CN104650070A - Dihydropyrimidine compound and application thereof to drugs - Google Patents

Abstract

The invention relates to a dihydropyrimidine compound and its use as medicine, especially the medicine for treating and preventing hepatitis B. Specifically, the present invention relates to compounds represented by general formula (I) or (Ia) or their enantiomers, diastereoisomers, tautomers, hydrates, solvates or pharmaceutically acceptable Accepted salts wherein each variable is as defined in the specification. The present invention also relates to compounds represented by general formula (I) or (Ia) or their enantiomers, diastereomers, tautomers, hydrates, solvates or pharmaceutically acceptable salts Use as a medicine, especially as a medicine for the treatment and prevention of hepatitis B.

Description

Dihydropyrimidine compounds and their application in medicine

technical field

The present invention specifically relates to a dihydropyrimidine compound and its pharmaceutical composition, and further relates to the use of the compound or the pharmaceutical composition in the preparation of medicines, especially in the preparation of drugs for the prevention, treatment, treatment or alleviation of Type B Use in medicine for hepatitis (HBV) infection.

Background technique

Hepatitis B virus belongs to the Hepaviridae family. It can cause acute and or persistent/progressive chronic disease. Hepatitis B virus also causes many other clinical features in the pathomorphology - notably chronic inflammation of the liver, cirrhosis and canceration of hepatocellular cells. In addition, co-infection with hepatitis D can have detrimental effects during the development of the disease.

Conventional drugs licensed for the treatment of chronic hepatitis are interferon and lamivudine. However, interferon has only moderate activity and high toxicity; although lamivudine (lamivudine) has good activity, its drug resistance increases rapidly during treatment and often A rebound effect appeared, and the IC ₅₀ value of lamivudine (3-TC) was 300nM (Science, 299(2003), 893-896).

Deres et al. reported heteroaryl ring-substituted dihydropyrimidine (HAP) compounds represented by Bay41-4109 and Bay39-5493, which can inhibit HBV replication by preventing the formation of normal nucleocapsid. Bay41-4109 showed better drug metabolism parameters in clinical research (Science, 299(2003), 893-896). The study of its mechanism of action found that the dihydropyrimidine compounds substituted by heteroaromatic rings interacted with the 113-143 amino acid residues of the core protein, changing the angle between the dimers forming the nucleocapsid, resulting in the formation of different Stabilizes swelling of the nucleocapsid, accelerating core protein degradation (Biochem. Pharmacol. 66 (2003), 2273-2279).

There is still a need for new compounds that can be effectively used as antiviral drugs, especially as drugs for the treatment and/or prevention of hepatitis B.

Contents of the invention

The present invention relates to a new dihydropyrimidine compound and its pharmaceutical composition, and the use of the compound or the pharmaceutical composition in the preparation of medicines for preventing, treating, treating or alleviating viral diseases , especially hepatitis B (HBV) infection or diseases caused by hepatitis B infection.

In one aspect, the present invention relates to a compound, which is a compound represented by formula (I) or (Ia) or an enantiomer, a diastereomer, or a compound represented by formula (I) or (Ia). tautomers, hydrates, solvates, prodrugs, stereoisomers, nitrogen oxides or pharmaceutically acceptable salts,

Wherein, A is a bond, -O-, -S- or -N(R ⁴ )-;

R is the following substructural formula:

R ¹ is C _6-10 aryl or C _1-9 heteroaryl;

R ³ is C _6-10 aryl or C _1-9 heteroaryl;

each R ² and R ⁴ is independently hydrogen or C _1-4 alkyl;

each ^R and ^R is independently hydrogen or alkyl;

each R ^is independently F, Cl, Br, hydroxy, or haloalkyl;

each R ⁶ is independently -(CR ⁷ R ^7a ) _m -C(=O)OR ^8a or C _1-4 alkyl;

Each R ⁹ is independently -S(=O) _q OR ^8a , -(CR ⁷ R ^7a ) _m -S(=O) _q N(R ^8a ) ₂ , triazolyl, -(CR ⁷ R ^7a ) _m -C(=O)OR ⁸ , -(CR ⁷ R ^7a ) _m -C(=O)O-(CR ⁷ R ^7a ) _m -OC(=O)OR ⁸ , -(CR ⁷ R ^7a ) _m - C(=O)O-(CR ⁷ R ^7a ) _m -OC(=O)-R ⁸ , -(CR ⁷ R ^7a ) _t -N(R ^8a ) ₂ , -(CR ⁷ R ^7a ) _m -C (=O)O-(CR ⁷ R ^7a ) _m -C(=O)OR ⁸ , -(CR ⁷ R ^7a ) _t -OC(=O)-R ⁸ , -(CR ⁷ R ^7a ) _m -C (=O)N(R ⁸ ) ₂ or -(CR ⁷ R ^7a ) _m -C(=O)NHR ⁸ ;

Each R ^9a is independently -(CR ⁷ R ^7a ) _m -OH, triazolyl, tetrazolyl, -(CR ⁷ R ^7a ) _m -C(=O)OR ^8a , -(CR ⁷ R ^7a ) _m -S(=O) _q N(R ^8a ) ₂ , -(CR ⁷ R ^7a ) _m -OC(=O)-R ^8a , -(CR ⁷ R ^7a ) _m -N(R ^8a ) ₂ , -S (=O) _q OR ^8a , -(CR ⁷ R ^7a ) _m -C(=O)O-(CR ⁷ R ^7a ) _m -OC(=O)OR ^8a , -(CR ⁷ R ^7a ) _m -C (=O)O-(CR ⁷ R ^7a ) _m -OC(=O)-R ^8a , -(CR ⁷ R ^7a ) _m -C(=O)O-(CR ⁷ R ^7a ) _m -C(= O)OR ^8a or -(CR ⁷ R ^7a ) _m -C(=O)N(R ^8a ) ₂ ;

each R ⁷ and R ^7a is independently hydrogen, haloalkyl or alkyl;

Each R ^8a is independently hydrogen, alkyl, alkoxy, alkyl-S(=O) _q- , aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl, heteroarylalkane Base, cycloalkylalkyl, heterocyclylalkyl, heterocyclyl-S(=O) _q- , heteroaryl-S(=O) _q- , cycloalkyl-S(=O) _q- , or Aryl-S(=O) _q- ;

Each ^R is independently alkyl-S(=O) _q- , aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heteroaryl Cycloalkyl, heterocyclyl-S(=O) _q- , heteroaryl-S(=O) _q- , cycloalkyl-S(=O) _q- or aryl-S(=O) _q -;

each n is independently 1, 2 or 3;

each t is independently 1, 2, 3 or 4;

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

each q is independently 0, 1 or 2;

Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^5a , R ^5b , R ⁶ , R ⁷ , R ^7a , R ⁸ , R ^8a , R ⁹ and R ^9a are alkoxy groups, Aryl, C _6-10 aryl, heteroaryl, C _1-9 heteroaryl, alkyl, C _1-4 alkyl, alkyl-S(=O) _q -, heterocyclyl-S(= O) _q -, heteroaryl-S(=O) _q -, cycloalkyl-S(=O) _q -, aryl-S(=O) _q -, heterocyclyl, arylalkyl, hetero Arylalkyl, cycloalkylalkyl, heterocyclylalkyl, tetrazolyl, triazolyl, haloalkyl, and cycloalkyl can be optionally substituted by hydrogen, fluorine, chlorine, bromine, iodine, oxo ( =O), methylene (= _CH2 ), alkyl, alkoxy, cyano, hydroxyl, nitro, alkylamino, amino, aryl, heteroaryl, heterocyclyl, cycloalkyl, trifluoro Methyl, trifluoromethoxy, haloalkyl-substituted aryl, halogen-substituted aryl or trifluoromethanesulfonyl monosubstituted or identical or different polysubstituted.

In some embodiments, R is the following substructural formula:

each R ⁵ and R ^5a is independently hydrogen or C _1-4 alkyl;

Each R ^5b is independently F, Cl, Br, hydroxyl or C _1-4 haloalkyl;

each R ⁶ is independently -(CR ⁷ R ^7a ) _m -C(=O)OR ^8a or C _1-4 alkyl;

Each R ⁹ is independently -S(=O) _q OR ^8a , -(CR ⁷ R ^7a ) _m -S(=O) _q N(R ^8a ) ₂ , triazolyl, -(CR ⁷ R ^7a ) _m -C(=O)OR ⁸ , -(CR ⁷ R ^7a ) _m -C(=O)O-(CR ⁷ R ^7a ) _m -OC(=O)OR ⁸ , -(CR ⁷ R ^7a ) _m - C(=O)O-(CR ⁷ R ^7a ) _m -OC(=O)-R ⁸ , -(CR ⁷ R ^7a ) _t -N(R ^8a ) ₂ , -(CR ⁷ R ^7a ) _m -C (=O)O-(CR ⁷ R ^7a ) _m -C(=O)OR ⁸ , -(CR ⁷ R ^7a ) _t -OC(=O)-R ⁸ , -(CR ⁷ R ^7a ) _m -C (=O)N(R ⁸ ) ₂ or -(CR ⁷ R ^7a ) _m -C(=O)NHR ⁸ ;

Each R ^9a is independently -(CR ⁷ R ^7a ) _m -OH, triazolyl, tetrazolyl, -(CR ⁷ R ^7a ) _m -C(=O)OR ^8a , -(CR ⁷ R ^7a ) _m -S(=O) _q N(R ^8a ) ₂ , -(CR ⁷ R ^7a ) _m -OC(=O)-R ^8a , -(CR ⁷ R ^7a ) _m -N(R ^8a ) ₂ , -S (=O) _q OR ^8a , -(CR ⁷ R ^7a ) _m -C(=O)O-(CR ⁷ R ^7a ) _m -OC(=O)OR ^8a , -(CR ⁷ R ^7a ) _m -C (=O)O-(CR ⁷ R ^7a ) _m -OC(=O)-R ^8a , -(CR ⁷ R ^7a ) _m -C(=O)O-(CR ⁷ R ^7a ) _m -C(= O)OR ^8a or -(CR ⁷ R ^7a ) _m -C(=O)N(R ^8a ) ₂ ;

each R ⁷ and R ^7a is independently hydrogen, C _1-4 haloalkyl or C _1-4 alkyl;

Each R ^8a is independently hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl-S(=O) _q -, C _6-10 aryl, C _1-9 hetero Aryl, C _3-6 cycloalkyl, C _2-9 heterocyclyl, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _3-6 Cycloalkyl C _1-4 alkyl, C _2-9 heterocyclyl C _1-6 alkyl, C _2-9 heterocyclyl-S(=O) _q -, C _1-9 heteroaryl-S( =O) _q -, C _3-6 cycloalkyl-S(=O) _q - or C _6-10 aryl-S(=O) _q -;

Each R ⁸ is independently C _1-6 alkyl-S(=O) _q -, C _6-10 aryl, C _1-9 heteroaryl, C _3-6 cycloalkyl, C _2-9 heterocycle C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _3-6 cycloalkyl C _1-4 alkyl, C _2-9 heterocyclyl C _1-6 alkyl, C _2-9 heterocyclyl-S(=O) _q -, C _1-9 heteroaryl-S(=O) _q -, C _3-6 cycloalkyl-S(= O) _q - or C _6-10 aryl -S(=O) _q -;

^{Among them , the} _C ^{1-6 alkoxy , C 6-10} _aryl ^, C _1-9 heteroaryl, C _1-4 alkyl, C _1-6 alkyl, C _1-4 haloalkyl, C _1-6 alkyl-S(=O) _q -, C _2-9 heterocycle Group-S(=O) _q -, C _1-9 heteroaryl-S(=O) _q -, C _3-6 cycloalkyl-S(=O) _q -, C _6-10 aryl-S (=O) _q -, C _2-9 heterocyclyl, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _3-6 cycloalkyl C _1-4 alkyl, C _2-9 heterocyclyl C _1-6 alkyl, tetrazolyl, triazolyl and C _3-6 cycloalkyl can be optionally replaced by hydrogen, fluorine, chlorine, bromine, iodine, Oxo (=O), methylene (=CH ₂ ), alkyl, alkoxy, cyano, hydroxyl, nitro, alkylamino, amino, aryl, heteroaryl, heterocyclyl, cycloalkyl , trifluoromethyl, trifluoromethoxy, haloalkyl-substituted aryl, halogen-substituted aryl or trifluoromethanesulfonyl monosubstituted or identical or different multiple substitutions.

In some other embodiments, R is the following substructural formula:

each R ^{and R} is independently hydrogen, methyl, ethyl or propyl;

each R is ^{independently} F, Cl, Br, hydroxy, or trifluoromethyl;

each R ⁶ is independently -(CR ⁷ R ^7a ) _m -C(=O)OR ^8a , methyl, ethyl or propyl;

Each R ⁹ is independently triazolyl, -S(=O) _q OR ^8a , -(CR ⁷ R ^7a ) _t -N(R ^8a ) ₂ , -(CR ⁷ R ^7a ) _m -C(=O) OR ⁸ , -(CR ⁷ R ^7a ) _m -C(=O)O-(CR ⁷ R ^7a ) _m -OC(=O)OR ⁸ , -(CR ⁷ R ^7a ) _m -S(=O) _q N(R ^8a ) ₂ , -(CR ⁷ R ^7a ) _m -C(=O)O-(CR ⁷ R ^7a ) _m -OC(=O)-R ⁸ , -(CR ⁷ R ^7a ) _m -C (=O)O-(CR ⁷ R ^7a ) _m -C(=O)OR ⁸ , -(CR ⁷ R ^7a ) _t -OC(=O)-R ⁸ , -(CR ⁷ R ^7a ) _m -C (=O)N(R ⁸ ) ₂ or -(CR ⁷ R ^7a ) _m -C(=O)NHR ⁸ ;

Each R ^9a is independently -(CR ⁷ R ^7a ) _m -OH, triazolyl, tetrazolyl, -(CR ⁷ R ^7a ) _m -C(=O)OR ^8a , -(CR ⁷ R ^7a ) _m -S(=O) _q N(R ^8a ) ₂ , -(CR ⁷ R ^7a ) _m -OC(=O)-R ^8a , -(CR ⁷ R ^7a ) _m -N(R ^8a ) ₂ , -S (=O) _q OR ^8a , -(CR ⁷ R ^7a ) _m -C(=O)O-(CR ⁷ R ^7a ) _m -OC(=O)OR ^8a , -(CR ⁷ R ^7a ) _m -C (=O)O-(CR ⁷ R ^7a ) _m -OC(=O)-R ^8a , -(CR ⁷ R ^7a ) _m -C(=O)O-(CR ⁷ R ^7a ) _m -C(= O)OR ^8a or -(CR ⁷ R ^7a ) _m -C(=O)N(R ^8a ) ₂ ;

each ^R7 and ^R7a is independently hydrogen, trifluoromethyl, methyl, ethyl or propyl;

_Each R ^8a is independently hydrogen, C _1-4 alkyl, C 1-4 alkoxy, C _1-4 alkyl-S(=O) _q -, phenyl, pyridyl, thiazolyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, Thiadiazolyl, pyrazinyl, pyranyl, triazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-S(=O) ₂ -, cyclobutyl-S( =O) ₂ -, cyclopentyl-S(=O) ₂ -, cyclohexyl-S(=O) ₂ -, naphthyl-S(=O) ₂ - or phenyl-S(=O) ₂ - ;

Each R ⁸ is independently C _1-4 alkyl-S(=O) _q -, phenyl, pyridyl, thiazolyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl , pyridazinyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl, triazinyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-S(=O) ₂ -, cyclobutyl-S(=O) ₂ -, cyclopentyl-S(=O) ₂ - , cyclohexyl-S(=O) ₂ -, naphthyl-S(=O) ₂ - or phenyl-S(=O) ₂ -.

In some embodiments, R ¹ is phenyl; R ³ is 1-methyl-1H-imidazolyl, pyridyl, phenyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, Pyrimidinyl, pyridazinyl, thiazolyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl or triazinyl; each R ² and R ⁴ are independently hydrogen, methyl or ethyl; wherein, the thiazolyl, 1-methyl-1H-imidazole described in R ¹ , R ² , R ³ and R ⁴ Base, pyridyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazole Base, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl, triazinyl, phenyl, methyl and ethyl can be optionally replaced by hydrogen, C _1-4 alkyl, Fluorine, chlorine or bromine monosubstitution or identical or different multiple substitutions.

In some embodiments, the present invention relates to a compound, which is a compound represented by formula (II) or (IIa) or an enantiomer or diastereoisomer of a compound represented by formula (II) or (IIa) isomers, tautomers, hydrates, solvates, prodrugs, stereoisomers, nitrogen oxides or pharmaceutically acceptable salts,

Wherein, R ² is hydrogen or C _1-4 alkyl;

^R3 is 1-methyl-1H-imidazolyl, pyridyl, phenyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, diazolyl , triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl or triazinyl;

R is the following substructural formula:

each R ⁵ and R ^5a is independently hydrogen or C _1-4 alkyl;

Each R ^5b is independently F, Cl, Br, hydroxyl or C _1-4 haloalkyl;

each R ⁶ is independently -(CR ⁷ R ^7a ) _m -C(=O)OR ^8a or C _1-4 alkyl;

Each R ⁹ is independently triazolyl, -S(=O) _q OR ^8a , -(CR ⁷ R ^7a ) _m -S(=O) _q N(R ^8a ) ₂ , -(CR ⁷ R ^7a ) _m -C(=O)OR ⁸ , -(CR ⁷ R ^7a ) _m -C(=O)O-(CR ⁷ R ^7a ) _m -OC(=O)OR ⁸ , -(CR ⁷ R ^7a ) _m - C(=O)O-(CR ⁷ R ^7a ) _m -OC(=O)-R ⁸ , -(CR ⁷ R ^7a ) _t -N(R ^8a ) ₂ , -(CR ⁷ R ^7a ) _m -C (=O)O-(CR ⁷ R ^7a ) _m -C(=O)OR ⁸ , -(CR ⁷ R ^7a ) _t -OC(=O)-R ⁸ , -(CR ⁷ R ^7a ) _m -C (=O)N(R ⁸ ) ₂ or -(CR ⁷ R ^7a ) _m -C(=O)NHR ⁸ ;

Each R ^9a is independently -(CR ⁷ R ^7a ) _m -OH, triazolyl, tetrazolyl, -(CR ⁷ R ^7a ) _m -C(=O)OR ^8a , -(CR ⁷ R ^7a ) _m -S(=O) _q N(R ^8a ) ₂ , -(CR ⁷ R ^7a ) _m -OC(=O)-R ^8a , -(CR ⁷ R ^7a ) _m -N(R ^8a ) ₂ , -S (=O) _q OR ^8a , -(CR ⁷ R ^7a ) _m -C(=O)O-(CR ⁷ R ^7a ) _m -OC(=O)OR ^8a , -(CR ⁷ R ^7a ) _m -C (=O)O-(CR ⁷ R ^7a ) _m -OC(=O)-R ^8a , -(CR ⁷ R ^7a ) _m -C(=O)O-(CR ⁷ R ^7a ) _m -C(= O)OR ^8a or -(CR ⁷ R ^7a ) _m -C(=O)N(R ^8a ) ₂ ;

each R ⁷ and R ^7a is independently hydrogen, C _1-4 haloalkyl or C _1-4 alkyl;

Each R ^8a is independently hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl-S(=O) _q -, C _6-10 aryl, C _1-9 hetero Aryl, C _3-6 cycloalkyl, C _2-9 heterocyclyl, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _3-6 Cycloalkyl C _1-4 alkyl, C _2-9 heterocyclyl C _1-6 alkyl, C _2-9 heterocyclyl-S(=O) _q -, C _1-9 heteroaryl-S( =O) _q -, C _3-6 cycloalkyl-S(=O) _q - or C _6-10 aryl-S(=O) _q -;

Each R ⁸ is independently C _1-6 alkyl-S(=O) _q -, C _6-10 aryl, C _1-9 heteroaryl, C _3-6 cycloalkyl, C _2-9 heterocycle C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _3-6 cycloalkyl C _1-4 alkyl, C _2-9 heterocyclyl C _1-6 alkyl, C _2-9 heterocyclyl-S(=O) _q -, C _1-9 heteroaryl-S(=O) _q -, C _3-6 cycloalkyl-S(= O) _q - or C _6-10 aryl -S(=O) _q -;

each R ¹⁰ is independently hydrogen, fluoro, chloro, or bromo;

each n is independently 1, 2 or 3;

each t is independently 1, 2, 3 or 4;

each q is independently 0, 1 or 2;

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

Wherein, R ² , R ³ , R ⁵ , R ^5a , R ^5b , R ⁶ , R ⁷ , R ^7a , R ⁸ , R ^8a , R ⁹ and R ^9a are C _1-6 alkoxy groups, C _6-10 aryl, C _1-9 heteroaryl, C _1-4 alkyl, C _1-6 alkyl, C _1-4 haloalkyl, C _1-6 alkyl-S(=O) _q -, C _2-9 heterocyclyl-S(=O) _q -, C _1-9 heteroaryl-S(=O) _q -, C _3-6 cycloalkyl-S(=O) _q -, C _{6 -10} aryl-S(=O) _q -, C _2-9 heterocyclyl, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _{3 -6} cycloalkyl C _1-4 alkyl, C _2-9 heterocyclyl C _1-6 alkyl, tetrazolyl, triazolyl, 1-methyl-1H-imidazolyl, pyridyl, phenyl, Furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, diazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadi Azolyl, pyrazinyl, pyranyl, triazinyl and C _3-6 cycloalkyl can be optionally replaced by hydrogen, fluorine, chlorine, bromine, iodine, oxo (=O), methylene (=CH ₂ ), alkyl, alkoxy, cyano, hydroxyl, nitro, alkylamino, amino, aryl, heteroaryl, heterocyclyl, cycloalkyl, trifluoromethyl, trifluoromethoxy, haloalkane substituted aryl, halogen substituted aryl or trifluoromethanesulfonyl monosubstituted or identical or different multiple substitutions.

In some other embodiments, R is the following substructural formula:

each R ^{and R} is independently hydrogen, methyl, ethyl or propyl;

each R is ^{independently} F, Cl, Br, hydroxy, or trifluoromethyl;

each R ⁶ is independently -(CR ⁷ R ^7a ) _m -C(=O)OR ^8a , methyl, ethyl or propyl;

Each R ⁹ is independently triazolyl, -S(=O) _q OR ^8a , -(CR ⁷ R ^7a ) _m -S(=O) _q N(R ^8a ) ₂ , -(CR ⁷ R ^7a ) _m -C(=O)OR ⁸ , -(CR ⁷ R ^7a ) _m -C(=O)O-(CR ⁷ R ^7a ) _m -OC(=O)OR ⁸ , -(CR ⁷ R ^7a ) _m - C(=O)O-(CR ⁷ R ^7a ) _m -OC(=O)-R ⁸ , -(CR ⁷ R ^7a ) _t -N(R ^8a ) ₂ , -(CR ⁷ R ^7a ) _m -C (=O)O-(CR ⁷ R ^7a ) _m -C(=O)OR ⁸ , -(CR ⁷ R ^7a ) _t -OC(=O)-R ⁸ , -(CR ⁷ R ^7a ) _m -C (=O)N(R ⁸ ) ₂ or -(CR ⁷ R ^7a ) _m -C(=O)NHR ⁸ ;

Each R ^9a is independently -(CR ⁷ R ^7a ) _m -OH, triazolyl, tetrazolyl, -(CR ⁷ R ^7a ) _m -C(=O)OR ^8a , -(CR ⁷ R ^7a ) _m -S(=O) _q N(R ^8a ) ₂ , -(CR ⁷ R ^7a ) _m -OC(=O)-R ^8a , -(CR ⁷ R ^7a ) _m -N(R ^8a ) ₂ , -S (=O) _q OR ^8a , -(CR ⁷ R ^7a ) _m -C(=O)O-(CR ⁷ R ^7a ) _m -OC(=O)OR ^8a , -(CR ⁷ R ^7a ) _m -C (=O)O-(CR ⁷ R ^7a ) _m -OC(=O)-R ^8a , -(CR ⁷ R ^7a ) _m -C(=O)O-(CR ⁷ R ^7a ) _m -C(= O)OR ^8a or -(CR ⁷ R ^7a ) _m -C(=O)N(R ^8a ) ₂ ;

each ^R7 and ^R7a is independently hydrogen, trifluoromethyl, methyl, ethyl or propyl;

_Each R ^8a is independently hydrogen, C _1-4 alkyl, C 1-4 alkoxy, C _1-4 alkyl-S(=O) _q -, phenyl, pyridyl, thiazolyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, Thiadiazolyl, pyrazinyl, pyranyl, triazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-S(=O) ₂ -, cyclobutyl-S( =O) ₂ -, cyclopentyl-S(=O) ₂ -, cyclohexyl-S(=O) ₂ -, naphthyl-S(=O) ₂ - or phenyl-S(=O) ₂ - ;

Each R ⁸ is independently C _1-4 alkyl-S(=O) ₂ -, phenyl, pyridyl, thiazolyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl , pyridazinyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl, triazinyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-S(=O) ₂ -, cyclobutyl-S(=O) ₂ -, cyclopentyl-S(=O) ₂ - , cyclohexyl-S(=O) ₂ -, naphthyl-S(=O) ₂ - or phenyl-S(=O) ₂ -.

In one aspect, the present invention relates to a pharmaceutical composition, which contains the compound described in the present invention, and its pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or their combination .

In some embodiments, the pharmaceutical composition of the present invention further comprises anti-HBV drugs.

In other embodiments, the pharmaceutical composition of the present invention, wherein the anti-HBV drug is an HBV polymerase inhibitor, an immunomodulator or an interferon.

In some other embodiments, the pharmaceutical composition of the present invention, wherein, the anti-HBV drug is selected from lamivudine, telbivudine, tenofovir dipivoxil, entecavir, adefovir dipivoxil, Alfaferone , Alloferon, simoleukin, clavudine, emtricitabine, faprovir, interferon, Bao Ganling CP, Interferon, interferon α-1b, interferon α, interferon α-2a, interference Interferon β-1a, interferon α-2, interleukin-2, mifutilate, nitazoxanide, pegylated interferon α-2a, ribavirin, rosferon-A, sizoran, At least one of Euforavac, Ampligen, Phosphazid, Heplisav, Interferon alpha-2b, levamisole, and propagermanium.

In another aspect, the present invention relates to the use of the compound or the pharmaceutical composition in the preparation of medicaments for preventing, treating, treating or alleviating viral diseases in patients.

In some embodiments, the use described in the present invention, wherein the viral disease refers to hepatitis B infection or a disease caused by hepatitis B infection.

In some other embodiments, the use described in the present invention, wherein the disease caused by hepatitis B infection refers to liver cirrhosis or hepatocellular carcinoma.

In another aspect, the present invention relates to the use of the compound or pharmaceutical composition to prepare a drug for preventing, treating, treating or alleviating hepatitis B disease in a patient, including administering to a patient such as the compound of the present invention or the drug of the present invention A therapeutically effective amount of the composition.

Another aspect of the present invention relates to a method for preventing, treating, treating or alleviating HBV symptoms in a patient, the method comprising administering to the patient a pharmaceutically acceptable effective dose of the compound of the present invention.

Another aspect of the present invention relates to a method for preventing, treating, treating or alleviating HBV disorders in a patient, the method comprising administering to the patient a pharmaceutically acceptable effective dose of a pharmaceutical composition containing the compound of the present invention.

Another aspect of the present invention relates to the use of a compound comprising the present invention for the manufacture of a medicament for preventing, treating or treating HBV disorders in a patient, and reducing the severity thereof.

Another aspect of the present invention relates to the use of a pharmaceutical composition comprising a compound of the present invention for the manufacture of a medicament for preventing, treating or treating HBV disorders in a patient, and reducing the severity thereof.

In some embodiments, the organism is a mammal and in other embodiments, the organism is a human. In other embodiments, the method further comprises contacting the kinase with an HBV therapeutic agent.

Another aspect of the present invention relates to a method for inhibiting HBV infection, the method comprising contacting cells with a dose of the compound of the present invention or a composition thereof capable of effectively inhibiting HBV. In some other embodiments, the method further comprises contacting the cells with an HBV agent.

Another aspect of the present invention relates to the treatment of HBV disease in a patient, the method comprising administering to the patient a dose of the compound of the present invention or a composition thereof required for effective treatment. In some other embodiments, the method further comprises the administration of HBV.

Another aspect of the present invention relates to a method of inhibiting HBV infection in a patient, the method comprising administering to the patient a dose of the compound of the present invention or a composition thereof required for effective treatment. In other embodiments, the method further comprises administration of HBV therapy.

Another aspect of the present invention relates to processes for the preparation, isolation and purification of compounds encompassed by formula (I) or formula (Ia).

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

Detailed Description of the Invention

Definitions and General Terms

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

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

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

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

As described in the present invention, the compounds of the present invention can be optionally substituted by one or more substituents, such as the above general formula compounds, specific compounds of the present invention, or special examples like the examples, subclasses, and a class of compounds encompassed by the present invention. It should be understood that the term "optionally substituted" and the term "substituted or unsubstituted" are used interchangeably. In general, the term "substituted" means that one or more hydrogen atoms in a given structure have been replaced by a particular substituent. Unless otherwise indicated, an optional substituent may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted by one or more substituents selected from a particular group, then the substituents can be substituted at each position the same or differently. The substituents mentioned therein can be, but are not limited to: hydrogen, fluorine, chlorine, bromine, iodine, oxo (=O), methylene (=CH ₂ ), alkyl, alkoxy, cyano, Hydroxy, Mercapto, Nitro, Alkylamino, Amino, Aryl, Arylalkyl, Heteroaryl, Heteroarylalkyl, Heterocyclyl, Heterocyclylalkyl, Cycloalkyl, Cycloalkylalkyl, Trifluoromethyl, trifluoromethoxy, haloalkyl-substituted aryl, halogen-substituted aryl, trifluoromethanesulfonyl, and the like.

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

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

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

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

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

The term "stereoisomer" refers to compounds that have the same chemical structure, but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, and the like.

The term "chiral" refers to molecules that have the property of being non-superimposable to their mirror images; while "achiral" refers to molecules that are superimposable to their mirror images.

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

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

The term "alkyl" or "alkyl group" means a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein said alkyl group can be independently optionally replaced by a Or a plurality of substituents described in the present invention are substituted. Unless otherwise specified, an alkyl group contains 1-20 carbon atoms. In some embodiments, the alkyl group contains 1-10 carbon atoms; in other embodiments, the alkyl group contains 1-8 carbon atoms; in other embodiments, the alkyl group contains 1-6 carbon atoms; in other embodiments, the alkyl group contains 1-4 carbon atoms; in other embodiments, the alkyl group contains 1-3 carbon atoms.

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

The term "haloalkyl" or "haloalkoxy" means that an alkyl or alkoxy group is substituted by one or more identical or different halogen atoms, wherein said alkyl and alkoxy have meaning of the above. Such examples include, but are not limited to, trifluoromethyl, trifluoroethyl, trifluoromethoxy, and the like.

The term "cycloalkyl" denotes a monovalent or polyvalent non-aromatic saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. Wherein, the cycloalkyl group may be optionally substituted by one or more substituents described in the present invention. In some embodiments, the cycloalkyl group contains 3-12 carbon atoms; in other embodiments, the cycloalkyl group contains 3-8 carbon atoms; in still other embodiments, the cycloalkyl group contains 3-6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

The term "cycloalkylalkyl" means that a cycloalkyl group is attached to the rest of the molecule through an alkyl group, wherein cycloalkyl and alkyl have the meanings described herein. Said cycloalkylalkyl groups may be optionally substituted with one or more substituents described herein. Such examples include, but are not limited to, cyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, and the like.

The term "heterocyclyl" refers to a non-aromatic saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3-12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. Wherein, the heterocyclyl group may be optionally substituted by one or more substituents described in the present invention. Unless otherwise stated, a heterocyclyl group can be carbonyl or nitrogenyl, and a _-CH2- group can optionally be replaced by -C(=O)-. Ring sulfur atoms can optionally be oxidized to S-oxides. Ring nitrogen atoms can optionally be oxidized to N-oxides. In some embodiments, the heterocyclic group is a C _2-10 heterocyclic group, which means that the heterocyclic group contains 2-10 carbon atoms and at least one heteroatom selected from O, S and N; in other embodiments, the heterocyclic The group is a C _2-9 heterocyclic group, which means that the heterocyclic group contains 2-9 carbon atoms and at least one heteroatom selected from O, S and N; in other embodiments, the heterocyclic group is a C _2-7 heterocyclic group Cyclic group means that heterocyclic group contains 2-7 carbon atoms and at least one heteroatom selected from O, S and N; in other embodiments, heterocyclic group is _C2-5 heterocyclic group, which means heterocyclic group Contains 2-5 carbon atoms and at least one heteroatom selected from O, S and N. Examples of heterocyclic groups include, but are not limited to: pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyrimidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine Base, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, epoxypropyl, 2-pyrrolinyl, indolinyl, pyrazoline group, 1,1-dioxothiomorpholinyl group, etc. Examples of -CH ₂ - groups in heterocyclic groups substituted by -C(=O)- include, but are not limited to: 2-oxopyrrolidinyl, 2-piperidinonyl, 3-morpholinonyl, 3 - Thiomorpholinone group and oxotetrahydropyrimidinyl group and the like.

The term "heterocyclylalkyl" means that a heterocyclyl group is attached to the rest of the molecule through an alkyl group, wherein heterocyclyl and alkyl have the meanings described herein. The heterocyclylalkyl group can be optionally substituted with one or more substituents described herein. Such examples include, but are not limited to: pyrrole-2-methyl, morpholin-4-methyl, pyrrolidinylmethyl, piperidinylmethyl, piperidinylethyl, morpholinylmethyl, morpholinylethyl Base etc.

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

The term "alkoxy" denotes an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning described herein. Examples of alkoxy groups include, but are not limited to: methoxy (MeO, -OCH ₃ ), ethoxy (EtO, -OCH ₂ CH ₃ ), propoxy (n-PrO, n-propoxy group, -OCH ₂ CH ₂ CH ₃ ), isopropoxy (i-PrO, i-propoxy, -OCH(CH ₃ ) ₂ ), n-butoxy (n-BuO, n-butoxy, -OCH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH ₂ CH(CH ₃ ) ₂ ), 2-butoxy (s -BuO, s-butoxy, -OCH(CH ₃ )CH ₂ CH ₃ ), tert-butoxy (t-BuO, t-butoxy, 2-methyl-2-propoxy, -OC( CH ₃ ) ₃ ), 1-pentyloxy (n-pentyloxy, -OCH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyloxy (-OCH(CH ₃ )CH ₂ CH ₂ CH ₃ ) , 3-pentyloxy (-OCH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butoxy (-OC(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butan Oxygen (-OCH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-l-butoxy (-OCH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-l-butoxy group (-OCH ₂ CH(CH ₃ )CH ₂ CH ₃ ) and the like.

The term "aryl" denotes monocyclic, bicyclic and tricyclic carbocyclic ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic family in which each ring system contains rings of 3-7 atoms and has one or more points of attachment to the rest of the molecule. The aryl group may be optionally substituted with one or more substituents described herein. The term "aryl" is used interchangeably with the term "aromatic ring". Examples of aryl groups include, but are not limited to, phenyl, 2,3-dihydro-1H-indenyl, naphthyl, anthracene, and the like.

The term "arylalkyl" means that an aryl group is attached to the rest of the molecule through an alkyl group, wherein aryl and alkyl have the meanings described herein. The arylalkyl group can be optionally substituted with one or more substituents described herein. Such examples include, but are not limited to, benzyl, phenylethyl, naphthylmethyl, and the like.

The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic ring systems containing 5-14 ring atoms, or 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least One ring system is aromatic, and at least one ring system contains one or more heteroatoms selected from nitrogen, oxygen, sulfur, wherein each ring system contains a ring composed of 5-7 atoms, and there are one or more The junction connects to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl" or "heteroaromatic". In some embodiments, heteroaryl is C _1-9 heteroaryl, which means that heteroaryl contains 1-9 carbon atoms and at least one heteroatom selected from O, S and N; in other embodiments, heteroaryl The base is a C _1-7 heteroaryl, which means that the heteroaryl contains 1-7 carbon atoms and at least one heteroatom selected from O, S and N; in other embodiments, the heteroaryl is a C _1-6 heteroaryl Aryl, means that heteroaryl contains 1-6 carbon atoms and at least one heteroatom selected from O, S and N; in other embodiments, heteroaryl is C _1-5 heteroaryl, means heteroaryl Containing 1-5 carbon atoms and at least one heteroatom selected from O, S and N; in other embodiments, the heteroaryl is C _1-4 heteroaryl, which means that the heteroaryl contains 1-4 carbon atoms and at least one heteroatom selected from O, _S and N; S and N heteroatoms. Such examples include, but are not limited to, the following monocyclic rings: furyl (such as 2-furyl and 3-furyl), imidazolyl (such as N-imidazolyl, 1-methyl-1H-imidazolyl, 2- imidazolyl, 4-imidazolyl and 5-imidazolyl), 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl Azolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazine (e.g. 3-pyridazinyl), thiazolyl (e.g. 2-thiazolyl, 4-thiazolyl and 5-thiazolyl), tetrazolyl (e.g. 5-tetrazolyl), triazolyl (e.g. 2-triazole and 5-triazolyl), 2-thienyl, 3-thienyl, pyranyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4- Thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, diazolyl, thiadiazolyl, triazinyl; also include bicyclic , but by no means limited to these bicyclic rings: benzothiazolyl, benzimidazolyl, benzofuryl, benzothienyl, indolyl (such as 2-indolyl), purinyl, quinolinyl (such as 2- quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (such as 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl) and the like.

The term "heteroarylalkyl" means that a heteroaryl group is attached to the rest of the molecule through an alkyl group, wherein alkyl and heteroaryl have the meanings given herein. The heteroarylalkyl group can be optionally substituted with one or more substituents described herein. Such examples include, but are not limited to: pyridin-2-ethyl, thiazol-2-methyl, imidazol-2-ethyl, pyrimidin-2-propyl, and the like.

The terms "alkyl-S(=O) _q- ", "heterocyclyl-S(=O) _q- ", "heteroaryl-S(=O)q-", "cycloalkyl-S(=O) _q- ", O) _q -" and "aryl-S(=O) _q -" represent alkyl, heterocyclyl, heteroaryl, cycloalkyl and aryl through sulfinyl (-S(=O)-) or Sulfonyl (-S(=O) ₂ -) is connected to the rest of the molecule, wherein, q, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl have the meanings as described in the present invention, such Examples include, but are not limited to: methylsulfinyl (-S(=O) _CH3 ), cyclopropyl-S(=O) _2- , cyclobutyl-S(=O) _2- , cyclopentyl -S(=O) ₂ -, cyclohexyl-S(=O) ₂ -, naphthyl-S(=O) ₂ -, phenyl-S(=O) ₂ -, methylsulfonyl (-S (=O) ₂ CH ₃ ) and the like.

The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino", wherein the amino groups are each independently substituted with one or two alkyl groups. Wherein, the alkyl group has the meaning as described in the present invention. Suitable alkylamino groups may be mono- or di-alkylamino, examples of which include, but are not limited to: N-methylamino, N-ethylamino, isopropylamino, propylamino, tert-butyl Amino, n-butylamino, 1-methylpropylamino, n-pentylamino, n-hexylamino, N,N-dimethylamino, N,N-diethylamino, etc.

The term "aryl substituted with haloalkyl" means that the aryl group can be substituted by one or more same or different haloalkyl groups, wherein haloalkyl and aryl have the meanings as described in the present invention. Examples of such include, but are not limited to: 2-trifluoromethylphenyl, 3,5-bis(trifluoromethyl)phenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl , 2,6-bis(trifluoromethyl)phenyl, etc.

The term "halogen-substituted aryl" means that the aryl group may be substituted by one or more same or different halogen atoms, wherein halogen and aryl have the meanings as described in the present invention. Such examples include, but are not limited to: fluorophenyl, difluorophenyl, trifluorophenyl, chlorophenyl, dichlorophenyl, trichlorophenyl, bromophenyl, tribromophenyl, dibromophenyl Base, fluorochlorophenyl, fluorobromophenyl, chlorobromophenyl, etc.

In addition, it should be noted that, unless otherwise clearly stated, the descriptions used throughout this article are "each ... and ... are independently", "... and ... are each independently" and "...and ... are independently "" is interchangeable and should be understood in a broad sense. It can mean that in different groups, the specific options expressed by the same symbols do not affect each other, and it can also mean that in the same group, the options expressed by the same symbols do not affect each other. The specific options expressed between them do not affect each other. For example, as in formula q, the specific options of multiple n are not affected by each other, and the specific options of multiple ^R9 are not affected by each other.

As described in the present invention, the substituents draw a bond to the central ring to form a ring system (as shown in the formula below) which means that any substitutable position of the substituent on the ring can be substituted. For example, formula a represents any possible substituted position on the ring, as shown in formulas b, c, d, e, f, g and h.

As described in the present invention, there are two connection points in the system that are connected to the rest of the molecule, for example, as shown in formula p, which means that either the E end or the E' end is connected to the rest of the molecule, that is, when the molecular structure is reasonable In the case of the two ends of the connection can be interchanged.

Unless otherwise indicated, the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereoisomers and geometric isomerism (or conformational isomerism)): for example, R containing an asymmetric center , S configuration, (Z), (E) isomers of the double bond, and (Z), (E) conformational isomers. Accordingly, individual stereochemical isomers of the compounds of the present invention or mixtures thereof as enantiomers, diastereomers, or geometric isomers (or conformational isomers) are within the scope of the present invention.

The term "prodrug" used in the present invention means that a compound is transformed into a compound represented by formula (I) or formula (Ia) in vivo. Such conversion is effected by prodrug hydrolysis in blood or enzymatic conversion in blood or tissue to the parent structure. The prodrug compound of the present invention can be an ester. In the existing invention, the ester can be used as a prodrug, including phenyl esters, aliphatic (C _1-24 ) esters, acyloxymethyl esters, and carbonates. , carbamates and amino acid esters. For example, a compound of the present invention that contains a hydroxyl group can be acylated to give a prodrug form of the compound. Other prodrug forms include phosphate esters, eg, phosphorylated parent hydroxyl groups. A complete discussion of prodrugs can be found in the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J.Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJHecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 5, 1 2328-2345.

Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention. In addition, unless otherwise indicated, the structural formulas of the compounds described herein include enriched isotopes of one or more different atoms.

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

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

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

All stereoisomeric forms of the compounds of the invention, including but not limited to: diastereomers, enantiomers, atropisomers and mixtures thereof, such as racemic mixtures, form part of the invention . Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D, L or R, S are used to indicate the absolute configuration of the molecular chiral center. The prefixes d, l or (+), (-) are used to name the symbol of the plane polarized light rotation of the compound, (-) or l means that the compound is left-handed, and the prefix (+) or d means that the compound is right-handed. The chemical structures of these stereoisomers are the same, but their three-dimensional structures are different. A particular stereoisomer may be an enantiomer, and a mixture of isomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is known as a racemic mixture or racemate, which can result in no stereoselectivity or stereospecificity during a chemical reaction. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers, devoid of optical activity.

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

The "pharmaceutically acceptable salt" used in the present invention refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19, 1977. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to: salts of inorganic acids formed by reaction with amino groups, such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate ; Organic acid salts, such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate; or by other methods such as ion exchange method recorded in books and literature Get those salts. Other pharmaceutically acceptable salts include, adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate Salt, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, transbutene Diate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, milk salt, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoic acid Salt, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecyl salts, pentanoates, etc. Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates the quaternary ammonium salts of any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali or alkaline earth metals which can form salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed as counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, _{C1 -8} sulfonates and aromatic sulfonates.

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

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

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

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

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

In addition, substitution with heavier isotopes, particularly deuterium (ie, ^2H or D), may afford certain therapeutic advantages resulting from greater metabolic stability. For example, due to increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It should be understood that deuterium in the present invention is considered as a substituent of the compound of formula (I). An isotopic enrichment factor can be used to define the concentration of such heavier isotopes, especially deuterium. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has, for each designated deuterium atom, at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), At least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation) Deuterium incorporation), an isotopic enrichment factor of at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the present invention include those wherein the solvent of crystallization may be isotopically substituted eg _D2O , acetone- _d6 , DMSO- _d6 .

DESCRIPTION OF THE COMPOUNDS OF THE INVENTION

The present invention relates to a new dihydropyrimidine compound and its pharmaceutical composition, and the use of the compound or the pharmaceutical composition in the preparation of medicines for preventing, treating, treating or alleviating viral diseases , especially hepatitis B (HBV) infection or diseases caused by hepatitis B infection.

In one aspect, the present invention relates to a compound, which is a compound represented by formula (I) or (Ia) or an enantiomer, a diastereomer, or a compound represented by formula (I) or (Ia). tautomers, hydrates, solvates, prodrugs, stereoisomers, nitrogen oxides or pharmaceutically acceptable salts,

Wherein, A is a bond, -O-, -S- or -N(R ⁴ )-;

R is the following substructural formula:

R ¹ is C _6-10 aryl or C _1-9 heteroaryl;

R ³ is C _6-10 aryl or C _1-9 heteroaryl;

each R ² and R ⁴ is independently hydrogen or C _1-4 alkyl;

each ^R and ^R is independently hydrogen or alkyl;

each R ^is independently F, Cl, Br, hydroxy, or haloalkyl;

each R ⁶ is independently -(CR ⁷ R ^7a ) _m -C(=O)OR ^8a or C _1-4 alkyl;

Each R ⁹ is independently -S(=O) _q OR ^8a , -(CR ⁷ R ^7a ) _m -S(=O) _q N(R ^8a ) ₂ , triazolyl, -(CR ⁷ R ^7a ) _m -C(=O)OR ⁸ , -(CR ⁷ R ^7a ) _m -C(=O)O-(CR ⁷ R ^7a ) _m -OC(=O)OR ⁸ , -(CR ⁷ R ^7a ) _m - C(=O)O-(CR ⁷ R ^7a ) _m -OC(=O)-R ⁸ , -(CR ⁷ R ^7a ) _t -N(R ^8a ) ₂ , -(CR ⁷ R ^7a ) _m -C (=O)O-(CR ⁷ R ^7a ) _m -C(=O)OR ⁸ , -(CR ⁷ R ^7a ) _t -OC(=O)-R ⁸ , -(CR ⁷ R ^7a ) _m -C (=O)N(R ⁸ ) ₂ or -(CR ⁷ R ^7a ) _m -C(=O)NHR ⁸ ;

Each R ^9a is independently -(CR ⁷ R ^7a ) _m -OH, triazolyl, tetrazolyl, -(CR ⁷ R ^7a ) _m -C(=O)OR ^8a , -(CR ⁷ R ^7a ) _m -S(=O) _q N(R ^8a ) ₂ , -(CR ⁷ R ^7a ) _m -OC(=O)-R ^8a , -(CR ⁷ R ^7a ) _m -N(R ^8a ) ₂ , -S (=O) _q OR ^8a , -(CR ⁷ R ^7a ) _m -C(=O)O-(CR ⁷ R ^7a ) _m -OC(=O)OR ^8a , -(CR ⁷ R ^7a ) _m -C (=O)O-(CR ⁷ R ^7a ) _m -OC(=O)-R ^8a , -(CR ⁷ R ^7a ) _m -C(=O)O-(CR ⁷ R ^7a ) _m -C(= O)OR ^8a or -(CR ⁷ R ^7a ) _m -C(=O)N(R ^8a ) ₂ ;

each R ⁷ and R ^7a is independently hydrogen, haloalkyl or alkyl;

Each R ^8a is independently hydrogen, alkyl, alkoxy, alkyl-S(=O) _q- , aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl, heteroarylalkane Base, cycloalkylalkyl, heterocyclylalkyl, heterocyclyl-S(=O) _q- , heteroaryl-S(=O) _q- , cycloalkyl-S(=O) _q- , or Aryl-S(=O) _q- ;

Each ^R is independently alkyl-S(=O) _q- , aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heteroaryl Cycloalkyl, heterocyclyl-S(=O) _q- , heteroaryl-S(=O) _q- , cycloalkyl-S(=O) _q- or aryl-S(=O) _q -;

each n is independently 1, 2 or 3;

each t is independently 1, 2, 3 or 4;

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

each q is independently 0, 1 or 2;

Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^5a , R ^5b , R ⁶ , R ⁷ , R ^7a , R ⁸ , R ^8a , R ⁹ and R ^9a are alkoxy groups, Aryl, C _6-10 aryl, heteroaryl, C _1-9 heteroaryl, alkyl, C _1-4 alkyl, alkyl-S(=O) _q -, heterocyclyl-S(= O) _q -, heteroaryl-S(=O) _q -, cycloalkyl-S(=O) _q -, aryl-S(=O) _q -, heterocyclyl, arylalkyl, hetero Arylalkyl, cycloalkylalkyl, heterocyclylalkyl, tetrazolyl, triazolyl, haloalkyl, and cycloalkyl can be optionally substituted by hydrogen, fluorine, chlorine, bromine, iodine, oxo ( =O), methylene (= _CH2 ), alkyl, alkoxy, cyano, hydroxyl, nitro, alkylamino, amino, aryl, heteroaryl, heterocyclyl, cycloalkyl, trifluoro Methyl, trifluoromethoxy, haloalkyl-substituted aryl, halogen-substituted aryl or trifluoromethanesulfonyl monosubstituted or identical or different polysubstituted.

In some embodiments, R is the following substructural formula:

each R ⁵ and R ^5a is independently hydrogen or C _1-4 alkyl;

Each R ^5b is independently F, Cl, Br, hydroxyl or C _1-4 haloalkyl;

each R ⁶ is independently -(CR ⁷ R ^7a ) _m -C(=O)OR ^8a or C _1-4 alkyl;

Each R ⁹ is independently -S(=O) _q OR ^8a , -(CR ⁷ R ^7a ) _m -S(=O) _q N(R ^8a ) ₂ , triazolyl, -(CR ⁷ R ^7a ) _m -C(=O)OR ⁸ , -(CR ⁷ R ^7a ) _m -C(=O)O-(CR ⁷ R ^7a ) _m -OC(=O)OR ⁸ , -(CR ⁷ R ^7a ) _m - C(=O)O-(CR ⁷ R ^7a ) _m -OC(=O)-R ⁸ , -(CR ⁷ R ^7a ) _t -N(R ^8a ) ₂ , -(CR ⁷ R ^7a ) _m -C (=O)O-(CR ⁷ R ^7a ) _m -C(=O)OR ⁸ , -(CR ⁷ R ^7a ) _t -OC(=O)-R ⁸ , -(CR ⁷ R ^7a ) _m -C (=O)N(R ⁸ ) ₂ or -(CR ⁷ R ^7a ) _m -C(=O)NHR ⁸ ;

Each R ^9a is independently -(CR ⁷ R ^7a ) _m -OH, triazolyl, tetrazolyl, -(CR ⁷ R ^7a ) _m -C(=O)OR ^8a , -(CR ⁷ R ^7a ) _m -S(=O) _q N(R ^8a ) ₂ , -(CR ⁷ R ^7a ) _m -OC(=O)-R ^8a , -(CR ⁷ R ^7a ) _m -N(R ^8a ) ₂ , -S (=O) _q OR ^8a , -(CR ⁷ R ^7a ) _m -C(=O)O-(CR ⁷ R ^7a ) _m -OC(=O)OR ^8a , -(CR ⁷ R ^7a ) _m -C (=O)O-(CR ⁷ R ^7a ) _m -OC(=O)-R ^8a , -(CR ⁷ R ^7a ) _m -C(=O)O-(CR ⁷ R ^7a ) _m -C(= O)OR ^8a or -(CR ⁷ R ^7a ) _m -C(=O)N(R ^8a ) ₂ ;

each R ⁷ and R ^7a is independently hydrogen, C _1-4 haloalkyl or C _1-4 alkyl;

Each R ^8a is independently hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl-S(=O) _q -, C _6-10 aryl, C _1-9 hetero Aryl, C _3-6 cycloalkyl, C _2-9 heterocyclyl, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _3-6 Cycloalkyl C _1-4 alkyl, C _2-9 heterocyclyl C _1-6 alkyl, C _2-9 heterocyclyl-S(=O) _q -, C _1-9 heteroaryl-S( =O) _q -, C _3-6 cycloalkyl-S(=O) _q - or C _6-10 aryl-S(=O) _q -;

Each R ⁸ is independently C _1-6 alkyl-S(=O) _q -, C _6-10 aryl, C _1-9 heteroaryl, C _3-6 cycloalkyl, C _2-9 heterocycle C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _3-6 cycloalkyl C _1-4 alkyl, C _2-9 heterocyclyl C _1-6 alkyl, C _2-9 heterocyclyl-S(=O) _q -, C _1-9 heteroaryl-S(=O) _q -, C _3-6 cycloalkyl-S(= O) _q - or C _6-10 aryl -S(=O) _q -;

^{Among them , the} _C ^{1-6 alkoxy , C 6-10} _aryl ^, C _1-9 heteroaryl, C _1-4 alkyl, C _1-6 alkyl, C _1-4 haloalkyl, C _1-6 alkyl-S(=O) _q -, C _2-9 heterocycle Group-S(=O) _q -, C _1-9 heteroaryl-S(=O) _q -, C _3-6 cycloalkyl-S(=O) _q -, C _6-10 aryl-S (=O) _q -, C _2-9 heterocyclyl, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _3-6 cycloalkyl C _1-4 alkyl, C _2-9 heterocyclyl C _1-6 alkyl, tetrazolyl, triazolyl and C _3-6 cycloalkyl can be optionally replaced by hydrogen, fluorine, chlorine, bromine, iodine, Oxo (=O), methylene (=CH ₂ ), alkyl, alkoxy, cyano, hydroxyl, nitro, alkylamino, amino, aryl, heteroaryl, heterocyclyl, cycloalkyl , trifluoromethyl, trifluoromethoxy, haloalkyl-substituted aryl, halogen-substituted aryl or trifluoromethanesulfonyl monosubstituted or identical or different multiple substitutions.

In some other embodiments, R is the following substructural formula:

each R ^{and R} is independently hydrogen, methyl, ethyl or propyl;

each R is ^{independently} F, Cl, Br, hydroxy, or trifluoromethyl;

each R ⁶ is independently -(CR ⁷ R ^7a ) _m -C(=O)OR ^8a , methyl, ethyl or propyl;

Each R ⁹ is independently triazolyl, -S(=O) _q OR ^8a , -(CR ⁷ R ^7a ) _t -N(R ^8a ) ₂ , -(CR ⁷ R ^7a ) _m -C(=O) OR ⁸ , -(CR ⁷ R ^7a ) _m -C(=O)O-(CR ⁷ R ^7a ) _m -OC(=O)OR ⁸ , -(CR ⁷ R ^7a ) _m -S(=O) _q N(R ^8a ) ₂ , -(CR ⁷ R ^7a ) _m -C(=O)O-(CR ⁷ R ^7a ) _m -OC(=O)-R ⁸ , -(CR ⁷ R ^7a ) _m -C (=O)O-(CR ⁷ R ^7a ) _m -C(=O)OR ⁸ , -(CR ⁷ R ^7a ) _t -OC(=O)-R ⁸ , -(CR ⁷ R ^7a ) _m -C (=O)N(R ⁸ ) ₂ or -(CR ⁷ R ^7a ) _m -C(=O)NHR ⁸ ;

Each R ^9a is independently -(CR ⁷ R ^7a ) _m -OH, triazolyl, tetrazolyl, -(CR ⁷ R ^7a ) _m -C(=O)OR ^8a , -(CR ⁷ R ^7a ) _m -S(=O) _q N(R ^8a ) ₂ , -(CR ⁷ R ^7a ) _m -OC(=O)-R ^8a , -(CR ⁷ R ^7a ) _m -N(R ^8a ) ₂ , -S (=O) _q OR ^8a , -(CR ⁷ R ^7a ) _m -C(=O)O-(CR ⁷ R ^7a ) _m -OC(=O)OR ^8a , -(CR ⁷ R ^7a ) _m -C (=O)O-(CR ⁷ R ^7a ) _m -OC(=O)-R ^8a , -(CR ⁷ R ^7a ) _m -C(=O)O-(CR ⁷ R ^7a ) _m -C(= O)OR ^8a or -(CR ⁷ R ^7a ) _m -C(=O)N(R ^8a ) ₂ ;

each ^R7 and ^R7a is independently hydrogen, trifluoromethyl, methyl, ethyl or propyl;

Each R ^8a is independently hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkyl-S(=O) _q -, phenyl, pyridyl, thiazolyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, Thiadiazolyl, pyrazinyl, pyranyl, triazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-S(=O) ₂ -, cyclobutyl-S( =O) ₂ -, cyclopentyl-S(=O) ₂ -, cyclohexyl-S(=O) ₂ -, naphthyl-S(=O) ₂ - or phenyl-S(=O) ₂ - ;

Each R ⁸ is independently C _1-4 alkyl-S(=O) _q -, phenyl, pyridyl, thiazolyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl , pyridazinyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl, triazinyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-S(=O) ₂ -, cyclobutyl-S(=O) ₂ -, cyclopentyl-S(=O) ₂ - , cyclohexyl-S(=O) ₂ -, naphthyl-S(=O) ₂ - or phenyl-S(=O) ₂ -.

In some embodiments, the present invention has compounds such as formula (II) or (IIa) or enantiomers, diastereomers, and tautomers of compounds shown in formula (II) or (IIa) conformers, hydrates, solvates, prodrugs, stereoisomers, nitrogen oxides or pharmaceutically acceptable salts,

Wherein, R ² is hydrogen or C _1-4 alkyl;

^R3 is 1-methyl-1H-imidazolyl, pyridyl, phenyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, diazolyl , triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl or triazinyl;

R is the following substructural formula:

each R ⁵ and R ^5a is independently hydrogen or C _1-4 alkyl;

Each R ^5b is independently F, Cl, Br, hydroxyl or C _1-4 haloalkyl;

each R ⁶ is independently -(CR ⁷ R ^7a ) _m -C(=O)OR ^8a or C _1-4 alkyl;

Each R ⁹ is independently triazolyl, -S(=O) _q OR ^8a , -(CR ⁷ R ^7a ) _m -S(=O) _q N(R ^8a ) ₂ , -(CR ⁷ R ^7a ) _m -C(=O)OR ⁸ , -(CR ⁷ R ^7a ) _m -C(=O)O-(CR ⁷ R ^7a ) _m -OC(=O)OR ⁸ , -(CR ⁷ R ^7a ) _m - C(=O)O-(CR ⁷ R ^7a ) _m -OC(=O)-R ⁸ , -(CR ⁷ R ^7a ) _t -N(R ^8a ) ₂ , -(CR ⁷ R ^7a ) _m -C (=O)O-(CR ⁷ R ^7a ) _m -C(=O)OR ⁸ , -(CR ⁷ R ^7a ) _t -OC(=O)-R ⁸ , -(CR ⁷ R ^7a ) _m -C (=O)N(R ⁸ ) ₂ or -(CR ⁷ R ^7a ) _m -C(=O)NHR ⁸ ;

Each R ^9a is independently -(CR ⁷ R ^7a ) _m -OH, triazolyl, tetrazolyl, -(CR ⁷ R ^7a ) _m -C(=O)OR ^8a , -(CR ⁷ R ^7a ) _m -S(=O) _q N(R ^8a ) ₂ , -(CR ⁷ R ^7a ) _m -OC(=O)-R ^8a , -(CR ⁷ R ^7a ) _m -N(R ^8a ) ₂ , -S (=O) _q OR ^8a , -(CR ⁷ R ^7a ) _m -C(=O)O-(CR ⁷ R ^7a ) _m -OC(=O)OR ^8a , -(CR ⁷ R ^7a ) _m -C (=O)O-(CR ⁷ R ^7a ) _m -OC(=O)-R ^8a , -(CR ⁷ R ^7a ) _m -C(=O)O-(CR ⁷ R ^7a ) _m -C(= O)OR ^8a or -(CR ⁷ R ^7a ) _m -C(=O)N(R ^8a ) ₂ ;

each R ⁷ and R ^7a is independently hydrogen, C _1-4 haloalkyl or C _1-4 alkyl;

Each R ^8a is independently hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl-S(=O) _q -, C _6-10 aryl, C _1-9 hetero Aryl, C _3-6 cycloalkyl, C _2-9 heterocyclyl, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _3-6 Cycloalkyl C _1-4 alkyl, C _2-9 heterocyclyl C _1-6 alkyl, C _2-9 heterocyclyl-S(=O) _q -, C _1-9 heteroaryl-S( =O) _q -, C _3-6 cycloalkyl-S(=O) _q - or C _6-10 aryl-S(=O) _q -;

Each R ⁸ is independently C _1-6 alkyl-S(=O) _q -, C _6-10 aryl, C _1-9 heteroaryl, C _3-6 cycloalkyl, C _2-9 heterocycle C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _3-6 cycloalkyl C _1-4 alkyl, C _2-9 heterocyclyl C _1-6 alkyl, C _2-9 heterocyclyl-S(=O) _q -, C _1-9 heteroaryl-S(=O) _q -, C _3-6 cycloalkyl-S(= O) _q - or C _6-10 aryl -S(=O) _q -;

each R ¹⁰ is independently hydrogen, fluoro, chloro, or bromo;

each n is independently 1, 2 or 3;

each t is independently 1, 2, 3 or 4;

each q is independently 0, 1 or 2;

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

Wherein, R ² , R ³ , R ⁵ , R ^5a , R ^5b , R ⁶ , R ⁷ , R ^7a , R ⁸ , R ^8a , R ⁹ and R ^9a are C _1-6 alkoxy groups, C _6-10 aryl, C _1-9 heteroaryl, C _1-4 alkyl, C _1-6 alkyl, C _1-4 haloalkyl, C _1-6 alkyl-S(=O) _q -, C _2-9 heterocyclyl-S(=O) _q -, C _1-9 heteroaryl-S(=O) _q -, C _3-6 cycloalkyl-S(=O) _q -, C _{6 -10} aryl-S(=O) _q -, C _2-9 heterocyclyl, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _{3 -6} cycloalkyl C _1-4 alkyl, C _2-9 heterocyclyl C _1-6 alkyl, tetrazolyl, triazolyl, 1-methyl-1H-imidazolyl, pyridyl, phenyl, Furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, diazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadi Azolyl, pyrazinyl, pyranyl, triazinyl and C _3-6 cycloalkyl can be optionally replaced by hydrogen, fluorine, chlorine, bromine, iodine, oxo (=O), methylene (=CH ₂ ), alkyl, alkoxy, cyano, hydroxyl, nitro, alkylamino, amino, aryl, heteroaryl, heterocyclyl, cycloalkyl, trifluoromethyl, trifluoromethoxy, haloalkane substituted aryl, halogen substituted aryl or trifluoromethanesulfonyl monosubstituted or identical or different multiple substitutions.

In some other embodiments, R is the following substructural formula:

each R ^{and R} is independently hydrogen, methyl, ethyl or propyl;

each R is ^{independently} F, Cl, Br, hydroxy, or trifluoromethyl;

each R ⁶ is independently -(CR ⁷ R ^7a ) _m -C(=O)OR ^8a , methyl, ethyl or propyl;

Each R ⁹ is independently triazolyl, -S(=O) _q OR ^8a , -(CR ⁷ R ^7a ) _m -S(=O) _q N(R ^8a ) ₂ , -(CR ⁷ R ^7a ) _m -C(=O)OR ⁸ , -(CR ⁷ R ^7a ) _m -C(=O)O-(CR ⁷ R ^7a ) _m -OC(=O)OR ⁸ , -(CR ⁷ R ^7a ) _m - C(=O)O-(CR ⁷ R ^7a ) _m -OC(=O)-R ⁸ , -(CR ⁷ R ^7a ) _t -N(R ^8a ) ₂ , -(CR ⁷ R ^7a ) _m -C (=O)O-(CR ⁷ R ^7a ) _m -C(=O)OR ⁸ , -(CR ⁷ R ^7a ) _t -OC(=O)-R ⁸ , -(CR ⁷ R ^7a ) _m -C (=O)N(R ⁸ ) ₂ or -(CR ⁷ R ^7a ) _m -C(=O)NHR ⁸ ;

Each R ^9a is independently -(CR ⁷ R ^7a ) _m -OH, triazolyl, tetrazolyl, -(CR ⁷ R ^7a ) _m -C(=O)OR ^8a , -(CR ⁷ R ^7a ) _m -S(=O) _q N(R ^8a ) ₂ , -(CR ⁷ R ^7a ) _m -OC(=O)-R ^8a , -(CR ⁷ R ^7a ) _m -N(R ^8a ) ₂ , -S (=O) _q OR ^8a , -(CR ⁷ R ^7a ) _m -C(=O)O-(CR ⁷ R ^7a ) _m -OC(=O)OR ^8a , -(CR ⁷ R ^7a ) _m -C (=O)O-(CR ⁷ R ^7a ) _m -OC(=O)-R ^8a , -(CR ⁷ R ^7a ) _m -C(=O)O-(CR ⁷ R ^7a ) _m -C(= O)OR ^8a or -(CR ⁷ R ^7a ) _m -C(=O)N(R ^8a ) ₂ ;

each ^R7 and ^R7a is independently hydrogen, trifluoromethyl, methyl, ethyl or propyl;

_Each R ^8a is independently hydrogen, C _1-4 alkyl, C 1-4 alkoxy, C _1-4 alkyl-S(=O) _q -, phenyl, pyridyl, thiazolyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, Thiadiazolyl, pyrazinyl, pyranyl, triazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-S(=O) ₂ -, cyclobutyl-S( =O) ₂ -, cyclopentyl-S(=O) ₂ -, cyclohexyl-S(=O) ₂ -, naphthyl-S(=O) ₂ - or phenyl-S(=O) ₂ - ;

Each R ⁸ is independently C _1-4 alkyl-S(=O) ₂ -, phenyl, pyridyl, thiazolyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl , pyridazinyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl, triazinyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-S(=O) ₂ -, cyclobutyl-S(=O) ₂ -, cyclopentyl-S(=O) ₂ - , cyclohexyl-S(=O) ₂ -, naphthyl-S(=O) ₂ - or phenyl-S(=O) ₂ -.

In other embodiments, the compound described in the present invention comprises one of the following structures, or an enantiomer, diastereomer, tautomer, hydrate, or Solvates, prodrugs, stereoisomers, nitrogen oxides or pharmaceutically acceptable salts:

In one aspect, the present invention relates to a pharmaceutical composition, which comprises the compound of the present invention, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

In some embodiments, the pharmaceutical composition of the present invention further comprises anti-HBV drugs.

In some embodiments, in the pharmaceutical composition of the present invention, the anti-HBV drug is an HBV polymerase inhibitor, an immunomodulator or an interferon.

In some embodiments, the pharmaceutical composition of the present invention, wherein, the anti-HBV drug is selected from lamivudine, telbivudine, tenofovir dipivoxil, entecavir, adefovir dipivoxil, Alfaferone, Alloferon, Cymoleukin, Clavudine, Emtricitabine, Faplovir, Interferon, Bao Ganling CP, Interferon, Interferon α-1b, Interferon α, Interferon α-2, Interferon α-2a, interferon α-2b, interferon β-1a, interleukin-2, mivotidate, nitazoxanide, pegylated interferon α-2a, ribavirin, rosiferin-A At least one of , sizoran, Euforavac, rintatolimod (Amplygen), Phosphazid, Heplisav, levamisole and propagermanium.

On the other hand, the present invention also relates to the use of the compound or the pharmaceutical composition in the preparation of medicaments for preventing, treating, treating or alleviating viral diseases in patients.

In some embodiments, the use described in the present invention, wherein the viral disease refers to hepatitis B infection or a disease caused by hepatitis B infection.

In some other embodiments, the use described in the present invention, wherein the disease caused by hepatitis B infection refers to liver cirrhosis or hepatocellular carcinoma.

In another aspect, the present invention relates to the use of said compound or pharmaceutical composition to prepare a drug for preventing, treating, treating or alleviating hepatitis B disease in a patient, including administering to a patient such as the compound or pharmaceutical composition of the present invention. A therapeutically effective dose of the pharmaceutical composition.

Another aspect of the present invention relates to a method for preventing, treating, treating or alleviating HBV symptoms in a patient, the method comprising administering to the patient a pharmaceutically acceptable effective dose of the compound of the present invention.

Another aspect of the present invention relates to a method for preventing, treating, treating or alleviating HBV disorders in a patient, the method comprising administering to the patient a pharmaceutically acceptable effective dose of a pharmaceutical composition containing the compound of the present invention.

Another aspect of the present invention relates to the use of a compound of the present invention for the manufacture of a medicament for preventing, treating or treating HBV disorders in a patient, and reducing the severity thereof.

Another aspect of the present invention relates to the use of a pharmaceutical composition comprising a compound of the present invention for the manufacture of a medicament for preventing, treating or treating HBV disorders in a patient, and reducing the severity thereof.

In some embodiments, the organism is a mammal, and in other embodiments, the organism is a human. In some other embodiments, the method further comprises contacting the kinase with an HBV therapeutic agent.

Another aspect of the present invention relates to a method for inhibiting HBV infection, the method comprising contacting cells with a dose of the compound of the present invention or a composition thereof capable of effectively inhibiting HBV. In some other embodiments, the method further comprises contacting the cells with an HBV agent.

Another aspect of the present invention relates to the treatment of HBV disease in a patient, the method comprising administering to the patient a dose of the compound of the present invention or a composition thereof required for effective treatment. In some other embodiments, the method further comprises the administration of HBV.

Another aspect of the present invention relates to a method of inhibiting HBV infection in a patient, the method comprising administering to the patient a dose of the compound of the present invention or a composition thereof required for effective treatment. In some other embodiments, the method further comprises administration of HBV therapy.

Another aspect of the present invention relates to processes for the preparation, isolation and purification of compounds encompassed by formula (I) or formula (Ia).

The present invention also encompasses the use of the compounds of the present invention and their pharmaceutically acceptable salts for the manufacture of medicinal products effective for inhibiting HBV infection, including those described herein. The application of the compound of the present invention in the production of drugs for effectively inhibiting HBV infection. The compounds of the present invention are also used in the manufacture of a medicament for alleviating, preventing, controlling or treating the symptoms of hepatitis B in patients. The present invention includes a pharmaceutical composition comprising a therapeutically effective amount of the compound represented by formula (I) or (Ia) in combination with at least one pharmaceutically acceptable carrier, adjuvant or diluent.

The present invention also includes a method for effectively inhibiting HBV-infected diseases, or being susceptible to such diseases, the method comprising treating patients with a therapeutically effective amount of the compound represented by formula (I) or (Ia).

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

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

The salts of the compounds of the present invention also include the salts of the intermediates of the compounds shown in the formula (I) or (Ia) or the separated enantiomers for the preparation or purification of the compounds shown in the formula (I) or (Ia), but Not necessarily a pharmaceutically acceptable salt.

If the compound of the invention is basic, the contemplated salts may be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids and the like. Alternatively use organic acids such as acetic, maleic, succinic, mandelic, fumaric, malonic, pyruvic, malic, 2-hydroxypropionic, citric, oxalic, glycolic, and salicylic ; pyranonic acids, such as glucuronic acid and galacturonic acid; alpha-hydroxy acids, such as citric acid and tartaric acid; amino acids, such as aspartic acid and glutamic acid; aromatic acids, such as benzoic acid and cinnamic acid; Sulfonic acids, such as p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, etc. or combinations thereof.

If the compound of the invention is acidic, the desired salts can be prepared by suitable methods, e.g., using inorganic or organic bases, such as ammonia (primary, secondary, tertiary), alkali metal hydroxides, ammonium , N ⁺ (R ¹⁴ ) ₄ salts and alkaline earth metal hydroxides, etc. Suitable salts include, but are not limited to: organic salts derived from amino acids, such as glycine and arginine, ammonia, such as primary, secondary and tertiary ammonia, salts of N ⁺ (R ¹⁴ ) ₄ , such as R ¹⁴ is H, C _1-4 alkyl, C _6-10 aryl, C _6-10 aryl C _1-4 alkyl, etc., and cyclic ammonia, such as piperidine, morpholine and piperazine, etc., and from sodium, Calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium give inorganic salts. Also included are suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C _1-8 sulfonates and Aromatic sulfonates.

Pharmaceutical Compositions, Formulations, Administration and Uses of Compounds and Pharmaceutical Compositions of the Invention

The characteristics of the pharmaceutical composition of the present invention include a compound of formula (I) or (Ia), a compound listed in the present invention, or a compound of Examples 1-25, and a pharmaceutically acceptable carrier, adjuvant or vehicle agent. The amount of the compound in the composition of the present invention can effectively inhibit the hepatitis B virus, and is suitable for treating or alleviating the diseases caused by the virus in patients, especially the acute and chronic persistent HBV virus infection, the chronic viral disease caused by HBV may lead to serious morbidity , chronic HBV infection can lead to cirrhosis and/or hepatocellular carcinoma in many cases.

The compound of the present invention is suitable for the treatment of acute and chronic viral infections of infectious hepatitis, especially can effectively inhibit hepatitis B virus (HBV), and is suitable for treating or alleviating diseases caused by viruses in patients, especially acute and chronic persistent HBV Viral infection, chronic viral disease caused by HBV may lead to severe morbidity, and chronic hepatitis B virus infection can lead to liver cirrhosis and/or hepatocellular carcinoma in many cases.

The present invention includes pharmaceutical preparations, which, in addition to non-toxic, inert pharmaceutically suitable carriers, also contain one or more compounds (I) or (Ia) or compositions of the present invention or contain one or more active ingredients (I) or (Ia) or the composition of the present invention.

The above pharmaceutical preparations may also contain other active pharmaceutical ingredients other than compound (I) or (Ia).

The compounds of the present invention exist in free form, or suitably, as pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other compounds that can be administered directly or indirectly according to the needs of patients. Adducts or derivatives, compounds described in other aspects of the invention, metabolites thereof or residues thereof.

As described herein, the pharmaceutically acceptable composition of the present invention further comprises a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used in the present invention, includes any solvent, diluent, or other Liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders or lubricants, etc., are suitable for the specific target dosage form. As described in: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-199 Marcel Dekker, New York, summarizing the literature herein, shows that different carriers can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. Except to the extent that any conventional carrier media is incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions in a deleterious manner with any other components of the pharmaceutically acceptable composition, they The purposes of the present invention are also considered scope.

Substances that can be used as pharmaceutically acceptable carriers include, but are not limited to: ion exchangers, aluminum, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid Acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acids, water, electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, salts such as sodium chloride, zinc salts, colloidal silicon, trisilicate Magnesium, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives substances such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered gums; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower Oils, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and hydrogen Aluminum oxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol; phosphate buffer solution; and other nontoxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants , release agents, coatings, sweeteners, flavorings and fragrances, preservatives and antioxidants. For convenience, local anesthetics, preservatives, buffers, etc. can be directly dissolved in the vehicle.

The pharmaceutical composition of the compound of the present invention can be administered in any of the following ways: oral administration, spray inhalation, rectal administration, nasal administration, topical administration, vaginal administration, parenteral administration such as Subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, or intracranial injection or infusion, or with the aid of an explanted reservoir. The preferred mode is oral administration, intramuscular injection, intraperitoneal administration or intravenous injection.

The compounds of this invention or pharmaceutically acceptable compositions containing them may be administered in unit dosage form. The dosage forms for administration may be liquid dosage forms or solid dosage forms. The liquid dosage forms can be true solutions, colloids, particulate dosage forms, and suspension dosage forms. Other dosage forms such as tablets, capsules, drop pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, lyophilized powder injections, clathrates, implants, patches, wipes agent etc.

Oral tablets and capsules may contain excipients such as binders such as syrup, acacia, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers such as lactose, sucrose, cornstarch, calcium phosphate, sorbitol, glycine ; lubricants such as magnesium stearate, talc, polyethylene glycol, silica; disintegrants such as potato starch; or acceptable emollients such as sodium lauryl sulfate. Tablets can be coated by methods known in pharmacy.

Oral solutions can be made into hydrated oil suspensions, solutions, emulsions, syrups or elixirs, and can also be made into dry products, which are supplemented with water or other suitable media before use. This liquid preparation may contain conventional additives such as suspending agent, sorbitol, cellulose methyl ether, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible Fats, emulsifiers, such as lecithin, sorbitan monooleate, acacia; or non-aqueous vehicles (which may contain edible oils), such as almond oil, fats such as glycerin, glycol, or ethanol; preservatives, Such as methyl or propyl paraben, sorbic acid. Flavoring or coloring agents may be added if desired.

Suppositories may contain conventional suppository bases, such as cocoa butter or other glycerides.

For parenteral administration, liquid dosage forms usually consist of the compound and a sterile carrier. The preferred carrier is water. Depending on the selected carrier and the concentration of the drug, the compound can be dissolved in the carrier or made into a suspension solution. When making a solution for injection, the compound is first dissolved in water, filtered and sterilized, and then filled into a sealed bottle or ampoule.

When applied topically to the skin, the compounds of this invention may be in the form of suitable ointments, lotions, or creams, wherein the active ingredient is suspended or dissolved in one or more carriers, wherein the carriers that can be used in ointment formulations include but Not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water; carriers that can be used for lotions and creams include but are not limited to: mineral oil, sorbitan mono Stearate, Tween 60, cetyl esters wax, cetyl aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.

In general, it has proven to be advantageous whether in human medicine or in veterinary medicine to administer the active compound according to the invention in a total amount of about 0.5-500 mg, preferably 1-100 mg/kg body weight per 24 hours, divided if appropriate. Multiple single doses are administered to achieve the desired effect. The amount of the active compound in a single dose is preferably about 1-80 mg, more preferably 1-50 mg/kg body weight, but may not follow the above-mentioned dosage, that is, depends on the type and body weight of the treatment object, the nature and severity of the disease , the type of preparation and the mode of administration of the drug, as well as the period or time interval of administration.

The pharmaceutical composition provided by the invention also includes anti-HBV drugs, wherein the anti-HBV drugs are HBV polymerase inhibitors, immunomodulators or interferon.

HBV drugs include lamivudine, telbivudine, tenofovir dipivoxil, entecavir, adefovir dipivoxil, Alfaferone, Alloferon, simoleukin, clavudine, emtricitabine, faprovir, interference Interferon, Bao Ganling CP, Interferon, Interferon α-1b, Interferon α, Interferon α-2a, Interferon β-1a, Interferon α-2, Interleukin-2, Milvotidate, Nitazoxanide, pegylated interferon α-2a, ribavirin, rosferon-A, sizoran, Euforavac, rintatolimod, Phosphazid, Heplisav, interferon α-2b, levamisole, propagermanium, etc.

Another aspect of the present invention relates to the use of a compound or pharmaceutical composition of the present invention to prepare medicines for preventing, treating, treating or alleviating hepatitis B disease in patients, including administering a pharmaceutically acceptable effective dose to the patient. medication. Hepatitis B disease refers to liver diseases caused by hepatitis B virus infection or hepatitis B infection, including acute hepatitis, chronic hepatitis, liver cirrhosis and stem cell carcinoma. Acute HBV infection can be asymptomatic or present with symptoms of acute hepatitis. Patients with chronic viral infection have active disease and can develop cirrhosis and hepatocellular carcinoma.

The anti-HBV drug may be administered separately from the composition comprising the compound of the invention as part of a multiple dosing regimen. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention to form a single composition. If administered as part of a multiple dosing regimen, the two active agents may be delivered to each other simultaneously, sequentially or over a period of time, such that the desired agent activity is achieved.

The amount of the compounds and compositions (those comprising a composition as described herein) which can be combined with the carrier materials to produce a single dosage form will vary depending on the indication and the particular mode of administration. Normally, the amount of the compositions of the present invention will not exceed the amount normally administered where the composition contains as the only active agent. In another aspect, the presently disclosed compositions range in amounts from about 50% to 100% of the normal amount of prior compositions, comprising the agent as the sole active therapeutic agent. In those included compositions, the compositions will act synergistically with the compounds of the invention.

The compound of the present invention shows strong antiviral effect. These compounds have unexpected antiviral activity against HBV, and are therefore suitable for treating various diseases caused by viruses, especially diseases caused by acute and chronic persistent HBV virus infection. Chronic viral disease caused by HBV can lead to syndromes of varying severity, and chronic HBV infection is known to lead to cirrhosis and/or hepatocellular carcinoma.

Examples of indications which may be treated with the compounds of the invention are: the treatment of acute and chronic viral infections which can lead to infectious hepatitis, eg heterohepatitis virus infections. Particularly preferred are the treatment of chronic hepatitis B infection and the treatment of acute hepatitis B virus infection.

The present invention relates to the use of the compound of the present invention and its composition for preparing medicines for treating and preventing viral diseases, especially hepatitis B.

General Synthesis Method

Generally, the compounds of the present invention can be prepared by the methods described in the present invention, and unless otherwise specified, the definitions of the substituents are as shown in formula (I) or (Ia). The following synthetic methods and examples are used to further illustrate the content of the present invention.

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

In the examples described below, all temperatures are in degrees Celsius (° C.) unless otherwise indicated. Unless otherwise indicated, reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, and used without further purification; general reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical The reagent factory can be purchased from Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.

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

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

The chromatographic column is a silica gel column, and the silica gel (200-300 mesh) is purchased from Qingdao Ocean Chemical Factory. NMR spectral data were determined by Bruker Avance400 NMR spectrometer or Bruker Avance III HD 600 NMR spectrometer, with CDCl ₃ , d ₆ -DMSO, CD ₃ OD or d ₆ -acetone as solvent (reported in ppm) , with TMS (0ppm) or chloroform (7.25ppm) as a reference standard. When multiplets appear, the following abbreviations will be used: s (singlet, singlet), s, s (singlet, singlet, singlet, singlet), d (doublet, doublet), t (triplet, triplet) ), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, quartet), ddd (doublet of doublet of doublets, double double doublet), dt (doublet of triplets, double triplet peak), ddt(doublet of doublet of triplets), dddd(doublet of doublet of doublet of doublets), td(triplet of doublets, triplet doublet), br.s(broadened singlet , broad unimodal). Coupling constants are expressed in Hertz (Hz).

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

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

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

Table 1: Gradient elution conditions for low-resolution mass spectrometry mobile phases

time (min) A ( _CH3CN , 0.1% HCOOH) B( _H2O , 0.1%HCOOH) 0-3 5-100 95-0 3-6 100 0 6-6.1 100-5 0-95 6.1-8 5 95

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

The chromatographic preparation and separation of the compound was realized by Agilent 1260 series high performance liquid chromatography (HPLC), wherein the UV detection was at 278nm, Daicel CHIRALPAK IC column, the specification was 10.0×250mm, 5μm, 40 minutes, the flow rate was 2.0mL/min, n-Hexane-ethanol (97:3, v/v), the column temperature was kept at 30°C.

The following abbreviations are used throughout this disclosure:

Boc tert-butoxycarbonyl

DCM,CH ₂ Cl ₂ dichloromethane

CH ₃ OH, MeOH Methanol

CDCl ₃ deuterated chloroform

CCl ₄ carbon tetrachloride

CDI N,N'-carbonyldiimidazole

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

Specific rotation, measured at 25°C, using D sodium light

PE petroleum ether

EDCI.HCl, EDCI 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride

HOAT N-Hydroxy-7-azabenzotriazole

EtOAc, EA ethyl acetate

NaHCO ₃ sodium bicarbonate

NBS N-Bromosuccinimide

mL mL

c Concentration

mol Mole

mmol

g grams

THF Tetrahydrofuran

Pd/C, Pd-C palladium carbon

DMSO-d ₆ deuterated dimethyl sulfoxide

Acetone-d ₆ deuterated acetone

D ₂ O deuterated water

resolve resolution

Synthetic method 1

Compound 5b can be prepared by Synthesis Method 1, wherein R ^8a has the meaning as described in the present invention. Compound 1b and compound 2b were reacted with CDI and DBU to generate compound 4b, and compound 4b was deprotected and salted under acidic conditions to obtain compound 5b.

Synthetic method 2

The target compound 7b can be prepared by Synthesis Method 2, wherein R ¹ , R ² , R ³ , A and R have the meanings described in the present invention. Compound 6b was reacted with RH under basic conditions to obtain the target compound 7b.

Synthetic method 3

The target compound 11b can be prepared by Synthesis Method 3, wherein, Q is -(CR ¹¹ R ^11a ) _m -; each R ¹¹ and R ^11a are independently hydrogen, halogen, alkyl or alkoxy, or R ¹¹ and R ^11a and the carbon atom connected to it form a cycloalkyl group or a heterocyclic group, or form the following group: -(C=CH ₂ )- or -(C=O)-; each R ¹² is independently hydrogen, alkyl , haloalkyl, halogen or alkoxy, or when two R ¹² are connected to the same carbon atom, R ¹² and R ¹² and the carbon atom connected to it form a cycloalkyl or heterocyclic group; k is 0, 1 , 2 or 3; Z is -O-, -(S=O) _q -or -N(R ⁴ )-; R ^8a , R ¹ , R ² , R ³ , R ⁴ , q, m and A have such The meaning described in the present invention. Compound 8b reacts with a brominating reagent to obtain compound 6b, reacts compound 6b with compound 9b or a salt of compound 9b to obtain compound 10b, and reacts compound 10b with R ^8a NH ₂ to obtain the target compound 11b.

Synthetic method 4

The target compound 15b can be prepared by synthetic method 4, wherein, Q, R ¹¹ , R ^11a , R ¹² , k, Z, R ^8a , R ^{1 , R 2 ,} R ³ , R ⁴ , q, m and A have The meaning described in Synthetic Method 3 of the present invention. Compound 8b is separated and purified to obtain compound 12b, compound 12b is reacted with a brominating reagent to obtain compound 13b, compound 13b is reacted with compound 9b or a salt of compound 9b to obtain compound 14b, compound 14b is reacted with R ^8a NH ₂ to obtain the target compound 15b .

Synthetic method 5

The target compound 16b can be prepared by Synthesis Method 5, wherein R ¹ , R ² , R ³ , A and R have the meanings described in the present invention. Compound 13b was reacted with RH under basic conditions to obtain the target compound 16b.

Synthetic method 6

The target compound 11b can be prepared by synthetic method 6, wherein, Q, R ¹¹ , R ^11a , R ¹² , k, Z, R ^8a , R ^{1 , R 2 ,} R ³ , R ⁴ , q, m and A have In the meaning described in Synthetic Method 3 of the present invention, Pg is an amino protecting group, such as Boc, Fmoc, Cbz, etc. Compound 9b is protected to obtain compound 17b, compound 17b is reacted with R ^8a NH ₂ to obtain compound 18b, compound 18b is deprotected to obtain compound 19b, compound 19b or a salt of compound 19b is reacted with compound 6b to obtain compound 11b.

Detailed ways

The following examples can further describe the present invention, however, these examples should not be construed as limiting the scope of the present invention.

Example 1 Compound 4-(2-bromo-4-fluorophenyl)-6-(((S)-3-((methylsulfonyl)carbamoyl)morpholino)methyl)-2-(thiazole Synthesis of ethyl -2-yl)-1,4-dihydropyrimidine-5-carboxylate

Step 1) Synthesis of compound (S)-3-((methylsulfonyl)carbamoyl)morpholine-4-carboxylic acid tert-butyl ester

(S)-N-Boc-3-morpholinecarboxylic acid (2g, 8.65mmol), CDI (2.1g, 12.98mmol) and anhydrous THF (40mL) were sequentially added to the reaction flask, and reacted at 70°C under nitrogen protection for 5 hours. Cool down to 5°C, add methanesulfonamide (1g, 10.38mmol) and DBU (1.98g, 12.98mmol) in turn, after the addition is complete, react at 25°C for 12 hours, concentrate the reaction solution, dissolve the residue in DCM (200mL), and dissolve the residue with 1% hydrochloric acid (50mL×2), dried over anhydrous sodium sulfate, concentrated, the residue was stirred and crystallized with ethyl acetate (30mL), filtered to obtain a white solid (1.98g, 74%). MS(ESI,pos.ion)m/z:209.1[M+H-100] ⁺ ;

¹ H NMR(600MHz,DMSO-d ₆ ):δ11.98(s,1H),4.35-4.24(m,1H),4.13(dd,1H),3.83(dd,1H),3.66-3.63(m, 1H),3.53(dd,1H),3.40-3.34(m,2H),3.26(d,3H),1.39(d,9H).

Step 2) Synthesis of compound (S)-N-(methylsulfonyl)morpholine-3-carboxamide trifluoroacetate

Dissolve (S)-3-((methylsulfonyl)carbamoyl)morpholine-4-carboxylic acid tert-butyl ester (0.9g, 2.92mmol) in DCM (10mL), add trifluoroacetic acid (10mL) at 25°C, After incubation for 12 hours, the reaction solution was concentrated, and the residue was dried with DCM (20 mL×2), slurried with EtOAc (10 mL), and filtered to obtain a white solid (0.78 g, 83%).

MS(ESI,pos.ion)m/z:209.1[M+H] ⁺ ;

¹ H NMR (400MHz, D ₂ O): δ4.26(dd,1H),4.13(dd,1H),3.99(dt,1H),3.87-3.74(m,2H),3.46(dt,1H), 3.32-3.20(m,1H),3.18(s,3H).

Step 3) Compound 4-(2-bromo-4-fluorophenyl)-6-(((S)-3-((methylsulfonyl)carbamoyl)morpholino)methyl)-2-(thiazole Synthesis of ethyl -2-yl)-1,4-dihydropyrimidine-5-carboxylate

Add (S)-N-(methylsulfonyl)morpholine-3-carboxamide trifluoroacetate (0.48g, 1.5mmol), 4-(2-bromo-4-fluorophenyl) -6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (refer to WO2010069147A for specific synthesis method) (0.75g, 1.5mmol), potassium carbonate ( 0.42g, 3mmol) and absolute ethanol (30mL), react under nitrogen protection at 25°C for 12 hours, filter, concentrate the filtrate, and separate and purify the residue by column chromatography (DCM/CH ₃ OH (v/v)=25/1) A yellow solid (0.4 g, 42%) was obtained.

MS(ESI,pos.ion)m/z:630.0[M+H] ⁺ ;

¹ H NMR(600MHz,DMSO-d ₆ ):δ11.96(br,1H),9.84(br.s,1H),8.04(d,1H),7.95(d,1H),7.58(dd,1H) ,7.42-7.39(m,1H),7.23-7.19(m,1H),6.03(s,1H),4.24-4.01(m,2H),3.98-3.83(m,4H),3.81-3.73(m, 1H), 3.69(br,2H), 3.45(br,1H), 3.23(s,3H), 3.10(br,1H), 1.05(t,3H).

Example 2 Compound 4-(2-bromo-4-fluorophenyl)-6-(((S)-3-((cyclopropylsulfonyl)carbamoyl)morpholine)methyl)-2-(thiazole Synthesis of ethyl -2-yl)-1,4-dihydropyrimidine-5-carboxylate

Step 1) Synthesis of compound (S)-3-((cyclopropylsulfonyl)carbamoyl)morpholine-4-carboxylic acid tert-butyl ester

(S)-N-Boc-3-morpholinecarboxylic acid (2g, 8.65mmol), CDI (2.1g, 12.98mmol) and anhydrous THF (40mL) were sequentially added to the reaction flask, and reacted at 70°C under nitrogen protection for 5 hours. Cool down to 5°C, add cyprosulfonamide (1.26g, 10.38mmol) and DBU (1.98g, 12.98mmol) in turn, after addition, react at 25°C for 12 hours, concentrate the reaction solution, dissolve the residue with DCM (200mL), 1 % hydrochloric acid (50mL×2), dried over anhydrous sodium sulfate, and concentrated to give a white solid (1.72g, 60%).

MS(ESI,pos.ion)m/z:235.1[M+H-100] ⁺ ;

¹ H NMR (600MHz, DMSO-d ₆ ): δ11.90(s, 1H), 4.35-4.25(m, 1H), 4.17-4.06(m, 1H), 3.88-3.79(m, 1H), 3.66( dd,1H),3.55(dd,1H),3.40-3.35(m,1H),3.27-3.20(m,1H),2.99-2.94(m,1H),1.65-1.54(m,1H),1.37( br.s,9H),1.19-1.04(m,4H).

Step 2) Synthesis of compound (S)-N-(cyclopropylsulfonyl)morpholine-3-carboxamide trifluoroacetate

Dissolve (S)-3-((cyclopropylsulfonyl)carbamoyl)morpholine-4-carboxylic acid tert-butyl ester (0.77g, 2.3mmol) in DCM (10mL), add trifluoroacetic acid (10mL) at 25°C , kept the reaction for 12 hours, concentrated the reaction solution, and dried the residue with DCM (20 mL×2), slurried with isopropyl ether (30 mL), and filtered to obtain a white solid (0.72 g, 90%).

MS(ESI,pos.ion)m/z:235.1[M+H] ⁺ ;

¹ H NMR (400MHz, D ₂ O): δ4.27(dd,1H),4.16(dd,1H),4.02(dt,1H),3.88-3.75(m,1H),3.47(dt,1H), 3.31-3.25(m,1H),2.91-2.85(m,1H),1.70-1.56(m,1H),1.21-1.04(m,4H).

Step 3) Compound 4-(2-bromo-4-fluorophenyl)-6-(((S)-3-((cyclopropylsulfonyl)carbamoyl)morpholine)methyl)-2-(thiazole Synthesis of ethyl -2-yl)-1,4-dihydropyrimidine-5-carboxylate

(S)-N-(cyclopropylsulfonyl)morpholine-3-carbamoyltrifluoroacetate (0.52g, 1.5mmol), 4-(2-bromo-4-fluorophenyl)-6- (Bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (0.75g, 1.5mmol), potassium carbonate (0.42g, 3mmol) and absolute ethanol ( 30 mL) according to the method described in step 3 of Example 1 to obtain a yellow solid (0.75 g, 76%).

MS(ESI,pos.ion)m/z:656.1[M+H] ⁺ ;

¹ H NMR(600MHz,DMSO-d ₆ ):δ11.91(br.s,1H),9.80(br,1H),8.04(d,1H),7.95(br,1H),7.57(dd,1H) ,7.43-7.38(m,1H),7.22-7.19(m,1H),6.03(br,1H),4.15-4.03(m,2H),3.97-3.78(m,4H),3.73-3.65(m, 2H),3.59-3.50(m,1H),3.21-3.13(m,1H),3.05-2.95(m,1H),1.65-1.53(m,1H),1.12-1.02(m,7H).

Example 3 Compound 6-((2-(3-(benzylamine)-3-oxopropyl)morpholine)methyl)-4-(2-bromo-4-fluorophenyl)-2-(thiazole Synthesis of ethyl -2-yl)-1,4-dihydropyrimidine-5-carboxylate

3-(4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidine-4- Base)methyl)morpholin-2-yl)propionic acid (0.5g, 0.86mmol) was dissolved in DCM (30mL), and benzylamine (0.14g, 1.3mmol), EDCI (0.19g, 1mmol), HOAT (0.14g, 1mmol) and triethylamine (0.17g, 1.7mmol) were incubated for 12 hours, DCM (100mL) was added, followed by hydrochloric acid (1mol/L, 80mL), saturated NaHCO ₃ solution (80mL) and saturated Washed with brine (80 mL), dried over anhydrous sodium sulfate, concentrated the organic layer, and the residue was separated and purified by column chromatography (DCM/CH ₃ OH (v/v)=100/1) to obtain a yellow solid (0.16 g, 28% ).

MS(ESI,pos.ion)m/z:670.1[M+H] ⁺ ;

¹ H NMR(400MHz,DMSO-d ₆ ):δ9.66(s,1H),8.36-8.29(m,1H),7.99(dd,1H),7.93(dd,1H),7.56(dd,1H) ,7.40(dt,1H),7.35-7.27(m,2H),7.25-7.20(m,4H),6.04(s,1H),4.32-4.16(m,2H),3.99-3.82(m,5H) ,3.61-3.47(m,2H),2.90-2.68(m,2H),2.37-2.05(m,4H),1.80-1.64(m,2H),1.05(t,3H).

Example 4 compound (R)-4-(2-bromo-4-fluorophenyl)-6-(((S)-3-(cyclopropylcarbamoyl)morpholino)methyl)-2-( Synthesis of ethyl thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

Step 1) Compound (R)-4-(2-bromo-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester Synthesis

Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (5 g, 11.8 mmol) ( The specific synthesis method refers to WO2010069147A) dissolved in a mixed solvent of MeOH and DCM (v:v=1:1, 20mL), prepared and separated by chromatography to obtain a yellow solid (2g, 40%).

${<span\; class="notranslate">\; [</span>\mathrm{<span\; class="notranslate">\; a</span>}<span\; class="notranslate">\; ]</span>}_{\mathrm{<span\; class="notranslate">\; D.</span>}}^{\mathrm{<span\; class="notranslate">\; 25</span>}}<span\; class="notranslate">\; =</span><span\; class="notranslate">\; -</span>\mathrm{<span\; class="notranslate">\; 80.71</span>}<span\; class="notranslate">\; (</span>\mathrm{<span\; class="notranslate">\; c</span>}<span\; class="notranslate">\; =</span>\mathrm{<span\; class="notranslate">\; 0.3023</span>}\mathrm{<span\; class="notranslate">\; g</span>}<span\; class="notranslate">\; /</span>\mathrm{<span\; class="notranslate">\; 100</span>}\mathrm{<span\; class="notranslate">\; mL</span>}<span\; class="notranslate">\; ,</span>\mathrm{<span\; class="notranslate">\; MeOH</span>}<span\; class="notranslate">\; )</span><span\; class="notranslate">\; ;</span>$

MS(ESI,pos.ion)m/z:424.0[M+H] ⁺ ;

¹ H NMR (400MHz,DMSO-d ₆ ):δ9.88(s,1H),7.97(d,1H),7.89(d,1H),7.54(dd,1H),7.35(dd,1H),7.23 (td,1H),5.96(s,1H),3.93(q,2H),2.46(s,3H),1.03(t,3H).

Step 2) Compound (R)-4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5- Synthesis of ethyl formate

(R)-4-(2-bromo-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (1g, 2.4mmol) was dissolved in CCl ₄ (20mL), NBS (0.47g, 2.64mmol) was added at 76°C, incubated for 30 minutes, cooled, and the reaction solution was concentrated, and the residue was separated and purified by column chromatography (PE/EtOAc (v/v )=5/1) a yellow solid (0.85 g, 70%) was obtained.

MS(ESI,pos.ion)m/z:503.9[M+H] ⁺ ;

¹ H NMR(600MHz,DMSO-d ₆ ):δ10.23(s,1H),8.01(d,1H),7.98(d,1H),7.62(dd,1H),7.42(dd,1H),7.29 (td,1H),6.01(s,1H),4.79(br,2H),4.01(q,2H),1.08(t,3H).

Step 3) compound (S)-4-(((R)-6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3, Synthesis of 6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid

Add (R)-4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine- Ethyl 5-formate (0.5g, 1mmol), (S)-morpholine-3-carboxylic acid (0.13g, 1mmol), potassium carbonate (0.28g, 2mmol) and ethanol (10mL) were reacted at 30°C under nitrogen protection for 12 hours , filtered, the filtrate was concentrated, and the residue was separated and purified by column chromatography (DCM/CH ₃ OH (v/v)=25/1) to obtain a yellow solid (0.34 g, 62%).

MS(ESI,pos.ion)m/z:553.2[M+H] ⁺ ;

¹ H NMR (400MHz,DMSO-d ₆ ):δ12.85(br,1H),9.80(s,1H),8.00(d,1H),7.91(d,1H),7.54(dd,1H),7.39 (dd,1H),7.19(td,1H),6.01(s,1H),4.25(d,1H),4.02(d,1H),3.97-3.91(m,3H),3.81(dd,1H), 3.72-3.69(m,1H),3.66-3.63(m,1H),3.61-3.58(m,1H),3.10-3.03(m,1H),2.42-2.35(m,1H),1.04(t,3H ).

Step 4) compound (R)-4-(2-bromo-4-fluorophenyl)-6-(((S)-3-(cyclopropylcarbamoyl)morpholino)methyl)-2-( Synthesis of ethyl thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

(S)-4-(((R)-6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-di Hydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (2g, 3.6mmol), HOAT (0.64g, 4.7mmol), EDCI (0.9g, 5mmol), triethylamine (0.73g, 7.2mmol) , DCM (40 mL) and cyclopropylamine (0.31 g, 5.4 mmol) were implemented according to the method described in Example 3 to obtain a pale yellow solid (0.64 g, 30%).

MS(ESI,pos.ion)m/z:591.6[M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ): δ9.44(s,1H),7.88(d,1H),7.48(d,1H),7.34(dd,1H),7.25(dd,1H),6.97(td ,1H),6.18(s,1H),4.14-3.99(m,4H),3.95-3.88(m,2H),3.77-3.71(m,2H),3.28-3.24(m,1H),2.95-2.91 (m,1H),2.77-2.73(m,1H),2.66-2.58(m,1H),1.14(t,3H),0.75-0.70(m,2H),0.39-0.37(m,2H).

Example 5 compound (R)-4-(2-chloro-4-fluorophenyl)-6-(((S)-3-(cyclopropylcarbamoyl)morpholino)methyl)-2-( Synthesis of ethyl thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

Step 1) Compound (R)-4-(2-chloro-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester Synthesis

Take 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (5g, 13.2mmol) ( The specific synthesis method refers to WO2010069147A) and the method described in step 1 of Example 4 was implemented to obtain a yellow solid (2.1 g, 42%).

${<span\; class="notranslate">\; [</span>\mathrm{<span\; class="notranslate">\; a</span>}<span\; class="notranslate">\; ]</span>}_{\mathrm{<span\; class="notranslate">\; D.</span>}}^{\mathrm{<span\; class="notranslate">\; 25</span>}}<span\; class="notranslate">\; =</span><span\; class="notranslate">\; -</span>\mathrm{<span\; class="notranslate">\; 59.6</span>}<span\; class="notranslate">\; (</span>\mathrm{<span\; class="notranslate">\; c</span>}<span\; class="notranslate">\; =</span>\mathrm{<span\; class="notranslate">\; 0.3020</span>}\mathrm{<span\; class="notranslate">\; g</span>}<span\; class="notranslate">\; /</span>\mathrm{<span\; class="notranslate">\; 100</span>}\mathrm{<span\; class="notranslate">\; mL</span>}<span\; class="notranslate">\; ,</span>\mathrm{<span\; class="notranslate">\; MeOH</span>}<span\; class="notranslate">\; )</span><span\; class="notranslate">\; ;</span>$

MS(ESI,pos.ion)m/z:380.2[M+H] ⁺ ;

¹ H NMR(600MHz,DMSO-d ₆ ):δ9.92(s,1H),7.97(d,1H),7.90(d,1H),7.41(dd,1H),7.37(dd,1H),7.19 (td,1H),6.00(s,1H),3.93(q,2H),2.46(s,3H),1.03(t,3H).

Step 2) Compound (R)-6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5- Synthesis of ethyl formate

(R)-4-(2-chloro-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (0.91g , 2.4mmol), CCl ₄ (20mL) and NBS (0.47g, 2.64mmol) were implemented according to the method described in step 2 of Example 4 to obtain a yellow solid (0.8g, 73%).

MS(ESI,pos.ion)m/z:457.9[M+H] ⁺ ;

¹ H NMR(400MHz,DMSO-d ₆ ):δ9.67(s,1H),8.01(d,1H),7.97(br,1H),7.44-7.41(m,2H),7.22(td,1H) ,5.99(s,1H),4.83(br,2H),4.02(q,2H),1.07(t,3H).

Step 3) compound (S)-4-(((R)-6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3, Synthesis of 6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid

(R)-6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (0.46g, 1mmol), (S)-morpholine-3-carboxylic acid (0.13g, 1mmol), potassium carbonate (0.28g, 2mmol) and ethanol (9mL) were implemented according to the method described in step 3 of Example 4 to obtain a yellow solid (0.29 g, 57%).

MS(ESI,pos.ion)m/z:509.2[M+H] ⁺ ;

¹ H NMR(400MHz,DMSO-d ₆ ):δ13.00(br,1H),9.95(s,1H),8.02(d,1H),7.93(d,1H),7.46-7.38(m,2H) ,7.17(td,1H),6.05(s,1H),4.20(d,1H),4.05-4.02(m,1H),3.97-3.91(m,3H),3.81(dd,1H),3.72-3.63 (m,2H),3.58-3.53(m,1H),3.08-3.05(m,1H),2.42-2.38(m,1H),1.06(t,3H).

Step 4) compound (R)-4-(2-chloro-4-fluorophenyl)-6-(((S)-3-(cyclopropylcarbamoyl)morpholino)methyl)-2-( Synthesis of ethyl thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

(S)-4-(((R)-6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-di Hydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (1.84g, 3.6mmol), HOAT (0.64g, 4.7mmol), EDCI (0.96g, 5mmol), triethylamine (0.73g, 7.2mmol ), DCM (40mL) and cyclopropylamine (0.31g, 5.4mmol) were implemented according to the method described in Example 3 to obtain a pale yellow solid (0.85g, 43%).

MS(ESI,pos.ion)m/z:548.1[M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ): δ9.51(s,1H),7.91(d,1H),7.52(d,1H),7.33-7.19(m,2H),7.17-7.03(m,1H) ,6.15(s,1H),4.17-3.96(m,4H),3.94-3.85(m,2H),3.77-3.70(m,2H),3.29-3.23(m,1H),2.96-2.91(m, 1H),2.78-2.72(m,1H),2.68-2.57(m,1H),1.12(t,3H),0.74-0.71(m,2H),0.39-0.34(m,2H).

Example 6 Compound (R)-6-(((S)-3-(cyclopropylcarbamoyl)morpholino)methyl)-4-(2,4-dichlorophenyl)-2-(thiazole Synthesis of ethyl -2-yl)-1,4-dihydropyrimidine-5-carboxylate

Step 1) compound (R)-4-(2,4-dichlorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester synthesis

Take 4-(2,4-dichlorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (5g, 12.6mmol) (specifically The synthesis method refers to WO2010069147A) and the method described in step 1 of Example 4 was implemented to obtain a yellow solid (1.9 g, 38%).

${<span\; class="notranslate">\; [</span>\mathrm{<span\; class="notranslate">\; a</span>}<span\; class="notranslate">\; ]</span>}_{\mathrm{<span\; class="notranslate">\; D.</span>}}^{\mathrm{<span\; class="notranslate">\; 25</span>}}<span\; class="notranslate">\; =</span><span\; class="notranslate">\; -</span>\mathrm{<span\; class="notranslate">\; 39.07</span>}<span\; class="notranslate">\; (</span>\mathrm{<span\; class="notranslate">\; c</span>}<span\; class="notranslate">\; =</span>\mathrm{<span\; class="notranslate">\; 0.3032</span>}\mathrm{<span\; class="notranslate">\; g</span>}<span\; class="notranslate">\; /</span>\mathrm{<span\; class="notranslate">\; 100</span>}\mathrm{<span\; class="notranslate">\; mL</span>}<span\; class="notranslate">\; ,</span>\mathrm{<span\; class="notranslate">\; MeOH</span>}<span\; class="notranslate">\; )</span><span\; class="notranslate">\; ;</span>$

MS(ESI,pos.ion)m/z:396.1[M+H] ⁺ ;

¹ H NMR (400MHz,DMSO-d ₆ ):δ9.93(s,1H),7.97(d,1H),7.90(d,1H),7.58(d,1H),7.41(dd,1H),7.35 (d,1H),6.00(s,1H),3.93(q,2H),2.46(s,3H),1.03(t,3H).

Step 2) Compound (R)-4-(2,4-dichlorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid Synthesis of Ethyl Ester

(R)-4-(2,4-dichlorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (0.95g, 2.4 mmol), CCl ₄ (20 mL) and NBS (0.47 g, 2.64 mmol) were carried out according to the method described in step 2 of Example 4 to obtain a yellow solid (0.74 g, 65%).

MS(ESI,pos.ion)m/z:475.6[M+H] ⁺ ;

¹ H NMR(600MHz,DMSO-d ₆ ):δ8.03(d,1H),7.98(d,1H),7.66-7.62(m,1H),7.47-7.35(m,2H),5.99(s, 1H), 4.82(br,2H), 4.02(q,2H), 1.09(t,3H).

Step 3) Compound (S)-4-(((R)-6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6 Synthesis of -dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid

(R)-6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester ( 0.48g, 1mmol), (S)-morpholine-3-carboxylic acid (0.13g, 1mmol), potassium carbonate (0.28g, 2mmol) and ethanol (9.5mL) were implemented according to the method described in step 3 of Example 4 to obtain a yellow solid (0.34g, 64%).

MS(ESI,pos.ion)m/z:524.7[M+H] ⁺ ;

¹ H NMR(400MHz,DMSO-d ₆ ):δ12.86(br,1H),9.84(s,1H),8.03(d,1H),7.94(d,1H),7.60(br,1H),7.42 -7.36(m,2H),6.05(s,1H),4.25(d,1H),4.09-3.91(m,4H),3.83(dd,1H),3.75-3.58(m,3H),3.12-3.03 (m,1H),2.43-2.36(m,1H),1.06(t,3H).

Step 4) Compound (R)-6-(((S)-3-(cyclopropylcarbamoyl)morpholino)methyl)-4-(2,4-dichlorophenyl)-2-( Synthesis of ethyl thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

(S)-4-(((R)-6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydro Pyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (1.89g, 3.6mmol), HOAT (0.64g, 4.7mmol), EDCI (0.9g, 5mmol), triethylamine (0.73g, 7.2mmol) , cyclopropylamine (0.31g, 5.4mmol) and DCM (40mL) were implemented according to the method described in Example 3 to obtain a pale yellow solid (0.93g, 46%).

MS(ESI,pos.ion)m/z:564.2[M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ): δ9.54(s,1H),7.96(d,1H),7.58(d,1H),7.40(br,1H),7.10(br,2H),6.12(s ,1H),4.15-3.96(m,4H),3.92-3.85(m,2H),3.79-3.70(m,2H),3.29-3.21(m,1H),2.96-2.92(m,1H),2.75 -2.72(m,1H),2.68-2.56(m,1H),1.10(t,3H),0.76-0.71(m,2H),0.38-0.34(m,2H).

Example 7 compound (R)-6-(((S)-3-(benzylcarbamoyl)morpholino)methyl)-4-(2-bromo-4-fluorophenyl)-2-( Synthesis of ethyl thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

(S)-4-(((R)-6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-di Hydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (1.11g, 2.01mmol), HOAT (0.36g, 2.6mmol), EDCI (0.47g, 2.5mmol), triethylamine (0.41g, 4.1 mmol), benzylamine (0.27g, 2.5mmol) and DCM (40mL) were implemented according to the method described in Example 3 to obtain a pale yellow solid (0.68g, 53%).

MS(ESI,pos.ion)m/z:642.0[M+H] ⁺ ;

¹ H NMR (400MHz,DMSO-d ₆ ):δ9.96(d,1H),8.73(br,1H),8.01(d,1H),7.91(d,1H),7.55(dd,1H),7.39 (dd,1H),7.34-7.16(m,6H),6.01(s,1H),4.42-4.25(m,2H),4.14-3.99(m,1H),3.96-3.89(m,3H),3.85 -3.75(m,2H),3.67-3.61(m,2H),3.45-3.39(m,2H),3.06-3.03(m,1H),1.04(t,3H).

Example 8 compound (R)-6-(((S)-3-(benzylcarbamoyl)morpholino)methyl)-4-(2-chloro-4-fluorophenyl)-2-( Synthesis of ethyl thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

(S)-4-(((R)-6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-di Hydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (1.02g, 2.01mmol), HOAT (0.36g, 2.6mmol), EDCI (0.47g, 2.5mmol), triethylamine (0.41g, 4.1 mmol), benzylamine (0.27g, 2.5mmol) and DCM (40mL) were implemented according to the method described in Example 3 to obtain a pale yellow solid (0.55g, 46%).

MS(ESI,pos.ion)m/z:598.16[M+H] ⁺ ;

¹ H NMR(400MHz,DMSO-d ₆ ):δ9.91(s,1H),8.73(br,1H),8.03(d,1H),7.94(d,1H),7.50-7.37(m,2H) ,7.33-7.14(m,6H),6.03(s,1H),4.43-4.25(m,2H),4.12-3.99(m,1H),3.93-3.89(m,3H),3.83-3.75(m, 2H),3.68-3.61(m,2H),3.47-3.39(m,2H),3.05-3.03(m,1H),1.03(t,3H).

Example 9 compound (R)-6-(((S)-3-(benzylcarbamoyl)morpholino)methyl)-4-(2,4-dichlorophenyl)-2-(thiazole Synthesis of ethyl -2-yl)-1,4-dihydropyrimidine-5-carboxylate

(S)-4-(((R)-6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydro Pyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (1.06g, 2.01mmol), HOAT (0.36g, 2.6mmol), EDCI (0.47g, 2.5mmol), triethylamine (0.41g, 4.1mmol ), benzylamine (0.27g, 2.5mmol) and DCM (40mL) were implemented according to the method described in Example 3 to obtain a yellow solid (0.47g, 38%).

MS(ESI,pos.ion)m/z:614.13[M+H] ⁺ ;

¹ H NMR (400MHz,DMSO-d ₆ ):δ9.87(s,1H),8.71(br,1H),8.02(d,1H),7.92(d,1H),7.55(br,1H),7.40 (br,1H),7.31-7.12(m,5H),6.00(s,1H),4.43-4.27(m,2H),4.12-3.95(m,1H),3.93-3.86(m,3H),3.83 -3.74(m,2H),3.68-3.63(m,2H),3.47-3.36(m,2H),3.05-3.01(m,1H),1.05(t,3H).

Example 10 compound (R)-4-(2-bromo-4-fluorophenyl)-6-(((S)-3-(phenylcarbamoyl)morpholino)methyl)-2-( Synthesis of ethyl thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

(S)-4-(((R)-6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-di Hydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (1.11g, 2.01mmol), HOAT (0.36g, 2.6mmol), EDCI (0.47g, 2.5mmol), triethylamine (0.41g, 4.1 mmol), aniline (0.23g, 2.5mmol) and DCM (40mL) were implemented according to the method described in Example 3 to obtain a pale yellow solid (0.26g, 23%).

MS(ESI,pos.ion)m/z:628.1[M+H] ⁺ ;

¹ H NMR(600MHz,DMSO-d ₆ ):δ9.96(d,1H),8.73(br,1H),8.02(d,1H),7.92(d,1H),7.56(dd,1H),7.42 (dd,1H),7.34-7.18(m,6H),6.01(s,1H),4.46-4.18(m,2H),4.16-4.00(m,1H),3.98-3.89(m,3H),3.86 -3.75(m,1H),3.67-3.58(m,2H),3.40(d,1H),3.04(d,1H),1.04(t,3H).

Example 11 Compound (R)-4-(2-chloro-4-fluorophenyl)-6-(((S)-3-(phenylcarbamoyl)morpholino)methyl)-2-( Synthesis of ethyl thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

(S)-4-(((R)-6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-di Hydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (1.02g, 2.01mmol), HOAT (0.36g, 2.6mmol), EDCI (0.47g, 2.5mmol), triethylamine (0.41g, 4.1 mmol), aniline (0.23g, 2.5mmol) and DCM (40mL) were implemented according to the method described in Example 3 to obtain a light yellow solid (0.25g, 21%).

MS(ESI,pos.ion)m/z:584.15[M+H] ⁺ ;

¹ H NMR(600MHz,DMSO-d ₆ ):δ9.87(d,1H),8.68(br,1H),8.01(d,1H),7.94(d,1H),7.48-7.38(m,2H) ,7.36-7.14(m,6H),6.01(s,1H),4.44-4.18(m,2H),4.13-4.00(m,1H),3.95-3.89(m,3H),3.87-3.75(m, 1H),3.68-3.58(m,2H),3.42(d,1H),3.06(d,1H),1.02(t,3H).

Example 12 Compound (R)-4-(2,4-dichlorophenyl)-6-(((S)-3-(phenylcarbamoyl)morpholino)methyl)-2-(thiazole Synthesis of ethyl -2-yl)-1,4-dihydropyrimidine-5-carboxylate

(S)-4-(((R)-6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydro Pyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (1.06g, 2.01mmol), HOAT (0.36g, 2.6mmol), EDCI (0.47g, 2.5mmol), triethylamine (0.41g, 4.1mmol ), aniline (0.23g, 2.5mmol) and DCM (40mL) were implemented according to the method described in Example 3 to obtain a light yellow solid (0.29g, 24%).

MS(ESI,pos.ion)m/z:600.52[M+H] ⁺ ;

¹ H NMR(600MHz,DMSO-d ₆ ):δ9.84(d,1H),8.69(br,1H),8.04(d,1H),7.96(d,1H),7.48-7.35(m,2H) ,7.36-7.16(m,6H),6.03(s,1H),4.44-4.16(m,2H),4.13-4.03(m,1H),3.95-3.87(m,3H),3.87-3.76(m, 1H),3.68-3.56(m,2H),3.41(d,1H),3.09(d,1H),1.03(t,3H).

Example 13 Compound (R)-4-(2-bromo-4-fluorophenyl)-2-(thiazol-2-yl)-6-(((S)-3-(thiazol-2-ylaminomethyl Synthesis of acyl)morpholino)methyl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester

(S)-4-(((R)-6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-di Hydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (1.11g, 2.01mmol), HOAT (0.36g, 2.6mmol), EDCI (0.47g, 2.5mmol), triethylamine (0.41g, 4.1 mmol), 2-aminothiazole (0.25 g, 2.5 mmol), and DCM (40 mL) were implemented according to the method described in Example 3 to obtain a pale yellow solid (0.37 g, 29%).

MS(ESI,pos.ion)m/z:635.1[M+H] ⁺ ;

¹ H NMR(400MHz,DMSO-d ₆ ):δ7.88(d,1H),7.84(d,1H),7.68(d,2H),7.65(d,1H),7.34-7.25(m,3H) ,6.05(s,1H),4.78(d,1H),4.06-3.96(m,3H),3.85-3.79(m,1H),3.68-3.54(m,3H),3.47-3.43(m,1H) ,2.97-2.94(m,1H),2.58-2.55(m,1H),1.02(t,3H).

Example 14 compound 4-(2-bromo-4-fluorophenyl)-6-((-2-(3-oxo-3-(aniline) propyl) morpholino) methyl)-2-( Synthesis of ethyl thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

3-(4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidine-4- base) methyl) morpholin-2-yl) propionic acid (0.52g, 0.9mmol), HOAT (0.15g, 1.1mmol), EDCI (0.21g, 1.1mmol), triethylamine (0.12g, 1.2mmol) , aniline (0.1 g, 1.1 mmol) and DCM (40 mL) were implemented according to the method described in Example 3 to obtain a pale yellow solid (0.19 g, 32%).

MS(ESI,pos.ion)m/z:656.2[M+H] ⁺ ;

¹ H NMR(400MHz,DMSO-d ₆ ):δ10.17(s,1H),9.90(s,1H),8.04(d,1H),7.94(d,1H),7.85(dd,1H),7.67 -7.54(m,2H),7.46-7.36(m,1H),7.32-7.19(m,3H),7.06(t,1H),5.98(s,1H),4.11-3.98(m,4H),3.94 -3.86(m,3H),3.84-3.78(m,1H),3.75-3.60(m,2H),3.56-3.45(m,2H),3.11-2.94(m,2H),2.59-2.56(m, 1H),1.00(t,3H).

Example 15 compound 4-(2-chloro-4-fluorophenyl)-6-((-2-(3-oxo-3-(aniline) propyl) morpholino) methyl)-2-( Synthesis of ethyl thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

3-(4-((6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidine-4- base) methyl) morpholin-2-yl) propionic acid (0.48g, 0.9mmol), HOAT (0.15g, 1.1mmol), EDCI (0.21g, 1.1mmol), triethylamine (0.12g, 1.2mmol) , aniline (0.1 g, 1.1 mmol) and DCM (40 mL) according to the method described in Example 3 to obtain a pale yellow solid (0.33 g, 60%).

MS(ESI,pos.ion)m/z:612.18[M+H] ⁺ ;

¹ H NMR (400MHz,DMSO-d ₆ ):δ10.12(s,1H),9.94(s,1H),8.01(d,1H),7.96(d,1H),7.81(dd,1H),7.60 -7.49(m,2H),7.44-7.32(m,1H),7.31-7.19(m,3H),7.03(t,1H),6.01(s,1H),4.13-3.98(m,4H),3.92 -3.86(m,3H),3.82-3.78(m,1H),3.73-3.60(m,2H),3.55-3.45(m,2H),3.14-2.94(m,2H),2.58-2.56(m, 1H), 1.01(t,3H).

Example 16 Compound 4-(2,4-dichlorophenyl)-6-((-2-(3-oxo-3-(aniline)propyl)morpholino)methyl)-2-(thiazole Synthesis of ethyl -2-yl)-1,4-dihydropyrimidine-5-carboxylate

3-(4-((6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl ) methyl) morpholin-2-yl) propionic acid (0.5g, 0.9mmol), HOAT (0.15g, 1.1mmol), EDCI (0.21g, 1.1mmol), triethylamine (0.12g, 1.2mmol), Aniline (0.1 g, 1.1 mmol) and DCM (40 mL) were carried out as described in Example 3 to obtain a pale yellow solid (0.29 g, 52%).

MS(ESI,pos.ion)m/z:628.15[M+H] ⁺ ;

¹ H NMR(400MHz,DMSO-d ₆ ):δ10.14(s,1H),9.87(s,1H),7.96(d,1H),7.94(d,1H),7.80(dd,1H),7.58 (br,2H),7.36(br,1H),7.34-7.15(m,3H),7.03(t,1H),6.03(s,1H),4.13-3.95(m,4H),3.93-3.86(m ,3H),3.81-3.77(m,1H),3.72-3.61(m,2H),3.56-3.44(m,2H),3.14-2.93(m,2H),2.56-2.53(m,1H),1.04 (t,3H).

Example 17 Compound 4-(2-bromo-4-fluorophenyl)-6-((-2-(3-oxo-3-(benzenesulfonamide) propyl) morpholino) methyl)-2 Synthesis of -(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid methyl ester

Step 1) Synthesis of Compound 3-(4-(tert-butoxycarbonyl)morpholin-2-yl)propionic acid

Add 3-(morpholin-2-yl)propionic acid (1.6g, 10mmol), di-tert-butyl dicarbonate (2.62g, 12mmol), ethanol (32mL) and triethylamine (1.01g, 10 mmol), reacted at 25°C for 12 hours, concentrated the reaction solution, and separated and purified the residue by column chromatography (DCM/CH ₃ OH (v/v)=50/1) to obtain a colorless oil (2.07 g, 80%).

MS(ESI,pos.ion)m/z:204.1[M+H-56] ⁺ .

Step 2) Synthesis of compound 2-(3-oxo-3-(benzenesulfonamide) propyl) morpholine-4-formic acid tert-butyl ester

3-(4-(tert-butoxycarbonyl)morpholin-2-yl)propionic acid (0.52g, 2mmol), benzenesulfonamide (0.32g, 2mmol), CDI (0.49g, 3mmol), THF (10mL) , DBU (0.46g, 3mmol) was implemented according to the method described in step 1 of Example 1 to obtain a colorless oil (0.32g, 40%). MS(ESI,pos.ion)m/z:343.2[M+H-56] ⁺ .

Step 3) Synthesis of compound 3-(morpholin-2-yl)-N-(benzenesulfonyl) propanamide hydrochloride

Add tert-butyl 2-(3-oxo-3-(benzenesulfonamide)propyl)morpholine-4-carboxylate (0.32g, 0.8mmol) and ethyl hydrogen chloride solution (4mol/L , 2 mL), reacted at 25°C for 6 hours, and filtered to obtain a white solid (0.2 g, 75%).

MS(ESI,pos.ion)m/z:299.1[M+H] ⁺ .

Step 4) Compound 4-(2-bromo-4-fluorophenyl)-6-((-2-(3-oxo-3-(benzenesulfonamide)propyl)morpholino)methyl)-2 Synthesis of -(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid methyl ester

4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid methyl ester (specific synthesis method Refer to WO2008154817A) (0.3g, 0.6mmol), 3-(morpholin-2-yl)-N-(benzenesulfonyl)propionamide hydrochloride (0.2g, 0.6mmol), potassium carbonate (83mg, 0.6mmol) and absolute ethanol (6 mL) according to the method described in step 3 of Example 1 to obtain a light yellow solid (0.11 g, 27%). MS(ESI,pos.ion)m/z:706.2[M+H] ⁺ ;

¹ H NMR(400MHz,DMSO-d ₆ ):δ9.67(s,1H),8.00(d,1H),7.93(d,1H),7.77-7.65(m,2H),7.54(dd,1H) ,7.40-7.30(m,4H),7.21(td,1H),5.99(s,1H),4.17(br,1H),3.90-3.74(m,2H),3.51(s,3H),3.45-3.40 (m,2H),3.15(br,1H),2.72(dd,2H),2.32-2.26(m,1H),2.05-1.95(m,2H),1.54-1.48(m,2H).

Example 18 Compound 4-(2-chloro-4-fluorophenyl)-6-((2-(3-oxo-3-(benzenesulfonamide) propyl) morpholino) methyl)-2- Synthesis of (thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid methyl ester

6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid methyl ester (specific synthesis method Refer to WO2008154818A) (0.27g, 0.6mmol), 3-(morpholin-2-yl)-N-(benzenesulfonyl)propionamide hydrochloride (0.2g, 0.6mmol), potassium carbonate (83mg, 0.6mmol) and absolute ethanol (6 mL) according to the method described in step 3 of Example 1 to obtain a light yellow solid (0.1 g, 24%). MS(ESI,pos.ion)m/z:662.12[M+H] ⁺ ;

¹ H NMR(400MHz,DMSO-d ₆ ):δ9.62(s,1H),8.03(d,1H),7.96(d,1H),7.72-7.63(m,2H),7.51(dd,1H) ,7.44-7.32(m,4H),7.18(td,1H),6.02(s,1H),4.15(br,1H),3.93-3.74(m,2H),3.52(s,3H),3.43-3.40 (m,2H),3.12(br,1H),2.73(dd,2H),2.35-2.26(m,1H),2.08-1.95(m,2H),1.56-1.44(m,2H).

Example 19 compound 4-(2,4-dichlorophenyl)-6-((2-(3-oxo-3-(benzenesulfonamide) propyl) morpholino) methyl)-2-( Synthesis of Methyl Thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid methyl ester (refer to WO2008154820A) (0.28g, 0.6mmol), 3-(morpholin-2-yl)-N-(benzenesulfonyl) propionamide hydrochloride (0.2g, 0.6mmol), potassium carbonate (83mg, 0.6mmol) and Absolute ethanol (6 mL) was carried out according to the method described in step 3 of Example 1 to obtain a light yellow solid (0.14 g, 35%). MS(ESI,pos.ion)m/z:678.09[M+H] ⁺ ;

¹ H NMR(400MHz,DMSO-d ₆ ):δ9.68(s,1H),8.02(d,1H),7.94(d,1H),7.72-7.61(m,2H),7.54(dd,1H) ,7.47-7.34(m,4H),7.21(br,1H),6.01(s,1H),4.12(br,1H),3.92-3.71(m,2H),3.50(s,3H),3.44-3.39 (m,2H),3.10(br,1H),2.75(dd,2H),2.37-2.23(m,1H),2.06-1.94(m,2H),1.58-1.47(m,2H).

Example 20 Compound 4-(2-bromo-4-fluorophenyl)-6-((2-(3-(cyclopropylamino)-3-oxopropyl)morpholino)methyl)-2- Synthesis of (thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid methyl ester

Step 1) Synthesis of compound 2-(3-(cyclopropylamine)-3-oxopropyl) morpholine-4-formic acid tert-butyl ester

3-(4-(tert-butoxycarbonyl)morpholin-2-yl)propionic acid (1.3g, 5mmol), cyclopropylamine (0.34g, 6mmol), EDCI (1.15g, 6mmol), HOAT (0.82g, 6mmol), triethylamine (0.61g, 6mmol) and DCM (26mL) were implemented according to the method described in Example 3 to obtain a colorless oil (1.04g, 70%).

MS(ESI,pos.ion)m/z:243.2[M+H] ⁺ .

Step 2) Synthesis of compound N-cyclopropyl-3-(morpholin-2-yl) propionamide hydrochloride

2-(3-(cyclopropylamine)-3-oxopropyl)morpholine-4-carboxylic acid tert-butyl ester (1g, 3.4mmol), hydrogen chloride ethyl acetate solution (4mol/L, 5mL) according to Example 17 The method described in step 3 was carried out to obtain a white solid (0.61 g, 76%).

MS(ESI,pos.ion)m/z:199.1[M+H] ⁺ ;

Step 3) Compound 4-(2-bromo-4-fluorophenyl)-6-((2-(3-(cyclopropylamino)-3-oxopropyl)morpholino)methyl)-2- Synthesis of (thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid methyl ester

4-(2-Bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid methyl ester (0.29g, 0.6mmol), N-cyclopropyl-3-(morpholin-2-yl) propionamide hydrochloride (0.14g, 0.6mmol), potassium carbonate (83mg, 0.6mmol) and absolute ethanol (6mL) according to implementation The method described in step 3 of Example 1 was carried out to obtain a pale yellow solid (0.14 g, 38%).

MS(ESI,pos.ion)m/z:606.2[M+H] ⁺ ;

¹ H NMR (400MHz,DMSO-d ₆ ):δ9.68(s,1H),8.01(d,1H),7.95(d,1H),7.91(s,1H),7.55(dd,1H),7.40 (dd,1H),7.21(td,1H),6.00(s,1H),3.96-3.91(m,1H),3.88(br,2H),3.63-3.54(m,2H),3.51(s,3H ),2.74(dd,2H),2.55(s,1H),2.33(t,1H),2.13-1.93(m,3H),1.59(dd,2H),0.55(d,2H),0.33(s, 2H).

Example 21 Compound (R)-4-(2-bromo-4-fluorophenyl)-6-(((R)-2-(3-(cyclopropylamino)-3-oxopropyl)morpholine Synthesis of methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid methyl ester (0.27g, 0.6mmol), N-cyclopropyl-3-(morpholin-2-yl) propionamide hydrochloride (0.14g, 0.6mmol), potassium carbonate (83mg, 0.6mmol) and absolute ethanol (6mL) according to implementation The method described in step 3 of Example 1 was carried out to obtain a pale yellow solid (0.11 g, 32%).

MS(ESI,pos.ion)m/z:562.16[M+H] ⁺ ;

¹ H NMR(400MHz,DMSO-d ₆ ):δ9.68(s,1H),8.01(d,1H),7.95(d,1H),7.91(s,1H),7.48-7.40(m,2H) ,7.18(td,1H),6.01(s,1H),3.97-3.91(m,1H),3.86(br,2H),3.65-3.54(m,2H),3.52(s,3H),2.76(dd ,2H),2.54(s,1H),2.35(t,1H),2.15-1.93(m,3H),1.58(dd,2H),0.56(d,2H),0.36(s,2H).

Example 22 compound 6-((2-(3-(cyclopropylamino)-3-oxopropyl)morpholino)methyl)-4-(2,4-dichlorophenyl)-2-( Synthesis of Methyl Thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

Methyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.28g, 0.6 mmol), N-cyclopropyl-3-(morpholin-2-yl) propionamide hydrochloride (0.14g, 0.6mmol), potassium carbonate (83mg, 0.6mmol) and absolute ethanol (6mL) according to the example 1. The method described in step 3 was carried out to obtain a light yellow solid (0.1 g, 30%).

MS(ESI,pos.ion)m/z:578.13[M+H] ⁺ ;

¹ H NMR(400MHz,DMSO-d ₆ ):δ9.64(s,1H),8.03(d,1H),7.96(d,1H),7.92(s,1H),7.60(br,1H),7.42 (br,2H)6.03(s,1H),3.98-3.91(m,1H),3.85(br,2H),3.65-3.53(m,2H),3.50(s,3H),2.73(dd,2H) ,2.56(s,1H),2.37(t,1H),2.16-1.93(m,3H),1.59(dd,2H),0.58(d,2H),0.35(s,2H).

Example 23 Compound 4-(2-bromo-4-fluorophenyl)-6-((2-(3-(cyclopropylsulfonamido)-3-oxopropyl)morpholino)methyl)- Synthesis of ethyl 2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

Step 1) Synthesis of compound 2-(3-(cyclopropylsulfonamido)-3-oxo)morpholine-4-carboxylic acid tert-butyl ester

3-(4-(tert-butoxycarbonyl)morpholin-2-yl)propionic acid (0.52g, 2mmol), cyclopropanesulfonamide (0.24g, 2mmol), CDI (0.49g, 3mmol), THF (10mL ) and DBU (0.46g, 3mmol) were implemented according to the method described in step 1 of Example 1 to obtain a colorless oil (0.33g, 45%).

MS(ESI,pos.ion)m/z:307.2[M+H-100] ⁺ .

Step 2) Synthesis of compound N-(cyclopropylsulfonyl)-3-(morpholin-2-yl) propanamide hydrochloride

Add tert-butyl 2-(3-(cyclopropylsulfonamido)-3-oxopropyl)morpholine-4-carboxylate (0.33g, 0.91mmol) and ethyl hydrogen chloride solution (4mol /L, 2mL), react at 25°C for 4 hours, and filter to obtain a white solid (0.22g, 80%).

MS(ESI,pos.ion)m/z:263.1[M+H] ⁺ .

Step 3) compound 4-(2-bromo-4-fluorophenyl)-6-((2-(3-(cyclopropylsulfonamido)-3-oxopropyl)morpholino)methyl)- Synthesis of ethyl 2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

4-(2-Bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (0.3g, 0.6mmol), N-(cyclopropanesulfonyl)-3-(morpholin-2-yl)propionamide hydrochloride (0.18g, 0.6mmol), potassium carbonate (83mg, 0.6mmol) and absolute ethanol (6mL ) according to the method described in step 3 of Example 1 to obtain a light yellow solid (0.12g, 29%).

MS(ESI,pos.ion)m/z:684.2[M+H] ⁺ ;

¹ H NMR (400MHz,DMSO-d ₆ ):δ9.68(s,1H),8.01(d,1H),7.93(d,1H),7.55(dd,1H),7.37(dd,1H),7.21 (td,1H),6.00(s,1H),4.01-3.85(m,4H),3.59-3.43(m,3H),2.82-2.73(m,2H),2.63-2.55(m,1H),2.35 -2.25(m,1H),2.06-1.95(m,3H),1.68-1.55(m,2H),1.04(t,3H),0.76-0.69(m,2H),0.65-0.55(m,2H) .

Example 24 compound 4-(2-chloro-4-fluorophenyl)-6-((2-(3-(cyclopropylsulfonamido)-3-oxopropyl)morpholino)methyl)- Synthesis of ethyl 2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydro(pyrimidine-5-carboxylic acid ethyl ester (0.28g , 0.6mmol), N-(cyclopropanesulfonyl)-3-(morpholin-2-yl)propionamide hydrochloride (0.18g, 0.6mmol), potassium carbonate (83mg, 0.6mmol) and absolute ethanol ( 6 mL) according to the method described in step 3 of Example 1 to obtain a light yellow solid (0.17 g, 45%).

MS(ESI,pos.ion)m/z:640.1[M+H] ⁺ ;

¹ H NMR(400MHz,DMSO-d ₆ ):δ9.81(s,1H),8.04(d,1H),7.96(d,1H),7.47-7.37(m,2H),7.16(td,1H) ,6.02(s,1H),4.03-3.85(m,4H),3.61-3.43(m,3H),2.82-2.73(m,2H),2.65-2.55(m,1H),2.33-2.25(m, 1H),2.03-1.95(m,3H),1.65-1.55(m,2H),1.03(t,3H),0.73-0.69(m,2H),0.63-0.55(m,2H).

Example 25 compound 6-(((2-(3-(cyclopropylsulfonamido)-3-oxopropyl)morpholino)methyl)-4-(2,4-dichlorophenyl)- Synthesis of ethyl 2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (0.29g, 0.6 mmol), N-(cyclopropylsulfonyl)-3-(morpholin-2-yl)propionamide hydrochloride (0.18g, 0.6mmol), potassium carbonate (83mg, 0.6mmol) and absolute ethanol (6mL) The method described in step 3 of Example 1 was carried out to obtain a light yellow solid (0.14 g, 36%).

MS(ESI,pos.ion)m/z:656.1[M+H] ⁺ ;

¹ H NMR (400MHz,DMSO-d ₆ ):δ9.68(s,1H),8.02(d,1H),7.98(d,1H),7.58(br,1H),7.40(br,2H),6.04 (s,1H),4.02-3.83(m,4H),3.61-3.44(m,3H),2.83-2.74(m,2H),2.66-2.57(m,1H),2.35-2.26(m,1H) ,2.04-1.94(m,3H),1.66-1.57(m,2H),1.02(t,3H),0.72-0.68(m,2H),0.64-0.56(m,2H).

Embodiment 26: Use HBV HepG2.2.15 cell line to carry out in vitro anti-HBV pharmacodynamic activity assay experiment

1. Experimental method:

qPCR detects the virus DNA content in the cell culture solution and calculates the concentration (EC ₅₀ ) of the compound when half of the virus is inhibited. The specific experimental method is as follows:

Inoculate HepG2.2.15 cells into a 96-well cell culture plate (40,000 cells/well), and add cell culture medium containing different concentrations of the compound to be tested the next day to treat the cells (the highest final concentration of the compound is 16.4 μM, 3-fold serial dilution, 9 Dilution points, duplicate wells). On the fifth day, the culture medium containing the drug to be tested was replaced, and on the eighth day, the culture supernatant was collected and the DNA in the supernatant was extracted.

Viral DNA extraction: refer to QIAamp 96DNA Blood Kit (QIAGEN 51161).

Quantitative PCR: configure the reaction mixture according to the PCR system, and add the mixture to a 96-well PCR reaction plate (for quantitative purposes); add a proportionally diluted standard template (the highest concentration of the standard template is 1× ¹⁰⁷ copy number/μl, 9-fold dilution with 7 points, the minimum concentration is 10 copies/μl); add sample template; seal the 96-well plate with sealing film; run the quantitative PCR instrument according to the set program.

Calculation of the percentage inhibition of HBV replication by the compound: %Inh.=[1-plus compound treated HBV DNA amount/DMSO control treated HBV DNA amount]×100.

Calculate the EC ₅₀ value of the compound on HBV replication: use the GraphPad Prism 5 analysis software, and select the "four-parameter logistic equation" to calculate the EC ₅₀ value.

2. Experimental results: see Table 2

Table 2: Anti-HBV activity of compounds in HBV HepG2.2.15 cell line

Example _EC50 (μmol) Example _EC50 (μmol) Example 1 1.0 Example 11 0.92 Example 2 2.302 Example 12 0.72 Example 3 0.1295 Example 13 1.4

Example 4 0.7 Example 14 0.54 Example 5 0.8 Example 15 0.67 Example 6 0.65 Example 16 0.49 Example 7 0.67 Example 17 0.65 Example 8 0.89 Example 18 0.74 Example 9 0.54 Example 19 0.56 Example 10 0.8

3. Conclusion:

The compound of the present invention shows strong anti-HBV virus effect. These compounds have unexpected antiviral activity against HBV, and are therefore suitable for treating various diseases caused by HBV virus infection.

Although, the present invention has been described in detail with general description, specific implementation and test above, but on the basis of the present invention, some modifications or improvements can be made to it, which will be obvious to those skilled in the art . Therefore, the modifications or improvements made on the basis of not departing from the spirit of the present invention all belong to the protection scope of the present invention.

Claims (14)

1. A compound which is a compound represented by formula (I) or (Ia) or an enantiomer, diastereomer, tautomer, hydrate, solvate, prodrug, stereoisomer, nitrogen oxide or a pharmaceutically acceptable salt of the compound represented by formula (I) or (Ia),

wherein A is a bond, -O-, -S-or-N (R)⁴)-；

R is the following subformula:

R¹is C_6-10Aryl or C_1-9A heteroaryl group;

R³is C_6-10Aryl or C_1-9A heteroaryl group;

each R²And R⁴Independently is hydrogen or C_1-4An alkyl group;

each R⁵And R^5aIndependently hydrogen or alkyl;

each R^5bIndependently F, Cl, Br, hydroxy or haloalkyl;

each R⁶Independently is- (CR)⁷R^7a)_m-C(＝O)O-R^8aOr C_1-4An alkyl group;

each R⁹Independently is-S (═ O)_qOR^8a、-(CR⁷R^7a)_m-S(＝O)_qN(R^8a)₂Triazolyl, - (CR)⁷R^7a)_m-C(＝O)O-R⁸、-(CR⁷R^7a)_m-C(＝O)O-(CR⁷R^7a)_m-OC(＝O)O-R⁸、-(CR⁷R^7a)_m-C(＝O)O-(CR⁷R^7a)_m-OC(＝O)-R⁸、-(CR⁷R^7a)t-N(R^8a)₂、-(CR⁷R^7a)_m-C(＝O)O-(CR⁷R^7a)_m-C(＝O)O-R⁸、-(CR⁷R^7a)_t-OC(＝O)-R⁸、-(CR⁷R^7a)_m-C(＝O)N(R⁸)₂Or- (CR)⁷R^7a)_m-C(＝O)NHR⁸；

Each R^9aIndependently is- (CR)⁷R^7a)_m-OH, triazolyl, tetrazolyl, - (CR)⁷R^7a)_m-C(＝O)O-R^8a、-(CR⁷R^7a)_m-S(＝O)_qN(R^8a)₂、-(CR⁷R^7a)_m-OC(＝O)-R^8a、-(CR⁷R^7a)_m-N(R^8a)₂、-S(＝O)_qOR^8a、-(CR⁷R^7a)_m-C(＝O)O-(CR⁷R^7a)_m-OC(＝O)O-R^8a、-(CR⁷R^7a)_m-C(＝O)O-(CR⁷R^7a)_m-OC(＝O)-R^8a、-(CR⁷R^7a)_m-C(＝O)O-(CR⁷R^7a)_m-C(＝O)O-R^8aOr- (CR)⁷R^7a)_m-C(＝O)N(R^8a)₂；

Each R⁷And R^7aIndependently hydrogen, haloalkyl or alkyl;

each R^8aIndependently hydrogen, alkyl, alkoxy, alkyl-S (═ O)_q-, aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, heterocyclyl-S (═ O)_q-, heteroaryl-S (═ O)_q-, cycloalkyl-S (═ O)_q-or aryl-S (═ O)_q-；

Each R⁸Independently is alkyl-S (═ O)_q-, aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, heterocyclyl-S (═ O)_q-, heteroaryl-S (═ O)_q-, cycloalkyl-S (═ O)_q-or aryl-S (═ O)_q-；

Each n is independently 1,2 or 3;

each t is independently 1,2, 3 or 4;

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

each q is independently 0, 1 or 2;

wherein R is¹、R²、R³、R⁴、R⁵、R^5a、R^5b、R⁶、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aAlkoxy, aryl, C as defined in_6-10Aryl, heteroaryl, C_1-9Heteroaryl, alkyl, C_1-4Alkyl, alkyl-S (═ O)_q-, heterocyclyl-S (═ O)_q-, heteroaryl-S (═ O)_q-, cycloalkyl-S (═ O)_q-, aryl-S (═ O)_q-, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, tetrazolyl, triazolyl, haloalkyl, and cycloalkyl may optionally be substituted with hydrogen, fluorine, chlorine, bromine, iodine, oxo (═ O), methylene (═ CH)₂) Alkyl, alkoxy, cyano, hydroxyl, nitro, alkylamino, amino, aryl, heteroaryl, heterocyclyl, cycloalkyl, trifluoromethyl, trifluoromethoxy, haloalkyl-substituted aryl, halogen-substituted aryl or trifluoromethanesulfonyl, in a single or in the same or in different polysubstitution.

2. The compound of claim 1, wherein,

r is the following subformula:

each R⁵And R^5aIndependently is hydrogen or C_1-4An alkyl group;

each R^5bIndependently is F, Cl, Br, hydroxy or C_1-4A haloalkyl group;

each R⁶Independently is- (CR)⁷R^7a)_m-C(＝O)O-R^8aOr C_1-4An alkyl group;

each R⁹Independently is-S (═ O)_qOR^8a、-(CR⁷R^7a)_m-S(＝O)_qN(R^8a)₂Triazolyl, - (CR)⁷R^7a)_m-C(＝O)O-R⁸、-(CR⁷R^7a)_m-C(＝O)O-(CR⁷R^7a)_m-OC(＝O)O-R⁸、-(CR⁷R^7a)_m-C(＝O)O-(CR⁷R^7a)_m-OC(＝O)-R⁸、-(CR⁷R^7a)_t-N(R^8a)₂、-(CR⁷R^7a)_m-C(＝O)O-(CR⁷R^7a)_m-C(＝O)O-R⁸、-(CR⁷R^7a)_t-OC(＝O)-R⁸、-(CR⁷R^7a)_m-C(＝O)N(R⁸)₂Or- (CR)⁷R^7a)_m-C(＝O)NHR⁸；

Each R^9aIndependently is- (CR)⁷R^7a)_m-OH, triazolyl, tetrazolyl, - (CR)⁷R^7a)_m-C(＝O)O-R^8a、-(CR⁷R^7a)_m-S(＝O)_qN(R^8a)₂、-(CR⁷R^7a)_m-OC(＝O)-R^8a、-(CR⁷R^7a)_m-N(R^8a)₂、-S(＝O)_qOR^8a、-(CR⁷R^7a)_m-C(＝O)O-(CR⁷R^7a)_m-OC(＝O)O-R^8a、-(CR⁷R^7a)_m-C(＝O)O-(CR⁷R^7a)_m-OC(＝O)-R^8a、-(CR⁷R^7a)_m-C(＝O)O-(CR⁷R^7a)_m-C(＝O)O-R^8aOr- (CR)⁷R^7a)_m-C(＝O)N(R^8a)₂；

Each R⁷And R^7aIndependently of one another is hydrogen, C_1-4Haloalkyl or C_1-4An alkyl group;

each R^8aIndependently of one another is hydrogen, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6alkyl-S (═ O)_q-、C_6-10Aryl radical, C_1-9Heteroaryl group, C_3-6Cycloalkyl radical, C_2-9Heterocyclic group, C_6-10Aryl radical C_1-6Alkyl radical, C_1-9Heteroaryl C_1-6Alkyl radical, C_3-6Cycloalkyl radical C_1-4Alkyl radical, C_2-9Heterocyclyl radical C_1-6Alkyl radical, C_2-9heterocyclyl-S (═ O)_q-、C_1-9heteroaryl-S (═ O)_q-、C_3-6cycloalkyl-S (═ O)_q-or C_6-10aryl-S (═ O)_q-；

Each R⁸Independently is C_1-6alkyl-S (═ O)_q-、C_6-10Aryl radical, C_1-9Heteroaryl group, C_3-6Cycloalkyl radical, C_2-9Heterocyclic group, C_6-10Aryl radical C_1-6Alkyl radical, C_1-9Heteroaryl C_1-6Alkyl radical, C_3-6Cycloalkyl radical C_1-4Alkyl radical, C_2-9Heterocyclyl radical C_1-6Alkyl radical, C_2-9heterocyclyl-S (═ O)_q-、C_1-9heteroaryl-S (═ O)_q-、C_3-6cycloalkyl-S (═ O)_q-or C_6-10aryl-S (═ O)_q-；

Wherein R is⁵、R^5a、R^5b、R⁶、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aC as described in (1)_1-6Alkoxy radical, C_6-10Aryl radical, C_1-9Heteroaryl group, C_1-4Alkyl radical, C_1-6Alkyl radical, C_1-4Haloalkyl, C_1-6alkyl-S (═ O)_q-、C_2-9heterocyclyl-S (═ O)_q-、C_1-9heteroaryl-S (═ O)_q-、C_3-6cycloalkyl-S (═ O)_q-、C_6-10aryl-S (═ O)_q-、C_2-9Heterocyclic group, C_6-10Aryl radical C_1-6Alkyl radical, C_1-9Heteroaryl C_1-6Alkyl radical, C_3-6Cycloalkyl radical C_1-4Alkyl radical, C_2-9Heterocyclyl radical C_1-6Alkyl, tetrazolyl, triazolyl and C_3-6Cycloalkyl groups may optionally be substituted by hydrogen, fluoro, chloro, bromo, iodo, oxo (═ O), methylene (═ CH)₂) Alkyl, alkoxy, cyano, hydroxyl, nitro, alkylamino, amino, aryl, heteroaryl, heterocyclyl, cycloalkyl, trifluoromethyl, trifluoromethoxy, haloalkyl-substituted aryl, halogen-substituted aryl or trifluoromethanesulfonyl, in a single or in the same or in different polysubstitution.

3. The compound of claim 2, wherein,

r is the following subformula:

each R⁵And R^5aIndependently hydrogen, methyl, ethyl or propyl;

each R^5bIndependently F, Cl, Br, hydroxy or trifluoromethyl;

each R⁶Independently is- (CR)⁷R^7a)_m-C(＝O)O-R^8aMethyl, ethyl or propyl;

each R⁹Independently triazolyl, -S (═ O)_qOR^8a、-(CR⁷R^7a)_t-N(R^8a)₂、-(CR⁷R^7a)_m-C(＝O)O-R⁸、-(CR⁷R^7a)_m-C(＝O)O-(CR⁷R^7a)_m-OC(＝O)O-R⁸、-(CR⁷R^7a)_m-S(＝O)_qN(R^8a)₂、-(CR⁷R^7a)_m-C(＝O)O-(CR⁷R^7a)_m-OC(＝O)-R⁸、-(CR⁷R^7a)_m-C(＝O)O-(CR⁷R^7a)_m-C(＝O)O-R⁸、-(CR⁷R^7a)_t-OC(＝O)-R⁸、-(CR⁷R^7a)_m-C(＝O)N(R⁸)₂Or- (CR)⁷R^7a)_m-C(＝O)NHR⁸；

Each R^9aIndependently is- (CR)⁷R^7a)_m-OH, triazolyl, tetrazolyl, - (CR)⁷R^7a)_m-C(＝O)O-R^8a、-(CR⁷R^7a)_m-S(＝O)_qN(R^8a)₂、-(CR⁷R^7a)_m-OC(＝O)-R^8a、-(CR⁷R^7a)_m-N(R^8a)₂、-S(＝O)_qOR^8a、-(CR⁷R^7a)_m-C(＝O)O-(CR⁷R^7a)_m-OC(＝O)O-R^8a、-(CR⁷R^7a)_m-C(＝O)O-(CR⁷R^7a)_m-OC(＝O)-R^8a、-(CR⁷R^7a)_m-C(＝O)O-(CR⁷R^7a)_m-C(＝O)O-R^8aOr- (CR)⁷R^7a)_m-C(＝O)N(R^8a)₂；

Each R⁷And R^7aIndependently hydrogen, trifluoromethyl, methyl, ethyl or propyl;

each R^8aIndependently of one another is hydrogen, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4alkyl-S (═ O)_q-, phenyl, pyridyl, thiazolyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, oxadiazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl, triazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-S (═ O)₂-, cyclobutyl-S (═ O)₂-, cyclopentyl-S (═ O)₂-, cyclohexyl-S (═ O)₂-, naphthyl-S (═ O)₂-or phenyl-S (═ O)₂-；

Each R⁸Independently is C_1-4alkyl-S (═ O)_q-, phenyl, pyridyl, thiazolyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, oxadiazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl, triazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-S (═ O)₂-, cyclobutyl-S (═ O)₂-, cyclopentyl-S (═ O)₂-, cyclohexyl-S (═ O)₂-, naphthyl-S (═ O)₂-or phenyl-S (═ O)₂-。

4. The compound of claim 1, wherein:

R¹is phenyl;

R³is 1-methyl-1H-imidazolyl, pyridyl, phenyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl or triazinyl;

each R²And R⁴Independently hydrogen, methyl or ethyl;

wherein R is¹、R²、R³And R⁴The thiazolyl, 1-methyl-1H-imidazolyl, pyridyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl, triazinyl, phenyl, methyl and ethyl group described in (1) may be optionally substituted with hydrogen, C_1-4Alkyl, fluorine, chlorine or bromine are monosubstituted or polysubstituted in an identical or different manner.

5. The compound of claim 1, which is a compound of formula (II) or (IIa) or an enantiomer, diastereomer, tautomer, hydrate, solvate, prodrug, stereoisomer, nitrogen oxide, or a pharmaceutically acceptable salt of a compound of formula (II) or (IIa),

wherein R is²Is hydrogen or C_1-4An alkyl group;

R³is 1-methyl-1H-imidazolyl, pyridyl, phenyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl or triazinyl;

r is the following subformula:

each R⁵And R^5aIndependently is hydrogen or C_1-4An alkyl group;

each R^5bIndependently is F, Cl, Br, hydroxy or C_1-4A haloalkyl group;

each R⁶Independently is- (CR)⁷R^7a)_m-C(＝O)O-R^8aOr C_1-4An alkyl group;

each R⁹Independently triazolyl, -S (═ O)_qOR^8a、-(CR⁷R^7a)_m-S(＝O)_qN(R^8a)₂、-(CR⁷R^7a)_m-C(＝O)O-R⁸、-(CR⁷R^7a)_m-C(＝O)O-(CR⁷R^7a)_m-OC(＝O)O-R⁸、-(CR⁷R^7a)_m-C(＝O)O-(CR⁷R^7a)_m-OC(＝O)-R⁸、-(CR⁷R^7a)_t-N(R^8a)₂、-(CR⁷R^7a)_m-C(＝O)O-(CR⁷R^7a)_m-C(＝O)O-R⁸、-(CR⁷R^7a)_t-OC(＝O)-R⁸、-(CR⁷R^7a)_m-C(＝O)N(R⁸)₂Or- (CR)⁷R^7a)_m-C(＝O)NHR⁸；

Each R^9aIndependently is- (CR)⁷R^7a)_m-OH, triazolyl, tetrazolyl, - (CR)⁷R^7a)_m-C(＝O)O-R^8a、-(CR⁷R^7a)_m-S(＝O)_qN(R^8a)₂、-(CR⁷R^7a)_m-OC(＝O)-R^8a、-(CR⁷R^7a)_m-N(R^8a)₂、-S(＝O)_qOR^8a、-(CR⁷R^7a)_m-C(＝O)O-(CR⁷R^7a)_m-OC(＝O)O-R^8a、-(CR⁷R^7a)_m-C(＝O)O-(CR⁷R^7a)_m-OC(＝O)-R^8a、-(CR⁷R^7a)_m-C(＝O)O-(CR⁷R^7a)_m-C(＝O)O-R^8aOr- (CR)⁷R^7a)_m-C(＝O)N(R^8a)₂；

Each R⁷And R^7aIndependently of one another is hydrogen, C_1-4Haloalkyl or C_1-4An alkyl group;

each R^8aIndependently of one another is hydrogen, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6alkyl-S (═ O)_q-、C_6-10Aryl radical, C_1-9Heteroaryl group, C_3-6Cycloalkyl radical, C_2-9Heterocyclic group, C_6-10Aryl radical C_1-6Alkyl radical, C_1-9Heteroaryl C_1-6Alkyl radical, C_3-6Cycloalkyl radical C_1-4Alkyl radical, C_2-9Heterocyclyl radical C_1-6Alkyl radical, C_2-9heterocyclyl-S (═ O)_q-、C_1-9heteroaryl-S (═ O)_q-、C_3-6cycloalkyl-S (═ O)_q-or C_6-10aryl-S (═ O)_q-；

Each R⁸Independently is C_1-6alkyl-S (═ O)_q-、C_6-10Aryl radical, C_1-9Heteroaryl group, C_3-6Cycloalkyl radical, C_2-9Heterocyclic group, C_6-10Aryl radical C_1-6Alkyl radical, C_1-9Heteroaryl C_1-6Alkyl radical, C_3-6Cycloalkyl radical C_1-4Alkyl radical, C_2-9Heterocyclyl radical C_1-6Alkyl radical, C_2-9heterocyclyl-S (═ O)_q-、C_1-9heteroaryl-S (═ O)_q-、C_3-6cycloalkyl-S (═ O)_q-or C_6-10aryl-S (═ O)_q-；

Each R¹⁰Independently hydrogen, fluorine, chlorine or bromine;

each n is independently 1,2 or 3;

each t is independently 1,2, 3 or 4;

each q is independently 0, 1 or 2;

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

wherein,R²、R³、R⁵、R^5a、R^5b、R⁶、R⁷、R^7a、R⁸、R^8a、R⁹and R^9aC as described in (1)_1-6Alkoxy radical, C_6-10Aryl radical, C_1-9Heteroaryl group, C_1-4Alkyl radical, C_1-6Alkyl radical, C_1-4Haloalkyl, C_1-6alkyl-S (═ O)_q-、C_2-9heterocyclyl-S (═ O)_q-、C_1-9heteroaryl-S (═ O)_q-、C_3-6cycloalkyl-S (═ O)_q-、C_6-10aryl-S (═ O)_q-、C_2-9Heterocyclic group, C_6-10Aryl radical C_1-6Alkyl radical, C_1-9Heteroaryl C_1-6Alkyl radical, C_3-6Cycloalkyl radical C_1-4Alkyl radical, C_2-9Heterocyclyl radical C_1-6Alkyl, tetrazolyl, triazolyl, 1-methyl-1H-imidazolyl, pyridyl, phenyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, oxadiazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl, triazinyl and C_3-6Cycloalkyl groups may optionally be substituted by hydrogen, fluoro, chloro, bromo, iodo, oxo (═ O), methylene (═ CH)₂) Alkyl, alkoxy, cyano, hydroxyl, nitro, alkylamino, amino, aryl, heteroaryl, heterocyclyl, cycloalkyl, trifluoromethyl, trifluoromethoxy, haloalkyl-substituted aryl, halogen-substituted aryl or trifluoromethanesulfonyl, in a single or in the same or in different polysubstitution.

6. The compound of claim 1 or 5, wherein:

r is the following subformula:

each R⁵And R^5aIndependently hydrogen, methyl, ethyl or propyl;

each R^5bIndependent of each otherGround is F, Cl, Br, hydroxy or trifluoromethyl;

each R⁶Independently is- (CR)⁷R^7a)_m-C(＝O)O-R^8aMethyl, ethyl or propyl;

each R⁹Independently triazolyl, -S (═ O)_qOR^8a、-(CR⁷R^7a)_m-S(＝O)_qN(R^8a)₂、-(CR⁷R^7a)_m-C(＝O)O-R⁸、-(CR⁷R^7a)_m-C(＝O)O-(CR⁷R^7a)_m-OC(＝O)O-R⁸、-(CR⁷R^7a)_m-C(＝O)O-(CR⁷R^7a)_m-OC(＝O)-R⁸、-(CR⁷R^7a)_t-N(R^8a)₂、-(CR⁷R^7a)_m-C(＝O)O-(CR⁷R^7a)_m-C(＝O)O-R⁸、-(CR⁷R^7a)_t-OC(＝O)-R⁸、-(CR⁷R^7a)_m-C(＝O)N(R⁸)₂Or- (CR)⁷R^7a)_m-C(＝O)NHR⁸；

Each R^9aIndependently is- (CR)⁷R^7a)_m-OH, triazolyl, tetrazolyl, - (CR)⁷R^7a)_m-C(＝O)O-R^8a、-(CR⁷R^7a)_m-S(＝O)_qN(R^8a)₂、-(CR⁷R^7a)_m-OC(＝O)-R^8a、-(CR⁷R^7a)_m-N(R^8a)₂、-S(＝O)_qOR^8a、-(CR⁷R^7a)_m-C(＝O)O-(CR⁷R^7a)_m-OC(＝O)O-R^8a、-(CR⁷R^7a)_m-C(＝O)O-(CR⁷R^7a)_m-OC(＝O)-R^8a、-(CR⁷R^7a)_m-C(＝O)O-(CR⁷R^7a)_m-C(＝O)O-R^8aOr- (CR)⁷R^7a)_m-C(＝O)N(R^8a)₂；

Each R⁷And R^7aIndependently hydrogen, trifluoromethyl, methyl, ethyl or propyl;

each R^8aIndependently of one another is hydrogen, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4alkyl-S (═ O)_q-, phenyl, pyridyl, thiazolyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, oxadiazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl, triazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-S (═ O)₂-, cyclobutyl-S (═ O)₂-, cyclopentyl-S (═ O)₂-, cyclohexyl-S (═ O)₂-, naphthyl-S (═ O)₂-or phenyl-S (═ O)₂-；

Each R⁸Independently is C_1-4alkyl-S (═ O)₂-, phenyl, pyridyl, thiazolyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, oxadiazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl, triazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-S (═ O)₂-, cyclobutyl-S (═ O)₂-, cyclopentyl-S (═ O)₂-, cyclohexyl-S (═ O)₂-, naphthyl-S (═ O)₂-or phenyl-S (═ O)₂-。

7. The compound of claim 1, comprising a structure of one of the following or an enantiomer, diastereomer, tautomer, hydrate, solvate, prodrug, stereoisomer, nitrogen oxide, or a pharmaceutically acceptable salt of one of the following:

8. a pharmaceutical composition comprising a compound of any one of claims 1-7, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof.

9. The pharmaceutical composition of claim 8, further comprising an anti-HBV drug.

10. The pharmaceutical composition of claim 9, wherein the anti-HBV agent is an HBV polymerase inhibitor, an immunomodulator, or an interferon.

11. The pharmaceutical composition according to claim 9, wherein the anti-HBV agent is at least one selected from lamivudine, telbivudine, tenofovir disoproxil, entecavir, adefovir dipivoxil, alfafenone, Alloferon, simon interleukin, cladribine, emtricitabine, faplovir, interferon, calamine CP, intefine, interferon alpha-1 b, interferon alpha-2 a, interferon beta-1 a, interferon alpha-2, interleukin-2, mefenate, nitazoxanide, peginterferon alpha-2 a, ribavirin, roscovitine-a, cizopyran, Euforavac, azapril, Phosphazid, heplisv, interferon alpha-2 b, levamisole, and propagum.

12. Use of a compound according to any one of claims 1 to 7 or a pharmaceutical composition according to any one of claims 8 to 11 in the manufacture of a medicament for the prevention, treatment or alleviation of a viral disease in a patient.

13. The use of claim 12, wherein the viral disease is hepatitis b infection or a disease caused by hepatitis b infection.

14. The use of claim 13, wherein the disease caused by hepatitis B infection is liver cirrhosis or hepatocellular carcinoma.