron tribromide (0.52 mL,0.52 mmol). The reaction was stirred at 25 ℃ for 1 hour. Product formation was detected by LCMS. The mixture was concentrated to dryness under reduced pressure to give crude product. The crude product was purified by high performance liquid chromatography (Phenomenex Gemini mm x 25mm x10 um column (eluent = acetonitrile: 0.025% ammonium bicarbonate = 30% to 60%) to give compound 0099 (12.29 mg,0.03mmol, y = 21.0%) as a white solid.

LC-MS(ESI):m/z=451.1[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:12.63(s,1H),9.56(s,1H),8.62(s,1H),7.54(d,J＝3.6Hz,1H),7.42(d,J＝7.2Hz,1H),7.13–7.02(m,2H),6.81(d,J＝7.2Hz,1H),4.29(q,J＝7.1Hz,2H),1.91(s,3H),1.86(s,3H),1.39(t,J＝7.2Hz,3H)

Example 36:

Synthesis of Compound 0102

Step 1 Synthesis of Compound I102-3

Compound I102-1 (0.9 g,2.78 mmol), compound I102-2 (0.64 g,2.78 mmol) was added to acetonitrile (20 mL), followed by TCFH (1.95 g,6.96mmol, an Naiji) and NMI (888.06. Mu.L, 11.14mmol, an Naiji). The reaction was stirred at 25 ℃ for 16 hours. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10:1 to 1:1) to give compound I102-3 (1.4 g,2.61mmol, y = 93.1%) as a yellow oil.

LC-MS(ESI):m/z=534.2/536.2[M-H]⁺

Step 2 Synthesis of Compound I102-4

To a mixed solution of compound I102-3 (1.4 g,2.61 mmol), compound 3.1 (0.82 mL,3.91mmol, an Naiji) and water (14 mL) was added tricyclohexylphosphine (146.38 mg,0.52mmol, an Naiji), tris (dibenzylidene-BASE acetone) dipalladium (238.98 mg,0.26mmol, an Naiji) and potassium carbonate (901.67 mg,6.52 mmol). The reaction was stirred under nitrogen at 95 ℃ for 18 hours. The reaction was then cooled to 25 ℃, then HCl (10 ml,40.00mmol,6mol/L, an Naiji) was added and stirred at 25 ℃ for 3 hours. The reaction mixture was quenched with aqueous solution, washed with saturated sodium bicarbonate (50 mL) solution, extracted with ethyl acetate (30 mL x 3), and the combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent = dichloromethane: methanol = 100:1 to 10:1) to give compound I102-4 (330 mg,1.11mmol, y = 42.5%) as a yellow solid.

¹H NMR(400MHz,DMSO-d₆)δ:13.26(s,1H),8.09(s,2H),7.68(s,1H),7.61–7.55(m,1H),7.44(d,J＝7.2Hz,1H),7.36(d,J＝8.5Hz,1H),6.57(d,J＝7.2Hz,1H),3.21–3.14(m,3H)

Step 3 Synthesis of Compound 0102

Compound I102-4 (100 mg,0.34 mmol) and compound I102-4.1 (58.61 mg,0.30 mmol) were added to dioxane (0.8 mL) and water (0.2 mL), followed by tris (dibenzylidene-BASE acetone) dipalladium (30.80 mg,0.03mmol, an Naiji), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (38.92 mg,0.07mmol, an Naiji) and cesium carbonate (328.73 mg,1.01 mmol). The reaction was stirred for 2.5 hours at 100 ℃ under nitrogen. The mixture was poured into water (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na ₂SO₄, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by preparative HPLC (Phenomenex Gemini 150mm*25mm*10u m colume (Waters-Xbridge-C18-10 μm-19 x 250mm, a:10mm ammonium bicarbonate/water B: acetonitrile) to give compound 0102 (3.03 mg,0.01mmol, y=2.6%) as a white solid.

LC-MS(ESI):m/z=455.1[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:13.29(s,1H),8.67–8.62(m,1H),7.76–7.71(m,1H),7.63–7.56(m,2H),7.44–7.37(m,2H),7.04–6.97(m,1H),6.88–6.80(m,1H),3.66–3.60(m,1H),2.16(s,3H),1.09–1.04(m,4H)

Example 37:

Synthesis of Compound 0105

Step 1 Synthesis of Compound I105-3

Compound I105-1 (89.91 mg,0.50 mmol) and compound I105-2 (129.16 mg,0.66 mmol) were added to 1, 4-dioxane (3 mL), tris (dibenzylideneacetone) dipalladium (30.39 mg,0.03mmol, an Naiji), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (38.40 mg,0.07mmol, an Naiji) and cesium carbonate (648.70 mg,1.99 mmol) were further added, and the system was purged with nitrogen 3 times and then heated to 100℃and stirred for 16 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3), the combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give crude product, which was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10:1 to 3:7) to give compound I105-3 (160 mg,0.35mmol, y = 52.70%) as a yellow solid.

LC-MS(ESI):m/z=459.2[M+H]⁺

Step 2 Synthesis of Compound 0105

Compound I105-3 (160 mg,0.35 mmol) was added to dichloromethane (3 mL) under nitrogen at-40℃and boron tribromide (1.74 mL,1.74mmol,1mol/L, an Naiji) was added, after which the reaction was warmed to 25℃and stirred for 2 hours. The temperature was controlled in an ice-water bath and the reaction was quenched by adding 1mL of methanol. The reaction was concentrated under reduced pressure to give crude product, which was purified by preparative high performance liquid chromatography (Waters-Xbridge-C18-10 μm-19 x 250mm, a:10mm ammonium bicarbonate/water B: acetonitrile) to give compound 0105 (6.2 mg,0.02mmol, y=6.5%) as a white solid.

LC-MS(ESI):m/z=445.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:12.59(br s,1H),9.48(s,1H),8.63(s,1H),7.44-7.37(m,2H),7.05-6.98(m,2H),6.85(d,J＝8.2Hz,1H),6.79(d,J＝7.2Hz,1H),3.67–3.59(m,1H),1.90(s,3H),1.81(s,3H),1.11–1.04(m,4H)

Example 38:

synthesis of Compound 0106

Step 1 Synthesis of Compound I106-2

To a solution of compound I106-1 (1 g,4.98mmol, obtained after completion) in acetonitrile (15 mL) was added sodium hydride (0.24 g,5.98mmol,60% purity) at 0℃and then ethyl iodide (0.60 mL,7.48 mmol) was added while maintaining the temperature at 0℃and the reaction mixture was heated to 50℃and stirred for 3 hours. The reaction system was concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (eluent=ethyl acetate: petroleum ether=0% to 20%) to give compound I106-2 (230 mg,1.01mmol, y=20.18%) as a white solid.

LC-MS(ESI):m/z=229.0[M+H]⁺

Step 2 Synthesis of Compound I106-3

To a solution of compound I106-2 (230 mg,1.01 mmol) in methylene chloride (4 ml) was added m-chloroperoxybenzoic acid (0.93 ml,3.02 mmol) at room temperature, and the reaction was stirred at 25℃for 3 hours. The reaction system was concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (eluent=ethyl acetate: petroleum ether=0% to 100%) to give compound I106-3 (450 mg,0.86mmol, y=85.82%) as a white solid.

LC-MS(ESI):m/z=261.0[M+H]⁺

Step 3 Synthesis of Compound I106-5

To a mixed solution of compound I106-3 (100 mg,0.38 mmol), zinc chloride (0.77 mL,0.77 mmol) and tetrahydrofuran (2 mL) of compound I106-4 (0.09 mL,1.15 mmol) at 0℃was added cesium carbonate (374.94 mg,1.15 mmol), and the reaction system was warmed to 70℃and stirred for 4 hours. The mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (eluent=ethyl acetate: petroleum ether=0% to 50%) to give compound I106-5 (22 mg,0.08mmol, y=20.63%) as a yellow solid.

LC-MS(ESI):m/z=253.0[M+H]⁺

Step 4 Synthesis of Compound 0106

To a solution of compound I106-5 (22 mg,0.09 mmol), compound I106-6 (25.02 mg,0.09 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (10.08 mg,0.02 mmol) and cesium carbonate (85.10 mg,0.26 mmol) in N, N-dimethylformamide (1 mL) was added tris (dibenzylideneacetone) dipalladium (7.97 mg,0.01 mmol), the mixture was replaced with nitrogen gas 3 times, and the temperature was raised to 90 ℃ and the reaction was stirred for 3 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3), the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product which was purified by preparative HPLC (Phenomenex Gemini 150mm*25mm*10um colume) (eluent = 28% to 58% (v/v) acetonitrile and water with 0.01% ammonium bicarbonate) to give compound 0106 (4.09 mg,0.01mmol, y = 9.33%) as a white solid.

LC-MS(ESI):m/z=504.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:13.23(br s,1H),9.54(s,1H),8.51(s,1H),7.45(d,J＝7.4Hz,1H),7.03(d,J＝8.4Hz,1H),6.86(d,J＝7.8Hz,2H),5.13–5.00(m,1H),4.49–4.38(m,2H),4.20–4.13(m,1H),3.97–3.92(m,1H),2.42–2.37(m,1H),2.32–2.25(m,1H),2.15–2.09(m,1H),2.03–1.97(m,1H),1.90(s,3H),1.81(s,3H),1.43(t,J＝7.2Hz,3H)

Example 39:

synthesis of Compounds 0114 and 0134

Step 1 Synthesis of Compound 0106

Under nitrogen, compound I114-1 (200 mg,1.98mmol, bi) and acetic anhydride (166.7. Mu.L, 1.78 mmol) were added to pyridine (1 mL) and the resulting mixture was stirred at 25℃for 3 hours to give a yellow solution. The reaction solution was concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (eluent=dichloromethane: methanol=100:1 to 10:1) to give compound I114-2 (190 mg,1.33mmol, y= 67.11%) as a yellow oil.

¹H NMR(400MHz,DMSO-d₆)δ4.91–4.77(m,1H),3.58–3.48(m,2H),3.21–2.89(m,2H),2.56–2.47(m,1H),2.01–1.94(m,3H),1.88–1.72(m,1H),1.72–1.57(m,1H),1.46–1.20(m,2H)

Step 2 Synthesis of Compounds 0114 and 0134

To a solution of compound I114-3 (50 mg,0.09 mmol) and compound I114-2 (79.5 mg,0.55 mmol) in dimethyl sulfoxide (1 mL) under nitrogen was added N, N-diisopropylethylamine (0.03 mL,0.23 mmol), and the solution was heated to 100℃and stirred for 16 hours. The mixture was filtered and the filter cake was washed with dimethyl sulfoxide (2 mL) to give a filtrate, which was purified by preparative HPLC (Phenomenex Gemini 150mm*25mm*10um colume (eluent=37 to 47% (v/v) acetonitrile and water with 0.1% formic acid) to give compound 0114 (3.96 mg,0.01mmol, y=7.09%) as a white solid, compound 0134 (3.58 mg,0.01mmol, y=6.59%) as a white solid.

Compound 0114

LC-MS(ESI):m/z=603.9[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ12.62(s,1H),9.58(s,1H),7.43(d,J＝7.3Hz,1H),7.21–7.14(m,1H),7.08(d,J＝11.4Hz,1H),6.91(s,1H),6.81(d,J＝7.2Hz,1H),5.20-5.11(m,1H),4.11–3.86(m,1H),3.63–3.54(m,2H),3.51–3.44(m,2H),2.23–2.14(m,1H),1.98(d,J＝21.7Hz,3H),1.91(s,3H),1.85(s,3H),1.81–1.62(m,2H),1.61–1.43(m,1H),1.05–0.97(m,4H)

Compound 0134

LC-MS(ESI):m/z=603.9[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ12.60(s,1H),9.57(s,1H),7.41(d,J＝7.4Hz,1H),7.20–7.14(m,1H),7.08(d,J＝11.4Hz,1H),6.88(s,1H),6.79(d,J＝7.2Hz,1H),5.20–5.13(m,1H),4.10–3.88(m,1H),3.63–3.54(m,2H),3.52–3.45(m,2H),2.24–2.14(m,1H),1.98(d,J＝24.3Hz,3H),1.91(s,3H),1.86(s,3H),1.82–1.64(m,2H),1.62–1.45(m,1H),1.05–0.98(m,4H)

Example 40:

synthesis of Compound 0115

Step 1 Synthesis of Compound I115-3

To a mixed solution of compound I115-1 (1.0 g,3.13 mmol), compound I115-2 (0.75 g,3.13 mmol) and cesium carbonate (3.06 g,9.39 mmol) in N, N-dimethylformamide were added [5- (diphenylphosphino) -9, 9-dimethyl-9H-oxa-4-yl ] diphenylphosphine (0.36 g,0.63 mmol) and tris (1, 5-diphenylpenta-1, 4-dien-3-one) palladium (0) (0.25 g,0.31 mmol), and the mixture was degassed and stirred with nitrogen for 3 times at elevated temperature to 100 ℃ under nitrogen atmosphere for 18 hours. The reaction was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3), the combined organic phases were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated under reduced pressure and purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10:1 to 1:1) to give compound I115-3 (750 mg,0.31 mmol) as a yellow solid.

LC-MS(ESI):m/z=523.2[M+H]⁺

Step 2 Synthesis of Compound I115-4

To a solution of compound I115-3 (750 mg,0.31 mmol) in dichloromethane (6 ml) was added tribromoborane (5.02 ml,5.02 mmol) at 0 ℃, and the reaction was then warmed to 25 ℃ and stirred for 1 hour. The reaction was poured into water (6 mL) and extracted with dichloromethane (10 mL x 3), the combined organic phases were washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude product, which was purified by silica gel chromatography (eluent = dichloromethane: methanol = 80:1 to 20:1) to give compound I115-4 (500 mg,0.98 mmol) as a yellow solid.

LC-MS(ESI):m/z=509.2[M+H]⁺

Step 3 Synthesis of Compound I115-5

To a solution of compound I115-4 (45 mg,0.89 mmol) in dichloromethane (10 mL) was added 3-chlorobenzene-1-carboperoxyacid (414.66 mg,2.40 mmol) at 0deg.C, and the reaction was then warmed to 25deg.C and stirred for 18 hours. The reaction was poured into water (30 mL) and extracted with dichloromethane (30 mL x 3), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give crude product, which was purified by silica gel chromatography (eluent = dichloromethane: methanol = 80:1 to 20:1) as yellow solid compound I115-5 (320 mg,0.59 mmol).

LC-MS(ESI):m/z=541.2[M+H]⁺

Step 4 Synthesis of Compound 0115

To a mixed solution of compound I115-5 (60 mg,0.11 mmol) and 3-methylbutane-1, 3-diol (69.36 mg,0.67mmol, obtained by completion) in dimethyl sulfoxide (2 mL) was added potassium tert-butoxide (31.14 mg,0.28 mmol) at room temperature, and the mixture was stirred at 100 ℃ for 4 hours. The reaction was filtered, the filter cake was washed with dimethyl sulfoxide (4 mL), and the filtrates were combined and purified by preparative HPLC (Phenomenex Gemini mm 25mm 10umcolume (eluent=30% to 60% (v/v) CH ₃ CN and H ₂O,0.025％NH₄HCO₃) to give compound 0115 (8.22 mg,0.01mmol, y=13.12%) as a white solid.

LC-MS(ESI):m/z=565.4[M+H]⁺

¹H NMR(400MHz,DMSO)δ12.55(br s,1H),9.59(br s,1H),7.42(d,J＝7.2Hz,1H),7.15(d,J＝3.6Hz,1H),7.08(d,J＝11.2Hz,1H),6.89(d,J＝3.2Hz,1H),6.80(d,J＝7.2Hz,1H),4.58(t,J＝7.2Hz,2H),4.40(s,1H),3.53-3.47(m,1H),1.96-1.92(m,2H),1.91(s,3H),1.85(s,3H),1.21(s,6H),1.05-0.98(m,4H)

Example 41:

Synthesis of Compound 0116

Step 1 Synthesis of Compound I116-2

To a solution of compound I116-1 (10 g,65.12 mmol) in 1, 2-dichloroethane (30 mL) was added cyclopropylboronic acid (9.14 g,106.38 mmol), copper acetate (9.66 g,53.19 mmol), 2- (pyridin-2-yl) pyridine (8.31 g,53.19 mmol) and sodium bicarbonate (8.94 g,106.38 mmol), and the reaction was warmed to 80℃and stirred for 18 hours. The reaction was filtered and the filter cake was washed with dichloromethane (50 ml x 3), the filtrates were combined and concentrated under reduced pressure to give crude product, which was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 100:1 to 5:1) to give compound I116-2 (5.0 g,21.92mmol, y = 41.2%) as a white solid.

LC-MS(ESI):m/z=228.0[M+H]⁺

Step 2 Synthesis of Compound I116-3

To a solution of compound I116-2 (2.8 g,12.28 mmol) in N, N-dimethylformamide (40 mL) was added sodium methyl mercaptide (0.86 g,12.28 mmol) in an ice-water bath, and the reaction was stirred at 25℃for 2 hours. The reaction was poured into water (50 mL) and extracted 3 times with ethyl acetate (100 mL x 3), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude product, which was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 100:1 to 10:1) to give compound I116-3 (2 g,8.34mmol, y = 67.9%) as a white solid.

LC-MS(ESI):m/z=240.0[M+H]⁺

Step 3 Synthesis of Compound I116-4

To a mixed solution of compound I116-3 (1 g,3.75 mmol) and cyclopropylboronic acid (0.32 g,3.75 mmol), potassium carbonate (1.30 g,9.39 mmol) in 1, 4-dioxane (10 mL) and water (2 mL) under nitrogen atmosphere was added palladium bis (triphenylphosphine) chloride (0.26 g,0.38 mmol), and the reaction system was warmed to 100℃and stirred for 18 hours. The reaction was poured into water (20 mL) and extracted 3 times with ethyl acetate (50 mL x 3), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product which was purified by preparative HPLC ((eluent = 5% to 65% (v/v) CH ₃CN/H₂ O, 0.1% hcooh) to give compound I116-4 (300 mg,1.04mmol, y = 27.7%) as a white solid.

LC-MS(ESI):m/z=246.5[M+H]⁺

Step 4 Synthesis of Compound I116-5

To a solution of compound I116-4 (200 mg,0.82 mmol) in dichloromethane (5 mL) was added m-chloroperoxybenzoic acid (281.34 mg,1.63 mmol) and the resulting mixture was stirred at 25℃for 2 hours. The reaction solution was quenched with sodium thiosulfate solution (5 mL) and extracted 3 times with methylene chloride (20 ml×3), the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude product, which was purified by silica gel chromatography (eluent=petroleum ether: ethyl acetate=100:1-4:1) to give compound I116-5 (80 mg,0.27mmol, y=33.6%) as a white solid.

LC-MS(ESI):m/z=278.1[M+H]⁺

Step 5 Synthesis of Compound I116-7

To a solution of compound I116-6 (70 mg,0.23 mmol) and compound I116-5 (80 mg,0.27 mmol) in dimethyl sulfoxide (3 mL) was added potassium tert-butoxide (78.2 mg,0.7 mmol), and the reaction system was warmed to 100℃and stirred for 18 hours. The reaction was poured into water (20 mL) and extracted 3 times with ethyl acetate (30 mL x 3), the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude product, which was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10:1 to 4:1) to give compound I116-7 (50 mg,0.08mmol, y = 34.10%) as a yellow solid.

LC-MS(ESI):m/z=499.2[M+H]⁺

Step 6 Synthesis of Compound 0116

To a solution of compound I116-7 (30 mg,0.06 mmol) in methylene chloride (2 mL) at 0℃was added boron tribromide (0.3 mL,0.3 mmol), and the reaction system was warmed to 25℃and stirred for 1 hour. The reaction was quenched with methanol (2 mL) in an ice-water bath and then ph=7-8 was adjusted with NH ₃ (7M in MeOH) and the mixture concentrated under reduced pressure to give the crude product which was purified by preparative HPLC (Phenomenex Gemini 150mm*25mm*10um colume) (eluent=5% to 60% (v/v) acetonitrile/water, 0.01% NH ₄HCO₃) to give compound 0116 (3.94 mg,0.01mmol, y=13.51%) as a white solid.

LC-MS(ESI):m/z=485.6[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:12.47(br s,1H),9.50(s,1H),7.40(d,J＝7.2Hz,1H),7.26(d,J＝3.6Hz,1H),7.02(d,J＝8.3Hz,1H),6.92(d,J＝3.6Hz,1H),6.85(d,J＝8.3Hz,1H),6.79(d,J＝7.2Hz,1H),3.63–3.55(m,1H),2.29–2.18(m,1H),1.90(s,3H),1.80(s,3H),1.33–1.26(m,2H),1.12–0.99(m,6H)

Example 42:

Synthesis of Compound 0120

Step 1 Synthesis of Compound I120-2

To a solution of compound I120-1 (10 g,65.12 mmol) and cyclopropylborodiol (9.14 g,106.38 mmol) in 1, 2-dichloroethane (150 mL) was added copper acetate (9.66 g,53.19 mmol), 2- (pyridin-2-yl) pyridine (8.31 g,53.19 mmol) and sodium bicarbonate (8.94 g,106.38 mmol) under nitrogen. The reaction solution was stirred at 80 ℃ for 18 hours. The reaction solution was filtered and the filter cake was washed with dichloromethane (50 ml×3), and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (eluent=ethyl acetate: petroleum ether=15-20%) to give compound I120-2 (5.04 g,22.10mmol, y= 41.55%) as a white solid.

LC-MS(ESI):m/z=228.0/230.0[M+H]⁺

Step 2 Synthesis of Compound I120-3

To a solution of compound I120-2 (1.00 g,4.38 mmol) in tetrahydrofuran (10 mL) was added ammonium hydroxide (40 mL,25% aqueous solution, an Naiji) at room temperature, and the resulting reaction solution was stirred at 90 ℃ for 18 hours. The reaction was poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude product, which was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 40 to 80%) to give compound I120-3 (510 mg,2.44mmol, y = 55.75%) as a white solid.

LC-MS(ESI):m/z=209.0/211.0[M+H]⁺

Step 3 Synthesis of Compound I120-4

To a solution of compound I120-3 (410 mg,1.97 mmol) and cyclopropylborodiol (843.97 mg,9.83 mmol) in 1, 4-dioxane (8 mL) and water (2 mL) was added a solution of bis [5- (diphenylphosphino) cyclopent-1, 3-dienyl ] - λ2-iron (II) palladium chloride (143.78 mg,0.20 mmol) and Cs2CO3 (1920.72 mg,5.90 mmol), the mixture was replaced with N ₂ times, and the reaction was stirred under nitrogen atmosphere at 110℃for 18 hours. The reaction was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude product, which was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 50 to 100%) to give compound I120-4 (220 mg,1.03mmol, y = 52.25%) as a white solid.

LC-MS(ESI):m/z=215.2[M+H]⁺

Step 4 Synthesis of Compound I120-5

To a solution of compound I31-8 (250 mg,0.71 mmol) and compound I120-4 (151.65 mg,0.71 mmol) in 1, 4-dioxane (3 mL) were added tris [ dibenzylideneacetone ] dipalladium (0) (64.81 mg,0.07 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (81.91 mg,0.14 mmol) and cesium carbonate (691.80 mg,2.12 mmol), the mixture was replaced with nitrogen for 3 times, and the reaction solution was warmed to 100℃and stirred for 18 hours. The reaction was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3), the combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude product, which was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 10 to 50%) to give compound I120-5 (275 mg,0.57mmol, y = 79.85%) as a brown solid.

LC-MS(ESI):m/z=487.2[M+H]⁺

Step 5 Synthesis of Compound 0120

To a solution of compound I120-5 (200 mg,0.41 mmol) in dichloromethane (4 mL) was added tribromoborane (2.04 mL,2.04 mmol) at 0℃and the reaction was stirred for 1 hour at room temperature after the addition. To the reaction solution was added 2mL of methanol at 0 ℃ to quench the reaction, the ph=8 was adjusted with an methanolic ammonia solution, the reaction system was concentrated under reduced pressure to give a crude product, which was purified by preparative high performance liquid chromatography (Waters-Xbridge-C18-10 μm-19 x 250mM column (eluent=36% to 66% (v/v) acetonitrile and water with 10mM NH ₄HCO₃) to give compound 0120 (86.28 mg,0.18mmol, y=59.23%) as a white solid.

LC-MS(ESI):m/z=473.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:12.41(br s,1H),9.33(s,1H),7.26(d,J＝3.6Hz,1H),6.94(d,J＝8.2Hz,1H),6.91(d,J＝3.6Hz,1H),6.78(d,J＝8.2Hz,1H),4.63(d,J＝3.4Hz,2H),3.63–3.56(m,1H),2.29-2.21(m,1H),2.04(s,3H),1.95(s,3H),1.36–1.28(m,2H),1.11–1.00(m,6H)

Example 43:

Synthesis of Compound 0127

Step 1 Synthesis of Compound I127-2

To a solution of compound I127-1 (480 mg,2.00 mmol) in methylene chloride (8 mL) at 0℃was added m-chloroperoxybenzoic acid (863 mg,5.01 mmol), and the reaction solution was warmed to 25℃and stirred for 3 hours. The mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (eluent=ethyl acetate: petroleum ether=10 to 50%) to give compound I127-2 (370 mg,1.36mmol, y= 68.01%) as a white solid.

LC-MS(ESI):m/z=272.0[M+H]⁺

Step 2 Synthesis of Compound I127-4

To a solution of compound I127-3 (150 mg,0.50 mmol), compound I127-2 (109.66 mg,0.40 mmol) and cesium carbonate (493.10 mg,1.51 mmol) in N, N-dimethylformamide (6 mL) under nitrogen was added 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (58.38 mg,0.10 mmol) and tris (dibenzylideneacetone) dipalladium (46.20 mg,0.05 mmol), and the mixture was stirred at 100℃for 18 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude product, which was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether: = 5-50%) to give compound I127-4 (50 mg,0.09mmol, y = 18.61%) as a yellow solid.

LC-MS(ESI):m/z=533.2[M+H]⁺

Step 3 Synthesis of Compound 0127

To a solution of cyclopropyl alcohol (110.15. Mu.L, 1.88mmol, bi) in tetrahydrofuran (2 mL) was added sodium bis (trimethylsilyl) amide (3760.00. Mu.L, 3.76 mmol) at 0℃and the resulting mixture was stirred at 25℃for 1 hour, then a solution of compound I127-4 (40 mg,0.08 mmol) in tetrahydrofuran was added to the above mixed solution and the mixture was stirred at 75℃for 18 hours. The mixture was concentrated under reduced pressure to give crude product, which was purified by preparative HPLC (Phenomenex Gemini 150mm*25mm*10um colume) (eluent=30 to 60% (v/v) acetonitrile/water, 1% mol/L ammonium bicarbonate) to give compound 0127 (0.81 mg,0.00mmol, y=2.11%) as a white solid.

LC-MS(ESI):m/z=511.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:13.27(br s,1H),7.72(s,1H),7.59(d,J＝8.4Hz,2H),7.39(d,J＝8.8Hz,1H),7.19(d,J＝3.6Hz,1H),6.91(d,J＝3.6Hz,1H),6.84(d,J＝7.4Hz,1H),4.50-4.44(m,1H),3.52-3.48(m,1H),2.15(s,3H),1.04-1.00(m,4H),0.85-0.82(m,4H).

Example 44:

Synthesis of Compound 0135

Step 1 Synthesis of Compound I135-2

To a solution of compound I135-1 (1.48 g,6.49 mmol) in tetrahydrofuran (10 mL) was added ammonia water (40 mL) at room temperature, and the reaction system was warmed to 90℃and stirred for 18 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure to give crude product, which was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 5:1 to 3:2) to give compound I135-2 (1.44 g,6.49mmol, y = 99.98%) as a white solid.

LC-MS(ESI):m/z=209.0[M+H]⁺

Step 2 Synthesis of Compound I135-4

To a solution of compound I135-2 (740 mg,3.55 mmol), compound I135-3 (1.52 g,17.73 mmol) and cesium carbonate (3.47 g,10.64 mmol) in 1, 4-dioxane (12 mL) and purified water (3 mL) under nitrogen was added bis [5- (diphenylphosphino) cyclopentyl-1, 3-dienyl ] - λ2-iron (II) palladium chloride (259.51 mg,0.35 mmol), and the reaction was warmed to 110℃and stirred for 18h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3), the combined organic phases were washed with saturated brine (5 mL) and concentrated under reduced pressure to give crude product which was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 5:1 to 3:2) to give compound I135-4 (260 mg,1.21mmol, y = 34.21%) as a white solid.

LC-MS(ESI):m/z=215.2[M+H]⁺

Step 3 Synthesis of Compound I135-6

To a solution of compound I135-5 (150 mg,0.34 mmol), compound I135-4 (79.4 mg,0.37 mmol) and cesium carbonate (274.4 mg,0.84 mmol) in N, N-dimethylformamide (6 mL) were added tris (dibenzylideneacetone) dipalladium (30.84 mg,0.03 mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (38.98 mg,0.07 mmol) under nitrogen atmosphere, and the mixture was heated to 100℃and stirred for 2 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3), the combined organic phases were washed with saturated brine (50 mL) and concentrated under reduced pressure to give crude product, which was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10:1 to 1:2) to give compound I135-6 (150 mg,0.26mmol, y = 76.95%) as a yellow solid.

LC-MS(ESI):m/z=579.4[M+H]⁺

Step 4 Synthesis of Compound 0135

Compound I135-6 (100 mg,0.17 mmol) was dissolved in dioxane hydrochloride solution (4 mL) and stirred at 25℃for 2 hours. The reaction was adjusted to ph=7-8 with ammonia (7M in MeOH) and concentrated to dryness to give the crude product. The crude product was purified by preparative HPLC (Phenomenex Gemini 150mm*25mm*10um colume) (eluent = 5% to 60% (v/v) acetonitrile/water, 0.01% nh ₄HCO₃) to give compound 0135 (30.5 mg,0.06mmol, y = 35.7%) as a white solid.

LC-MS(ESI):m/z=495.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ13.28(s,1H),12.52(s,1H),7.73(s,1H),7.63-7.56(m,2H),7.40(d,J＝8.4Hz,1H),7.28(d,J＝3.6Hz,1H),6.93(d,J＝3.6Hz,1H),6.84(d,J＝7.2Hz,1H),3.66-3.53(m,1H),2.29-2.10(m,1H),2.16(s,3H),1.33-1.27(m,2H),1.11–0.99(m,6H).

Example 45:

synthesis of Compound 0140

Step 1 Synthesis of Compound I140-2

To a solution of compound I140-1 (500 mg,2.54 mmol) in N, N-dimethylformamide (10 mL) was added sodium hydride (152.3 mg,3.81mmol,60% purity) at 0 ℃. The mixture was replaced with nitrogen 3 times and the reaction was stirred for 30 minutes at 0 ℃ under nitrogen. Methyl iodide (189.6. Mu.L, 3.05 mmol) was further added, and the reaction system was stirred at 25℃for 17.5 hours. The mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL x 3), the combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product which was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 5% -50%) to give compound I140-2 (630 mg,2.54mmol, y = 93.5%) as a yellow solid.

LC-MS(ESI):m/z=211.0/213.0[M+H]⁺

Step 2 Synthesis of Compound 0140

To a solution of compound I140-2 (125.3 mg,0.50 mmol) in N, N-dimethylformamide (2 mL) was added compound I140-3 (150 mg,0.50 mmol), tris (dibenzylideneacetone) dipalladium (0) (46.20 mg,0.05 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (58.40 mg,0.10 mmol) and cesium carbonate (493.10 mg,1.51 mmol), the mixture was replaced with nitrogen gas 3 times, and the reaction was stirred under 100 ℃ microwave under nitrogen atmosphere for 2 hours. The reaction was purified by direct prep HPLC (Waters-Xbridge-C18-10 μm-19×250mM (eluent=37% to 67% (v/v) acetonitrile and water, 10mM ammonium bicarbonate) to give compound 0140 (34.41 mg,0.08mmol, y=15.96%) as a white solid.

LC-MS(ESI):m/z=428.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:13.27(s,1H),12.17(s,1H),8.06(d,J＝5.8Hz,1H),7.75–7.70(m,1H),7.61–7.54(m,2H),7.42–7.37(m,2H),7.25(dd,J＝6.0,1.0Hz,1H),7.16(d,J＝3.2Hz,1H),6.80(d,J＝7.4Hz,1H),3.83(s,3H),2.16(s,3H)

Example 46:

synthesis of Compound 0141

Step 1 Synthesis of Compound 0141

Compound I141-1 (200 mg,0.67 mmol), compound I141-2 (121.50 mg,0.67 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (77.84 mg,0.67 mmol), cesium carbonate (657.47 mg,2.02 mmol) and 1, 4-dioxane (3 mL) were added to a10 mL microwave tube, and the resulting mixture was added tris (dibenzylideneacetone) dipalladium (61.59 mg,0.07 mmol) under nitrogen, and then the resulting mixture was stirred for 2 hours at 120℃and then cooled to room temperature. The mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (eluent=methanol: dichloromethane=0% to 10%) to give 150mg of the crude product. The crude product was purified by preparative HPLC (Phenomenex Gemini mm x 25mm x 10um column (eluent = 30% to 60% (v/v) acetonitrile and water with 0.025% ammonium bicarbonate) to give compound 0141 (47.63 mg,0.11mmol, y = 16.04%) as a white solid.

LC-MS(ESI):m/z=442.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ13.27(s,1H),12.16(s,1H),8.04(d,J＝5.8Hz,1H),7.75-7.70(m,1H),7.61-7.58(m,1H),7.56(d,J＝7.3Hz,1H),7.46(d,J＝3.4Hz,1H),7.39(d,J＝8.6Hz,1H),7.28(dd,J＝5.9,0.9Hz,1H),7.20-7.16(m,1H),6.80(d,J＝7.2Hz,1H),4.25(q,J＝7.2Hz,2H),2.16(s,3H),1.37(t,J＝7.2Hz,3H)

Example 47:

Synthesis of Compound 0142

Step 1 Synthesis of Compound I142-2

To a solution of compound I142-1 (2 g,13.02mmol, b.i.) in N, N-dimethylformamide (20 mL) was added sodium hydride (1.04 g,26.04mmol,60% purity) in portions under ice-bath, and the resulting mixture was stirred at 25 ℃ for 16 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (50 mL x 3), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude product, which was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10:1 to 1:1) to give compound I142-2 (2 g,9.36mmol, y = 71.87%) as a colorless transparent oil.

LC-MS(ESI):m/z=181.1[M-H]^-

Step 2 Synthesis of Compound 0142

To a solution of compound I142-3 (150 mg,0.50 mmol), compound I142-2 (111.98 mg,0.55 mmol) and potassium carbonate (174.30 mg,1.26 mmol) in N, N-dimethylformamide (6 mL) were added tris (dibenzylideneacetone) dipalladium (6.41 mg,0.01 mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (8.10 mg,0.01 mmol) under nitrogen atmosphere, and the mixture was replaced 3 times with nitrogen gas and stirred at 100℃for 2 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (30 mL x 3), the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude product, which was purified by preparative HPLC (Phenomenex 150mm x 25mm x 10um column) (eluent = 5% to 60% (v/v) acetonitrile/water, 0.01% ammonium bicarbonate) to give compound 0142 (14.3 mg,0.03mmol, y = 6.72%) as a white solid.

LC-MS(ESI):m/z=443.6[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:13.28(s,1H),8.63(s,1H),7.73(s,1H),7.63-7.57(m,2H),7.55(d,J＝3.5Hz,1H),7.39(d,J＝8.6Hz,1H),7.07(d,J＝3.5Hz,1H),6.85(d,J＝7.2Hz,1H),4.35–4.24(m,2H),2.16(s,3H),1.39(t,J＝7.2Hz,3H)

Example 48:

Synthesis of Compound 0143

Step 1 Synthesis of Compound 0143

Compound I143-1 (49.13 mg,0.27 mmol) and compound I143-2 (100 mg,0.34 mmol) were added to dioxane (3 mL), followed by tris (dibenzylidene-BASE acetone) dipalladium (5.07 mg,0.01mmol, an Naiji), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (38.92 mg,0.07mmol, an Naiji) and cesium carbonate (328.73 mg,1.01 mmol). The reaction was stirred under nitrogen at 100 ℃ for 2.5 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3), the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude product which was purified by preparative high performance liquid chromatography (Waters-Xbridge-C18-10 μm-19 x 250mM (a: 10mM ammonium bicarbonate _/ water B: acetonitrile, agilent-Poroshell HPH-C18-2.7um-4.6 x50 mM, 10-95) to give compound 0143 (15.92 mg,0.05mmol, y=13.4%) as a white solid.

LC-MS(ESI):m/z=444.1[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:13.29(s,1H),8.77(s,1H),8.54(s,1H),7.74(s,1H),7.68–7.54(m,2H),7.40(d,J＝8.6Hz,1H),6.89(d,J＝7.2Hz,1H),4.46(q,J＝7.1Hz,2H),2.16(s,3H),1.43(t,J＝7.2Hz,3H)

Example 49:

Synthesis of Compound 0144

Step 1 Synthesis of Compound I144-2

To a solution of compound I144-1 (200 mg,1.01mmol, after completion) in N, N-dimethylformamide (3 mL) was added sodium hydride (60.60 mg,1.51mmol,60% purity) under nitrogen at 0 ℃ and then ethyl iodide (81.6 μl,1.02 mmol) was added for reaction. The reaction was stirred at 25 ℃ for 16 hours. The reaction mixture was quenched with aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0% to 14%) to give compound I144-2 (350 mg,1.93mmol, y = 59.19%) as a white solid.

LC-MS(ESI):m/z=226.0/228.0[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ8.22(d,J＝1.0Hz,1H),8.17(d,J＝6.0Hz,1H),7.82(dd,J＝6.0,0.9Hz,1H),4.50(q,J＝7.2Hz,2H),1.43(t,J＝7.2Hz,3H)

Step 2 Synthesis of Compound 0144

To a solution of compound I144-3 (72.3 mg,0.24 mmol), compound I144-2 (50 mg,0.22 mmol), cesium carbonate (216.18 mg,0.66 mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (25.59 mg,0.04 mmol) in 1, 4-dioxane (1.5 mL) under nitrogen was added tris (dibenzylideneacetone) dipalladium (20.25 mg,0.02 mmol), and the mixture was reacted 3 times under nitrogen at 90℃for 40 minutes. The mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (eluent=methanol: dichloromethane=0% to 10%) to give 50mg of the crude product. The crude product was purified by preparative HPLC (Phenomenex Gemini 150mm*25mm*10um colume (eluent = 30% to 60% (v/v) acetonitrile and water with 0.025% ammonium bicarbonate) to give compound 0144 (25.63 mg,0.06mmol, y = 26.19%) as a white solid.

LC-MS(ESI):m/z=443.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ13.28(s,1H),12.69(s,1H),8.66(s,1H),8.18(d,J＝6.2Hz,1H),7.73(s,1H),7.62–7.57(m,2H),7.42–7.37(m,2H),6.84(d,J＝7.2Hz,1H),4.46(d,J＝7.2Hz,2H),2.16(s,3H),1.41(t,J＝7.2Hz,3H)

Example 50:

Synthesis of Compound 0145

Step 1 Synthesis of Compound I145-2

To a solution of compound I145-1 (1 g,5.08mmol, pickle) in N, N-dimethylformamide (20 mL) was added sodium hydride (0.41 g,10.15mmol,60% purity, pickle) and stirred at 0deg.C for 10 minutes, and ethyl iodide (0.08 mL,6.09mmol, pickle) was added. The resulting mixture was stirred at 25 ℃ for 18 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL. Times.3). The combined organic phases were washed with saturated brine (20 mL. Times.4), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel (eluent = petroleum ether: ethyl acetate = 10:1 to 3:1) to give compound I145-2 (1 g,4.44mmol, y = 79.6%) as a brown oil.

LC-MS(ESI):m/z=225.0/227.0[M+H]⁺

Step 2 Synthesis of Compound 0145

To a solution of compound I145-3 (150 mg,0.50 mmol), compound I145-2 (114 mg,0.50 mol) and cesium carbonate (493.10 mg,1.51 mmol) in 1.4-dioxane (5 mL) was added 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (58.38 mg,0.10 mmol), tris (dibenzylideneacetone) dipalladium (46.20 mg,0.05 mmol). The mixture was replaced 3 times with nitrogen and warmed to 100 ℃ and stirred for 2.5 hours. The mixture was poured into water (5 mL) and extracted with ethyl acetate (10 mL x 3), the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product which was purified by preparative HPLC (Waters-SunFire-C18-10 μm-19 x 250mm (eluent = 25% to 75% (v/v) acetonitrile and water, 0.1% formic acid) to give compound 0145 (40.13 mg,0.09mmol, y = 18.02%) as a white solid.

LC-MS(ESI):m/z=442.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ:13.30(s,1H),11.15(br s,1H),8.26-8.22(m,2H),7.74(s,1H),7.63-7.57(m,2H),7.52(d,J＝3.6Hz,1H),7.39(d,J＝8.6Hz,1H),6.92-6.85(m,2H),4.30(q,J＝7.2Hz,2H),2.16(s,3H),1.39(t,J＝7.2Hz,3H)

Example 51:

Other compounds were synthesized following similar procedures to those described above for examples 1 through 50.

Biological example:

EXAMPLE A PKMYT test for inhibitory Activity

1、PKMYT1-Fusion vector DNA transient transfection HEK293 cells

The medium was removed from the flask by aspiration, trypsinized and the cells dissociated from the flask. Trypsin was neutralized using cell culture medium and centrifuged at 200×g for 5 min to pellet the cells. The medium was aspirated and the cells resuspended in assay medium. The density was adjusted to 2X 10 ⁵ cells/ml using the assay medium.

Lipid DNA complexes were prepared as follows:

a. Preparation of a 10. Mu.g/ml DNA Opti-MEM solution:

(1)1mL Opti-MEM(gibco,11058021)。

(2) 9.0. Mu.g/ml of transfection vector DNA (Promega, E4881),

(3)1.0μg/ml PMYT1-Fusion vector DNA (Promega, NV 1871)

B. thoroughly mixed.

C. will 30 μlHD transfection reagent (Promega, E2311) was added to the DNA solution to form lipid DNA complexes.

D. mixing the materials in an inverted manner for 5-10 times.

E. Incubate for 20 minutes at room temperature to form complexes.

In a sterile conical tube, 1 part of lipid-DNA complex (e.g., 1 ml) is mixed with 20 parts of 2X 10 ⁵ cells/ml HEK293 cells (e.g., 20 ml). Mix gently 5 times with inversion.

Mu.L of [ cell+lipid: DNA ] complex was dispensed into 384-well assay plates and incubated for 20-30 hours.

2. Preparation NanoBRET ^TM of tracer reagent and addition to cells

Preparation of 20X tracer (final concentration 2. Mu.M)

(1) 100 Xtracer (200. Mu.M) was prepared in 100% DMSO and 43. Mu.L of 400. Mu.M tracer was added to 43. Mu.L of DMSO.

(2) 20 Xtracer was prepared and 86. Mu.L of 200. Mu.M tracer was added to 344. Mu.L of tracer dilution buffer.

Mu.L of 4 Xtracer reagent was dispensed per well of cells. 1000rpm,1 minute.

3. Addition of test Compounds

40NL of compound solution was transferred per well in 384 plates by Echo 655. Plates were incubated at 37 ℃ for 2 hours at 5% co 2.

4、NanoBRET^TMAssay

A3 Xsubstrate plus inhibitor solution was prepared in Opti-MEM. Mix gently 5-10 times in a conical tube upside down. (final inhibitor concentration was 20. Mu.M). mu.L of 3 Xwhole substrate plus inhibitor solution was added to 384 well plates. Incubating for 2-3 min at room temperature. Donor emission wavelength (450 nm) and acceptor emission wavelength (610 nm) were measured using EnVision Xcite Multilabel Reader.

5. Data analysis

%Inhibition=(Signalcompound-SignalAve_PC)/(SignalAve_NC-SignalAve_PC)*100

EXAMPLE B anti-HCC 1569 cell proliferation Activity assay

Cell culture

HCC1569 cells were cultured in T150 cell flasks in RPMI-1640,10% FBS,1% P/S at 37℃in a 5% CO ₂ incubator.

Experimental procedure

Day 0

Compounds were formulated at 10 concentrations from 10000nM, 3-fold dilution. mu.L of the compound solution was added to 384-well plates according to the plate layout. According to the plate layout, 1.11x10 ⁴(6ml)/5.55x10³ (6 ml) cells were seeded in each well of 384 well plates with 45 μl of medium. Cells were incubated at 37 ℃,5% co ₂ for 7 days.

Day 7

The test plates were removed from the incubator and equilibrated for 30 minutes at room temperature. To each well was added 25 μl of cell titration (Promega) reagent. Plates were centrifuged at 1000rpm for 1 min and then incubated at room temperature for 10min to stabilize the luminescence signal. The luminescence signal was recorded by Envision.

Data analysis

Proliferation Inhibition%=100%-(Avg.compound-Avg.PC)/(Avg.NC-Avg.PC)x100%

TABLE 1 cell Activity data

While the invention has been described and illustrated with reference to specific embodiments thereof, the description and illustration is not intended to be limiting. It will be understood by those skilled in the art that various changes may be made and equivalents substituted without departing from the true spirit and scope of the invention as defined by the appended claims. The illustrations may not be drawn to scale. There may be a distinction between process reproduction and actual equipment in the present invention due to manufacturing processes and tolerances. Other embodiments of the invention not specifically described are possible. The specification and drawings are to be regarded in an illustrative rather than a restrictive sense. Modifications may be made to adapt a particular situation, material, composition of matter, method or process to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the appended claims. Although the methods disclosed herein have been described with reference to particular operations being performed in a particular order, it should be understood that these operations may be combined, sub-divided, or reordered to form an equivalent method without departing from the teachings of the present invention. Accordingly, unless specifically indicated herein, the order and grouping of operations is not a limitation of the present invention.

Claims (25)

1. A compound of formula (I), or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate, hydrate or isotope-labeled compound thereof, in: Ring A is a 5-7 membered monocyclic aryl, heterocyclic or heteroaryl group or an 8-11 membered fused bicyclic aryl, heterocyclic or heteroaryl group; Ring B is a 5-6-membered monocyclic aromatic group, heterocyclic group or heteroaryl group; Ring C is a 5-7 membered monocyclic aryl, heterocyclic or heteroaryl group or an 8-11 membered fused bicyclic aryl, heterocyclic or heteroaryl group; _RA is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, halogen, hydroxy, oxo, cyano or amine; _RB is hydrogen, C1-C6 alkyl, halogen, hydroxyl, oxo, cyano or amine; R _C is LQR ₁ , hydrogen, halogen, hydroxyl, oxo, cyano, amine, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), C3-C6 cycloalkyl, C1-C6 haloalkyl, -O-(C1-C6 haloalkyl), -NH-(C1-C6 haloalkyl), -N(C1-C6 haloalkyl)(C1-C6 haloalkyl), pentafluorosulfur, C1-C6 haloalkoxy or halocycloalkyl, -NH-S(O) ₂ -(C1-C6 alkyl), -NHP(＝O)-(C1-C6 alkyl), -NHC(O)-(C1-C6 alkyl), -C(O)NH-(C1-C6 alkyl), -NHC(O)NH-(C1-C6 alkyl), -S(O) ₂ -(C1-C6 alkyl), -P(=O)(C1-C6 alkyl) ₂ ; L is a direct bond, O or NH; Q is absent, a direct bond, or a C1-C6 alkyl group; R ₁ is C1-C6 alkyl, C3-C6 cycloalkyl or a 4-7 membered heterocyclic group containing one or two heteroatoms selected from N, O, and S, wherein the alkyl, cycloalkyl or heterocyclic group is optionally substituted by one or two substituents R ₂ ; _R2 is C1-C6 alkyl, halogen, hydroxyl, oxo, cyano, amine, -(C=O)(C1-C6 alkyl) or -N(C1-C6 alkyl)(C1-C6 alkyl); Y is O, CR ₃ , CR ₃ R ₄ , N or NH; _R3 and _R4 are independently hydrogen, C1-C6 alkyl, halogen, hydroxyl, oxo, cyano or amine, or _R3 and _R4 attached to the same carbon atom together with the carbon atom to which they are attached form a C3-C7 cycloalkyl, or _R3 and _R4 attached to different carbon atoms together with the carbon atom to which they are attached form a C3-C7 cycloalkyl; m is 1, 2, 3 or 4; n is 0 or 1; p is 1, 2, or 3; q is 1 or 2. 2. The compound according to claim 1, wherein q is 1, and Y is CR ₃ R ₄ ; R ₃ and R ₄ are as defined in claim 1. The compound according to claim 1 , wherein q is 1 and Y is NH. 4. The compound according to claim 1, wherein q is 2, and Y is CR ₃ or N; R ₃ is as defined in claim 1. 5. The compound according to claim 1, wherein q is 2, and Y is CR ₃ R ₄ ; R ₃ and R ₄ are as defined in claim 1. 6. The compound according to any one of claims 1 to 5, wherein ring B is a 5-6 membered heteroaryl group containing at least one N atom. The compound according to claim 6 , wherein ring B is thiazole or pyridine. 8. The compound according to any one of claims 1 to 7, wherein ring A is selected from a phenyl group, a 5-6 membered heteroaryl group containing at least one N atom, or an 8-11 membered fused bicyclic heteroaryl group containing at least two N atoms. 9. The compound according to claim 8, wherein ring A is selected from a phenyl group, a 6-membered heteroaryl group containing at least one N atom, or a 9-membered fused bicyclic heteroaryl group containing at least two N atoms. 10. The compound according to claim 9, wherein ring A is selected from _RA , m are as defined in claim 1. 11. The compound according to claim 10, wherein ring A is selected from _RA1 , _RA2 , _RA3 , _RA4 , _RA5 and _RA6 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, halogen, hydroxy, oxo, cyano or amine. 12. The compound according to claim 11, wherein ring A is _RA1 and _RA2 are methyl groups. 13. The compound according to claim 11, wherein ring A is _RA1 and _RA2 are methyl groups; _RA3 is halogen. 14. The compound according to claim 11, wherein ring A is _RA5 is methyl. 15. The compound according to claim 11, wherein ring A is selected from 16. The compound according to any one of claims 1 to 15, wherein ring C is a 5-7 membered monocyclic heteroaryl group or an 8-11 membered condensed bicyclic heteroaryl group containing at least two N atoms. The compound according to claim 16 , wherein Ring C is a 9-membered fused bicyclic heteroaryl group containing at least two N atoms. 18. The compound according to claim 17, wherein ring C is selected from R _C , p are as defined in claim 1. 19. The compound according to claim 18, wherein _RC is selected from -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CF ₃ , 20. The compound according to claim 1, wherein the compound of formula (I) is selected from: 21. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, prodrug or solvate thereof, and a pharmaceutically acceptable carrier or excipient. 22. Use of a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, prodrug or solvate thereof, for the manufacture of a medicament for treating cancer in an individual in need thereof. 23. The use according to claim 22, wherein the compound or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, prodrug or solvate thereof is co-administered to the subject with a second anticancer agent, surgical therapy, ionizing radiation or a combination thereof. 24. The use according to claim 22, wherein the second anticancer agent is selected from: targeted cancer drugs such as trastuzumab, ramucirumab, bevacizumab, everolimus, tamoxifen, toremifene, fulvestrant, anastrozole, exemestane, lapatinib, letrozole, pertuzumab, adotrastuzumab emtansine, palbociclib, cetuximab, panitumumab, zulafalib, regorafenib, imatinib mesylate, lanreotide acetate, sunitinib, regorafenib, denosumab, alitretinoin, sorafenib, pazopanib, temsirolimus, everolimus, tretinoin, dasatinib, nilotinib, Bosutinib, rituximab, alemtuzumab, ofavumab, obinumab, ibrutinib, idexib, brinumab, soranib, crizotinib, erlotinib, gefitinib, afatinib dimaleate, ceritinib, ramucirumab, nivolumab, pembrolizumab, osimertinib, and lecithinib; alkylating agents, such as busulfan, chlorambucil, cyclophosphamide, ifosfamide, melphalan, mechlorethamine, streptozotocin, thiotepa, uracil mustard, triethylenemelamine, temozolomide, and 2-chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU); antibiotics or plant alkaloids, such as actinomycetes hormones or steroids, such as 5α-reductase inhibitors, aminoglutethimide, anastrozole, bicalutamide, chlortetracycline, diethylstilbestrol (DES), drostanolone, estramustine, ethinyl estradiol, flutamide, fluoxymesterone, goserelin, hydroxyprogesterone, letrozole, leuprolide, medroxyprogesterone acetate, acetylcholine, dapoxetine, tadalafil, oxadiazine, chlortetracycline, dapoxetine, chlortetracycline, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine megestrol acetate, methylprednisolone, methyltestosterone, mitotane, nilutamide, prednisolone, arzoxifene (SERM-3), tamoxifen, testolactone, testosterone, triamcinolone, and Zoladex; synthetic preparations such as all-trans retinoic acid, carmustine (BCNU), carboplatin (CBDCA), lomustine (CCNU), cis-diamminedichloroplatinum (cisplatin), dacarbazine, golidel, altretinoin, hydroxyurea, levamisole, mitoxantrone, o,p'-dichlorodiphenyldichloroethane (o,p'-DDD) (also known as mitotane), oxaliplatin, porfimer sodium, procarbazine, and imatinib mesylate antimetabolites, such as chlorodeoxyadenosine, cytosine arabinoside, 2'-deoxycoformycin, fludarabine phosphate, 5-fluorouracil (5-FU), 5-fluoro-2'-deoxyuridine (5-FUdR), gemcitabine, camptothecin, 6-mercaptopurine, methotrexate, 4-methylamphetamine (4-MTA), and thioguanine; and biologics, such as interferon alpha, bacillus Calmette-Guérin (BCG), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2, and Herceptin. 25. The use according to claim 22, wherein the cancer is a cardiac cancer, such as a sarcoma (e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma), a myxoma, a rhabdomyosarcoma, a fibroma, a lipoma, and a teratoma; a lung cancer, such as a bronchial cancer (e.g., squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, and adenocarcinoma), an alveolar cancer (e.g., bronchiolar carcinoma), a bronchial adenoma, a sarcoma, a lymphoma, a chondroma, and a mesothelioma; a gastrointestinal cancer, such as an esophageal cancer (e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma), a gastric cancer (e.g., a lymphoma and a leiomyosarcoma), a pancreatic cancer (e.g., a ductal adenocarcinoma, an insulinoma, a glucagonoma, a gastrinoma, a carcinoid, and a vipoma), a small intestinal cancer (e.g., adenocarcinoma, a lymphoma, a carcinoid, a Kaposi's sarcoma, a leiomyoma, an hemangioma, a lipoma, a neurofibroma and fibroma), colorectal cancer (e.g., adenocarcinoma, ductal adenoma, villous adenoma, hamartoma, and leiomyoma); genitourinary tract cancers, such as kidney cancer (e.g., adenocarcinoma, Wilms' tumor [Nephroblastoma], lymphoma, and leukemia), bladder and urethral cancer (e.g., squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma), prostate cancer (e.g., adenocarcinoma and sarcoma), testicular cancer (e.g., spermatoma, teratoma, embryonal tumor, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, and lipoma); liver cancers, such as hepatocellular carcinoma (e.g., hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma; bone cancers, such as osteogenic sarcomas (e.g., osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphomas (e.g., reticulum cell sarcoma), multiple myeloma, Malignant giant cell tumors Chordoma, osteochondroma (e.g., osteochondroma, exostoses), benign enchondroma, chondroblastoma, chondromyxoma, osteoid osteoma, and giant cell tumor; Nervous system cancers, such as skull cancer (e.g., osteoma, hemangioma, granuloma, xanthomas, and osteitis malformation), meningeal cancer (e.g., meningioma, meningeal sarcoma, and gliosis), brain cancer (e.g., astrocytoma, medulloblastoma, glioma, ependymoma, blastoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, and congenital tumors), spinal neurofibroma, meningioma, glioma, and sarcoma; Gynecological cancers, such as uterine cancer (e.g., endometrial cancer), cervical cancer (e.g., cervical cancer and preneoplastic cervical dysplasia), ovarian cancer (e.g., ovarian cancer [e.g., serous cystadenocarcinoma, mucinous cystadenocarcinoma and carcinoma of unspecified type], granulosa cell tumor, Stoli-Redig cell tumor, dysgerminoma, and malignant teratoma), vulvar cancer (e.g., squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, and melanoma), vaginal cancer (e.g., clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma [e.g., embryonal rhabdomyosarcoma], and fallopian tube cancer); blood cancers, such as blood cancers (myeloid leukemias [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, and myelodysplasia), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; skin cancers, such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; adrenal gland cancers, such as neuroblastoma; or breast cancer.