Carboxyl-containing tri-heterocyclic derivative and application thereof in medicine

Abstract

The invention relates to a carboxyl-containing tri-heterocyclic derivative and an application thereof in medicine, in particular to a compound shown in a general formula (I), (II) or (IIa) or a racemate, a stereoisomer, a tautomer and pharmaceutically acceptable salt thereof, an intermediate and a preparation method thereof, and an application in preparation of medicines for treating PI3Kalpha-related diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a compound of general formula (I) or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt, as well as its intermediates and preparation methods, and its application in the preparation of drugs for treating diseases related to PI3Kα inhibitors. Background Art

[0002] Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that regulates cell proliferation, survival, and migration after activation by growth factor receptors and integrins. Up to 70% of breast cancers have molecular mutations in some form of the PI3K-AKT-mTOR pathway. Activation of PIK3CA (encoding the p110α subunit of PI3K) mutations is very common in breast cancer and solid tumor malignancies.

[0003] WT PI3Kα plays a central role in regulating the body's glucose homeostasis. PBK inhibition in patients usually leads to hyperglycemia and / or hyperinsulinemia (Busaidy NL, et al, Management of metabolic effects associated with anticancer agents targeting the PBK-Akt-mTOR pathway. J Clin Oncol 2012; 30: 2919-28). In the case of cancers with mutant PI3Kα, the development of selective inhibitors for mutant PI3Kα can effectively overcome the compensatory problems of insulin and / or glucose caused by WT PI3Kα inhibition, which can increase the drug dosing window, thereby selectively inhibiting the pathological signals of mutant PI3Kα in cancer cells without affecting the WT PI3Ka of the host itself.

[0004] The current development of PI3Kα inhibitors focuses on the active or orthosteric site, which has the same effect on wild-type and mutant PI3Kα. Its efficacy is limited by the toxicity mediated by targeting WT PI3Kα, including dose limitation, hyperglycemia, and / or hyperinsulinemia, etc. Since the mutation position of PI3Kα is far from the active site, mutant-selective inhibitors have been difficult to obtain. Inhibitors targeting the second peripheral binding pocket near known mutations (such as H1047R) are expected to become the targets for the research and development of new anticancer drugs. Summary of the Invention

[0005] The object of the present invention is to provide a compound capable of inhibiting a target protein or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt, as well as its intermediates and preparation methods, and its application in the preparation of drugs for treating diseases related to PI3Kα inhibitors.

[0006] The compounds of the present invention are highly selective for PI3Kα H1047R, superior to WT PI3Kα and other PI3K isoforms, and do not cause hyperglycemic side effects.

[0007] The compounds of the present invention have good bioavailability.

[0008] The present invention provides a compound of general formula (I) or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt, wherein

[0009]

[0010] In certain embodiments, general formula (I) is selected from those shown in general formula (Ia),

[0011] The present invention also provides a compound of general formula (II) or its stereoisomer, tautomer, pharmaceutically acceptable salt, wherein

[0012]

[0013] The present invention provides a compound of general formula (IIa) or its stereoisomer, tautomer, pharmaceutically acceptable salt, wherein

[0014]

[0015] In certain embodiments, general formula (II) is selected from those shown in general formula (IIb),

[0016] In certain embodiments, X2 is selected from O, S;

[0017] In certain embodiments, X1 is selected from O, S, NR x , C(R x )2;

[0018] In certain embodiments, when X2 is selected from O, X1 is selected from O, S;

[0019] In certain embodiments, when X2 is selected from S, X1 is selected from O, S; in certain embodiments, when X2 is selected from O, X1 is selected from O;

[0020] In certain embodiments, Y is selected from O, S, NR y ;

[0021] In certain embodiments, Y is selected from O, S, NH;

[0022] In certain embodiments, is selected from

[0023] In certain embodiments, in general formula (II) or (IIa), selected from

[0024] In certain embodiments, in general formula (I) or (Ia), ring A is selected from 6-membered heteroaryl, and said ring A is optionally substituted with 1 to 4 substituents selected from R a ;

[0025] In certain embodiments, in general formula (I) or (Ia), ring A is selected from 6-membered nitrogen-containing heteroaryl, and said ring A is optionally substituted with 1 to 4 substituents selected from R a ;

[0026] In certain embodiments, in general formula (I) or (Ia), ring A is selected from one of the following structures optionally substituted with 1 to 4 R a : pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl;

[0027] In certain embodiments, in general formula (II) or (IIa) or (IIb) or (IIc), ring A is selected from 4-7-membered hetero monocycloalkyl, 5-12-membered hetero fused cycloalkyl, 5-12-membered hetero spirocycloalkyl, 7-10-membered hetero bridged cycloalkyl, C 3-8 monocycloalkyl, C 6-14 fused cycloalkyl, C 6-12 membered spirocycloalkyl, C 5-12 membered bridged cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and said ring A is optionally substituted with 1 to 4 substituents selected from R a ;

[0028] In certain embodiments, in general formula (II) or (IIa) or (IIb) or (IIc), ring A is selected from 4-7-membered hetero monocycloalkyl, 5-10-membered hetero fused cycloalkyl, 5-10-membered hetero spirocycloalkyl, 7-10-membered hetero bridged cycloalkyl, C 3-8 monocycloalkyl, C 6-10 fused cycloalkyl, C 6-10 membered spirocycloalkyl, C 5-10 membered bridged cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and said ring A is optionally substituted with 1 to 4 substituents selected from R a ;

[0029] In certain embodiments, in general formula (II) or (IIa) or (IIb) or (IIc), ring A is selected from one of the following structures optionally substituted with 1 to 4 R a : phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, pyrrolidinyl, piperidinyl, piperazinyl, bicyclo[1,1,1]pentyl, bicyclo[2,1,1]hexyl, bicyclo[2,2,1]heptyl;

[0030] In certain embodiments, ring A in formula (II) or (IIa) or (IIb) or (IIc) is selected from one of the following structures optionally substituted with 1 to 3 R a substituents:

[0031]

[0032] In certain embodiments, ring A in formula (II) or (IIa) or (IIb) or (IIc) is selected from one of the following structures:

[0033] In certain embodiments, ring A in formula (I) or (Ia) is selected from one of the following structures optionally substituted with 1 to 3 R a substituents: In certain embodiments, ring A in formula (I) or (Ia) is selected from one of the following structures:

[0034] In certain embodiments, R x , R y are each independently selected from H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-4 alkylene-C 3-10 carbocyclic group, -C 0-4 alkylene-4- to 10-membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 R k substituents;

[0035] In certain embodiments, R x , R y are each independently selected from H, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C 0-4 alkylene-C 3-8 carbocyclic group, -C 0-4 alkylene-4- to 8-membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 R k substituents;

[0036] In certain embodiments, R x , R yEach independently selected from H, deuterium, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and said methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl are optionally substituted by 1 to 4 R k substituted;

[0037] In certain embodiments, R 1 , R 2 each independently selected from H, deuterium, halogen, OH, CN, NO2, NH2, C 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl)2, -C 0-4 alkylene-C(=O)R 1a , -C 0-4 alkylene-S(=O)2R 1a , -C 0-4 alkylene-P(=O)R 1a R 1b , -O-C 0-4 alkylene-C 3-10 carbocyclic group, -O-C 0-4 alkylene-4 to 10-membered heterocyclic group, -S-C 0-4 alkylene-C 3-10 carbocyclic group, -S-C 0-4 alkylene-4 to 10-membered heterocyclic group, -NH-C 0-4 alkylene-C 3-10 carbocyclic group, -NH-C 0-4 alkylene-4 to 10-membered heterocyclic group, -C 0-4 alkylene-C 3-10 carbocyclic group, -C 0-4 alkylene-4 to 10-membered heterocyclic group, and said alkyl, alkenyl, alkynyl, alkylene, carbocyclic group or heterocyclic group are optionally substituted by 1 to 4 R k substituted;

[0038] In certain embodiments, R 1 , R 2 each independently selected from H, deuterium, halogen, OH, CN, NO2, NH2, C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, C 2-4Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -C 0-4 Alkylene-C(=O)R 1a , -C 0-4 Alkylene-S(=O)2R 1a , -C 0-4 Alkylene-P(=O)R 1a R 1b , -O-C 0-4 Alkylene-C 3-8 Carbocyclic group, -O-C 0-4 Alkylene-4- to 8-membered heterocyclic group, -S-C 0-4 Alkylene-C 3-8 Carbocyclic group, -S-C 0-4 Alkylene-4- to 8-membered heterocyclic group, -NH-C 0-4 Alkylene-C 3-8 Carbocyclic group, -NH-C 0-4 Alkylene-4- to 8-membered heterocyclic group, -C 0-4 Alkylene-C 3-8 Carbocyclic group, -C 0-4 Alkylene-4- to 8-membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k ;

[0039] In certain embodiments, R 1 , R 2 Each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NO2, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methylthio, -C(=O)R 1a , -S(=O)2R 1a , -P(=O)R 1a R 1b , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl is optionally substituted by 1 to 4 R k ;

[0040] In certain embodiments, R 1Each independently selected from H, deuterium, F, Cl, Br, OH, CN, NO2, CHF2, CH2F, CF3, OCHF2, OCF3, CD3, OCD3, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methylthiocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl;

[0041] In certain embodiments, R 2 Each independently selected from H, deuterium, F, Cl, Br, OH, CN, NO2, CHF2, CH2F, CF3, OCHF2, OCF3, CD3, OCD3, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl;

[0042] In certain embodiments, R 5 and R 6 Each independently selected from H, deuterium, halogen, OH, CN, NO2, NH2, C 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl)2, C 0-4 alkylene-5- to 10-membered heteroaryl, C 0-4 alkylene-C 3-10 carbocyclic group, C 0-4 alkylene-4- to 10-membered heterocyclic group, wherein the alkyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k ;

[0043] In certain embodiments, R 5 and R 6 Each independently selected from H, deuterium, halogen, OH, CN, NO2, NH2, C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl)2, C 0-4 alkylene-5- to 8-membered heteroaryl, C 0-4 alkylene-C 3-8 carbocyclic group, C 0-4 alkylene-4- to 8-membered heterocyclic group, wherein the alkyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k ;

[0044] In certain embodiments, R 5 , R 6 are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NO2, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl are optionally substituted by 1 to 4 R k ;

[0045] In certain embodiments, ring B is selected from 4- to 7-membered hetero monocycles, 5- to 12-membered hetero fused rings, 5- to 12-membered hetero spiro rings, 7- to 10-membered hetero bridged rings, C 3-8 monocyclic carbonyl groups, C 6-14 fused cycloalkyl groups, C 6-12 membered spirocycloalkyl groups, C 5-12 membered bridged cycloalkyl groups, benzo C 3-8 carbonyl groups, benzo 3- to 8-membered heterocyclic groups, C 6-10 aryl groups, 5- to 10-membered heteroaryl groups, and the ring B is optionally substituted by 1 to 4 R b ;

[0046] In certain embodiments, ring B is selected from phenyl, benzo C 3-8 carbonyl groups, benzo 3- to 8-membered heterocyclic groups, 5- to 6-membered heteroaryl groups, 5-fused 5-membered heteroaryl groups, 5-fused 6-membered heteroaryl groups, 6-fused 6-membered heteroaryl groups, and the ring B is optionally substituted by 1 to 4 R b ;

[0047] In certain embodiments, ring B is selected from one of the following structures optionally substituted by 1 to 3 R b : benzene, naphthalene, pyridine, pyrazine, pyridazine, pyrimidine,

[0048] In certain embodiments, is selected from

[0049] In certain embodiments, is selected from

[0050] In certain embodiments, is selected from In certain embodiments, is selected from

[0051] In certain embodiments, in general formula (IIa), is selected from one of the following structures optionally substituted with 1 to 4 R b : In certain embodiments, in general formula (IIa), is selected from In certain embodiments, in general formula (IIa), is selected from one of the following structures optionally substituted with 1 to 3 R b :

[0052] In certain embodiments, B1, B2, B3, and B6 are each independently selected from N or CR b1 ; in certain embodiments, at most two of B1, B2, B3, and B6 are selected from N; in certain embodiments, three of B1, B2, B3, and B6 are selected from CR b1 , and the remaining one is selected from N; in certain embodiments, B1, B2, B3, and B6 are each independently selected from CR b1 ; in certain embodiments, B3 is independently selected from N or CH; in certain embodiments, R b1 are each independently selected from H or R b ;

[0053] In certain embodiments, ring C is selected from a 4- to 8-membered heterocyclic ring or a C 4-8 carbocyclic ring, and the said ring C is optionally substituted with 1 to 4 R c ;

[0054] In certain embodiments, ring C is selected from one of the following groups optionally substituted with 1 to 4 R c : cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, oxethenyl, oxolanyl, oxanyl, azetidinyl, pyrrolidinyl, piperidinyl, 1,3-dioxolanyl, 1,4-dioxanyl;

[0055] In certain embodiments, is selected from The said ring C is optionally substituted with 1 to 3 R c ;

[0056] In certain embodiments, is selected from The said ring C is optionally substituted with 1 to 3 R c ; n1 is selected from 1, 2, 3;

[0057] In certain embodiments, selected from ring C is optionally substituted with 1 to 3 R c ;

[0058] In certain embodiments, selected from ring C is optionally substituted with 1 to 3 R c ; n1 is selected from 1, 2, 3;

[0059] In certain embodiments, R a , R b , R c are each independently selected from deuterium, halogen, ═O, OH, CN, NO2, NH2, C 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl)2, -C 0-4 alkylene-C(═O)R 1a , -C 0-4 alkylene-S(═O)2R 1a , -C 0-4 alkylene-P(═O)R 1a R 1b , -O-C 0-4 alkylene-C 3-10 carbocyclic group, -O-C 0-4 alkylene-4 to 10-membered heterocyclic group, -S-C 0-4 alkylene-C 3-10 carbocyclic group, -S-C 0-4 alkylene-4 to 10-membered heterocyclic group, -NH-C 0-4 alkylene-C 3-10 carbocyclic group, -NH-C 0-4 alkylene-4 to 10-membered heterocyclic group, -C 0-4 alkylene-C 3-10 carbocyclic group, -C 0-4 alkylene-4 to 10-membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 R k ;

[0060] In certain embodiments, R a , R b , R c are each independently selected from deuterium, deuterium, halogen, ═O, OH, CN, NO2, NH2, C 1-4 alkyl, OC 1-4Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -C 0-4 Alkylene-C(=O)R 1a , -C 0-4 Alkylene-S(=O)2R 1a , -C 0-4 Alkylene-P(=O)R 1a R 1b , -O-C 0-4 Alkylene-C 3-8 Carbocyclic group, -O-C 0-4 Alkylene-4- to 8-membered heterocyclic group, -S-C 0-4 Alkylene-C 3-8 Carbocyclic group, -S-C 0-4 Alkylene-4- to 8-membered heterocyclic group, -NH-C 0-4 Alkylene-C 3-8 Carbocyclic group, -NH-C 0-4 Alkylene-4- to 8-membered heterocyclic group, -C 0-4 Alkylene-C 3-8 Carbocyclic group, -C 0-4 Alkylene-4- to 8-membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k ;

[0061] In certain embodiments, R a , R c Each independently selected from deuterium, F, Cl, Br, I, OH, =O, NH2, CN, NO2, NHCH3, N(CH3)2, COOH, CONH2 or one of the following groups optionally substituted by 1 to 4 R k : methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, thienyl, thiazolyl, furyl, oxazolyl, isoxazolyl;

[0062] In certain embodiments, R a , R cEach independently selected from deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, NO2, CHF2, CH2F, CF3, OCHF2, OCF3, CD3, OCD3, NHCH3, N(CH3)2, COOH, CONH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, thienyl, thiazolyl, furyl, oxazolyl, isoxazolyl;

[0063] In certain embodiments, R b is selected from deuterium, F, Cl, Br, I, OH, ═O, CN, NH2, NO2, NHCH3, N(CH3)2, COOH, CONH2, -CH2-C(═O)R 1a , -CH2-S(═O)2R 1a , -CH2-P(═O)R 1a R 1b , -C(═O)R 1a , -S(═O)2R 1a , -P(═O)R 1a R 1b , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-pyrrolidinyl, -O-cyclopropyl, -O-cyclobutyl, -O-pyrrolidinyl, -S-cyclopropyl, -S-cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, -OCH2-cyclopropyl, imidazole, pyrazole, pyrrole or thiophene, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole or thiophene is optionally substituted by 1 to 4 R k ;

[0064] In certain embodiments, R b is selected from deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, NO2, CHF2, CH2F, CF3, OCHF2, OCF3, CD3, OCD3, NHCH3, N(CH3)2, COOH, CONH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl;

[0065] In certain embodiments, R b is selected from deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, NO2, CHF2, CH2F, CF3, OCHF2, OCF3, CD3, OCD3, NHCH3, N(CH3)2, COOH, CONH2, -S(═O)2NH2, -P(═O)(NH2)(NH2), CON(CH3)2, -S(═O)2N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl;

[0066] In certain embodiments, R 1a and R 1b are each independently selected from H, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy, NHC 1-6 alkyl, N(C 1-6 alkyl)2, C 3-8 carbocyclic group, 4- to 8-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, -O-C 3-8 carbocyclic group, -O-4- to 8-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group, heterocyclic group, aryl or heteroaryl is optionally substituted by 1 to 4 R k ;

[0067] In certain embodiments, R 1a and R 1b are each independently selected from H, OH, NH2, C 1-4 alkyl, C 1-4 alkoxy, NHC 1-4 alkyl, N(C 1-4 alkyl)2, C 3-6 carbocyclic group, 4- to 8-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, -O-C 3-8 carbocyclic group, -O-4- to 8-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group, heterocyclic group, aryl or heteroaryl is optionally substituted by 1 to 4 R k ;

[0068] In certain embodiments, R 1a and R 1bEach independently selected from H, OH, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, -O-cyclopropyl, -O-cyclobutyl, imidazole, pyrazole, pyrrole or thiophene, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole or thiophene is optionally substituted with 1 to 3 Rs k and is substituted;

[0069] In certain embodiments, R k Each independently selected from deuterium, halogen, OH, ═O, CN, NH2, COOH, CONH2, C 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl)2, -O-C 3-6 carbocycle, -O-3- to 7-membered heterocycle, -NH-C 3-6 carbocycle, -NH-3- to 7-membered heterocycle, -C 0-4 alkylene-C 3-6 carbocycle, -C 0-4 alkylene-3- to 7-membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, ═O, CN, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy;

[0070] In certain embodiments, R k Each independently selected from deuterium, halogen, OH, ═O, CN, NH2, COOH, CONH2, C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl)2, -O-C 3-6 carbocycle, -O-3- to 7-membered heterocycle, -NH-C 3-6 carbocycle, -NH-3- to 7-membered heterocycle, -C 0-4 alkylene-C 3-6 carbocycle, -C 0-4Alkylene-3 to 7-membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, ═O, CN, OH, NH2, C 1-4 alkyl, C 1-4 alkoxy;

[0071] In certain embodiments, R k each independently selected from deuterium, F, Cl, Br, I, OH, ═O, CN, NH2, COOH, CONH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, ═O, CN, OH, NH2, C 1-4 alkyl, C 1-4 alkoxy;

[0072] In certain embodiments, R k each independently selected from deuterium, F, Cl, Br, I, OH, ═O, COOH, CN, CHF2, CH2F, CF3, OCHF2, OCF3, CD3, OCD3, NH2, NHCH3, N(CH3)2, CH2OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio.

[0073] In certain embodiments, in formula (II) or (IIa), R a each independently selected from deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, NO2, NHCH3, N(CH3)2, COOH, CONH2 or one of the following groups optionally substituted with 1 to 4 R k substituents: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, thienyl, thiazolyl, furyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl;

[0074] In certain embodiments, in formula (II) or (IIa), R aEach independently selected from deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, NO2, CHF2, CH2F, CF3, OCHF2, OCF3, CD3, OCD3, NHCH3, N(CH3)2, COOH, CONH2 or one of the following groups optionally substituted by 1 to 3 Rs k : methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, thienyl, thiazolyl, furyl, oxazolyl, isoxazolyl

[0075] In certain embodiments, R in formula (II) or (IIa) c Each independently selected from deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, NO2, NHCH3, N(CH3)2, COOH, CONH2 or one of the following groups optionally substituted by 1 to 4 Rs k : methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl

[0076] In certain embodiments, R in formula (II) or (IIa) c Each independently selected from deuterium, F, Cl, Br, I, OH, ═O,, NH2, CN, NO2, CHF2, CH2F, CF3, OCHF2, OCF3, CD3, OCD3, NHCH3, N(CH3)2, COOH, CONH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl

[0077] In certain embodiments, R 1a , R 1b Each independently selected from H, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy, NHC 1-6 alkyl, N(C 1-6 alkyl)2, C 3-8 carbocyclic group, 4- to 8-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, -O-C 3-8 carbocyclic group, -O-4- to 8-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group, heterocyclic group, aryl or heteroaryl is optionally substituted by 1 to 4 Rs k ;

[0078] Optionally, formula (I) or (Ia) is not selected from one of the structures shown in Table E.

[0079] As the first embodiment of the present invention, the compound represented by the foregoing general formula (I), (II) or (IIa), or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt,

[0080] X2 is selected from O, S;

[0081] X1 is selected from O, S, NR x , C(R x )2;

[0082] Y is selected from O, S, NR y ;

[0083] R x , R y are each independently selected from H, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C 0-4 alkylene-C 3-8 carbocyclic group, -C 0-4 alkylene-4- to 8-membered heterocyclic group, and the alkyl, alkenyl, alkynyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k ;

[0084] In general formula (I), ring A is selected from 6-membered heteroaryl, and the ring A is optionally substituted by 1 to 4 selected from R a ;

[0085] In general formula (II) or (IIa), ring A is selected from 4- to 7-membered hetero monocyclic alkyl, 5- to 12-membered hetero fused ring alkyl, 5- to 12-membered hetero spiro ring alkyl, 7- to 10-membered hetero bridged ring alkyl, C 3-8 monocyclic alkyl, C 6-14 fused ring alkyl, C 6-12 spiro ring alkyl, C 5-12 bridged ring alkyl, phenyl, 5- to 6-membered heteroaryl, and the ring A is optionally substituted by 1 to 4 selected from R a ;

[0086] Ring B is selected from 4- to 7-membered hetero monocyclic, 5- to 12-membered hetero fused ring, 5- to 12-membered hetero spiro ring, 7- to 10-membered hetero bridged ring, C 3-8 monocarbon ring group, C 6-14 fused ring alkyl, C 6-12 spiro ring alkyl, C 5-12 bridged ring alkyl, benzo C 3-8 carbocyclic group, benzo 3- to 8-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, and the ring B is optionally substituted by 1 to 4 R b ;

[0087] Ring C is selected from 4- to 8-membered heterocycles or C 4-8 carbocyclic rings, and said ring C is optionally substituted by 1 to 4 R c groups;

[0088] R a , R b , R c are each independently selected from deuterium, halogen, ═O, OH, CN, NO2, NH2, C 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl)2, -C 0-4 alkylene-C(═O)R 1a , -C 0-4 alkylene-S(═O)2R 1a , -C 0-4 alkylene-P(═O)R 1a R 1b , -O-C 0-4 alkylene-C 3-10 carbocyclic group, -O-C 0-4 alkylene-4- to 10-membered heterocyclic group, -S-C 0-4 alkylene-C 3-10 carbocyclic group, -S-C 0-4 alkylene-4- to 10-membered heterocyclic group, -NH-C 0-4 alkylene-C 3-10 carbocyclic group, -NH-C 0-4 alkylene-4- to 10-membered heterocyclic group, -C 0-4 alkylene-C 3-10 carbocyclic group, -C 0-4 alkylene-4- to 10-membered heterocyclic group, and said alkyl, alkenyl, alkynyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k groups;

[0089] R 1 , R 2 are each independently selected from H, deuterium, halogen, OH, CN, NO2, NH2, C 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl)2, -C 0-4 alkylene-C(═O)R 1a , -C0-4 Alkylene-S(=O)2R 1a 、-C 0-4 Alkylene-P(=O)R 1a R 1b 、-O-C 0-4 Alkylene-C 3-10 Carbocyclic group, -O-C 0-4 Alkylene-4- to 10-membered heterocyclic group, -S-C 0-4 Alkylene-C 3-10 Carbocyclic group, -S-C 0-4 Alkylene-4- to 10-membered heterocyclic group, -NH-C 0-4 Alkylene-C 3-10 Carbocyclic group, -NH-C 0-4 Alkylene-4- to 10-membered heterocyclic group, -C 0-4 Alkylene-C 3-10 Carbocyclic group, -C 0-4 Alkylene-4- to 10-membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k substituents;

[0090] R 5 、R 6 are each independently selected from H, deuterium, halogen, OH, CN, NO2, NH2, C 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl)2, C 0-4 alkylene-5- to 10-membered heteroaryl, C 0-4 alkylene-C 3-10 carbocyclic group, C 0-4 alkylene-4- to 10-membered heterocyclic group, wherein the alkyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k substituents;

[0091] R 1a 、R 1b are each independently selected from H, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy, NHC 1-6 alkyl, N(C 1-6 alkyl)2, C 3-8 carbocyclic group, 4- to 8-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, -O-C 3-8A carbocyclic group, -O-heterocyclic group having 4 to 8 members, and said alkyl group, alkoxy group, carbocyclic group, heterocyclic group, aryl group or heteroaryl group are optionally substituted by 1 to 4 R k substituted;

[0092] R k each independently selected from deuterium, halogen, OH, =O, CN, NH2, COOH, CONH2, C 1-4 alkyl group, OC 1-4 alkyl group, SC 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, NHC 1-4 alkyl group, N(C 1-4 alkyl group)2, -O-C 3-6 carbocyclic ring, -O-heterocyclic ring having 3 to 7 members, -NH-C 3-6 carbocyclic ring, -NH-heterocyclic ring having 3 to 7 members, -C 0-4 alkylene-C 3-6 carbocyclic ring, -C 0-4 alkylene-heterocyclic ring having 3 to 7 members, and said alkyl group, alkylene group, alkenyl group, alkynyl group, carbocyclic ring or heterocyclic ring are optionally substituted by 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH2, C 1-4 alkyl group, C 1-4 alkoxy group;

[0093] Provided that the general formula (II) or (IIa) is not selected from any of the structures shown in Table E below.

[0094] As a second embodiment of the present invention, the compound represented by the foregoing general formula (I), (II) or (IIa), or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt,

[0095] Ring B is selected from phenyl, benzoC 3-8 carbocyclic group, benzoheterocyclic group having 3 to 8 members, 5-6 membered heteroaryl group, 5-fused 5 membered heteroaryl group, 5-fused 6 membered heteroaryl group, 6-fused 6 membered heteroaryl group, and said Ring B is optionally substituted by 1 to 4 R b substituted;

[0096] In the general formula (I), Ring A is selected from 6 membered nitrogen-containing heteroaryl group, and said Ring A is optionally substituted by 1 to 4 selected from R a substituted;

[0097] In the general formula (II) or (IIa), Ring A is selected from 4-7 membered hetero monocyclic alkyl group, 5-10 membered hetero fused ring alkyl group, 5-10 membered hetero spiro ring alkyl group, 7-10 membered hetero bridged ring alkyl group, C 3-8 monocyclic alkyl group, C 6-10 fused ring alkyl group, C 6-10 membered spiro ring alkyl group, C 5-10A bicyclic alkyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, and the ring A is optionally substituted with 1 to 4 substituents selected from R a ;

[0098] R 1 , R 2 are each independently selected from H, deuterium, halogen, OH, CN, NO2, NH2, C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl)2, -C 0-4 alkylene-C(=O)R 1a , -C 0-4 alkylene-S(=O)2R 1a , -C 0-4 alkylene-P(=O)R 1a R 1b , -O-C 0-4 alkylene-C 3-8 carbocyclic group, -O-C 0-4 alkylene-4- to 8-membered heterocyclic group, -S-C 0-4 alkylene-C 3-8 carbocyclic group, -S-C 0-4 alkylene-4- to 8-membered heterocyclic group, -NH-C 0-4 alkylene-C 3-8 carbocyclic group, -NH-C 0-4 alkylene-4- to 8-membered heterocyclic group, -C 0-4 alkylene-C 3-8 carbocyclic group, -C 0-4 alkylene-4- to 8-membered heterocyclic group, and the alkyl, alkenyl, alkynyl, alkylene, carbocyclic group, or heterocyclic group is optionally substituted with 1 to 4 R k ;

[0099] R 5 , R 6 are each independently selected from H, deuterium, halogen, OH, CN, NO2, NH2, C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl)2, C 0-4 alkylene-5- to 8-membered heteroaryl, C 0-4 alkylene-C 3-8 carbocyclic group, C 0-4An alkylene-4 to 8-membered heterocyclic group, wherein the alkyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k substituted;

[0100] R a 、R b 、R c are each independently selected from deuterium, deuterium, halogen, =O, OH, CN, NO2, NH2, C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl)2, -C 0-4 alkylene-C(=O)R 1a 、-C 0-4 alkylene-S(=O)2R 1a 、-C 0-4 alkylene-P(=O)R 1a R 1b 、-O-C 0-4 alkylene-C 3-8 carbocyclic group, -O-C 0-4 alkylene-4 to 8-membered heterocyclic group, -S-C 0-4 alkylene-C 3-8 carbocyclic group, -S-C 0-4 alkylene-4 to 8-membered heterocyclic group, -NH-C 0-4 alkylene-C 3-8 carbocyclic group, -NH-C 0-4 alkylene-4 to 8-membered heterocyclic group, -C 0-4 alkylene-C 3-8 carbocyclic group, -C 0-4 alkylene-4 to 8-membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k substituted;

[0101] The definitions of the remaining substituents are the same as those described in the first embodiment of the present invention.

[0102] As the third embodiment of the present invention, the compound represented by the foregoing general formula (I), (II) or (IIa), or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt,

[0103] X1 is selected from O, S, NR x ;

[0104] R x 、R yEach independently selected from H, deuterium, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl are optionally substituted with 1 to 4 R k substituted;

[0105] R 1a and R 1b each independently selected from H, OH, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, -O-cyclopropyl, -O-cyclobutyl, imidazole, pyrazole, pyrrole or thiophene, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole or thiophene are optionally substituted with 1 to 3 R k substituted;

[0106] R 1 and R 2 each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NO2, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propargyl, alkynyl, methylthio, -C(=O)R 1a -S(=O)2R 1a -P(=O)R 1a R 1b and R k substituted;

[0107] R 5 and R 6Each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NO2, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl are optionally substituted by 1 to 4 R k substituted;

[0108] R a and R c each independently selected from deuterium, F, Cl, Br, I, OH, =O, NH2, CN, NO2, NHCH3, N(CH3)2, COOH, CONH2 or one of the following groups optionally substituted by 1 to 4 R k substituted: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, thienyl, thiazolyl, furyl, oxazolyl, isoxazolyl;

[0109] In general formula (II) or (IIa), R a each independently selected from deuterium, F, Cl, Br, I, OH, =O, NH2, CN, NO2, NHCH3, N(CH3)2, COOH, CONH2 or one of the following groups optionally substituted by 1 to 4 R k substituted: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, thienyl, thiazolyl, furyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl;

[0110] In general formula (II) or (IIa), R c each independently selected from deuterium, F, Cl, Br, I, OH, =O, NH2, CN, NO2, NHCH3, N(CH3)2, COOH, CONH2 or one of the following groups optionally substituted by 1 to 4 R k substituted: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl;

[0111] R b Each independently selected from deuterium, F, Cl, Br, I, OH, ═O, CN, NH2, NO2, NHCH3, N(CH3)2, COOH,

[0112] CONH2, -CH2-C(═O)R 1a , -CH2-S(═O)2R 1a , -CH2-P(═O)R 1a R 1b , -C(═O)R 1a , -S(═O)2R 1a , -P(═O)R 1a R 1b , methyl

[0113] group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, isopropoxy group, vinyl group, ethynyl group, methylthio group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, azetidinyl group, oxetanyl group, pyrrolidinyl group, piperidinyl group, morpholinyl group, -CH2-cyclopropyl group, -CH2-cyclobutyl group, -CH2-pyrrolidinyl group, -O-cyclopropyl group, -O-cyclobutyl group, -O-pyrrolidinyl group, -S-cyclopropyl group, -S-cyclobutyl group, -NH-cyclopropyl group, -NH-cyclobutyl group, -OCH2-cyclopropyl group, imidazole, pyrazole, pyrrole or thiophene, and the methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, isopropoxy group, vinyl group, ethynyl group, methylthio group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, azetidinyl group, oxetanyl group, pyrrolidinyl group, piperidinyl group, morpholinyl group, imidazole, pyrazole, pyrrole or thiophene are optionally substituted by 1 to 4 R k ;

[0114] In general formula (I), ring A is selected from one of the following structures optionally substituted by 1 to 4 R a : pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl;

[0115] In general formula (II) or (IIa), ring A is selected from one of the following structures optionally substituted by 1 to 4 R a : phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, pyrrolidinyl, piperidinyl, piperazinyl, bicyclo[1,1,1]pentyl, bicyclo[2,1,1]hexyl, bicyclo[2,2,1]heptyl;

[0116] Ring C is selected from one of the following groups optionally substituted by 1 to 4 R c : cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, oxethenyl, oxolanyl, oxohexenyl, azethenyl, azolanyl, azohexenyl, 1,3-dioxolanyl, 1,4-dioxohexenyl;

[0117] The definitions of the remaining substituents are the same as those described in Embodiment 1 and Embodiment 2 of the present invention.

[0118] As the fourth embodiment of the present invention, the compound represented by the foregoing general formula (I), (II) or (IIa), or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt,

[0119] Y is selected from O, S, NH;

[0120] X2 is selected from O; X1 is selected from O, S;

[0121] Ring B is selected from one of the following structures optionally substituted by 1 to 3 Rs b : benzene, naphthalene, pyridine, pyrazine, pyridazine, pyrimidine,

[0122] R k Each is independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH2, COOH, CONH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH2, C 1-4 alkyl, C 1-4 alkoxy;

[0123] The definitions of the remaining substituents are the same as those described in Embodiment 1, Embodiment 2 and Embodiment 3 of the present invention.

[0124] As the fifth embodiment of the present invention, the compound represented by the foregoing general formula (I), (II) or (IIa), or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt,

[0125] selected from The said ring C is optionally substituted by 1 to 3 Rs c ;

[0126] selected from The said ring C is optionally substituted by 1 to 3 Rs c ; R in the general formula (II) or (IIa) cEach independently selected from deuterium, F, Cl, Br, I, OH, =O, NH2, CN, NO2, CHF2, CH2F, CF3, OCHF2, OCF3, CD3, OCD3, NHCH3, N(CH3)2, COOH, CONH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl;

[0127] Selected from

[0128] In general formula (IIa) Selected from any one of the following structures optionally substituted by 1 to 4 Rs b as follows:

[0129] In general formula (II) or (IIa), ring A is selected from any one of the following structures optionally substituted by 1 to 3 Rs a as follows:

[0130] R b Each independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH2, NO2, NHCH3, N(CH3)2, COOH, CONH2, -CH2-C(=O)NH2, -CH2-S(=O)2NH2, -CH2-P(=O)(NH2)(NH2), -C(=O)NH2, -S(=O)2NH2, -P(=O)(NH2)(NH2), CON(CH3)2, -S(=O)2N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-pyrrolidinyl, -O-cyclopropyl, -O-cyclobutyl, -O-pyrrolidinyl, -S-cyclopropyl, -S-cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, -OCH2-cyclopropyl, imidazole, pyrazole, pyrrole or thiophene, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole or thiophene are optionally substituted by 1 to 4 Rs k substituted;

[0131] In general formula (I), ring A is selected from any one of the following structures optionally substituted by 1 to 3 Rs a as follows:

[0132] R k Each independently selected from deuterium, F, Cl, Br, I, OH, ═O, COOH, CN, CHF2, CH2F, CF3, OCHF2, OCF3, CD3, OCD3, NH2, NHCH3, N(CH3)2, CH2OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio;

[0133] The definitions of the remaining substituents are the same as those described in the first, second, third, and fourth embodiments of the present invention.

[0134] As the sixth embodiment of the present invention, the compound represented by the foregoing general formula (I), (II) or (IIa), or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt,

[0135] R 2 Each independently selected from H, deuterium, F, Cl, Br, OH, CN, NO2, CHF2, CH2F, CF3, OCHF2, OCF3, CD3, OCD3, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl;

[0136] R 1 Each independently selected from H, deuterium, F, Cl, Br, OH, CN, NO2, CHF2, CH2F, CF3, OCHF2, OCF3, CD3, OCD3, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methylthiocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl;

[0137] R in general formula (I) a 、R c Each independently selected from deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, NO2, CHF2, CH2F, CF3, OCHF2, OCF3, CD3, OCD3, NHCH3, N(CH3)2, COOH, CONH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, thienyl, thiazolyl, furyl, oxazolyl, isoxazolyl;

[0138] R in general formula (II) or (IIa) aEach independently selected from deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, NO2, CHF2, CH2F, CF3, OCHF2, OCF3, CD3, OCD3, NHCH3, N(CH3)2, COOH, CONH2 or one of the following groups optionally substituted by 1 to 3 R k Substituted one of the following groups: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, thienyl, thiazolyl, furyl, oxazolyl, isoxazolyl,

[0139] Selected from

[0140] Or in general formula (II) or (IIa) Selected from

[0141] Selected from

[0142] In general formula (IIa) Selected from one of the following structures optionally substituted by 1 to 3 R b Substituted one of the following structures:

[0143] The definitions of the remaining substituents are the same as those described in the first, second, third, fourth, and fifth aspects of the present invention.

[0144] As the seventh embodiment of the present invention, the compound represented by the foregoing general formula (Ia), (IIb) or (IIc) or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt,

[0145] R b1Each independently selected from deuterium, F, Cl, Br, I, OH, ═O, CN, NH2, NO2, NHCH3, N(CH3)2, COOH, CONH2, -CH2-C(═O)NH2, -CH2-S(═O)2NH2, -CH2-P(═O)(NH2)(NH2), -C(═O)NH2, -S(═O)2NH2, -P(═O)(NH2)(NH2), CON(CH3)2, -S(═O)2N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-pyrrolidinyl, -O-cyclopropyl, -O-cyclobutyl, -O-pyrrolidinyl, -S-cyclopropyl, -S-cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, -OCH2-cyclopropyl, imidazole, pyrazole, pyrrole or thiophene, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole or thiophene are optionally substituted by 1 to 4 R k and; preferably, R b1 is selected from deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, NO2, CHF2, CH2F, CF3, OCHF2, OCF3, CD3, OCD3, NHCH3, N(CH3)2, COOH, CONH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl;

[0146] B3 each independently is selected from N or CR b1 ; preferably, B3 each independently is selected from N or CH;

[0147] In general formula (Ia), ring A is selected from one of the following structures optionally substituted by 1 to 3 R a substituents: or ring A is selected from

[0148] In general formula (IIb) or (IIc), ring A is selected from one of the following structures optionally substituted by 1 to 3 R a substituents:

[0149] R aEach independently selected from deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, NO2, CHF2, CH2F, CF3, OCHF2, OCF3, CD3, OCD3, NHCH3, N(CH3)2, COOH, CONH2 or optionally substituted by 1 to 3 Rs k One of the following groups: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, thienyl, thiazolyl, furyl, oxazolyl, isoxazolyl, optionally substituted by 1 to 3 Rs

[0150] The present invention relates to the following compounds or their racemates, stereoisomers, tautomers, pharmaceutically acceptable salts, wherein the compounds are selected from one of the structures in Table A;

[0151] The present invention relates to a pharmaceutical composition comprising the compound of the present invention or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

[0152] The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

[0153] The present invention relates to the use of the compound of the present invention or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt in the preparation of a drug for treating diseases related to PI3Kα, preferably in the preparation of a drug for tumors or cancers (such as breast cancer).

[0154] In some embodiments, the pharmaceutical composition of the present invention can be in the form of a unit dosage form (the amount of the active ingredient in the unit dosage form is also referred to as the "formulation specification").

[0155] As used herein, the term "effective amount" or "therapeutically effective amount" means an amount of a compound disclosed herein that, to some extent, will alleviate one or more symptoms of the disease or disorder being treated (e.g., treating a PI3Kα-related disease such as cancer). In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is an amount of a compound disclosed herein that is required to provide a clinically significant reduction in the symptoms of the disease.Examples of a therapeutically effective amount include, but are not limited to, 1 - 1500 mg, 1 - 1200 mg, 1 - 1000 mg, 1 - 900 mg, 1 - 800 mg, 1 - 700 mg, 1 - 600 mg, 2 - 600 mg, 3 - 600 mg, 4 - 600 mg, 5 - 600 mg, 6 - 600 mg, 10 - 600 mg, 20 - 600 mg, 25 - 600 mg, 30 - 600 mg, 40 - 600 mg, 50 - 600 mg, 60 - 600 mg, 70 - 600 mg, 75 - 600 mg, 80 - 600 mg, 90 - 600 mg, 100 - 600 mg, 200 - 600 mg, 1 - 500 mg, 2 - 500 mg, 3 - 500 mg, 4 - 500 mg, 5 - 500 mg, 6 - 500 mg, 10 - 500 mg, 20 - 500 mg, 25 - 500 mg, 30 - 500 mg, 40 - 500 mg, 50 - 500 mg, 60 - 500 mg, 70 - 500 mg, 75 - 500 mg, 80 - 500 mg, 90 - 500 mg, 100 - 500 mg, 125 - 500 mg, 150 - 500 mg, 200 - 500 mg, 250 - 500 mg, 300 - 500 mg, 400 - 500 mg, 5 - 400 mg, 10 - 400 mg, 20 - 400 mg, 25 - 400 mg, 30 - 400 mg, 40 - 400 mg, 50 - 400 mg, 60 - 400 mg, 70 - 400 mg, 75 - 400 mg, 80 - 400 mg, 90 - 400 mg, 100 - 400 mg, 125 - 400 mg, 150 - 400 mg, 200 - 400 mg, 250 - 400 mg, 300 - 400 mg, 1 - 300 mg, 2 - 300 mg, 5 - 300 mg, 10 - 300 mg, 20 - 300 mg, 25 - 300 mg, 30 - 300 mg, 40 - 300 mg, 50 - 300 mg, 60 - 300 mg, 70 - 300 mg, 75 - 300 mg, 80 - 300 mg, 90 - 300 mg, 100 - 300 mg, 125 - 300 mg, 150 - 300 mg, 200 - 300 mg, 250 - 300 mg, 1 - 200 mg, 2 - 200 mg, 5 - 200 mg, 10 - 200 mg, 20 - 200 mg, 25 - 200 mg, 30 - 200 mg, 40 - 200 mg, 50 - 200 mg, 60 - 200 mg, 70 - 200 mg, 75 - 200 mg, 80 - 200 mg, 90 - 200 mg, 100 - 200 mg, 125 - 200 mg, 150 - 200 mg, 80 - 1000 mg, 80 - 800 mg.

[0156] In some embodiments, the pharmaceutical composition comprises, but is not limited to, 1 - 1000 mg, 20 - 800 mg, 40 - 800 mg, 40 - 400 mg, 25 - 200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg of the compound of the present invention or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt.

[0157] A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the compound of the present invention or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt, the therapeutically effective amount preferably being 1 - 1500 mg, and the disease preferably being a PI3Kα inhibitor-related disease (such as a tumor).

[0158] A method for treating a disease in a mammal, the method comprising administering to a subject the drug, the compound of the present invention or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt, at a daily dose of 1 - 1000 mg / day, the daily dose may be a single dose or divided doses. In some embodiments, the daily dose comprises, but is not limited to, 10 - 1500 mg / day, 10 - 1000 mg / day, 10 - 800 mg / day, 25 - 800 mg / day, 50 - 800 mg / day, 100 - 800 mg / day, 200 - 800 mg / day, 25 - 400 mg / day, 50 - 400 mg / day, 100 - 400 mg / day, 200 - 400 mg / day. In some embodiments, the daily dose comprises, but is not limited to, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 80 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 160 mg / day, 200 mg / day, 300 mg / day, 320 mg / day, 400 mg / day, 480 mg / day, 600 mg / day, 640 mg / day, 800 mg / day, 1000 mg / day.

[0159] The present invention relates to a kit, which may include a composition in single-dose or multi-dose form. The kit contains the compound of the present invention or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt, and the amount of the compound of the present invention or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt is the same as that in the above-mentioned pharmaceutical composition.

[0160] The present invention relates to the use of the above-mentioned compound of the present invention or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt, or the above-mentioned pharmaceutical composition in the preparation of a drug for treating diseases related to PI3Kα inhibitors.

[0161] The use of the above-mentioned compound of the present invention or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt, or the above-mentioned pharmaceutical composition according to the present invention is characterized in that the diseases are selected from tumors or cancers, preferably breast cancer.

[0162] The amount of the compound of the present invention or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt is converted in the form of the free base in each case.

[0163] Unless otherwise specified, the terms used in the specification and claims have the following meanings.

[0164] The carbon, hydrogen, oxygen, sulfur, nitrogen, or F, Cl, Br, I involved in the groups and compounds of the present invention all include their isotope situations, and the carbon, hydrogen, oxygen, sulfur, or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, where the isotopes of carbon include 12 C, 13 C, and 14 C. The isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called superheavy hydrogen). The isotopes of oxygen include 16 O, 17 O, and 18 O. The isotopes of sulfur include 32 S, 33 S, 34 S, and 36 S. The isotopes of nitrogen include 14 N, and 15 N. The isotopes of fluorine include 17 F, and 19 F. The isotopes of chlorine include 35 Cl, and 37 Cl. The isotopes of bromine include 79 Br, and 81 Br.

[0165] "CN" refers to a cyano group.

[0166] "Halogen" means F, Cl, Br or I.

[0167] "Halogen-substituted" means substituted with F, Cl, Br or I, including but not limited to being substituted with 1 to 10 substituents selected from F, Cl, Br or I, being substituted with 1 to 6 substituents selected from F, Cl, Br or I, being substituted with 1 to 4 substituents selected from F, Cl, Br or I. "Halogen-substituted" is abbreviated as "halogenated".

[0168] "Alkyl" means a substituted or unsubstituted straight-chain or branched-chain saturated aliphatic hydrocarbon group, including but not limited to an alkyl group having 1 to 20 carbon atoms, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and their various branched isomers; the alkyl group can be monovalent, divalent, trivalent or tetravalent.

[0169] "Heteroalkyl" means that one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms in a substituted or unsubstituted alkyl group are replaced by heteroatoms (including but not limited to N, O or S). Non-limiting examples include -X-(CH2)v-X-(CH2)v-X-(CH2)v-H (v is an integer from 1 to 5, X are each independently selected from a bond or a heteroatom, the heteroatoms include but not limited to N, O or S, and at least one X is selected from a heteroatom, and N or S in the heteroatoms can be oxidized to various oxidation states). The heteroalkyl group can be monovalent, divalent, trivalent or tetravalent.

[0170] "Alkylene" means a substituted or unsubstituted straight-chain and branched-chain divalent saturated hydrocarbon group, including -(CH2) v -(where v is an integer from 1 to 10), alkylene examples include but not limited to methylene, ethylene, propylene and butylene, etc.

[0171] "Heteroalkylene" means that one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms in a substituted or unsubstituted alkylene group are replaced by heteroatoms (including but not limited to N, O or S). Non-limiting examples include -X-(CH2)v-X-(CH2)v-X-(CH2)v-, v is an integer from 1 to 5, X are each independently selected from a bond, N, O or S, and at least one X is selected from N, O or S.

[0172] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, usually having 3 to 12 carbon atoms. The cycloalkyl group can be monocyclic, fused-ring, bridged-ring, and spiro-ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-fused-cyclobutyl, cyclobutyl-spiro-cyclobutyl, adamantane, etc. The cycloalkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0173] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 12 atoms, 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O, S, or Se. The C, N, S on the ring of the heterocycloalkyl group can be oxidized to various oxidation states. The heterocycloalkyl group can be monocyclic, fused-ring, bridged-ring, and spiro-ring. The heterocycloalkyl group can be attached to a heteroatom or a carbon atom. Non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl, The heterocycloalkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0174] "Alkenyl" refers to a substituted or unsubstituted straight-chain and branched-chain unsaturated hydrocarbon group, which has at least 1, usually 1, 2, or 3 carbon-carbon double bonds. The main chain includes but not limited to 2 to 10, 2 to 6, or 2 to 4 carbon atoms. Examples of alkenyl include but not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene, etc.; the alkenyl group can be monovalent, divalent, trivalent, or tetravalent.

[0175] "Alkynyl" refers to a substituted or unsubstituted straight-chain or branched-chain unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, with a main chain comprising 2 to 10 carbon atoms, including but not limited to having 2 to 6 carbon atoms in the main chain, having 2 to 4 carbon atoms in the main chain. Examples of alkynyl include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, etc.; alkynyl can be monovalent, divalent, trivalent or tetravalent.

[0176] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropoxy and cyclobutoxy.

[0177] "Carbocyclic group" or "carbocycle" refers to a substituted or unsubstituted aromatic ring or non-aromatic ring. The aromatic ring or non-aromatic ring can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, a 10- to 15-membered tricyclic ring, or a 12- to 18-membered tetracyclic system. The carbocyclic group can be attached to an aromatic ring or a non-aromatic ring, and the ring is optionally a monocyclic ring, a fused ring, a bridged ring or a spiro ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclic group" or "carbocycle" can be monovalent, divalent, trivalent or tetravalent.

[0178] "Heterocyclic group" or "heterocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, a 10- to 15-membered tricyclic ring, or a 12- to 18-membered tetracyclic system, and contains one or more (including but not limited to 2, 3, 4, or 5) heteroatoms selected from N, O, S, or Se. Optionally substituted C, N, S, or Se in the ring of the heterocyclic group can be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom, and can be attached to an aromatic or non-aromatic ring. The heterocyclic group is optionally a monocyclic, bridged, fused, or spiro ring. Non-limiting examples include epoxyethyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, pyridinyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiolyl, dihydrofuryl, dihydropyranyl, dithiolanyl, tetrahydrofuryl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuryl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl, benzofuryl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecanyl, azadamantyl, oxaspiro[3.3]heptanyl, "Heterocyclic group" or "heterocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0179] "Spiro ring" or "spiro group" refers to a polycyclic group in which a substituted or unsubstituted monocyclic ring shares one atom (called a spiro atom). The number of ring atoms in the spiro system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, and one or more of the rings can contain zero or more (including but not limited to 1, 2, 3, or 4) double bonds, and optionally can contain 0 to 5 heteroatoms selected from N, O, or S(=O) n (n is 0, 1, or 2).

[0180]

[0181] "Spiro ring" or "spiro group" can be monovalent, divalent, trivalent, or tetravalent.

[0182] "Fused ring" or "fused ring group" refers to a polycyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, where one or more rings may contain zero or more (including but not limited to 1, 2, 3, or 4) double bonds, and may be substituted or unsubstituted. Each ring in the fused ring system may contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to those selected from N, S(=O) n or O, where n is 0, 1, or 2). The number of ring atoms in the fused ring system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include:

[0183]

[0184] "Fused ring" or "fused ring group" can be monovalent, divalent, trivalent, or tetravalent.

[0185] "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two non-directly connected atoms, which may contain zero or more double bonds. Any ring in the bridged ring system may contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to N, S(=O)n or O, where n is 0, 1, 2). The number of ring atoms includes but is not limited to 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include

[0186] Cubane, adamantane. "Bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent, or tetravalent.

[0187] "Carbospiro", "spirocarbocyclic group", "spirocarbon group" or "carbospiro group" refers to a "spiro ring" whose ring system is composed only of carbon atoms.

[0188] "Carbofused ring", "fused carbocyclic group", "carbofused group" or "carbofused ring group" refers to a "fused ring" whose ring system is composed only of carbon atoms.

[0189] "Carbobridged ring", "bridged carbocyclic group", "bridged carbon group" or "carbobridged ring group" refers to a "bridged ring" whose ring system is composed only of carbon atoms.

[0190] "Heteromonocycle", "monocyclic heterocyclic group" or "heteromonocyclic group" refers to a "heterocyclic group" or "heterocycle" of a monocyclic system,

[0191] "Heterofused ring", "heterofused ring group", "fused heterocyclic group" or "heterofused heterocyclic group" refers to a "fused ring" containing heteroatoms.

[0192] "Heterospirocycle", "heterospirocyclic group", "spiroheterocyclic group" or "spirohetero group" refers to a "spirocycle" containing a heteroatom.

[0193] "Heterobicyclic ring", "heterobicyclic group", "bicyclic heterocyclic group" or "bicyclic hetero group" refers to a "bicyclic ring" containing a heteroatom.

[0194] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a monocyclic or fused ring, and the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12 or 6 to 10 carbon atoms. The aryl ring can be fused to a saturated or unsaturated carbocyclic ring, and the ring connected to the parent structure is the aryl ring. Non-limiting examples include benzene ring, naphthalene ring, "Aryl" or "aromatic ring" can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the connection site is on the aryl ring.

[0195] "Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or groups containing heteroatoms (including, but not limited to, N, O, S(=O)n or Se(=O)n, n is 0, 1, 2), and the number of ring atoms in the heteroaromatic ring includes, but is not limited to, 5 to 15, 5 to 10 or 5 to 6. The atoms C, N, S on the ring are optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, n is 1, 2). Non-limiting examples of heteroaryl include, but are not limited to, pyridyl, furyl, thienyl, selenophenyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, pyridone group, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbocyclic ring or heterocyclic ring, and the ring connected to the parent structure is the aryl ring. Non-limiting examples include

[0196] The heteroaryl appearing in this article has the same definition as this definition. Heteroaryl can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the connection site is on the aromatic ring.

[0197] "Substituted" or "substitution" means being substituted by one or more (including, but not limited to, 2, 3, 4 or 5) substituents, and the substituents include, but are not limited to, H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, mercaptan, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic group, bridged ring group, spirocyclic group, fused ring group, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -

[0198] (CH2) m -C(=O)-R a, -O-(CH2) m , -C(=O)-R a , -(CH2) m , -C(=O)-NR b R c , -(CH2) m , S(=O) n R a , -(CH2) m , -alkenyl-R a , OR d or -(CH2) m , -alkynyl-R a (where m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c and other groups, where R b and R c are independently selected from the group consisting of H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl. Optionally, R b and R c can form a five- or six-membered cycloalkyl or heterocyclic group, R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic group, carbonyl, ester group, bridged ring group, spiro ring group or fused ring group.

[0199] "Substituted by 1 to X substituents selected from..." means substituted by 1, 2, 3... X substituents selected from..., and X is any integer between 1 and 10. For example, "substituted by 1 to 4 R k " means substituted by 1, 2, 3 or 4 R k ". For example, "substituted by 1 to 5 substituents selected from..." means substituted by 1, 2, 3, 4 or 5 substituents selected from.... For example, "the heterobridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means the heterobridged ring is optionally substituted by 1, 2, 3 or 4 substituents selected from H or F.

[0200] The X-Y membered ring (X, Y are integers, and 3 ≤ X < Y, X < Y ≤ 20, X and Y are any integers between 4 and 20) includes X, X + 1, X + 2, X + 3, X + 4... Y membered rings. The ring includes heterocyclic ring, carbocyclic ring, aromatic ring, aryl, heteroaryl, cycloalkyl, heteromonocyclic ring, heteropolycyclic ring, heterospiro ring or heterobridged ring. For example, "4-7 membered heteromonocyclic ring" means a 4-membered, 5-membered, 6-membered or 7-membered heteromonocyclic ring, and "5-10 membered heteropolycyclic ring" means a 5-membered, 6-membered, 7-membered, 8-membered, 9-membered or 10-membered heteropolycyclic ring.

[0201] C x-yCarbocyclic rings (including aryl, cycloalkyl, monocyclic carbocyclic, spirocarbocyclic, fused carbocyclic or bridged carbocyclic rings) include C x 、C x+1 、C x+2 、C x+3 、C x+4 …C y -membered rings (x is an integer, and 3 ≤ x < y, where y is any integer selected from 4 to 20), for example. Such as C 3-6 "Cycloalkyl" refers to C3, C4, C5 or C6 cycloalkyl;

[0202] When a group has one or more connectable sites, any one or more of these sites of the group can be connected to other groups by chemical bonds. When the connection mode of the chemical bond is non-specific and there are hydrogen atoms at the connectable sites, then when connecting the chemical bonds, the number of H atoms at these sites will correspondingly decrease according to the number of connected chemical bonds to form groups with corresponding valences. For example indicates that any connectable site on this piperidyl group can be connected to other groups by 1 chemical bond, including at least these 4 connection modes. Even if H atoms are drawn on -N-, it also includes For example indicates that the R group on this piperidyl group can be located on C or on N, including at least

[0203] When the listed connecting groups do not specify their connection directions, their connection directions include connecting in the directions of the reading orders from left to right and from right to left. For example, for A-L-B, when L is selected from -M-W-, it includes A-M-W-B and A-W-M-B.

[0204] "Optional" or "optionally" means that the subsequent described event or circumstance can but does not have to occur, and this description includes the occasions where the event or circumstance occurs or does not occur. For example: "Optionally fluorine-substituted alkyl" means that the alkyl can but does not have to be fluorine-substituted, and this description includes the cases where the alkyl is fluorine-substituted and the cases where the alkyl is not fluorine-substituted.

[0205] "Pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" means a salt in which the compound of the present invention retains the biological effectiveness and characteristics of the free acid or free base, and the described free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the described free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0206] "Pharmaceutical composition" refers to a mixture formed by one or more compounds described in the present invention, or their stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals and other chemical components. Among them, "other chemical components" refer to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0207] "Dosage form specification" refers to the weight of the active ingredient contained in each vial, tablet or other unit dosage form.

[0208] "Carrier" refers to a material that does not cause obvious irritation to organisms and does not eliminate the biological activity and characteristics of the administered compound.

[0209] "Prodrug" refers to a compound of the present invention that can be metabolically converted in vivo into a biologically active compound. The prodrugs of the present invention are prepared by modifying the amino group or carboxyl group in the compounds of the present invention, and this modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian individual, the prodrug is cleaved to form a free amino group or carboxyl group.

[0210] "Cocrystal" refers to a crystal formed by the combination of an active pharmaceutical ingredient (API) and a cocrystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, where both the pure states of the API and the CCF are solids at room temperature and there is a fixed stoichiometric ratio between the components. Cocrystals are a type of multi-component crystal, including binary cocrystals formed between two neutral solids and multi-component cocrystals formed between a neutral solid and a salt or solvate.

[0211] "Animal" refers to including mammals, such as humans, companion animals, zoo animals and livestock, preferably humans, horses or dogs.

[0212] "Stereoisomer" refers to an isomer produced by the different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereoisomers and conformational isomers.

[0213] "Tautomer" refers to a functional group isomer produced by the rapid movement of a certain atom in a molecule between two positions, such as keto-enol tautomerism and amide-imidol tautomerism, etc.

[0214] "IC 50 " is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a certain component in the process, such as an enzyme, receptor, cell, etc.) by half.

[0215] Synthesis method:

[0216]

[0217] PG is independently selected from amino protecting groups, preferably Boc (tert-butyloxycarbonyl), Cbz (benzyloxycarbonyl), PMB (p-methoxybenzyl), tBuS(=O);

[0218] X is selected from leaving groups, preferably halogen, OMs, OTs or OTf,

[0219] The definitions of the remaining groups are the same as those of the aforementioned general formula compound (I);

[0220] The compound of general formula (M-1) is obtained by a condensation reaction to give the compound of general formula (M-2);

[0221] The compound of general formula (M-2) is obtained by a rearrangement reaction to give the compound of general formula (M-3);

[0222] The compound of general formula (M-3) is obtained by a halogenation reaction to give the compound of general formula (M-4);

[0223] The compound of general formula (M-4) is obtained by a cyclization reaction to give the compound of general formula (M-5);

[0224] The compound of general formula (M-5) reacts in the presence of a metal catalyst to give the compound of general formula (M-6);

[0225] The compound of general formula (M-6) reacts in the presence of a Lewis acid to give the compound of general formula (M-7);

[0226] The compound of general formula (M-7) is obtained by a reduction reaction to give the compound of general formula (M-8);

[0227] The compound of general formula (M-8) undergoes a deprotection reaction under acidic conditions to give the compound of general formula (M-9);

[0228] The compound of general formula (M-9) is obtained by a nucleophilic substitution reaction or a coupling reaction in the presence of a metal catalyst to give the compound of general formula (M-10);

[0229] The compound of general formula (M-10) reacts under basic conditions (such as sodium hydroxide, lithium hydroxide, potassium hydroxide) or acidic conditions (such as hydrochloric acid, trifluoroacetic acid) to give the compound of general formula (M-11); Detailed implementation mode

[0230] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to this.

[0231] The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is in 10 -6Given in the unit of (ppm). The NMR measurements were performed using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic resonance spectrometers, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) as solvents, and tetramethylsilane (TMS) as the internal standard;

[0232] The MS measurements were performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0233] The HPLC measurements were performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C18 100×4.6 mm, 3.5 μM);

[0234] The TLC silica gel plates used were Yantai Huanghai HSGF 254 or Qingdao GF 254 silica gel plates. The specifications of the silica gel plates used for thin-layer chromatography (TLC) were 0.15 mm - 0.20 mm, and the specifications of the silica gel plates used for separating and purifying products by thin-layer chromatography were 0.4 mm - 0.5 mm;

[0235] Column chromatography generally used silica gel with 200 - 300 mesh from Yantai Huanghai as the carrier;

[0236] To achieve the objectives of the present invention, according to the organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in chemical literature, the compounds used in the reactions described herein "commercially available chemicals" were obtained from standard commercial sources, including Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai Macklin Biochemical Co., Ltd., Sigma-Aldrich, Alfa Aesar (China) Chemical Co., Ltd., TCI (Shanghai) Chemical Industry Development Co., Ltd., Energy Chemical, Shanghai Titan Technology Co., Ltd., Kelong Chemical Industry, J&K Scientific Ltd., etc.

[0237] In the synthesis experiments, unless otherwise specified, the temperature was room temperature;

[0238] THF: tetrahydrofuran; DMF: N,N-dimethylformamide; DIPEA: N,N-diisopropylethylamine; HATU: CAS 148893-10-1; Boc: tert-butoxycarbonyl; Ts: p-toluenesulfonyl; Cbz: benzyloxycarbonyl; TMS: trimethylsilyl.

[0239] Preparation of Intermediate 1

[0240]

[0241] First step: Preparation of 5b

[0242] Pyridine (4.36 g, 55.10 mmol) and propionyl chloride (3.74 g, 40.42 mmol) were added to a solution of 1A (5.00 g, 37.26 mmol) in dichloromethane (100 mL), and the mixture was stirred at room temperature for 16 h. Water (100 mL) was added, and the layers were separated. The aqueous phase was extracted once with dichloromethane (50 mL), and the organic phases were combined. The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether:tetrahydrofuran (v:v) = 96:4) to obtain 1B (7.00 g, yield 99%).

[0243] LCMS m / z = 191.1 [M+H] +

[0244] Step 2: Preparation of 1C

[0245] Aluminum trichloride (14.72 g, 110.39 mmol) was added to a solution of 1B (7.00 g, 36.80 mmol) in carbon disulfide (14 mL), and the reaction was carried out at 80 °C for 3.5 h. After cooling to room temperature, dilute hydrochloric acid (200 mL, 1 N) and ethyl acetate (100 mL) were added, and the mixture was stirred until clear. The layers were separated, and the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether:tetrahydrofuran (v:v) = 98:2) to obtain 1C (6.27 g, yield 90%).

[0246] 1H NMR (400 MHz, DMSO) δ 12.21 (s, 1H), 7.75 (s, 1H), 6.82 (s, 1H), 3.13 - 3.03 (m, 2H), 2.87 - 2.78 (m, 4H), 2.06 - 1.97 (m, 2H), 1.10 (t, 3H).

[0247] Step 3: Preparation of Intermediate 1

[0248] N-Bromosuccinimide (4.68 g, 26.30 mmol) was added to a solution of 1C (5.00 g, 26.28 mmol) in N,N-dimethylformamide (50 mL), and the reaction was carried out at room temperature for 16 h. The reaction mixture was poured into water (500 mL), and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was triturated with a mixed solvent (petroleum ether:ethyl acetate (v:v) = 10:1) to obtain Intermediate 1 (4.44 g, yield 63%).

[0249] LCMS m / z = 269.1 [M+H] +

[0250] 1 H NMR (400 MHz, DMSO-d6) δ 13.06 (s, 1H), 7.82 (s, 1H), 3.13 (q, 2H), 2.97 (t, 2H), 2.91 (t, 2H), 2.14 - 2.00 (m, 2H), 1.11 (t, 3H).

[0251] Preparation of Intermediate 2

[0252]

[0253] Intermediate 2 was prepared by referring to 1A as the starting material and referring to the synthesis method of Intermediate 1.

[0254] LCMS m / z = 255.2 [M+H] +

[0255] 1 H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 7.80 (s, 1H), 2.97 (t, 2H), 2.91 (t, 2H), 2.65 (s, 3H), 2.11 - 2.03 (m, 2H).

[0256] Example 1: Preparation of Compound 1

[0257]

[0258] First step: Preparation of 1b

[0259] Dicyclohexylcarbodiimide (2.40 g, 11.63 mmol) and 4-dimethylaminopyridine (129 mg, 1.06 mmol) were added to a solution of 1a (1.64 g, 11.62 mmol) in dichloromethane (40 mL), and the reaction was carried out at room temperature for 2 h. Intermediate 2 (2.70 g, 10.58 mmol) was added, and the reaction was carried out at 35 °C for 16 h. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product, and the crude product was separated and purified by column chromatography (petroleum ether:tetrahydrofuran (v / v) = 10:1) to obtain 1b (2.70 g, 67%).

[0260] LCMS m / z = 378.0 [M+1] +

[0261] Second step: Preparation of 1c

[0262] Sodium hydride (0.86 g, 21.50 mmol, content: 60%) was added to a solution of 1b (2.70 g, 7.14 mmol) in dimethyl sulfoxide (25 mL), and the reaction was carried out at 35 °C for 3 h. After cooling to room temperature, the reaction solution was added to a saturated aqueous ammonium chloride solution (100 mL), and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was dissolved in acetic acid (10 mL) and concentrated hydrochloric acid (1 mL, 12 N), and the reaction was carried out at 95 °C for 2 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain a crude product, and the crude product was slurried with (petroleum ether:

[0263] ethyl acetate (v / v) = 5:1) to obtain 1c (2.40 g, 93%).

[0264] LCMS m / z = 360.0 [M+1] +

[0265] Step 3: Preparation of 1d

[0266] 1c (2.40 g, 6.66 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.23 g, 0.33 mmol), and tributyl(1-ethoxyvinyl)tin (3.37 g, 9.33 mmol) were dissolved in dioxane (25 mL). Under a nitrogen atmosphere, the reaction was carried out at 95 °C for 16 h. After cooling to room temperature, 3 N hydrochloric acid (10 mL) was added and stirred for 1 h. Saturated aqueous potassium fluoride solution (10 mL) was added and stirred for 1 h. The mixture was filtered, and the filter cake was washed with dichloromethane (30 mL × 3). Water (50 mL) was added to the filtrate, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (dichloromethane:tetrahydrofuran (v / v) = 5:1) to obtain 1d (1.40 g, 65%).

[0267] LCMS m / z = 324.1 [M+1] +

[0268] Step 4: Preparation of 1e

[0269] At 0 °C, sodium borohydride (70 mg, 1.85 mmol) was added to a solution of 1d (400 mg, 1.24 mmol) in dichloromethane (4 mL) and methanol (4 mL), and the reaction was carried out at room temperature for 4 h. Saturated ammonium chloride (0.5 mL) and water (15 mL) were added, and the mixture was extracted with dichloromethane (15 mL × 3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1e (390 mg, crude product).

[0270] LCMS m / z = 326.1 [M+1] +

[0271] Step 5: Preparation of 1f

[0272] At 0 °C, phosphorus tribromide (1.14 g, 4.21 mmol) was added to a solution of 1e (390 mg, crude) in dichloromethane (4 mL). The reaction was carried out at room temperature for 16 h. Saturated aqueous sodium chloride (1 mL) was added, and the pH was adjusted to about 7 with saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane (20 mL x 3), and the combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1f (300 mg, crude).

[0273] LCMS m / z = 388.1 [M+1] +

[0274] Step 6: Preparation of 1h

[0275] 1f (100 mg, crude) and 1g (100 mg, 0.52 mmol) were dissolved in N,N-dimethylformamide (4 mL), and the reaction was carried out at 90 °C for 4 h. After cooling to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (dichloromethane:tetrahydrofuran (v:v)

[0276] = 10:1) to obtain 1h (60 mg).

[0277] LCMS m / z = 501.3 [M+1] +

[0278] Step 7: Preparation of Compound 1

[0279] 1h (60 mg, 0.12 mmol) was dissolved in trifluoroacetic acid (2 mL) and dichloromethane (2 mL), and the reaction was carried out at 50 °C for 4 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain a residue. Water (2 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by preparative thin layer chromatography (dichloromethane:methanol (v / v)

[0280] = 10:1) to obtain Compound 1.

[0281] LCMS m / z = 445.1 [M+1] +

[0282] Preparation of Compound 1-A and Compound 1-B

[0283]

[0284] Compound 1 was purified by SFC on a Chiral AS column (instrument and preparative column: Waters 150Prep-SFC, preparative column model: Chiral AS column. Preparation method: Compound 1 was dissolved in acetonitrile and dichloromethane and filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: A for CO2; B for 0.1% NH3·H2O in methanol. Gradient elution method: Isocratic elution with 45% mobile phase B (flow rate: 120 mL / min; elution time 5.7 min), and after lyophilization, Compound 1-A (Compound 1-A is one of the structures of Compound 1-1 and Compound 1-2) and Compound 1-B (Compound 1-B is one of the structures of Compound 1-1 and Compound 1-2) were obtained.

[0285] Analysis method (instrument and preparative column: SHIMADZU LC-30AD sf, analytical column model: Chiral AS column, mobile phase system: A for CO2; B for 0.05% DEA in methanol, gradient elution method: Isocratic elution with 5-40% mobile phase B, column temperature: 35 °C, flow rate:

[0286] 3.0 mL / min. The retention time T = 2.137 min was for Compound 1-A (Compound 1-A is one of the structures of Compound 1-1 and Compound 1-2), and the retention time T = 2.500 min was for Compound 1-B (Compound 1-B is one of the structures of Compound 1-1 and Compound 1-2).

[0287] Compound 1-A

[0288] LCMS m / z = 445.1 [M+H] + ;

[0289] 1 H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 8.83 (d, 1H), 8.63 - 8.51 (m, 1H), 8.40 - 8.30 (m, 1H), 8.05 - 7.96 (m, 1H), 7.84 - 7.74 (m, 2H), 7.26 - 7.12 (m, 2H), 6.57 - 6.44 (m, 2H), 5.51 - 5.38 (m, 1H), 3.27 - 3.20 (m, 1H), 3.02 - 2.81 (m, 3H), 2.12 - 1.99 (m, 2H), 1.73 (d, 3H).

[0290] Compound 1-B

[0291] LCMS m / z = 445.1 [M+H] + ;

[0292] 1 H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.83 (d, 1H), 8.73 - 8.51 (m, 1H), 8.40 - 8.30 (m, 1H), 8.05 - 7.96 (m, 1H), 7.84 - 7.74 (m, 2H), 7.26 - 7.12 (m, 2H), 6.57 - 6.44 (m, 2H), 5.51 - 5.38 (m, 1H), 3.27 - 3.20 (m, 1H), 3.02 - 2.81 (m, 3H), 2.12 - 1.99 (m, 2H), 1.73 (d, 3H).

[0293] Example 2: Preparation of Compound 2

[0294]

[0295] Compound 2 was obtained by using intermediate 1 as the starting material and referring to the synthesis method of Example 1.

[0296] LCMS m / z = 459.2 [M+H] + .

[0297] Preparation of Compound 2-A and Compound 2-B

[0298]

[0299] Compound 2 was purified by SFC on AD column (instrument and preparative column: Waters 150Prep-SFC was used, and the preparative column model is: Chiral AS column. Preparation method: Compound 2 was dissolved in acetonitrile and dichloromethane, filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: A for CO2 and B for 0.1% NH3·H2O in methanol). Gradient elution method: Isocratic elution with 30% mobile phase B (flow rate: 120 mL / min; elution time 5.2 min)), and after lyophilization, Compound 2-A (Compound 2-A is one of the structures of Compound 2-1 and Compound 2-2) and Compound 2-B (Compound 2-B is one of the structures of Compound 2-1 and Compound 2-2) were obtained.

[0300] Analysis method (instrument and preparation column: high performance liquid chromatograph – normal phase chromatography, analytical column model: Chiral AS column, mobile phase system: A for CO2; B for 0.05% DEA in methanol, column temperature: 35 °C, flow rate: 3.0 mL / min. The retention time T = 1.574 min is for compound 2-A (compound 2-A is one of the structures of compound 2-1 and compound 2-2), and the retention time T = 1.910 min is for compound 2-B (compound 2-B is one of the structures of compound 2-1 and compound 2-2).

[0301] Compound 2-A:

[0302] LCMS m / z = 459.1 [M+H] + 。

[0303] 1 H NMR (400 MHz, DMSO-d6) δ12.58 (s, 1H), 8.83 (d, 1H), 8.64 - 8.33 (m, 1H), 8.21 - 8.07 (m, 1H), 8.06 - 7.95 (m, 1H), 7.81 (s, 1H), 7.79 - 7.72 (m, 1H), 7.17 (t, 1H), 6.48 (t, 1H), 6.43 (d, 1H), 5.34 - 5.19 (m, 1H), 3.25 - 3.17 (m, 1H), 3.02 - 2.79 (m, 3H), 2.21 (s, 3H), 2.13 - 1.96 (m, 2H), 1.66 (d, 3H).

[0304] Compound 2-B:

[0305] LCMS m / z = 459.1 [M+H] + 。

[0306] 1 H NMR (400 MHz, DMSO-d6) δ12.50 (s, 1H), 8.83 (d, 1H), 8.64 - 8.33 (m, 1H), 8.21 - 8.07 (m, 1H), 8.06 - 7.95 (m, 1H), 7.81 (s, 1H), 7.79 - 7.72 (m, 1H), 7.17 (t, 1H), 6.48 (t, 1H), 6.43 (d, 1H), 5.34 - 5.19 (m, 1H), 3.25 - 3.17 (m, 1H), 3.02 - 2.79 (m, 3H), 2.21 (s, 3H), 2.13 - 1.96 (m, 2H), 1.65 (d, 3H).

[0307] Example 3: Synthesis of Compound 3

[0308]

[0309] Step 1: Preparation of 3a

[0310] Tetraethyl orthotitanate (3.52 g, 15.43 mmol) was added to a solution of 1d (1.00 g, 3.09 mmol) and (R)-(+)-tert-butylsulfinamide (0.75 g, 6.19 mmol) in dioxane (20 mL). The reaction was carried out at 110 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, water (10 mL) was added, and the mixture was filtered. The filter cake was washed with dichloromethane containing 10% MeOH (30 mL x 3), and the filtrate was allowed to stand for phase separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (dichloromethane:tetrahydrofuran (v:v) = 10:1) to obtain 3a (680 mg, 52%).

[0311] LCMS m / z = 427.2 [M+1] +

[0312] Step 2: Preparation of 3b

[0313] At 0 °C, lithium tri-tert-butoxyaluminum hydride (2.39 mL, 2.39 mmol, 1N solution in tetrahydrofuran) was added to a solution of 3a (680 mg, 1.60 mmol) in tetrahydrofuran (30 mL). After reacting at room temperature for 5 minutes, the reaction was carried out at 40 °C for 6 h. At 0 °C, saturated aqueous ammonium chloride solution was added until precipitation occurred, and the mixture was filtered. The filtrate was concentrated to obtain a crude product, and the crude product was separated and purified by column chromatography (dichloromethane:tetrahydrofuran = 5:1) to obtain 3b (340 mg, 50%).

[0314] LCMS m / z = 429.2 [M+1] +

[0315] Step 3: Preparation of 3c

[0316] A solution of hydrogen chloride in 1,4-dioxane (2 mL, 4N) was added to a mixed solution of 3b (340 mg, 0.79 mmol) in dioxane (2 mL) and methanol (1 mL). The reaction was carried out at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. Water (10 mL) was added, and the pH value was adjusted to 7 - 8 with saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane containing 10% methanol (10 mL x 3). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 3c (250 mg, crude product).

[0317] LCMS m / z = 325.1 [M+1] +

[0318] Step 4: Preparation of 3e

[0319] N,N-Diisopropylethylamine (142 mg, 1.10 mmol) was added to a solution of 3c (70 mg, crude product) and 3d (50 mg, 0.26 mmol) in N,N-dimethylformamide (4 mL), and the reaction was carried out at 100 °C for 16 h. After cooling to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (methylene chloride:tetrahydrofuran (v:v) = 10:1) to obtain 3e (50 mg).

[0320] LCMS m / z = 494.0 [M+1] +

[0321] Step 5: Preparation of Compound 3

[0322] 1,5,7-Triazabicyclo[4.4.0]dec-5-ene (42 mg, 0.30 mmol) was added to a solution of 3e (50 mg, 0.10 mmol) in acetonitrile (3 mL) and water (1 mL), and the reaction was carried out at room temperature for 16 h. Water (10 mL) was added, and the pH value was adjusted to 3 - 4 with 1N hydrochloric acid aqueous solution. The mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by Pre-HPLC (instrument and preparative column: using SHIMADZU LC-20AP preparative liquid phase, the preparative column model is Phenomenex C18, 5 μm, inner diameter * length = 19 mm * 150 mm). Preparation method: The crude product was dissolved in methanol and filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile / water (containing 0.05% ammonium bicarbonate). Gradient elution method: Acetonitrile was eluted from 32% to 62% (elution time 15 min) in a gradient manner. After lyophilization, Compound 3 (15 mg, 31%) was obtained.

[0323] LCMS m / z = 480.0 [M+1] +

[0324] 11H NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H), 9.09 - 8.56 (m, 2H), 8.45 - 8.26 (m, 1H), 8.05 - 7.95 (m, 1H), 7.81 (s, 1H), 7.34 - 7.20 (m, 1H), 7.16 (s, 1H), 7.06 - 6.96 (m, 1H), 5.54 - 5.34 (m, 1H), 3.25 - 3.17 (m, 1H), 3.00 - 2.79 (m, 3H), 2.11 - 1.97 (m, 2H), 1.73 (d, 3H).

[0325] Example 4: Synthesis of Compound 4

[0326]

[0327] Step 1: Preparation of 4b

[0328] Xant-phos (6 mg, 0.01 mmol), Pd2(dba)3 (20 mg, 0.02 mmol), and cesium carbonate (143 mg, 0.44 mmol) were added to a solution of 3c (70 mg, 0.22 mmol) and 4a (121 mg, 0.44 mmol) in dioxane (2 mL). The reaction was carried out at 100 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, water (2 mL) was added, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:tetrahydrofuran (v / v) = 5:1) to give 4b (60 mg, 54%).

[0329] LCMS m / z = 519.0 [M+1] +

[0330] Step 2: Preparation of Compound 4

[0331] Compound 4b (60 mg, 0.12 mmol) was dissolved in a mixed solution of dichloromethane (2 mL) and trifluoroacetic acid (2 mL). The reaction was carried out at 35 °C for 16 h. The reaction mixture was concentrated under reduced pressure to obtain a residue, to which water (10 mL) was added, and the mixture was extracted with dichloromethane (15 mL × 3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by Pre-HPLC (instrument and preparative column: SHIMADZU LC-20AP preparative liquid phase, preparative column model Phenomenex C18, 5 μm, inner diameter × length = 19 mm × 150 mm). Preparation method: The crude product was dissolved in methanol and filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile / water (containing 0.05% ammonium bicarbonate). Gradient elution method: acetonitrile was eluted from 32% to 62% (elution time 15 min) in a gradient manner. After lyophilization, compound 4 (25 mg, 45%) was obtained.

[0332] LCMS m / z = 463.0 [M+1] +

[0333] 1 1H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.83 (d, 1H), 8.77 - 8.54 (m, 1H), 8.41 - 8.31 (m, 1H), 8.06 - 7.96 (m, 1H), 7.80 (s, 1H), 7.50 (dd, 1H), 7.16 (s, 1H), 7.10 - 7.00 (m, 1H), 6.54 - 6.37 (m, 1H), 5.49 - 5.32 (m, 1H), 3.26 - 3.19 (m, 1H), 3.00 - 2.81 (m, 3H), 2.12 - 1.97 (m, 2H), 1.71 (d, 3H).

[0334] Example 5: Preparation of Compound 5

[0335]

[0336] First step: Preparation of 5a

[0337] 2,4-Dimethoxybenzylamine (500 mg, 2.99 mmol) was added to 2e (600 mg, 1.49 mmol) in N,N-dimethylformamide (3 mL), and the reaction was carried out at 80 °C for 16 h. After cooling to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (petroleum ether:tetrahydrofuran (v:v) = 70:30) to obtain 5a (700 mg, yield 96%).

[0338] LCMS m / z = 489.2 [M+H] + 。

[0339] Step 2: Preparation of 5b

[0340] Trifluoromethanesulfonic acid (6 mL) was added to 5a (680 mg, 1.39 mmol) in trifluoroacetic acid (9 mL), and the mixture was reacted at 80 °C for 7 h. After cooling to room temperature, it was concentrated under reduced pressure. The residue was adjusted to pH 8 - 9 with saturated aqueous sodium bicarbonate solution at 0 °C, and extracted with dichloromethane (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, and the crude product was separated and purified by column chromatography (dichloromethane:methanol (v:v) = 90:10) to obtain 5b (130 mg, yield 28%).

[0341] LCMS m / z = 339.1 [M+H] +

[0342] Step 3: Preparation of 5c

[0343] Methyl 6-chloro-3-fluoropyridine-2-carboxylate (45 mg, 0.24 mmol) and N,N-diisopropylethylamine (120 mg, 0.93 mmol) were added to 5b (65 mg, 0.19 mmol) in N,N-dimethylformamide (3 mL), and the mixture was reacted at 100 °C for 16 h. After cooling to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, and the crude product was separated and purified by column chromatography (petroleum ether:tetrahydrofuran (v:v) = 75:15) to obtain 5c (50 mg, yield 52%).

[0344] LCMS m / z = 508.2 [M+H] + 。

[0345] Step 4: Preparation of Compound 5

[0346] Lithium hydroxide (12 mg, 0.50 mmol) was added to a solution of 5c (50 mg, 0.098 mmol) in tetrahydrofuran (1 mL) and water (1 mL), and the reaction was carried out at room temperature for 16 h. The mixture was concentrated under reduced pressure, and the residue was adjusted to pH 5 - 6 with 1 N aqueous hydrochloric acid at 0 °C, and then extracted with ethyl acetate (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was separated and purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.05% ammonium bicarbonate)) to obtain compound 5 (5 mg, yield 10%).

[0347] LCMS m / z = 494.1 [M + H] +

[0348] 1 H NMR (400 MHz, DMSO-d6) δ 9.04 - 8.63 (m, 2H), 8.21 - 8.11 (m, 1H), 8.04 - 7.96 (m, 1H), 7.82 (s, 1H), 7.20 (d, 1H), 6.89 (d, 1H), 5.28 - 5.17 (m, 1H), 3.26 - 3.17 (m, 1H), 3.00 - 2.78 (m, 3H), 2.20 (s, 3H), 2.12 - 1.95 (m, 2H), 1.65 (d, 3H).

[0349] Example 6: Preparation of Compound 6-A and Compound 6-B

[0350]

[0351] Compound 6 was obtained using 5b and 4a as substrates with reference to the synthesis method of Example 4. Compound 6 was purified by SFC on an AD column (instrument and preparative column: Waters 150Prep-SFC, preparative column model: Chiral OJ column. Preparation method: Compound 6 was dissolved in acetonitrile and methanol, filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: A for CO2 and B for 0.1% NH3·H2O in methanol). Gradient elution method: Isocratic elution with 20% mobile phase B (flow rate: 110 mL / min; elution time 4.0 min)), and after lyophilization, compound 6-A (compound 6-A is one of the structures of compound 6-1 and compound 6-2) and compound 6-B (compound 6-B is one of the structures of compound 6-1 and compound 6-2) were obtained.

[0352] Analysis method (instrument and preparation column: high performance liquid chromatograph – normal phase chromatography, analytical column model: Chiral OJ column; mobile phase system: A for CO2; B for 0.05% DEA in methanol; column temperature: 35 °C; flow rate: 3.0 mL / min. The retention time T = 1.142 min is for compound 6-A (compound 6-A is one of the structures of compound 6-1 and compound 6-2). The retention time T = 1.445 min is for compound 6-B (compound 6-B is one of the structures of compound 6-1 and compound 6-2).

[0353] Compound 6-A:

[0354] LCMS m / z = 477.0 [M+H] + 。

[0355] 1 H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 8.82 (d, 1H), 8.34 - 8.17 (m, 1H), 8.16 - 8.08 (m, 1H), 8.04 - 7.95 (m, 1H), 7.82 (s, 1H), 7.48 (dd, 1H), 7.18 - 7.04 (m, 1H), 6.50 - 6.37 (m, 1H), 5.33 - 5.17 (m, 1H), 3.25 - 3.17 (m, 1H), 3.00 - 2.80 (m, 3H), 2.20 (s, 3H), 2.11 - 1.98 (m, 2H), 1.64 (d, 3H).

[0356] Compound 6-B:

[0357] LCMS m / z = 477.0 [M+H] + 。

[0358] 1 H NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H), 8.82 (d, 1H), 8.55 - 8.24 (m, 1H), 8.19 - 8.08 (m, 1H), 8.04 - 7.95 (m, 1H), 7.81 (s, 1H), 7.48 (dd, 1H), 7.15 - 7.01 (m, 1H), 6.50 - 6.37 (m, 1H), 5.33 - 5.17 (m, 1H), 3.25 - 3.17 (m, 1H), 3.00 - 2.80 (m, 3H), 2.21 (s, 3H), 2.11 - 1.98 (m, 2H), 1.64 (d, 3H).

[0359] Example 7: Synthesis of Compound 7

[0360]

[0361] Compound 7 was obtained using Intermediate 2 as the raw material with reference to the synthesis method of Example 4.

[0362] LCMS m / z = 452.2 [M+1] +

[0363] 1 H NMR (400 MHz, DMSO-d6) δ 13.06 (s, 1H), 8.41 - 8.14 (m, 1H), 7.73 (s, 1H), 7.49 (dd, 1H), 7.24 - 7.15 (m, 1H), 6.50 - 6.39 (m, 1H), 6.26 (s, 1H), 5.18 - 5.04 (m, 1H), 3.30 - 3.17 (m, 1H), 3.06 - 2.83 (m, 3H), 2.62 - 2.52 (m, 6H), 2.18 - 1.98 (m, 2H), 1.64 (d, 3H).

[0364] Example 8: Synthesis of Compound 8

[0365]

[0366] Compound 8 was obtained using Intermediate 1 as the raw material with reference to the synthesis method of Example 4.

[0367] LCMS m / z = 466.2 [M+1] +

[0368] 1 H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H), 8.36 - 8.16 (m, 1H), 7.74 (s, 1H), 7.50 (dd, 1H), 7.24 - 7.13 (m, 1H), 6.49 - 6.39 (m, 1H), 5.21 - 5.06 (m, 1H), 3.27 - 3.14 (m, 1H), 3.01 - 2.81 (m, 3H), 2.74 - 2.64 (m, 6H), 2.12 - 1.96 (m, 5H), 1.64 (d, 3H).

[0369] Example 9: Synthesis of Compound 9-A and Compound 9-B

[0370]

[0371] First step: Preparation of Int-b

[0372] Int-a (5.00 g, 32.55 mmol), diphenylketimine (8.85 g, 48.82 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.50 g, 2.59 mmol) and cesium carbonate (21.21 g, 65.10 mmol) were added to 1,4-dioxane (80 mL). After purging with nitrogen, tris(dibenzylideneacetone)dipalladium(0) (1.50 g, 2.61 mmol) was added, and the mixture was reacted at 100 °C for 16 h. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether:tetrahydrofuran (v:v) = 85:15) to obtain Int-b (3.60 g, yield 44%).

[0373] LCMS m / z = 299.2 [M+1] +

[0374] Step 2: Preparation of Int-c

[0375] Int-b (6.30 g, 21.11 mmol) was added to 1,4-dioxane (60 mL) and methanol (3 mL). Hydrogen chloride - 1,4-dioxane solution (4.0 M, 252 mmol, 63 mL) was added, and the mixture was reacted at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The pH of the residue was adjusted to about 8 with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether:tetrahydrofuran (v:v) = 1:1) to obtain Int-c (2.00 g, yield 71%).

[0376] LCMS m / z = 135.1 [M+1] +

[0377] Step 3: Preparation of Int-d

[0378] Int-c (2.00 g, 14.91 mmol) was added to tetrahydrofuran (50 mL). N-Bromosuccinimide (3.18 g, 17.89 mmol) was added at 0 °C, and the mixture was reacted at room temperature for 3 h. The pH of the reaction mixture was adjusted to about 8 with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was separated and purified by column chromatography (petroleum ether:tetrahydrofuran (v:v) = 80:20) to obtain Int-d (1.40 g, yield 44%)

[0379] LCMS m / z = 213.0 [M+1] +

[0380] Step 4: Preparation of 9b

[0381] N,N'-carbonyldiimidazole (6.85 g, 42.24 mmol) was added to a solution of 9a (5.00 g, 38.43 mmol) in tetrahydrofuran (100 mL), and the reaction was carried out at room temperature for 3 h. Magnesium chloride (5.49 g, 57.66 mmol) and potassium monomethyl malonate (9.81 g, 62.81 mmol) were added, and the reaction was carried out at 45 °C for 16 h. After cooling to room temperature, 1N aqueous hydrochloric acid was added dropwise to the reaction mixture until the system became clear. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to obtain 9b (5.50 g, 77%).

[0382] LCMS m / z = 187.1 [M+1] +

[0383] Step 5: Preparation of 9c

[0384] Bismuth chloride (22 mg, 0.07 mmol) was added to a mixture of Int-d (500 mg, 2.35 mmol) and 9b (875 mg, 4.70 mmol), and the reaction was carried out at 120 °C for 36 h. After cooling to room temperature, the reaction system was separated and purified by column chromatography (petroleum ether:tetrahydrofuran (v / v) = 5:1) to obtain 9c (350 mg, 43%)

[0385] LCMS m / z = 349.0 [M+1] +

[0386] Step 6: Preparation of 9d

[0387] 9c (340 mg, 0.97 mmol), bis(triphenylphosphine)palladium(II) dichloride (68 mg, 0.10 mmol), and tributyl(1-ethoxyvinyl)tin (490 mg, 1.36 mmol) were dissolved in dioxane (5 mL). Under a nitrogen atmosphere, the reaction was carried out at 95 °C for 16 h. After cooling to room temperature, 3N aqueous hydrochloric acid (10 mL) was added and stirred for 1 h. Saturated aqueous potassium fluoride (10 mL) was added and stirred for 1 h. The mixture was filtered, and the filter cake was washed with dichloromethane (10 mL × 3). Water (10 mL) was added to the filtrate, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (dichloromethane:tetrahydrofuran (v / v) = 5:1) to obtain 9d (300 mg, 99%).

[0388] LCMS m / z = 313.2 [M+1] +

[0389] Step 7: Preparation of 9e

[0390] At 0 °C, sodium borohydride (36 mg, 0.96 mmol) was added to a solution of 9d (150 mg, 0.48 mmol) in dichloromethane (2 mL) and methanol (2 mL). The reaction was carried out at room temperature for 4 h. Saturated ammonium chloride aqueous solution (0.5 mL) and water (15 mL) were added, and the mixture was extracted with dichloromethane (15 mL x 3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 9e (150 mg, crude product).

[0391] LCMS m / z = 315.2 [M+1] +

[0392] Step 8: Preparation of 9f

[0393] At 0 °C, phosphorus tribromide (195 mg, 0.72 mmol) was added to a solution of 9e (150 mg, crude product) in dichloromethane (4 mL). The reaction was carried out at room temperature for 16 h. Saturated sodium chloride aqueous solution (1 mL) was added, and the pH value was adjusted to about 7 with saturated sodium bicarbonate aqueous solution. The mixture was extracted with dichloromethane (20 mL x 3), and the organic phases were combined. The organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 9f (180 mg, crude product).

[0394] LCMS m / z = 377.1 [M+1] +

[0395] Step 9: Preparation of 9g

[0396] 9f (180 mg, crude product) and 9h (190 mg, 0.96 mmol) were dissolved in N,N-dimethylformamide (2 mL), and the reaction was carried out at 85 °C for 16 h. After cooling to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined. The organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (dichloromethane:tetrahydrofuran (v:v) = 10:1) to obtain 9g (140 mg).

[0397] LCMS m / z = 490.4 [M+1] +

[0398] Step 10: Preparation of Compound 9

[0399] Dissolve 9 g (140 mg, 0.29 mmol) in trifluoroacetic acid (2 mL) and dichloromethane (2 mL), and react at room temperature for 4 h. Concentrate under reduced pressure to obtain a residue. Add water (2 mL), and extract with dichloromethane (10 mL × 3). Combine the organic phases. Wash the organic phase with saturated brine (5 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product is separated and purified by preparative plate to obtain Compound 9.

[0400] LCMS m / z = 434.2 [M+1] +

[0401] Step 11: Preparation of Compound 9-A and Compound 9-B

[0402] Compound 9 is purified by SFC on Chiral OD column (instrument and preparative column: Waters 150Prep-SFC, preparative column model: Chiral OD column. Preparation method: Dissolve Compound 9 in acetonitrile and methanol, and filter through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: A for CO2; B for methanol. Gradient elution method: Isocratic elution with 30% mobile phase B (flow rate: 120 mL / min; elution time 2.8 min), and after lyophilization, Compound 9-A and Compound 9-B are obtained. Analytical method (instrument and preparative column: SHIMADZU LC-30AD SFC, analytical column model: Chiral OD column, mobile phase system: A for CO2; B for 0.05% DEA in methanol, gradient elution method: Isocratic elution with 5-40% mobile phase B, column temperature: 35 °C, flow rate: 3.0 mL / min. Retention time T = 1.744 min is Compound 9-A, and retention time T = 1.923 min is Compound 9-B (one of Compound 9-A and Compound 9-B is Compound 9-1, and the other is Compound 9-2).

[0403] Compound 9-A:

[0404] LCMS m / z = 434.1 [M+H] +

[0405] 11H NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 8.77 (s, 1H), 8.60 (s, 1H), 7.77 (dd, 1H), 7.25 - 7.15 (m, 1H), 6.58 - 6.43 (m, 2H), 6.28 (s, 1H), 5.64 - 5.45 (m, 1H), 3.28 - 3.20 (m, 1H), 3.09 - 2.82 (m, 3H), 2.49 - 2.45 (m, 6H), 2.15 - 1.98 (m, 2H), 1.64 (d, 3H).

[0406] Compound 9-B:

[0407] LCMS m / z = 434.1 [M+H] +

[0408] 1 1H NMR (400 MHz, DMSO-d6) δ 12.56 (s, 1H), 8.77 (s, 1H), 8.60 (s, 1H), 7.77 (dd, 1H), 7.25 - 7.15 (m, 1H), 6.58 - 6.43 (m, 2H), 6.28 (s, 1H), 5.64 - 5.45 (m, 1H), 3.28 - 3.20 (m, 1H), 3.09 - 2.82 (m, 3H), 2.49 - 2.45 (m, 6H), 2.15 - 1.98 (m, 2H), 1.64 (d, 3H).

[0409] Example 10: Synthesis of Compound 10-A and Compound 10-B

[0410]

[0411] First step: Preparation of 10a

[0412] N-Bromosuccinimide (615 mg, 3.46 mmol) was added to a solution of 9d (900 mg, 2.88 mmol) in N,N-dimethylformamide (9 mL), and the reaction was carried out at room temperature for 2 h. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (25 mL × 3). The organic phases were combined. The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (dichloromethane:tetrahydrofuran (v:v) = 5:1) to obtain 10a (900 mg, yield: 80%).

[0413] LCMS m / z = 391.0 [M+H] +

[0414] Second step: Preparation of 10b

[0415] Bis(triphenylphosphine)palladium(II) dichloride (45 mg, 0.06 mmol), potassium carbonate (442 mg, 3.20 mmol), and methylboronic acid (153 mg, 2.56 mmol) were added to a solution of 10a (500 mg, 1.28 mmol) in dioxane (5 mL) and water (0.5 mL). The reaction was carried out at 95 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (25 mL × 3). The organic layers were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:tetrahydrofuran (v:v) = 10:1) to give 10b (110 mg, yield: 27%).

[0416] LCMS m / z = 327.2 [M+H] +

[0417] Compound 10 was obtained using 10b as a substrate according to the synthesis method of Example 9.

[0418] LCMS m / z = 448.2 [M+H] +

[0419] Preparation of Compound 10-A and Compound 10-B

[0420] Compound 10 was purified by SFC on a Chiral AD column (instrument and preparative column: Waters 150Prep-SFC, preparative column model: Chiral AD column. Preparation method: Compound 10 was dissolved in acetonitrile and methanol, filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: A for CO2; B for 0.1% NH3·H2O in isopropanol. Gradient elution method: Isocratic elution with 25% mobile phase B (flow rate: 100 mL / min; elution time 5 min), and after lyophilization, Compound 10-A and Compound 10-B were obtained.

[0421] Analysis method (instrument and preparative column: SHIMADZU LC-30AD SFC, analytical column model: Chiral AD column, mobile phase system: A for CO2; B for 0.05% DEA in isopropanol, gradient elution method: Isocratic elution with 5-40% mobile phase B, column temperature: 35 °C, flow rate: 3.0 mL / min. Retention time T = 1.503 min for Compound 10-A, retention time T = 1.612 min for Compound 10-B (one of Compound 10-A and Compound 10-B is Compound 10-1, and the other is Compound 10-2).

[0422] Compound 10-A:

[0423] LCMS m / z = 448.2 [M+H] +

[0424] 1 H NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 8.69 (s, 1H), 8.55 (s, 1H), 7.77 (dd, 1H), 7.25 - 7.15 (m, 1H), 6.58 - 6.43 (m, 2H), 5.64 - 5.45 (m, 1H), 3.28 - 3.17 (m, 1H), 3.05 - 2.81 (m, 3H), 2.69 - 2.54 (m, 6H), 2.20 (s, 3H), 2.10 - 1.98 (m, 2H), 1.65 (d, 3H).

[0425] Compound 10-B:

[0426] LCMS m / z = 448.2 [M+H] +

[0427] 1 H NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 8.69 (s, 1H), 8.55 (s, 1H), 7.77 (dd, 1H), 7.25 - 7.15 (m, 1H), 6.58 - 6.43 (m, 2H), 5.64 - 5.45 (m, 1H), 3.28 - 3.17 (m, 1H), 3.05 - 2.81 (m, 3H), 2.69 - 2.54 (m, 6H), 2.20 (s, 3H), 2.10 - 1.98 (m, 2H), 1.65 (d, 3H).

[0428] Example 11: Synthesis of Compound 11-A and Compound 11-B

[0429]

[0430] First step: Preparation of 11a

[0431] At 0 °C, sodium borohydride (210 mg, 5.55 mmol) was added to a solution of 10a (1.80 g, 4.60 mmol) in dichloromethane (20 mL) and methanol (20 mL), and the reaction was carried out at 0 °C for 2 h. Saturated ammonium chloride aqueous solution (10 mL) was added, and the mixture was extracted with dichloromethane (25 mL x 3). The organic phases were combined. The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (dichloromethane:tetrahydrofuran (v:v) = 10:1) to obtain 11a (1.10 g, yield: 61%).

[0432] LCMS m / z = 393.0 [M+H] +

[0433] Step 2: Preparation of 11b

[0434] Add palladium(0) tris(triphenylphosphine) (970 mg, 0.84 mmol) and zinc cyanide (1.64 g, 14.00 mmol) to a solution of 11a (1.10 g, 2.80 mmol) in N,N-dimethylformamide (15 mL). React at 100 °C for 16 h under a nitrogen atmosphere. Cool to room temperature, add water (20 mL), and extract with ethyl acetate (25 mL × 3). Combine the organic phases. Wash the organic phase with saturated brine (10 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product is separated and purified by column chromatography (methylene chloride:tetrahydrofuran (v:v) = 10:1) to obtain 11b (700 mg, yield: 74%).

[0435] LCMS m / z = 340.1 [M+H] +

[0436] Preparation of Compound 11

[0437] Compound 11 is obtained using 11b as the substrate with reference to the synthesis method of Example 9.

[0438] LCMS m / z = 459.1 [M+H] +

[0439] Compound 11 is purified by SFC on Chiral Cellulose-2 column (instrument and preparative column: Waters 150 Prep-SFC, preparative column model: Chiral Cellulose-2 column. Preparation method: Dissolve Compound 11 in acetonitrile and methanol, filter through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: A for CO2; B for methanol and acetonitrile. Gradient elution method: Isocratic elution with 52% mobile phase B (flow rate: 100 mL / min; elution time 4 min), and after lyophilization, Compound 11-A and Compound 11-B are obtained).

[0440] Analysis method (instrument and preparation column: SHIMADZU LC-30AD SFC, analytical column model: ChiralCellulose-2 column, mobile phase system: A for CO2; B for 0.05% DEA in methanol and acetonitrile, gradient elution method: isocratic elution with 40% mobile phase B, column temperature: 35 °C, flow rate: 3.0 mL / min. The retention time T = 1.081 min is for compound 11-A, and the retention time T = 1.414 min is for compound 11-B (one of compound 11-A and compound 11-B is compound 11-1, and the other is compound 11-2).

[0441] Compound 11-A:

[0442] LCMS m / z = 459.1 [M+H] +

[0443] 1 H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 8.86 (s, 1H), 8.57 (d, 1H), 7.77 (dd, 1H), 7.27 - 7.16 (m, 1H), 6.58 - 6.43 (m, 2H), 5.64 - 5.45 (m, 1H), 3.41 - 3.31 (m, 1H), 3.14 - 2.90 (m, 3H), 2.73 - 2.63 (m, 6H), 2.17 - 2.01 (m, 2H), 1.65 (d, 3H).

[0444] Compound 11-B:

[0445] LCMS m / z = 459.1 [M+H] +

[0446] 1 H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.86 (s, 1H), 8.57 (d, 1H), 7.77 (dd, 1H), 7.27 - 7.16 (m, 1H), 6.58 - 6.43 (m, 2H), 5.64 - 5.45 (m, 1H), 3.41 - 3.31 (m, 1H), 3.14 - 2.90 (m, 3H), 2.73 - 2.63 (m, 6H), 2.17 - 2.01 (m, 2H), 1.65 (d, 3H).

[0447] Example 12: Preparation of Compound 12-A and Compound 12-B

[0448]

[0449] 12a (1.15 g, 7.18 mmol) and Int-d (1.0 g, 4.69 mmol) were added to a solution of ethylene glycol (20 mL), and the mixture was stirred at 100 °C for 16 h. After cooling to room temperature, water (30 mL) was added, and the mixture was extracted twice with ethyl acetate (40 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (dichloromethane:tetrahydrofuran (v:v) = 4:1) to obtain 12b (1.2 g, yield 75%).

[0450] LCMS m / z = 341.1 [M+H] +

[0451] Compound 12 was obtained using 12b as the starting material with reference to the synthesis method of Example 9.

[0452] LCMS m / z = 426.1 [M+H] +

[0453] Compound 12 was purified by SFC on an IK column (instrument and preparative column: Waters 150Prep-SFC, preparative column model: Chiral IK column. Preparation method: Compound 12 was dissolved in acetonitrile and filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: A for CO2; B for 0.1% DEA in ethanol. Gradient elution method: Isocratic elution with 45% mobile phase B (flow rate: 120 mL / min; elution time 4.6 min)). After lyophilization, Compound 12-A and Compound 12-B were obtained. Analytical method (instrument and preparative column: SHIMADZU LC-30AD SFC, analytical column model: Chiral IK column, mobile phase system: A for CO2; B for 0.05% DEA in ethanol, gradient elution method: Isocratic elution with 40% mobile phase B, column temperature: 35 °C, flow rate: 3.0 mL / min). The retention time T = 1.131 min was for Compound 12-A, and the retention time T = 1.519 min was for Compound 12-B (one of Compound 12-A and Compound 12-B is Compound 12-1, and the other is Compound 12-2).

[0454] Compound 12-A

[0455] LCMS m / z = 426.2 [M+H] +

[0456] 11H NMR (400 MHz, DMSO-d6) δ 12.66 (s, 1H), 8.40 (s, 1H), 7.80 (dd, 1H), 7.66 - 7.56 (m, 5H), 7.51 (s, 1H), 7.29 - 7.17 (m, 1H), 6.53 (t, 1H), 6.42 (d, 1H), 6.28 (s, 1H), 5.70 - 5.57 (m, 1H), 3.24 - 3.11 (m, 1H), 2.80 - 2.61 (m, 2H), 2.60 - 2.51 (m, 1H), 1.97 - 1.82 (m, 2H), 1.57 (d, 3H).

[0457] Compound 12-B

[0458] LCMS m / z = 426.1 [M+H] +

[0459] 1 1H NMR (400 MHz, DMSO-d6) δ 12.65 (s, 1H), 8.52 (s, 1H), 7.80 (dd, 1H), 7.66 - 7.56 (m, 5H), 7.50 (s, 1H), 7.29 - 7.17 (m, 1H), 6.51 (t, 1H), 6.40 (d, 1H), 6.27 (s, 1H), 5.70 - 5.57 (m, 1H), 3.24 - 3.11 (m, 1H), 2.80 - 2.61 (m, 2H), 2.60 - 2.51 (m, 1H), 1.97 - 1.82 (m, 2H), 1.56 (d, 3H).

[0460] Example 13: Preparation of Compound 13-A and Compound 13-B

[0461]

[0462] Compound 13 was obtained using 13a as the starting material with reference to the synthesis method of Example 12.

[0463] Compound 13 was purified by SFC on an IG column (instrument and preparative column: Waters 150Prep-SFC, preparative column model: Chiral IG column. Preparation method: Compound 13 was dissolved in acetonitrile and filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: A for CO2; B for 0.1% NH3·H2O in ethanol and acetonitrile. Gradient elution method: Isocratic elution with 50% mobile phase B (flow rate: 110 mL / min; elution time 9.0 min)), and after lyophilization, Compound 13-A and Compound 13-B were obtained. Analytical method (instrument and preparative column: SHIMADZU LC-30AD SFC, analytical column model: Chiral IG column, mobile phase system: A for CO2; B for 0.05% DEA in ethanol and acetonitrile, gradient elution method: Isocratic elution with 40% mobile phase B, column temperature: 35 °C, flow rate: 3.0 mL / min.). The retention time T = 0.925 min was for Compound 13-A, and the retention time T = 1.259 min was for Compound 13-B (for Compound 13-A and Compound 13-B, one is Compound 13-1 and the other is Compound 13-2).

[0464] Compound 13-A

[0465] LCMS m / z = 444.2 [M+H] +

[0466] 1 H NMR (400 MHz, DMSO-d6) δ 12.65 (s, 1H), 8.57 (s, 1H), 7.80 (dd, 1H), 7.69 - 7.60 (m, 1H), 7.58 - 7.50 (m, 2H), 7.49 - 7.40 (m, 2H), 7.19 (t, 1H), 6.51 (t, 1H), 6.39 (d, 1H), 6.31 (s, 1H), 5.67 - 5.54 (m, 1H), 3.23 - 3.12 (m, 1H), 2.84 - 2.62 (m, 2H), 2.61 - 2.52 (m, 1H), 1.98 - 1.79 (m, 2H), 1.56 (d, 3H).

[0467] Compound 13-B

[0468] LCMS m / z = 444.2 [M+H] +

[0469] 11H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.56 (s, 1H), 7.80 (dd, 1H), 7.69 - 7.60 (m, 1H), 7.58 - 7.50 (m, 2H), 7.49 - 7.40 (m, 2H), 7.20 (t, 1H), 6.51 (t, 1H), 6.39 (d, 1H), 6.31 (s, 1H), 5.67 - 5.54 (m, 1H), 3.23 - 3.12 (m, 1H), 2.84 - 2.62 (m, 2H), 2.61 - 2.52 (m, 1H), 1.98 - 1.79 (m, 2H), 1.56 (d, 3H).

[0470] Example 14: Synthesis of Compound 14-A and Compound 14-B

[0471]

[0472] Step 1: Preparation of 14b

[0473] Add N,N-dimethylformamide (0.05 mL) and oxalyl chloride (4.02 g, 31.68 mmol) to dichloromethane (40 mL) of 14a (2.49 g, 21.12 mmol), and react at room temperature for 2 h. Concentrate under reduced pressure at 30 °C to obtain 14b (crude product).

[0474] Step 2: Preparation of 14c

[0475] At 0 °C, add intermediate d (4.50 g, 21.12 mmol) to the dichloromethane (40 mL) solution of 14b (crude product), and react at room temperature for 48 h. Filter to obtain 14c (3.00 g, overall yield in two steps: 48%).

[0476] LCMS m / z = 295.0 [M+1] +

[0477] Step 3: Preparation of 14d

[0478] Dissolve 14c (3.00 g, 10.17 mmol), potassium carbonate (4.22 g, 30.51 mmol), and benzyl bromide (2.61 mmol, 15.25 mmol) in N,N-dimethylformamide (30 mL), and react at 100 °C for 1 h. Cool to room temperature, add water (20 mL), extract with ethyl acetate (30 mL × 3), and combine the organic phases. Dry the organic phase over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain the crude product, and purify the crude product by column chromatography (petroleum ether:tetrahydrofuran (v:v) = 10:1) to obtain 14d (2.80 g, yield: 72%).

[0479] LCMS m / z = 385.0 [M+1] +

[0480] Step 4: Preparation of 14e

[0481] Dissolve 14d (2.30 g, 5.97 mmol), bis(triphenylphosphine)palladium(II) dichloride (420 mg, 0.60 mmol), and tributyl(1-ethoxyvinyl)stannane (3.02 g, 8.36 mmol) in dioxane (30 mL), and react at 95 °C for 16 h. Cool to room temperature, add 3N hydrochloric acid aqueous solution (10 mL), stir for 1 h, add saturated potassium fluoride aqueous solution (10 mL), and stir for 1 h. Filter, and wash the filter cake with dichloromethane (10 mL x 3). Add water (20 mL) to the filtrate, and extract with dichloromethane (20 mL x 3). Combine the organic phases, wash the organic phases with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product is separated and purified by column chromatography (dichloromethane:tetrahydrofuran (v / v) = 5:1) to obtain 14e (2.00 g, yield: 96%).

[0482] LCMS m / z = 349.2 [M+1] +

[0483] Step 5: Preparation of 14f

[0484] At 0 °C, add sodium borohydride (290 mg, 7.57 mmol) to a solution of 14d (2.20 g, 6.31 mmol) in dichloromethane (10 mL) and methanol (10 mL), and react at room temperature for 4 h. Add saturated ammonium chloride aqueous solution (2 mL) and water (15 mL), and extract with dichloromethane (15 mL x 3). Combine the organic phases, wash the organic phases with saturated brine (5 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 14f (2.20 g, crude product).

[0485] LCMS m / z = 351.2 [M+1] +

[0486] Step 6: Preparation of 14g

[0487] At 0 °C, add phosphorus tribromide (930 mg, 3.42 mmol) to a solution of 14f (1.00 g, crude product) in dichloromethane (10 mL), and react at room temperature for 16 h. Add water (10 mL), and extract with dichloromethane (20 mL x 3). Combine the organic phases, wash the organic phases with saturated brine (15 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 14g (1.10 g, crude product).

[0488] LCMS m / z = 413.1 [M+1] +

[0489] Step 7: Preparation of 14h

[0490] Dissolve 14g (1.10g, crude product), methyl anthranilate (800mg, 5.32mmol) in N,N-dimethylformamide (10mL), and react at 85°C for 16h. Cool to room temperature, add water (10mL), and extract with ethyl acetate (15mL x 3). Combine the organic phases, wash the organic phase with saturated brine (5mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product is separated and purified by column chromatography (dichloromethane:tetrahydrofuran (v:v) = 10:1) to obtain 14h (900mg).

[0491] LCMS m / z = 484.2 [M+1] +

[0492] Step 8: Preparation of 14j

[0493] Add palladium hydroxide (90mg, palladium hydroxide content 10%, water content 55%) to a solution of 14h (900mg, 1.86mmol) in ethyl acetate (10mL), and react at room temperature for 2h. Filter, and concentrate the filtrate under reduced pressure to obtain 14j (700mg, yield: 96%).

[0494] LCMS m / z = 394.1 [M+1] +

[0495] Step 9: Preparation of 14k

[0496] At 0°C, add trifluoromethanesulfonic anhydride (260mg, 0.91mmol) to a solution of 14j (300mg, 0.76mmol) and N,N-diisopropylethylamine (200mg, 1.67mmol) in dichloromethane (10mL), and react at 0°C for 5min. Add water (10mL), extract with dichloromethane (20mL x 3), and combine the organic phases. Wash the organic phase with saturated brine (5mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product is separated and purified by column chromatography (petroleum ether:tetrahydrofuran (v:v) = 10:1) to obtain 14k (170mg, yield: 42%).

[0497] LCMS m / z = 526.1 [M+1] +

[0498] Step 10: Preparation of 14m

[0499] Add dichloromethane complex of [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (26 mg, 0.03 mmol) and potassium carbonate (133 mg, 0.96 mmol) to a solution of 14k (170 mg, 0.32 mmol) and 3-fluorobenzeneboronic acid (90 mg, 0.64 mmol) in dioxane (8 mL) and water (4 mL). Under nitrogen protection, react at 100 °C for 2 h. Cool to room temperature, add water (10 mL), and extract with ethyl acetate (20 mL × 3). Combine the organic phases. Wash the organic phase with saturated brine (5 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product is separated and purified by column chromatography (petroleum ether:tetrahydrofuran (v:v) = 10:1) to obtain 14m (120 mg, yield: 79%).

[0500] LCMS m / z = 472.2 [M+1] +

[0501] Step 11: Preparation of Compound 14

[0502] Add lithium hydroxide (5 mg, 0.11 mmol) to a mixed solution of 14m (10 mg, 0.02 mmol) in methanol (1 mL) and water (1 mL). React at 40 °C for 16 h. Cool to room temperature, adjust the pH to about 3 with 1N hydrochloric acid, add water (10 mL), and extract with ethyl acetate (10 mL × 3). Combine the organic phases. Wash the organic phase with saturated brine (5 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product is separated and purified by preparative plate (dichloromethane:tetrahydrofuran (v:v) = 5:1) to obtain Compound 14.

[0503] LCMS m / z = 458.1 [M+1] +

[0504] Step 12: Preparation of Compound 14-A and Compound 64B

[0505] Compound 6 is purified by SFC to obtain Compound 14-A and Compound 14-B (Compound 14-A and Compound 14-B, one of which is Compound 14-1 and the other is Compound 14-2).

[0506] Compound 14-A

[0507] LCMS m / z = 458.2 [M+1] +

[0508] 11H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.78 (s, 1H), 8.49 (s, 1H), 7.78 (d, 1H), 7.65 - 7.51 (m, 3H), 7.41 - 7.27 (m, 1H), 7.17 (t, 1H), 6.49 (t, 1H), 6.42 (d, 1H), 5.81 - 5.67 (m, 1H), 3.28 - 3.15 (m, 1H), 3.03 - 2.76 (m, 3H), 2.23 (s, 3H), 2.09 - 1.95 (m, 2H), 1.60 (d, 3H).

[0509] Compound 14-B

[0510] LCMS m / z = 458.2 [M+1] +

[0511] 1 1H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 8.78 (s, 1H), 8.48 (s, 1H), 7.78 (d, 1H), 7.65 - 7.51 (m, 3H), 7.41 - 7.27 (m, 1H), 7.17 (t, 1H), 6.49 (t, 1H), 6.42 (d, 1H), 5.81 - 5.67 (m, 1H), 3.28 - 3.15 (m, 1H), 3.03 - 2.76 (m, 3H), 2.23 (s, 3H), 2.09 - 1.95 (m, 2H), 1.60 (d, 3H).

[0512] Example 15: Synthesis of Compound 15-A and Compound 15-B

[0513]

[0514] Compound 15 was obtained using 14k and methyl anthranilate as substrates with reference to the synthesis method of Example 7.

[0515] LCMS m / z = 440.1 [M+H] +

[0516] Compound 15 was purified by SFC to obtain Compound 15-A and Compound 15-B (one of Compound 15-A and Compound 15-B is Compound 15-1, and the other is Compound 15-2).

[0517] Compound 15-A

[0518] LCMS m / z = 440.2 [M+H] +

[0519] 11H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 8.77 (s, 1H), 8.46 (s, 1H), 7.83 - 7.71 (m, 3H), 7.58 - 7.46 (m, 3H), 7.17 (t, 1H), 6.49 (t, 1H), 6.42 (d, 1H), 5.89 - 5.65 (m, 1H), 3.28 - 3.15 (m, 1H), 3.03 - 2.76 (m, 3H), 2.23 (s, 3H), 2.09 - 1.95 (m, 2H), 1.59 (d, 3H).

[0520] Compound 15-B

[0521] LCMS m / z = 440.2 [M+H] +

[0522] 1 1H NMR (400 MHz, DMSO-d6) δ 12.65 (s, 1H), 8.77 (s, 1H), 8.48 (s, 1H), 7.83 - 7.71 (m, 3H), 7.58 - 7.46 (m, 3H), 7.16 (t, 1H), 6.49 (t, 1H), 6.41 (d, 1H), 5.89 - 5.65 (m, 1H), 3.28 - 3.15 (m, 1H), 3.03 - 2.76 (m, 3H), 2.23 (s, 3H), 2.09 - 1.95 (m, 2H), 1.59 (d, 3H).

[0523] Biological test examples

[0524] 1. Inhibitory experiment on MDA-MB-453 cell proliferation

[0525] MDA-MB-453 cells (ATCC, Cat#30-2008) were cultured in L-15 medium (supplemented with 10% FBS and 1% penicillin-streptomycin) under CO2-free conditions. When the cell confluence reached 80%-90%, the cells were collected and seeded. The medium was discarded, and the cells were rinsed with 1×PBS and then digested with trypsin (Gibco, Cat#15400-054). When the cells became round and began to detach, the digestion was terminated by adding medium. The cells were pipetted down and transferred to a sterile centrifuge tube, centrifuged at 1000 rpm for 3 minutes. After centrifugation, the supernatant was discarded. The cells in the centrifuge tube were resuspended with medium and counted. According to the counting results, the cell suspension was adjusted to an appropriate concentration and then added to a 96-well cell culture plate (Corning, Cat#3903). The compound was dissolved in DMSO to 10 mM for storage, and during the experiment, the compound stock solution was serially diluted. Twenty-four hours after seeding, the compound was added, and the cells were further cultured for 4 days at 37°C under CO2-free conditions. After incubation, CELL VIABILITY reagent (Promega, Cat#G7573) was added to each well and incubated at room temperature for 10 minutes. After incubation, the plate was gently shaken 5 times, and then the chemiluminescence readings were detected using a BMG microplate reader (PHERAstar FSX). The cell proliferation inhibition rate was calculated according to the formula: [(1–(RLU compound –RLU blank ) / (RLU control –RLU blank ))×100%]. The IC 50 value was obtained by four-parameter non-linear fitting using GraphPad Prism software.

[0526] Conclusion: The compounds of the present invention, such as the compounds of the examples, have good inhibitory activity against MDA-MB-453 cells.

[0527] Table 1 Cell proliferation inhibitory activity of the compounds against MDA-MB-453 cells

[0528] Serial number Compound number <![CDATA[GI 50 (nM)]]> 1 Compound 10-A ＜100 2 Compound 11-B ＜100

[0529] Conclusion: The compounds of the present invention, such as the compounds of the examples, have good inhibitory activity against MDA-MB-453 cells.

[0530] 2. T47D cell proliferation inhibition assay

[0531] T47D cells (ATCC, Cat#HTB-133) were cultured with RPMI Medium 1640 (with 10% FBS, 1% double antibody and 0.02mg / mL bovine insulin) at 37°C and 5% CO2. When the cell confluence reached 80%-90%, the cells were collected and plated. The culture medium was discarded, and trypsin (Gibco, Cat#15400-054) was added for digestion after rinsing with 1×PBS. When the cells became round and began to fall off, the culture medium was added to terminate the digestion. The cells were blown down and transferred to a sterile centrifuge tube, centrifuged at 1000rpm for 3 minutes, and the supernatant was discarded. The centrifuge tube was added with culture medium to resuspend the cells and counted. According to the counting results, the cell suspension was adjusted to an appropriate concentration and added to a 96-well cell culture plate (LABSELECT, Cat#11515). The compound was dissolved to 10mM with DMSO and stored for later use. The compound mother solution was diluted in sequence during the experiment. Compounds were added 24 hours after plating, and the culture was continued for 4 days at 37°C and 5% CO2. After the incubation, CELL VIABILITY reagent (Promega, Cat#G7573) was added to each well, and the cells were gently shaken for 3 minutes, incubated at room temperature for 10 minutes, and then the chemiluminescence readings were detected using a BMG microplate reader (PHERAstar FSX). The formula [(1–(RLU compound –RLU blank ) / (RLU control –RLU blank )) × 100%] to calculate the cell proliferation inhibition rate. The IC was obtained by four-parameter nonlinear fitting using GraphPad Prism software. 50 value.

[0532] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good inhibitory activity against T47D cells.

[0533] 3. PI3K enzyme activity test method

[0534] The compounds were serially diluted with DMSO in a 384PP Plate compound dilution plate, and 0.1 μL of the compounds was transferred to a 384-well reaction microplate (Optiplate 384) using Echo, ensuring that the final concentration of DMSO was 1% (duplicate wells). 5 μL of 2X enzyme solution (PIK3CA, PIK3CA[H1047R]) was added to each well of the 384-well reaction microplate, centrifuged at 1000 rpm for 1 minute, and incubated at 25 °C for 10 minutes. 5 μL of 2X ATP and PIP2:3PS solution was added to each well, centrifuged at 1000 rpm for 1 minute, and incubated at 25 °C for 180 minutes. 5 μL of ADP-Glo Reagent was added to each well, centrifuged at 1000 rpm for 1 minute, and incubated at 25 °C for 40 minutes. 10 μL of ADP-Glo Detection buffer was added to each well, centrifuged at 1000 rpm for 1 minute, and incubated at 25 °C for 40 minutes. The RLU (Relative luminescence unit) signal was read on a BMG (PHERAstar FSX) microplate reader. The wells containing 1% DMSO and enzyme were used as High Control, and the wells containing 1% DMSO and buffer were used as Low Control. The percentage of inhibition of the compound-treated wells was normalized between High Control and Low Control (% inhibition = (RLU HighControl - RLU compound reading) / (RLU High Control - RLU Low Control) * 100). Then, a four-parameter IC 50 curve was fitted and analyzed using XLfit5.5.0, and the IC 50 is the compound concentration corresponding to an inhibition rate of 50%.

[0535] Table 2 Inhibitory activities of the compounds against PIK3CA[H1047R] and WT PIK3CA enzymes

[0536]

[0537] Conclusion: The compounds of the present invention, such as the example compounds, have good inhibitory activity against the PIK3CA[H1047R] enzyme, poor inhibitory activity against the WT PIK3CA enzyme, and good selectivity.

[0538] 4. Inhibitory effect of the compounds on P-AKT in cells

[0539] 4.1 Inhibitory effect of the compounds on P-AKT in MDA-MB-453 cells

[0540] MDA-MB-453 cells (ATCC, Cat# HTB-131) were cultured in L-15 medium (supplemented with 10% FBS and 1% penicillin-streptomycin) at 37°C under a CO2-free condition. When the cell confluence reached 80%-90%, the cells were collected for seeding. The medium was discarded, and the cells were rinsed with 1×PBS and then digested with trypsin (Gibco, Cat# 15400-054). When the cells became round and started to detach, the digestion was terminated by adding medium. The cells were pipetted down and transferred to a sterile centrifuge tube, centrifuged at 1000 rpm for 3 minutes. After centrifugation, the supernatant was discarded. The cells in the centrifuge tube were resuspended with medium and counted. According to the counting results, the cell suspension was adjusted to an appropriate concentration and then added to a 384-well plate (Perkin Elmer, Cat: 6007680). The compound was dissolved in DMSO to 10 mM for storage. During the experiment, the compound stock solution was serially diluted. Eighteen hours after seeding, the compound was added, and the cells were further cultured at 37°C under a CO2-free condition for 2 h. After incubation, Lysis Buffer (Perkin Elmer, Cat: ALSU-PAKT-B500) was added to each well and shaken at room temperature for 10 minutes. Acceptor Mix was added to each well, shaken at room temperature for 1-2 min to mix evenly, and then incubated at room temperature for 1 h. Donor Mix was added to each well, shaken at room temperature for 1-2 min in the dark to mix evenly, and then incubated at room temperature for 1 h. Then, it was detected using a BMG microplate reader (PHERAstar FSX), and the IC 50 value was obtained by four-parameter non-linear fitting using GraphPad Prism software.

[0541] 4.2 Inhibitory effect of the compound on P-AKT in SKBR3 cells

[0542] SKBR3 cells (ATCC, Cat# HTB-30) were cultured in McCoy's 5A Medium supplemented with 10% FBS and 1% penicillin-streptomycin at 37°C under 5% CO2. Cells were harvested for seeding when the confluence reached 80%-90%. The medium was discarded, and the cells were rinsed with 1×PBS and then digested with trypsin (Gibco, Cat# 15400-054). When the cells became round and started to detach, the digestion was terminated by adding medium. The cells were pipetted down and transferred to a sterile centrifuge tube, centrifuged at 1000 rpm for 3 minutes. After centrifugation, the supernatant was discarded. The cells in the centrifuge tube were resuspended with medium and counted. According to the counting results, the cell suspension was adjusted to an appropriate concentration and then added to a 384-well plate (Perkin Elmer, Cat: 6007680). The compound was dissolved in DMSO to 10 mM for storage. During the experiment, the stock solution of the compound was serially diluted. 18 hours after seeding, the compound was added, and the cells were further cultured at 37°C under 5% CO2 for 2 h. After incubation, Lysis Buffer (Perkin Elmer, Cat: ALSU-PAKT-B500) was added to each well and shaken at room temperature for 10 minutes. Acceptor Mix was added to each well, shaken at room temperature for 1-2 min to mix evenly, and then incubated at room temperature for 1 h. Donor Mix was added to each well, shaken at room temperature for 1-2 min in the dark to mix evenly, and then incubated at room temperature for 1 h. Then, it was detected with a BMG microplate reader (PHERAstar FSX), and the IC 50 value was obtained by four-parameter non-linear fitting using GraphPad Prism software.

[0543] Test results: The compounds of the present invention, such as the compounds of the examples, have good inhibitory activity against P-AKT in MDA-MB-453 cells, poor inhibitory activity against P-AKT in SKBR3 cells, and good selectivity.

[0544] 5. Inhibitory effect of the compound on glucose uptake in human adipocytes

[0545] 3T3-L1 differentiated adipocytes were cultured in a 96-well plate, and on the day of the experiment, they were changed to DMEM medium without FBS for starvation culture for 2 hours. The compound was dissolved to 10mM with DMSO and stored for later use. The compound mother solution was diluted in sequence during the experiment. After washing the 3T3-L1 adipocytes with buffer, the compound was added to the corresponding wells and incubated at 37°C in a 5% CO2 incubator for 60 minutes. 25μL human insulin was added to the human insulin control well, the drug addition well, and the negative well (containing 100μM cytochalasin B), and 25μL experimental buffer was added to the blank control well, and incubated at 37°C in a 5% CO2 incubator for 10 minutes. [3H]-deoxy-d-glucose solution was prepared with experimental buffer, added to the detection well, and incubated at 37°C in a 5% CO2 incubator for 20 minutes. The solution in the detection well was removed and washed with cold DPBS to stop the reaction. Adipocytes were lysed with 10% NaOH, and the lysate was transferred to a Pico Prias tube and Ultima Gold was added. The reading was then performed using Tri-Carb (PerkinElmer, 4910TR), and the IC50 value was obtained by four-parameter nonlinear fitting using GraphPad Prism software.

[0546] Test results: The compounds of the present invention have poor inhibitory activity on glucose uptake in human adipocytes and do not cause side effects of hyperglycemia.

[0547] 5. Pharmacokinetic Test in Mice

[0548] 5.1 Experimental animals: Male Balb / c mice, about 22 g, 6 to 8 weeks old, 6 mice / compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0549] 5.2 Experimental design: On the day of the experiment, Balb / c mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours one day before administration and fed 4 hours after administration.

[0550] Table 5. Dosing Information

[0551]

[0552] Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; intragastric administration solvent: 0.5% MC

[0553] Before and after drug administration, 0.03 ml of blood was collected from the eye socket under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 2, 5, 15, 30 min, 1, 2, 4, and 7 h; all samples were stored at -80°C before analysis and testing.

[0554] Conclusion: The compounds of the present invention, such as the compounds of the examples, have good pharmacokinetic properties, with high exposure and good bioavailability in mice.

[0555] 6. Rat Pharmacokinetic Test

[0556] 6.1 Test Animals: Male SD rats, about 220 g, 6 - 8 weeks old, 6 rats per compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0557] 6.2 Test Design: On the day of the test, the SD rats were randomly grouped by body weight. They were fasted but allowed water for 12 - 14 h one day before dosing, and fed 4 h after dosing.

[0558] Table 7. Dosing Information

[0559]

[0560] Note: Solvent for intravenous administration: 5% DMA + 5% Solutol + 90% Saline; Solvent for gavage administration: 0.5% MC

[0561] (DMA: Dimethylacetamide; Solutol: Polyethylene glycol - 15 - hydroxystearate; Saline: Normal saline; MC: Methylcellulose)

[0562] Before and after dosing, 0.15 ml of blood was taken from the orbit under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, centrifuged at 5000 rpm at 4°C for 10 min, and plasma was collected. The blood sampling time points for both the intravenous group and the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h. Before analysis and detection, all samples were stored at -80°C, and the samples were quantitatively analyzed by LC - MS / MS.

[0563] Conclusion: The compounds of the present invention, such as the compounds of the examples, have good pharmacokinetic properties, with high exposure and good bioavailability in rats.

[0564] 7. CYP450 Enzyme Inhibition Test

[0565] The purpose of this study was to evaluate the effects of the test substance on the activities of five isozymes of cytochrome P450 (CYP) in human liver microsomes (CYP1A2, CYP2C19, CYP2D6, and CYP3A4) using an in vitro test system. The specific probe substrates of CYP450 isozymes were incubated with human liver microsomes and different concentrations of the test substance, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction ended, the samples were processed and the metabolites produced by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS) method to determine the changes in CYP enzyme activity, calculate the IC50 value, and evaluate the inhibitory potential of the test substance on each CYP enzyme subtype.

[0566] Conclusion: The compounds of the present invention, such as the compounds of the examples, have poor inhibitory activity against CYP enzymes.

[0567] 8. hERG potassium channel function test

[0568] Experimental platform: Electrophysiological manual patch clamp system

[0569] Cell line: Chinese Hamster Ovary (CHO) cell line stably expressing hERG potassium channel

[0570] Experimental method: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channel were used to record hERG potassium channel current by whole-cell patch clamp technique at room temperature. The glass microelectrode was pulled from a glass electrode blank (BF150-86-10, Sutter) by a puller, and the tip resistance after perfusion with the electrode internal solution was about 2-5 MΩ. The glass microelectrode was inserted into the amplifier probe and then connected to the patch clamp amplifier. The clamping voltage and data recording were controlled and recorded by pClamp 10 software through a computer, with a sampling frequency of 10 kHz and a filtering frequency of 2 kHz. After obtaining the whole-cell recording, the cell was clamped at -80 mV, and a 2 s depolarizing voltage from -80 mV to +20 mV was given to induce the hERG potassium current (I hERG ) The step voltage was then repolarized to -50 mV, held for 1 s, and then returned to -80 mV. This voltage stimulation was given every 10 s. After the hERG potassium current was stable (at least 1 minute), the drug administration process was started. Each test concentration of the compound was given for at least 1 minute, and at least 2 cells were tested for each concentration (n≥2).

[0571] Data processing: Data analysis and processing were performed using pClamp 10, GraphPad Prism 5, and Excel software. The inhibition degree of different compound concentrations on the hERG potassium current (peak value of the hERG tail current induced at -50 mV) was calculated using the following formula:

[0572] Inhibition% = [1–(I / Io)]×100%

[0573] Among them, Inhibition% represents the inhibition percentage of the compound on the hERG potassium current, and I and Io represent the amplitudes of the hERG potassium current after and before adding the drug, respectively.

[0574] Compound IC 50 Calculated by fitting through the following equation using GraphPad Prism 5 software:

[0575] Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X)*HillSlope))

[0576] Among them, X is the Log value of the test sample detection concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0577] Conclusion: The compounds of the present invention, such as the compounds in the examples, have poor inhibitory activity on hERG.

[0578] 9. Liver microsome stability test

[0579] In this experiment, human liver microsomes were used as an in vitro model to evaluate the metabolic stability of the test substance.

[0580] Under the condition of 37 °C, 1 μM of the test substance was incubated with microsomal protein and coenzyme NADPH. At a certain reaction time (5, 10, 20, 30, 60 min), ice-cold acetonitrile containing an internal standard was added to terminate the reaction. The concentration of the test substance in the sample was detected by LC-MS / MS method. The T was obtained from the ln value of the remaining rate of the drug in the incubation system and the incubation time 1 / 2 , and the intrinsic hepatic clearance rate CL of the liver microsome was further calculated int(Liver) .

[0581] Conclusion: The compounds of the present invention have good metabolic stability in human liver microsomes.

[0582] 10. Pharmacokinetics test of Beagle dogs

[0583] Experimental purpose: By administering the test substance to Beagle dogs by single-dose intravenous injection and gavage, the concentration of the test substance in the plasma of Beagle dogs was measured to evaluate the pharmacokinetic characteristics of the test substance in Beagle dogs.

[0584] Test animals: Male Beagle dogs, about 8 - 11 kg, 6 per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0585] Test method: On the day of the experiment, the Beagle dogs were randomly grouped according to body weight. They were fasted for 12 - 14 h without water deprivation 1 day before dosing and fed 4 h after dosing.

[0586] Table 11. Administration Information

[0587]

[0588] Solvent for intravenous administration: 5% DMA + 5% Solutol + 90% Saline; Solvent for gavage administration: 0.5% MC

[0589] Sampling: 1 ml of blood was collected from the limb veins before and after administration and placed in an EDTAK2 centrifuge tube. Centrifuge at 5000 rpm at 4 °C for 10 min to collect plasma.

[0590] Blood sampling time points: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24 h. Before analysis and detection, all samples were stored at -80 °C. The samples were quantitatively analyzed by LC-MS / MS.

[0591] Conclusion: The compounds of the present invention, such as the compounds of the examples, have a high exposure and good pharmacokinetic properties in beagle dogs.

[0592] 11. Pharmacokinetic Test in Monkeys

[0593] 11.1 Test animals: Male cynomolgus monkeys, 3 - 5 kg, 3 - 6 years old, 6 monkeys / compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0594] 11.2 Test method: On the day of the test, cynomolgus monkeys were randomly grouped according to body weight. Fast for 14 - 18 h without water restriction 1 day before administration, and feed was given 4 h after administration.

[0595] Table 12. Administration Information

[0596]

[0597] Note: Solvent for intravenous administration: 5% DMA + 5% Solutol + 90% Saline; Solvent for gavage administration: 0.5% MC (containing 0.5% Tween 80);

[0598] (DMA: Dimethylacetamide; Solutol: Polyethylene glycol-15-hydroxystearate; Saline: Normal saline; MC: Methylcellulose solution;)

[0599] Before and after drug administration, 1.0 mL of blood was collected from the limb veins and placed in an EDTAK2 centrifuge tube. Centrifugation was carried out at 5000 rpm at 4 °C for 10 min to collect the plasma. The blood sampling time points for both the intravenous group and the gavage group were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, 48 h. Before analysis and detection, all samples were stored at -80 °C, and LC-MS / MS was used for quantitative analysis of the samples.

[0600] Conclusion: The compounds of the present invention, such as the example compounds, have a high exposure and good pharmacokinetic properties in monkeys.

Claims

1. A compound or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt, wherein the compound is selected from the compounds represented by general formula (I), (II) or (IIa), X2 is selected from O, S; X1 is selected from O, S, NR x , C(R x )2; Y is selected from O, S, NR y ; R x 、R y are each independently selected from H, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C 0-4 alkylene-C 3-8 carbocyclic group, -C 0-4 alkylene-4- to 8-membered heterocyclic group, and the alkyl, alkenyl, alkynyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k ; In general formula (I), ring A is selected from 6-membered heteroaryl groups, and said ring A is optionally substituted by 1 to 4 substituents selected from R a ; In general formula (II) or (IIa), ring A is selected from 4- to 7-membered hetero monocyclic alkyl, 5- to 12-membered hetero fused ring alkyl, 5- to 12-membered hetero spiroalkyl, 7- to 10-membered hetero bridged ring alkyl, C 3-8 monocyclic alkyl, C 6-14 fused ring alkyl, C 6-12 membered spiroalkyl, C 5-12 membered bridged ring alkyl, phenyl, 5- to 6-membered heteroaryl, and the said ring A is optionally substituted by 1 to 4 selected from R a substituted; Ring B is selected from 4- to 7-membered hetero monocyclic rings, 5- to 12-membered hetero fused rings, 5- to 12-membered hetero spiro rings, 7- to 10-membered hetero bridged rings, C 3-8 monocyclic carbocyclic groups, C 6-14 fused cycloalkyl groups, C 6-12 membered spirocycloalkyl groups, C 5-12 membered bridged cycloalkyl groups, benzo C 3-8 carbocyclic groups, benzo 3- to 8-membered heterocyclic groups, C 6-10 aryl groups, 5- to 10-membered heteroaryl groups, and the said ring B is optionally substituted by 1 to 4 R b substituents; Ring C is selected from 4- to 8-membered heterocycles or C 4-8 carbocycles, and said ring C is optionally substituted by 1 to 4 R c groups; R a 、R b 、R c are each independently selected from deuterium, halogen, ═O, OH, CN, NO2, NH2, C 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl)2, -C 0-4 alkylene-C(═O)R 1a 、-C 0-4 alkylene-S(═O)2R 1a 、-C 0-4 alkylene-P(═O)R 1a R 1b 、-O-C 0-4 alkylene-C 3-10 carbocyclic group, -O-C 0-4 alkylene-4- to 10-membered heterocyclic group, -S-C 0-4 alkylene-C 3-10 carbocyclic group, -S-C 0-4 alkylene-4- to 10-membered heterocyclic group, -NH-C 0-4 alkylene-C 3-10 carbocyclic group, -NH-C 0-4 alkylene-4- to 10-membered heterocyclic group, -C 0-4 alkylene-C 3-10 carbocyclic group, -C 0-4 alkylene-4- to 10-membered heterocyclic group, and the alkyl, alkenyl, alkynyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k ; R 1 and R 2 are each independently selected from H, deuterium, halogen, OH, CN, NO2, NH2, C 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl)2, -C 0-4 alkylene-C(=O)R 1a , -C 0-4 alkylene-S(=O)2R 1a , -C 0-4 alkylene-P(=O)R 1a R 1b , -O-C 0-4 alkylene-C 3-10 carbocyclic group, -O-C 0-4 alkylene-4- to 10-membered heterocyclic group, -S-C 0-4 alkylene-C 3-10 carbocyclic group, -S-C 0-4 alkylene-4- to 10-membered heterocyclic group, -NH-C 0-4 alkylene-C 3-10 carbocyclic group, -NH-C 0-4 alkylene-4- to 10-membered heterocyclic group, -C 0-4 alkylene-C 3-10 carbocyclic group, -C 0-4 alkylene-4- to 10-membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k ; R 5 and R 6 are each independently selected from H, deuterium, halogen, OH, CN, NO2, NH2, C 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl)2, C 0-4 alkylene-5- to 10-membered heteroaryl, C 0-4 alkylene-C 3-10 carbocyclic group, C 0-4 alkylene-4- to 10-membered heterocyclic group, and the alkyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k ; R 1a 、R 1b are each independently selected from H, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy, NHC 1-6 alkyl, N(C 1-6 alkyl)2, C 3-8 carbocyclic group, 4- to 8-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, -O-C 3-8 carbocyclic group, -O-4- to 8-membered heterocyclic group, and the alkyl, alkoxy, carbocyclic group, heterocyclic group, aryl or heteroaryl is optionally substituted by 1 to 4 R k ; R k Each independently selected from deuterium, halogen, OH, ═O, CN, NH2, COOH, CONH2, C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl)2, -O-C 3-6 carbocycle, -O-3- to 7-membered heterocycle, -NH-C 3-6 carbocycle, -NH-3- to 7-membered heterocycle, -C 0-4 alkylene-C 3-6 carbocycle, -C 0-4 alkylene-3- to 7-membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 substituents selected from deuterium, halogen, ═O, CN, OH, NH2, C 1-4 alkyl, C 1-4 alkoxy; provided that general formula (II) or (IIa) is not selected from any one of the structures shown in Table E below:

2. The compound or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt according to claim 1, wherein, Ring B is selected from phenyl, benzo C 3-8 carbocyclic group, benzo 3- to 8-membered heterocyclic group, 5- to 6-membered heteroaryl group, 5-fused 5-membered heteroaryl group, 5-fused 6-membered heteroaryl group, 6-fused 6-membered heteroaryl group, and said Ring B is optionally substituted with 1 to 4 R b substituted; In the general formula (I), ring A is selected from a 6-membered nitrogen-containing heteroaryl group, and the ring A is optionally substituted by 1 to 4 groups selected from R a replaced by; In general formula (II) or (IIa), ring A is selected from 4- to 7-membered hetero monocyclic alkyl, 5- to 10-membered hetero fused ring alkyl, 5- to 10-membered hetero spiroalkyl, 7- to 10-membered hetero bridged ring alkyl, C 3-8 monocyclic alkyl, C 6-10 fused ring alkyl, C 6-10 membered spiroalkyl, C 5-10 membered bridged ring alkyl, phenyl, 5- to 6-membered heteroaryl, and said ring A is optionally substituted by 1 to 4 selected from R a substituted; R 1 and R 2 are each independently selected from H, deuterium, halogen, OH, CN, NO2, NH2, C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl)2, -C 0-4 alkylene-C(=O)R 1a and -C 0-4 alkylene-S(=O)2R 1a and -C 0-4 alkylene-P(=O)R 1a R 1b and -O-C 0-4 alkylene-C 3-8 carbocyclic group, -O-C 0-4 alkylene-4- to 8-membered heterocyclic group, -S-C 0-4 alkylene-C 3-8 carbocyclic group, -S-C 0-4 alkylene-4- to 8-membered heterocyclic group, -NH-C 0-4 alkylene-C 3-8 carbocyclic group, -NH-C 0-4 alkylene-4- to 8-membered heterocyclic group, -C 0-4 alkylene-C 3-8 carbocyclic group, -C 0-4 alkylene-4- to 8-membered heterocyclic group, and the alkyl, alkenyl, alkynyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k ; R 5 and R 6 are each independently selected from H, deuterium, halogen, OH, CN, NO2, NH2, C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl)2, C 0-4 alkylene-5- to 8-membered heteroaryl, C 0-4 alkylene-C 3-8 carbocyclic group, C 0-4 alkylene-4- to 8-membered heterocyclic group, and the alkyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k ; R a 、R b 、R c are each independently selected from deuterium, deuterium, halogen, =O, OH, CN, NO2, NH2, C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl)2, -C 0-4 alkylene-C(=O)R 1a 、-C 0-4 alkylene-S(=O)2R 1a 、-C 0-4 alkylene-P(=O)R 1a R 1b 、-O-C 0-4 alkylene-C 3-8 carbocyclic group, -O-C 0-4 alkylene-4- to 8-membered heterocyclic group, -S-C 0-4 alkylene-C 3-8 carbocyclic group, -S-C 0-4 alkylene-4- to 8-membered heterocyclic group, -NH-C 0-4 alkylene-C 3-8 carbocyclic group, -NH-C 0-4 alkylene-4- to 8-membered heterocyclic group, -C 0-4 alkylene-C 3-8 carbocyclic group, -C 0-4 alkylene-4- to 8-membered heterocyclic group, and the alkyl, alkenyl, alkynyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k .

3. The compound or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt according to claim 2, X1 is selected from O, S, NR x ; R x and R y are each independently selected from H, deuterium, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl are optionally substituted by 1 to 4 R k groups; R 1a 、 R 1b are each independently selected from H, OH, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, -O-cyclopropyl, -O-cyclobutyl, imidazole, pyrazole, pyrrole or thiophene, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole or thiophene are optionally substituted by 1 to 3 R k substituents; R 1 and R 2 are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NO2, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methylthio, -C(=O)R 1a , -S(=O)2R 1a , -P(=O)R 1a R 1b , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, and the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl are optionally substituted by 1 to 4 R k ; R 5 and R 6 are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NO2, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl are optionally substituted by 1 to 4 R k groups; R a 、R c are each independently selected from deuterium, F, Cl, Br, I, OH, =O, NH2, CN, NO2, NHCH3, N(CH3)2, COOH, CONH2 or one of the following groups optionally substituted by 1 to 4 R k substituents: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, thienyl, thiazolyl, furanyl, oxazolyl, isoxazolyl; R in general formula (II) or (IIa) a each independently selected from deuterium, F, Cl, Br, I, OH, =O, NH2, CN, NO2, NHCH3, N(CH3)2, COOH, CONH2 or one of the following groups optionally substituted by 1 to 4 R k : methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, thienyl, thiazolyl, furyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl; R in general formula (II) or (IIa) c Each independently selected from deuterium, F, Cl, Br, I, OH, =O, NH2, CN, NO2, NHCH3, N(CH3)2, COOH, CONH2 or one of the following groups optionally substituted by 1 to 4 R k Substituted: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl; R b Each independently selected from deuterium, F, Cl, Br, I, OH, ═O, CN, NH2, NO2, NHCH3, N(CH3)2, COOH, CONH2, -CH2-C(=O)R 1a , -CH2-S(=O)2R 1a , -CH2-P(=O)R 1a R 1b , -C(=O)R 1a , -S(=O)2R 1a , -P(=O)R 1a R 1b , A a group, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-pyrrolidinyl, -O-cyclopropyl, -O-cyclobutyl, -O-pyrrolidinyl, -S-cyclopropyl, -S-cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, -OCH2-cyclopropyl, imidazole, pyrazole, pyrrole or thiophene, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole or thiophene is optionally substituted by 1 to 4 R k substituted; In general formula (I), ring A is selected from one of the following structures optionally substituted by 1 to 4 Rs a : pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl; In general formula (II) or (IIa), ring A is selected from one of the following structures optionally substituted by 1 to 4 R a : phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, pyrrolidinyl, piperidinyl, piperazinyl, bicyclo[1,1,1]pentyl, bicyclo[2,1,1]hexyl, bicyclo[2,2,1]heptyl; Ring C is selected from one of the following groups optionally substituted by 1 to 4 Rs c : cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, oxethenyl, oxolanyl, oxanyl, azetidinyl, pyrrolidinyl, piperidinyl, 1,3-dioxolanyl, 1,4-dioxanyl.

4. The compound or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt according to claim 3, Y is selected from O, S, NH; X2 is selected from O; X1 is selected from O, S; Ring B is selected from one of the following structures optionally substituted by 1 to 3 Rs b : benzene, naphthalene, pyridine, pyrazine, pyridazine, pyrimidine, R k Each independently selected from deuterium, F, Cl, Br, I, OH, ═O, CN, NH2, COOH, CONH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, ═O, CN, OH, NH2, C 1-4 alkyl, C 1-4 alkoxy.

5. The compound or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt according to claim 4, Selected from The said ring C is optionally substituted by 1 to 3 R c substituted; Selected from Said ring C is optionally substituted by 1 to 3 R c Substituted; R in formula (II) or (IIa) c Each independently selected from deuterium, F, Cl, Br, I, OH, =O, NH2, CN, NO2, CHF2, CH2F, CF3, OCHF2, OCF3, CD3, OCD3, NHCH3, N(CH3)2, COOH, CONH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl; Selected from In general formula (IIa) selected from one of the following structures optionally substituted by 1 to 4 R b as follows: In general formula (II) or (IIa), ring A is selected from one of the following structures optionally substituted with 1 to 3 R a substituents: R b each independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH2, NO2, NHCH3, N(CH3)2, COOH, CONH2, -CH2-C(=O)NH2, -CH2-S(=O)2NH2, -CH2-P(=O)(NH2)(NH2), -C(=O)NH2, -S(=O)2NH2, - P(=O)(NH2)(NH2), CON(CH3)2, -S(=O)2N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-pyrrolidinyl, -O-cyclopropyl, -O-cyclobutyl, -O-pyrrolidinyl, -S-cyclopropyl, -S-cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, -OCH2-cyclopropyl, imidazole, pyrazole, pyrrole or thiophene, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole or thiophene is optionally substituted by 1 to 4 R k substituted; In general formula (I), ring A is selected from one of the following structures optionally substituted by 1 to 3 Rs a substituted as follows: R k Each independently selected from deuterium, F, Cl, Br, I, OH, ═O, COOH, CN, CHF2, CH2F, CF3, OCHF2, OCF3, CD3, OCD3, NH2, NHCH3, N(CH3)2, CH2OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio.

6. The compound or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt according to claim 5, R 2 each independently selected from H, deuterium, F, Cl, Br, OH, CN, NO2, CHF2, CH2F, CF3, OCHF2, OCF3, CD3, OCD3, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl; R 1 each independently selected from H, deuterium, F, Cl, Br, OH, CN, NO2, CHF2, CH2F, CF3, OCHF2, OCF3, CD3, OCD3, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methylthiocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl; R in general formula (I) a and R c are each independently selected from deuterium, F, Cl, Br, I, OH, =O, NH2, CN, NO2, CHF2, CH2F, CF3, OCHF2, OCF3, CD3, OCD3, NHCH3, N(CH3)2, COOH, CONH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, thienyl, thiazolyl, furyl, oxazolyl, isoxazolyl; R in general formula (II) or (IIa) a Each independently selected from deuterium, F, Cl, Br, I, OH, =O, NH2, CN, NO2, CHF2, CH2F, CF3, OCHF2, OCF3, CD3, OCD3, NHCH3, N(CH3)2, COOH, CONH2 or one of the following groups optionally substituted by 1 to 3 R k : methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, thienyl, thiazolyl, furyl, oxazolyl, isoxazolyl Selected from or in general formula (II) or (IIa) selected from in general formula (IIa) selected from one of the following structures optionally substituted by 1 to 3 R b as follows: Selected from 7. A compound or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt, wherein the compound is selected from any one of the structures shown in Table A below: Table A 8. A pharmaceutical composition comprising the compound or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt according to any one of claims 1-7, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition contains 1-1500 mg of the compound or its stereoisomer, tautomer, racemate, pharmaceutically acceptable salt according to any one of claims 1-7.

9. Use of the compound or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt according to any one of claims 1-8 or the composition of claim 8 in the preparation of a drug for treating PI3Kα-related diseases.

10. The application according to claim 9, wherein The diseases are selected from tumors or cancers, preferably breast cancer.

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