Pyrimido-pyridine compound, pharmaceutical composition thereof and use thereof

Abstract

A pyrimido-pyridine compound, a pharmaceutical composition thereof and the use thereof. The compound and the pharmaceutical composition thereof as KRAS G12D inhibitors can be used for preparing a drug for preventing or treating KRAS G12D-related diseases, and can be particularly used for preparing a drug for preventing or treating cancers.

Description

Pyrimidopyridine compound, pharmaceutical composition and use thereof Technical Field

[0001] The present invention belongs to the field of medicine. Specifically, the present invention relates to a new class of pyrimidopyridine compounds as KRAS G12D inhibitors, pharmaceutical compositions thereof, and uses of the compounds and pharmaceutical compositions thereof in preparing drugs for preventing or treating KRAS G12D-related diseases. Background Art

[0002] RAS genes are among the most commonly mutated genes in cancer (20%-25%). Known members of the RAS gene family include KRAS, NRAS, and HRAS, with KRAS mutations being the most common, accounting for approximately 85%. KRAS mutation rates are highest in pancreatic ductal adenocarcinoma (PDAC), reaching 97%, followed by colorectal cancer, multiple myeloma, and lung cancer, at 52%, 42%, and 32%, respectively. The most common KRAS mutation is a point mutation, with common mutations including KRAS G12D (41%), KRAS G12V (28%), and KRAS G12C (14%). RAS gene mutations are often associated with poor prognosis in cancer. KRAS can be transiently activated by upstream growth factors or tyrosine kinases (such as EGFR). Activated KRAS can activate downstream pathways, including the PI3K-AKT-mTOR signaling pathway that controls cell generation and the RAS-RAF-MEK-ERK signaling pathway that controls cell proliferation. This also lays a biological foundation for the combined use of many targets.

[0003] In recent years, research has made progress in drug development by exploiting the allosteric sites of the KRAS G12C mutant. For example, in 2013, a research team reported the discovery of a small molecule inhibitor of KRAS G12C (Nature, 2013, 503, 548-551). However, research on KRAS G12D is less extensive. Compared to the KRAS G12C mutation, other mutation types, such as KRAS G12D and KRAS G12V, are more common in pancreatic cancer. Therefore, inhibiting the KRAS G12D mutation is a potentially effective approach for treating pancreatic cancer. Mirati, in patent application WO20211041671, has disclosed a series of KRAS G12D inhibitors that demonstrate specificity for the KRAS G12D mutant and exhibit anti-pancreatic cancer activity.

[0004] Currently, the development of compounds that target and inhibit KRAS G12D mutations to treat KRAS G12D-related diseases remains highly attractive and urgently needed.

[0005] Summary of the Invention

[0006] The present invention provides a compound, or a pharmaceutical composition thereof, which can be used as a KRAS inhibitor, particularly a KRAS G12D inhibitor. The present invention also relates to the use of the compound or pharmaceutical composition thereof for preparing a medicament for treating a disease and / or condition, particularly cancer, by inhibiting KRAS activity.

[0007] The compounds of the present invention are a class of non-covalent KRAS G12D specific inhibitors that can effectively bind to KRAS G12D-GTP and inhibit the phosphorylation of ERK downstream of KRAS G12D.

[0008] In one aspect, the present invention provides a compound represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I),

[0009] in,

[0010] R 1 is -H, -D, -CN, -NH2, -C(=O)H, -C(=O)OH, -C(=O)OR 6a 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 、-NR 6a C(=O)NR 6 R 7 、-C(=O)R 6a 、-NR 6 S(=O)2R 7 、-S(=O)2NR 6 R 7 、-NR 6a S(=O)2NR 6 R 7 、-NR 6 R 7 、-C 1-6 Alkyl-NR 6 C(=O)R 7 、-C 1-6 Alkyl-NR 6 R 7 、-C 1-6 Alkyl-C(=O)OR 6 、-C 1-6 Alkyl-C(=O)NR 6 R 7 、C 1-6Alkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, (C 3-12 Cycloalkyl)-C 1-6 Alkyl, (3-12 membered heterocyclic)-C 1-6 Alkyl, (C 6-10 Aryl)-C 1-6 Alkyl, (5-12 membered heteroaryl)-C 1-6 Alkyl, (C 3-12 Cycloalkyl)-OC 1-6 Alkyl, (3-12 membered heterocyclic)-OC 1-6 Alkyl, C 1-6 Mercaptoalkyl, C 6-12 Aryl, 5-12 membered heteroaryl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group; wherein the C 1-6 Alkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, (C 3-12 Cycloalkyl)-C 1-6 Alkyl, (3-12 membered heterocyclic)-C 1-6 Alkyl, (C 6-10 Aryl)-C 1-6 Alkyl, (5-12 membered heteroaryl)-C 1-6 Alkyl, (C 3-12 Cycloalkyl)-OC 1-6 Alkyl, (3-12 membered heterocyclic)-OC 1-6 Alkyl, C 1-6 Mercaptoalkyl, C 6-12 Aryl, 5-12 membered heteroaryl, C 3-12 Cycloalkyl and 3-12 membered heterocyclyl are each independently optionally substituted by 1, 2, 3 or 4 groups selected from D, -OH, -F, -Cl, -Br, -I, CN, -C(=O)OR 6e 、-NR 6e R 7e 、-C(=O)NR 6e R 7e 、-NR 6e C(=O)R 7e and C 1-6 substituted by an alkyl substituent;

[0011] Y is a bond, O or S;

[0012] R 2 for

[0013] L 1 , L 2 and L 3 Each independently is C 1-6 Alkylene or C 1-6 Heteroalkylene, wherein the C 1-6 Alkylene and C 1-6 Each heteroalkylene group is independently optionally substituted by 1, 2, 3 or 4 R a replace;

[0014] R a is -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, C 1-6 Alkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; or two R attached to the same carbon atom a Together they form C 3-6 Cycloalkyl;

[0015] Ring B1 and Ring C1 are each independently a 3-7 membered monocyclic heterocyclic group;

[0016] Ring B2, Ring B3 and Ring C2 are each independently C 3-7 a monocyclic cycloalkyl group or a 3-7 membered monocyclic heterocyclyl group;

[0017] Ring D1, ring D2 and ring D3 are each independently C 3-7 a monocyclic cycloalkyl group or a 3-7 membered monocyclic heterocyclyl group;

[0018] R A1 、R A2 、R A3 and R A4 Each independently represents -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6d R 7d 、-C(=O)NR 6d R 7d 、-CH2NR 6d R 7d 、-CH2OC(=O)NR 6d R 7d 、C 1-6 Alkyl, C1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, (C 6-10 Aryl)-C 1-6 Alkyl, (5-12 membered heteroaryl)-C 1-6 Alkyl, (3-6 membered heterocyclic)-C 1-6 Alkyl, (C 3-6 Cycloalkyl)-C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0019] Or, two R attached to the same carbon atom A1 Together Or, two R attached to the same carbon atom A1 Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 3-6 The cycloalkyl and 3-6 membered heterocyclic groups are each independently optionally substituted by 1, 2, 3 or 4 R 8a or, two R connected to two adjacent atoms A1 Together with the two adjacent atoms it is connected to form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 3-6 The cycloalkyl and 3-6 membered heterocyclic groups are each independently optionally substituted by 1, 2, 3 or 4 R 8a* replaced by;

[0020] Or, two R attached to the same carbon atom A2 Formed together Or, two R attached to the same carbon atom A2 Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 3-6 The cycloalkyl and 3-6 membered heterocyclic groups are each independently optionally substituted by 1, 2, 3 or 4 R 9a or, two R connected to two adjacent atoms A2 Together with the two adjacent atoms it is connected to form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 3-6 The cycloalkyl and 3-6 membered heterocyclic groups are each independently optionally substituted by 1, 2, 3 or 4 R 9a* replaced by;

[0021] Or, two R attached to the same carbon atom A3 Together Or, two R attached to the same carbon atom A3 Together with the carbon atom to which it is attached, it forms C3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 3-6 The cycloalkyl and 3-6 membered heterocyclic groups are each independently optionally substituted by 1, 2, 3 or 4 R 10a or, two R connected to two adjacent atoms A3 Together with the two adjacent atoms it is connected to form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 3-6 The cycloalkyl and 3-6 membered heterocyclic groups are each independently optionally substituted by 1, 2, 3 or 4 R 10a* replaced by;

[0022] R A1a 、R A1b 、R A2a 、R A2b 、R A3a 、R A3b 、R A1a* 、R A1b* 、R A2a* 、R A2b* 、R A3a* and R A3b* Each is independently -H, -D, -F, -Cl, -Br, -I, -CN, -C 1-6 Alkyl-NR 6 C(=O)R 7 、-C 1-6 Alkyl-NR 6 R 7 、-C 1-6 Alkyl-C(=O)OR 6 、-C 1-6 Alkyl-C(=O)NR 6 R 7 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, (C 3-12 Cycloalkyl)-C 1-6 Alkyl, (3-12 membered heterocyclic)-C 1-6 Alkyl, (C 3-12 Cycloalkyl)-OC 1-6 Alkyl, (3-12 membered heterocyclic)-OC 1-6 Alkyl, C 6-12 Aryl, 5-12 membered heteroaryl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group;

[0023] R 8a 、R 8a*、R 9a 、R 9a* 、R 10a and R 10a* Each is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)OH, -C(=O)NH2, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(=O)OC 1-6 Alkyl, -C(=O)NHC 1-6 Alkyl or -C(=O)N(C 1-6 Alkyl)2;

[0024] R 3 for

[0025] R 11a 、R 11b 、R 11c and R 11d Each independently represents -H, -D, -OH, -SH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OR 6a 、-C(=O)NR 6 R 7 、C 1-6 Alkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or 5-6 membered heteroaryl;

[0026] R 4 is -H, -D, -OH, -SH, -F, -Cl, -Br, -I, -CN, methyl, ethyl, n-propyl, isopropyl, n-butyl or C 1-4 alkyl halide;

[0027] Ring A is C 6-12 Aryl or 5-12 membered heteroaryl;

[0028] Each R 5 are independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH2C(=O)NR 6b R 7b 、-C(=O)R 6c 、-C(=O)OR 6c 、-C(=O)NR 6b R7b 、-NR 6b C(=O)R 7b 、-NR 6b R 7b 、C 1-6 Alkyl, C 1-6 Alkylthio, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Hydroxyalkynyl, C 1-6 Alkoxy, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 2-6 Halogenated alkenyl, C 2-6 Haloalkynyl, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkylthio, 6-12 membered aryl, 5-12 membered heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Alkylthio, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Hydroxyalkynyl, C 1-6 Alkoxy, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 2-6 Halogenated alkenyl, C 2-6 Haloalkynyl, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkylthio, 6-12 membered aryl, 5-12 membered heteroaryl, C 3-6 The cycloalkyl and 3-6 membered heterocyclyl groups are each independently optionally substituted by 1, 2, 3 or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 substituted by a cycloalkyl group or a 3-6 membered heterocyclic group;

[0029] R 6 、R 7 、R 6a 、R 6b 、R 6c 、R 7b 、R 6d 、R 7d 、R 6e and R 7e Each is independently -H, -D or C 1-6 Alkyl, wherein the C1-6 The alkyl group is optionally substituted by 1, 2, 3 or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NH2, C 1-6 Alkoxy, C 6-12 Aryl, C 3-6 substituted by a cycloalkyl group or a 3-6 membered heterocyclic group;

[0030] n is 0, 1, 2, 3, 4, 5, 6 or 7; and

[0031] q1, q2 and q3 are each independently 0, 1, 2, 3, 4, 5 or 6;

[0032] Each q4 is independently 0, 1, 2, 3 or 4;

[0033] Wherein, the compound of formula (I) is not

[0034] In some embodiments, R 1 is -H, -D, -CN, -NH2, -C(=O)H, -C(=O)OH, -C(=O)OR 6a 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 、-NR 6a C(=O)NR 6 R 7 、-C(=O)R 6a 、-NR 6 S(=O)2R 7 、-S(=O)2NR 6 R 7 、-NR 6a S(=O)2NR 6 R 7 、-NR 6 R 7 、-C 1-4 Alkyl-NR 6 C(=O)R 7 、-C 1-4 Alkyl-NR 6 R 7 、-C 1-4 Alkyl-C(=O)OR 6 、-C 1-4 Alkyl-C(=O)NR 6 R 7 、C 1-4 Alkyl, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, (C 3-6 Cycloalkyl)-C 1-4 Alkyl, (C 7-12 Cycloalkyl)-C 1-4 Alkyl, (3-6 membered heterocyclic)-C 1-4 Alkyl, (7-12 membered heterocyclyl)-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, (5-6 membered heteroaryl)-C 1-4 Alkyl, (C 3-6 Cycloalkyl)-OC 1-4 Alkyl, (C 7-12 Cycloalkyl)-OC 1-4 Alkyl, (3-7 membered heterocyclic)-OC 1-6 Alkyl, (7-12 membered heterocyclic)-OC 1-4 Alkyl, C 1-4 Mercaptoalkyl, C 6-10 Aryl, 5-12 membered heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; wherein the C 1-4 Alkyl, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, (C 3-6 Cycloalkyl)-C 1-4 Alkyl, (C 7-12 Cycloalkyl)-C 1-4 Alkyl, (3-6 membered heterocyclic)-C 1-4 Alkyl, (7-12 membered heterocyclyl)-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, (5-6 membered heteroaryl)-C 1-4 Alkyl, (C 3-6 Cycloalkyl)-OC 1-4 Alkyl, (C 7-12 Cycloalkyl)-OC 1-4 Alkyl, (3-7 membered heterocyclic)-OC 1-6 Alkyl, (7-12 membered heterocyclic)-OC 1-4 Alkyl, C 1-4 Mercaptoalkyl, C 6-10 Aryl, 5-12 membered heteroaryl, C 3-6Cycloalkyl and 3-6 membered heterocyclyl are each independently optionally substituted by 1, 2, 3 or 4 groups selected from D, -OH, -F, -Cl, -Br, -I, CN, -C(=O)OR 6e 、-NR 6e R 7e 、-C(=O)NR 6e R 7e 、-NR 6e C(=O)R 7e and C 1-4 substituted by an alkyl substituent; wherein R 6 、R 7 、R 6a 、R 6e and R 7e Each has the definition as described in the present invention.

[0035] In some embodiments, R 1 is -H, -D, -CN, -NH2, -C(=O)H, -C(=O)OH, -C(=O)OR 6a 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 、-NR 6a C(=O)NR 6 R 7 、-C(=O)R 6a 、-NR 6 S(=O)2R 7 、-S(=O)2NR 6 R 7 、-NR 6a S(=O)2NR 6 R 7 、-NR 6 R 7 、-CH2NR 6 C(=O)R 7 、-CH2NR 6 R 7 、-(CH2)2NR 6 R 7 、-CH2C(=O)OR 6 、-(CH2)2C(=O)OR 6 、-(CH2)3C(=O)OR 6 、-CH2C(=O)NR 6 R 7 、-(CH2)2C(=O)NR 6 R 7 、-(CH2)3C(=O)NR 6 R7, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CN, -(CH2) 2CN, -(CH2)3CN, -CH(CH3)CN, -C(CH3)2CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -(CH2)2C HF2, -(CH2)2CF(CF3)2, -CF3, -CHF2, -CH2F, -(CH2)2F, -(CH2)2Cl, -CH2CF3, -OCH3, -OCH2CH3, -O (CH2)2CH3, -O(CH2)3CH3, -OC(CH3)3, -OCH(CH3)2, -CH2OCH3, -(CH2)2OCH3, -(CH2)2OCH2CH3, -CH 2OCH2CH3, -CH2OC(CH3)3, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -(CH2)2-cyclopentyl, -(CH2)3-cyclopentyl, -(CH2)2-cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -(CH2)2-cyclobutyl, -CH2-cyclopentyl, -(CH2)2-cyclopentyl, -CH2-azetidinyl, -CH2-pyrrolidine yl, -CH2-piperidinyl, -CH2-morpholinyl, -CH2-phenyl, -CH2-imidazolyl, -CH2-pyrazolyl, -CH2O-cyclopropyl, -CH2O-cyclobutyl, -(CH2)2O-cyclobutyl, -CH2O-cyclopentyl, -(CH2)2O-cyclopentyl, -CH2O-azetidinyl, -CH2O-oxetanyl, -CH2O-tetrahydrofuranyl, -CH2O-spiro[2.3]hexane, -CH2O-spiro[3.3] heptyl-, -CH2SH, -(CH2)2SH, phenyl, naphthyl, pyridyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydropyranyl, azetidinyl or pyrrolidinyl; wherein -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH(CH3)CN, -C(CH3)2CN, -CH2OH, - (CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -(CH2)2CHF2, -(CH2)2CF(CF3)2, -CHF2, -CH2F, -(CH2)2F, -(CH2)2Cl, -CH2CF3, -OCH3, -OC H2CH3, -O(CH2)2CH3, -O(CH2)3CH3, -OC(CH3)3, -OCH(CH3)2, -CH2OCH3, -(CH2)2OCH3, -(CH2)2OCH2CH3, -CH2OCH2CH3, -CH2OC(C H3)3, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -(CH2)2-cyclopentyl, -(CH2)3-cyclopentyl, -(CH2)2-cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -(CH2)2-cyclobutyl, -CH2-cyclopentyl, -(CH2)2-cyclopentyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-morpholinyl, -CH2-phenyl, -CH2-imidazolyl, -CH2-pyrazolyl, -CH2O-cyclopropyl, -CH2O-cyclobutyl, -(CH2)2O-cyclobutyl, -CHO-cyclopentyl, -(CH2)2O-cyclopentyl, -CHO-azetidinyl, -CHO-oxetanyl, -CHO-tetrahydrofuranyl, -CHO-spiro[2.3]hexanyl, -CHO-spiro[3.3]heptanyl-, phenyl, naphthyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydropyranyl, azetidinyl and pyrrolidinyl are each independently optionally substituted by 1, 2, 3 or 4 groups selected from D, -OH, -F, -Cl, -Br, -I, CN, -C(=O)OR. 6e 、-NR 6e R 7e 、-C(=O)NR 6e R 7e 、-NR 6e C(=O)R 7e, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; wherein, R 6 、R 7 、R 6a 、R 6e and R 7e Each has the same definition as in the present invention.

[0036] In some embodiments, R A1 、R A2 、R A3 and R A4 Each independently represents -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6d R 7d 、-C(=O)NR 6d R 7d 、-CH2NR 6d R 7d 、-CH2OC(=O)NR 6d R 7d 、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, phenyl-C 1-4 Alkyl, (5-6 membered heteroaryl)-C 1-4 Alkyl, (3-6 membered heterocyclic)-C 1-4 Alkyl, (C 3-6 Cycloalkyl)-C 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; or, R A1 、R A2 、R A3 and R A4 Each independently represents -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6d R 7d 、-C(=O)NR 6d R 7d 、-CH2NR 6d R 7d 、-CH2OC(=O)NR 6d R 7d, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, -OCH3 , -OCH2CH3, -OCH2CH3, -OC(CH3)3, -(CH2)2CHF2, -(CH2)2CF(CF3)2, -CF3, -CHF2, -CH2F, -(CH2)2F, -(CH2)2Cl, -CH2CF3, -OCF3, -OCHF2, -CH2-phenyl, -CH2-pyridyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-cyclopropyl, -CH2-cyclopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydropyranyl, morpholinyl, azetidinyl or pyrrolidinyl; wherein R 6d and R 7d Each has the definition as described in the present invention;

[0037] Or, two R attached to the same carbon atom A1 Together Or, two R attached to the same carbon atom A1 and the carbon atom to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl, wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholinyl are each independently optionally substituted by 1, 2, 3 or 4 R 8a or, two R connected to two adjacent atoms A1 and the two adjacent atoms to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl, wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholinyl are each independently optionally substituted by 1, 2, 3 or 4 R 8a* replaced by;

[0038] Or, two R attached to the same carbon atom A2Together Or, two R attached to the same carbon atom A2 and the carbon atom to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl, wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholinyl are each independently optionally substituted by 1, 2, 3 or 4 R 9a or, two R connected to two adjacent atoms A2 and the two adjacent atoms to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl, wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholinyl are each independently optionally substituted by 1, 2, 3 or 4 R 9a* replaced by;

[0039] Or, two R attached to the same carbon atom A3 Together Or, two R attached to the same carbon atom A3 and the carbon atom to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl, wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholinyl are each independently optionally substituted by 1, 2, 3 or 4 R 10a or, two R connected to two adjacent atoms A3and the two adjacent atoms to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl, wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholinyl are each independently and optionally replaced by 1, 2, 3 or 4 R 10a* replaced by;

[0040] R A1a 、R A1b 、R A2a 、R A2b 、R A3a 、R A3b 、R A1a* 、R A1b* 、R A2a* 、R A2b* 、R A3a* and R A3b* Each is independently -H, -D, -F, -Cl, -Br, -I, -CN, -C 1-4 Alkyl-NR 6 C(=O)R 7 、-C 1-4 Alkyl-NR 6 R 7 、-C 1-4 Alkyl-C(=O)OR 6 、-C 1-4 Alkyl-C(=O)NR 6 R 7 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, (C 3-6 Cycloalkyl)-C 1-4 Alkyl, (3-6 membered heterocyclic)-C 1-4 Alkyl, (C 3-6 Cycloalkyl)-OC 1-4 Alkyl, (3-6 membered heterocyclic)-OC 1-4 Alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein R 6 and R 7 Each has the definition as described in the present invention;

[0041] R 8a 、R 8a* 、R 9a 、R 9a* 、R 10a and R 10a* Each is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)OH, -C(=O)NH2, oxo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, phenyl, 5-6 membered heteroaryl, -C(=O)OC 1-4 Alkyl, -C(=O)NHC 1-4 Alkyl or -C(=O)N(C 1-4 Alkyl)2.

[0042] In some embodiments, R A1a 、R A1b 、R A2a 、R A2b 、R A3a 、R A3b 、R A1a* 、R A1b* 、R A2a* 、R A2b* 、R A3a* and R A3b* Each is independently -H, -D, -F, -Cl, -Br, -I, -CN, -CH2NR 6 C(=O)R 7 、-CH2NR 6 R 7 、-CH2C(=O)OR 6 、-(CH2)2C(=O)OR 6 、-(CH2)3C(=O)OR 6 、-CH2C(=O)NR 6 R 7 、(CH2)2C(=O)NR 6 R 7 、-(CH2)3C(=O)NR 6 R 7, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, -(CH 2)2CHF2, -(CH2)2CF(CF3)2, -CF3, -CHF2, -CH2F, -(CH2)2F, -(CH2)2Cl, -CH2CF3, -CH2 CN, -(CH2)2CN, -(CH2)3CN, -CH(CH3)CN, -C(CH3)2CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -CH2OCH3, -(CH2)2OCH3, -(CH2)2OCH2CH3, -CH2OCH2CH3, -CH2OC(CH3)3, - -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -(CH2)2-cyclopentyl, -(CH2)3-cyclopentyl, -(CH2)2-cyclohexyl, -CH2-cyclopentyl, -CH2-azetidinyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, -CH2-morpholinyl, -CH2O-cyclopropyl, -CH2O-cyclobutyl, -(CH2)3-cyclopentyl, -(CH2)2-cyclohexyl, -CH2-cyclopentyl, -CH2-azetidinyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, -CH2-morpholinyl, -CH2O-cyclopropyl, -CH2O-cyclobutyl, -( wherein R 6 and R 7 Each has the definition as described in the present invention;

[0043] R 8a 、R 8a* 、R 9a 、R 9a* 、R 10a and R 10a*Each is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)OH, -C(=O)NH2, oxo, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, -(CH2)2CHF2, -(CH2)2CF(CF3)2, -CF3, -CHF2, -CH2F, -(CH2)2F, -(CH2)2Cl, -CH2CF3, -OCH3, -OCH2CH3, -OCH2CH3, -OC(CH3)3, -CH2OH, -(CH2)2OH, -(CH2)3OH, phenyl, pyridyl, pyrimidinyl, -C(=O)OCH3, -C(=O)NHCH3 or -C(=O)N(CH3)2.

[0044] In some embodiments, Ring A is one of the following substructures,

[0045] Each R 5 are independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH2C(=O)NR 6b R 7b 、-C(=O)R 6c 、-C(=O)OR 6c 、-C(=O)NR 6b R 7b 、-NR 6b C(=O)R 7b 、-NR 6b R 7b 、C 1-4 Alkyl, C 1-4 Alkylthio, C 2-4 Alkenyl, C 2-4 Alkynyl, C 2-4 Hydroxyalkynyl, C 1-4 Alkoxy, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl, C 2-4 Halogenated alkenyl, C 2-4 Haloalkynyl, C 1-4 Halogenated alkoxy, C 1-4 Halogenated alkylthio, 6-12 membered aryl, 5-12 membered heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 1-4 Alkyl, C 1-4 Alkylthio, C 2-4 Alkenyl, C 2-4 Alkynyl, C 2-4Hydroxyalkynyl, C 1-4 Alkoxy, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl, C 2-4 Halogenated alkenyl, C 2-4 Haloalkynyl, C 1-4 Halogenated alkoxy, C 1-4 Halogenated alkylthio, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 The cycloalkyl and 3-6 membered heterocyclyl groups are each independently optionally substituted by 1, 2, 3 or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Substituted by cycloalkyl and 3-6 membered heterocyclic substituents; wherein R 6b 、R 7b and R 6c Each has the definition as described in the present invention.

[0046] In some embodiments, each R 5 are independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH2C(=O)NR 6b R 7b 、-C(=O)R 6c 、-C(=O)OR 6c 、-C(=O)NR 6b R 7b 、-NR 6b C(=O)R 7b 、-NR 6b R 7b, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡ CH, -C≡CCH2OH, -C≡C(CH2)2OH, -OCH3, -OCH2CH3, -O(CH2)2CH3, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -( -(CH2)2Cl, -CH=CHF, -CH=CHCl, -CH=CHCH2F, -C≡CCH2F, -C≡C(CH2)2F, -C≡CF, -OCF3, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCHClCHCl2, -OCH2CH2F, -SCF3, -SCH2CF3, -SCH2CHF2, phenyl, naphthyl, pyridyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl or piperazinyl,wherein -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, -C≡CCH2OH, -C≡C(CH2)2OH, -OCH3, -OCH2CH3, -O(CH2)2CH3, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -(CH2)2F, -CH2CHF2, -CH2CF3, -CHF2, - CH2F, -(CH2)2Cl, -CH=CHF, -CH=CHCl, -CH=CHCH2F, -C≡CCH2F, -C≡C(CH2)2F, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCHClCHCl2, -OCH2CH2F , -SCH2CF3, -SCH2CHF2, phenyl, naphthyl, pyridyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl and piperazinyl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl and piperazinyl; wherein R, 6b 、R 7b and R 6c Each has the definition as described in the present invention.

[0047] In some embodiments, R 6 、R 7 、R 6a 、R 6b 、R 6c 、R 7b 、R 6d 、R 7d 、R 6e and R 7eEach is independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl is each independently optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NH2, methoxy, ethoxy, n-propyloxy, isopropyloxy, isobutyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, oxiranyl, oxetanyl, azetidinyl and pyrrolidinyl.

[0048] In some embodiments, R 2 for Among them, R A1a 、R A1b 、R A2a 、R A2b 、R A1 、R A2 , q1 and q2 each have the definition as described in the present invention.

[0049] In some embodiments, R 2 for wherein ring D1, ring D2 and ring D3 are each independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxetanyl, azetidinyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl and piperazinyl, wherein R A1 、R A2 、R A3 、R A4 , q1, q2, q3 and q4 each have the definition as described in the present invention.

[0050] In some embodiments, R 2 for Among them, R A1a 、R A1b 、R A2a 、R A2b 、R A1 、R A2 、R A1a* and R A1b* Each has the definition as described in the present invention.

[0051] In some embodiments, R 2 for

[0052] In some embodiments, the compound of the present invention is a compound represented by formula (I-1), (I-2) or (I-3), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound represented by formula (I-1), (I-2) or (I-3).

[0053] Among them, R 1 、R 4 、R 5 、R A1 、R A1a 、R A1b 、R 11a , n and q1 each have the meanings as described in the present invention.

[0054] In some embodiments, the compound of the present invention is a compound represented by formula (I-1a), (I-1b) or (I-1c), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I-1a), (I-1b) or (I-1c).

[0055] Among them, R 1 、R 4 、R 5 、R A1 、R A1a 、R A1b 、R A1a* 、R A1b* 、R 11a 、R A4 , q4, and n each have the definitions described in the present invention.

[0056] In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention.

[0057] In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable adjuvant.

[0058] In some embodiments, the adjuvants of the present invention include, but are not limited to, carriers, excipients, diluents, solvents, or combinations thereof. In some embodiments, the pharmaceutical composition can be in liquid, solid, semi-solid, gel or spray form.

[0059] In another aspect, the present invention provides use of the pharmaceutical composition of the present invention in the preparation of a medicament for preventing, treating or alleviating KRAS G12D-related diseases.

[0060] In some embodiments, the KRAS G12D-related disease described herein is cancer.

[0061] In some embodiments, the cancer described herein is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, colon cancer, small intestine cancer, pancreatic cancer, uterine cancer, gastric cancer, esophageal cancer, prostate cancer, ovarian cancer, breast cancer, leukemia, melanoma, lymphoma, or neuroma.

[0062] In another aspect, the present invention further provides a method for preventing or treating a KRAS G12D-related disease, comprising administering to a patient a therapeutically effective amount of the compound of the present invention or a pharmaceutical composition thereof.

[0063] In another aspect, the present invention relates to methods for preparing, isolating and purifying compounds of formula (I), (I-1), (I-2), (I-3), (I-1a) or (I-1b).

[0064] Unless otherwise indicated, all stereoisomers, tautomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs of the compounds of the present invention are within the scope of the present invention.

[0065] The term "pharmaceutically acceptable" includes that the substance or composition must be suitable chemically and toxicologically with respect to the other ingredients that make up the formulation and the mammal to be treated.

[0066] The salts of the compounds of the present invention also include intermediates used to prepare or purify compounds represented by formula (I), (I-1), (I-2), (I-3), (I-1a) or (I-1b) or salts of separated enantiomers of compounds represented by formula (I), (I-1), (I-2), (I-3), (I-1a) or (I-1b), but are not necessarily pharmaceutically acceptable salts.

[0067] The foregoing description only summarizes certain aspects of the present invention, but is not intended to limit the present invention to these aspects. These and other aspects will be described in more detail and fully below.

[0068] Detailed description of the present invention

[0069] Definitions and General Terms

[0070] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0071] It will be further appreciated that certain features of the invention, which, for clarity, are described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which, for brevity, are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0072] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0073] As used herein, the term "subject" refers to an animal. Typically, the animal is a mammal. A subject also refers, for example, to primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0074] The term "patient" used in the present invention refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to humans.

[0075] The term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0076] "Stereoisomers" refer to compounds with the same chemical structure but with different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans isomers), atropisomers, and the like. Unless otherwise indicated, all stereoisomers or mixtures of stereoisomers of the structural formulas described herein are within the scope of the present invention. In addition, unless otherwise indicated, the structural formulas of the compounds described herein may include enriched isotopes of one or more different atoms.

[0077] Stereochemical definitions and conventions used herein generally follow SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994.

[0078] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, and diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0079] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of the tautomers can be reached. For example, proton tautomers (also known as prototropic tautomers) include interconversions performed by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions performed by the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0080] As described herein, the compounds of the present invention may be independently optionally substituted with one or more substituents, as described above for the general formula compounds, or as described in the specific examples, subclasses, and classes of compounds encompassed by the present invention. It should be understood that the terms "independently optionally substituted with" or "optionally substituted with" are used interchangeably with the term "substituted or unsubstituted." In general, the term "substituted" refers to the replacement of one or more hydrogen atoms in a given structure with a specified substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from the specified group, the substituents may be the same or different at each position.

[0081] In addition, it should be noted that, unless otherwise explicitly stated, the description methods used in the present invention such as "each...independently is" and "...each independently is" and "...independently is" can be interchanged and should be understood in a broad sense. They can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0082] In various parts of this specification, substituents of compounds disclosed herein are disclosed in terms of group types or ranges. It is specifically noted that the present invention includes every independent subcombination of the individual members of these group types and ranges. For example, the term "C 1-6 "Alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl as disclosed independently.

[0083] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood to be a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.

[0084] The term "alkyl" refers to a saturated, linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described herein. In one embodiment, the alkyl group contains 1 to 6 carbon atoms and is represented by C 1-6 Alkyl; In another embodiment, the alkyl group contains 1-4 carbon atoms and is represented by C 1-4 Alkyl; In another embodiment, the alkyl group contains 1-3 carbon atoms, represented by C 1-3Alkyl. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -CH(CH3)CH2CH3), u, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1 -butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3 ), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, and the like.

[0085] The term "alkylene" refers to a saturated divalent hydrocarbon group derived by removing two hydrogen atoms from a saturated straight or branched hydrocarbon. In some embodiments, the alkylene group contains 1 to 6 carbon atoms and is represented by C 1-6 In other embodiments, the alkylene group contains 1-4 carbon atoms and is represented by C 1-4 In other embodiments, the alkylene group contains 1-3 carbon atoms and is represented by C 1-3 In other embodiments, the alkylene group contains 1-2 carbon atoms and is represented by C 1-2 Alkylene. Examples of alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, -CH(CH3)CH2-, and the like.

[0086] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e., a carbon-carbon sp 2 Double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including "cis" and "trans" orientations, or "E" and "Z" orientations. In one embodiment, the alkenyl group contains 2-6 carbon atoms, represented by C 2-6 In another embodiment, the alkenyl group contains 2-4 carbon atoms and is represented by C 2-4 Alkenyl. Examples of alkenyl groups include, but are not limited to, ethenyl (—CH═CH 2 ), allyl (—CH 2 CH═CH 2 ), 1-propenyl (ie, propenyl, —CH═CH—CH 3 ), and the like.

[0087] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein at least one site of unsaturation, i.e., a carbon-carbon sp triple bond, is present, wherein the alkynyl group may be optionally substituted with one or more substituents as described herein. In one embodiment, the alkynyl group contains 2 to 6 carbon atoms and is represented by C 2-6 In another embodiment, the alkynyl group contains 2-4 carbon atoms and is represented by C 2-4 Alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl (—C≡CH), propargyl (—CH2C≡CH), 1-propynyl (—C≡C-CH3), and the like.

[0088] The term "cyanoalkyl" refers to an alkyl group substituted with one or more cyano groups, wherein the cyano group and the alkyl group have the definitions as described herein. In some embodiments, "cyanoalkyl" refers to an alkyl group substituted with one cyano group. In some embodiments, "cyanoalkyl" is C 1-6 Cyanoalkyl, that is, C substituted by one or more cyano groups 1-6 In some preferred embodiments, C 1-6 Cyanoalkyl is a C substituted with a cyano group. 1-6 In other embodiments, "cyanoalkyl" is C 1-4 Cyanoalkyl, that is, C substituted by one or more cyano groups 1-4 Examples of cyanoalkyl groups include, but are not limited to, -CH2CN, -CH2CH2CH2CH2CN, -CH2CH2CN, -CH2CH(CN)CH2CH2CN, -CH2CH(CN)CH2CH(CH3)CN, and the like.

[0089] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein the alkyl and hydroxy groups have the definitions described herein. In some embodiments, hydroxyalkyl refers to an alkyl group substituted with 1, 2, 3, or 4 hydroxy groups. In some embodiments, hydroxyalkyl refers to an alkyl group substituted with one or two hydroxy groups. In some embodiments, hydroxyalkyl refers to a C 1-6 Hydroxyalkyl, i.e. C 1-6 The alkyl group is substituted with one or more hydroxyl groups, preferably C 1-6 Hydroxyalkyl represents C 1-6 In some embodiments, hydroxyalkyl represents a C 1-4 In some embodiments, hydroxyalkyl represents C 1-3 Examples of hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2CH2CH2OH, -CH2CH2OH, -CH2CH(OH)CH2CH2OH, -CH2CH(OH)CH2CH(CH3)OH, and the like.

[0090] The term "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms, wherein alkyl and halogen have the definitions described herein. In some embodiments, the haloalkyl group is C 1-6 Halogenated alkyl, indicating C 1-6 The alkyl group is substituted with one or more halogen atoms; in other embodiments, the haloalkyl group is C 1-4 Halogenated alkyl, indicating C 1-4 The alkyl group is substituted with one or more halogen atoms; in other embodiments, the haloalkyl group is C 1-3 Halogenated alkyl, indicating C 1-3 The alkyl group is substituted with one or more halogen atoms. Examples include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl, 1-chloroethyl, 1,2-dichloroethyl, 1,1-dichloroethyl, 2,2-dichloroethyl, 1,1-dibromoethyl, and the like.

[0091] The term "haloalkenyl" refers to an alkenyl group substituted with one or more halogen atoms, wherein alkenyl has the definition as described herein. In some embodiments, haloalkenyl is C 2-6 Halogenated alkenyl, representing C 2-6 The alkenyl group is substituted with one or more halogen atoms; in other embodiments, the haloalkenyl group is C 2-4 Halogenated alkenyl, representing C 2-4Alkenyl groups are substituted with one or more halogen atoms. Examples include, but are not limited to, 1-chlorovinyl (-CCl=CH2), 2-fluorovinyl (-CH=CHF), 1-fluoroallyl (-CHFCH=CH2), 3-fluoropropenyl (i.e., -CH=CH-CH2F), and 3,3-difluoropropenyl (i.e., -CH=CH-CHF2).

[0092] The term "haloalkynyl" refers to an alkynyl group substituted with one or more halogen atoms, wherein the alkynyl group has the definition as described herein. In some embodiments, the haloalkynyl group is C 2-6 Haloalkynyl, representing C 2-6 Alkynyl groups are substituted with one or more halogen atoms; in other embodiments, haloalkynyl is C 2-4 Haloalkynyl, representing C 2-4 Alkynyl groups are substituted with one or more halogen atoms. Examples include, but are not limited to, 2-chloroethynyl (-C≡CCl), 1-chloropropargyl (-CHClC≡CH), 3-chloropropynyl (-C≡C-CH2Cl), and the like.

[0093] The term "hydroxyalkynyl" refers to an alkynyl group substituted with one or more hydroxy groups, wherein hydroxy and alkynyl are as defined herein. In some embodiments, the hydroxyalkynyl group is C 2-6 Hydroxyalkynyl, representing C 2-6 Alkynyl groups are substituted with one or more hydroxyl groups; in other embodiments, hydroxyalkynyl groups are C 2-4 Hydroxyalkynyl, representing C 2-4 Alkynyl groups are substituted with one or more hydroxyl groups. Examples include, but are not limited to, 3-hydroxypropynyl (-C≡C-CH2OH), 4-hydroxybutynyl (-C≡C-(CH2)2OH), and the like.

[0094] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group, wherein alkoxy and alkyl have the definitions described herein. In some embodiments, alkoxyalkyl refers to a C 1-6 Alkoxy C 1-6 Alkyl; in other embodiments, alkoxyalkyl represents C 1-4 Alkoxy C 1-4 Alkyl; in other embodiments, alkoxyalkyl represents C 1-4 Alkoxy C 1-3 Alkyl; in some embodiments, alkoxyalkyl represents C 1-3 Alkoxy C 1-3Examples of alkoxy groups include, but are not limited to, methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, methoxyethyl, methoxy-n-propyl, methoxy-isopropyl, ethoxyethyl, ethoxy-n-propyl, ethoxy-isopropyl, n-propoxyethyl, isopropoxyethyl, n-propoxy-n-propyl, n-propoxy-isopropyl, isopropoxy-n-propyl, isopropoxy-isopropyl, and the like.

[0095] The term "mercaptoalkyl" refers to an alkyl group substituted with one or more mercapto groups, wherein the alkyl group has the meaning as described herein. In some embodiments, mercaptoalkyl refers to a C 1-6 Mercaptoalkyl is a C substituted by one or more mercapto groups. 1-6 Alkyl; preferably, C 1-6 Mercaptoalkyl is a C substituted with a mercapto group. 1-6 In other embodiments, mercaptoalkyl represents C 1-4 In other embodiments, mercaptoalkyl represents C 1-3 Mercaptoalkyl. Examples of mercaptoalkyl include, but are not limited to, mercaptomethyl (—CH 2 SH), 2-mercaptoethyl (—(CH 2 ) 2 SH), 3-mercaptopropyl (—(CH 2 ) 3 SH), 2,3-dimercaptopropyl (—CH 2 CH (SH) CH 2 (SH)), and the like.

[0096] The term "alkoxy" means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as defined herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms, indicating C 1-6 Alkoxy; In another embodiment, the alkoxy group contains 1-4 carbon atoms, representing C 1-4 Alkoxy; in yet another embodiment, the alkoxy group contains 1-3 carbon atoms, representing C 1-3Alkoxy. The alkoxy group can be optionally substituted with one or more substituents described herein. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2- Propoxy (t-BuO, t-butoxy, -OC(CH3)3), 1-pentyloxy (n-pentyloxy, -OCH2CH2CH2CH2CH3), 2-pentyloxy (-OCH(CH3)CH2CH2CH3), 3-pentyloxy (-OCH(CH2CH3)2), 2-methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-methyl-l-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-l-butoxy (-OCH2CH(CH3)CH2CH3), and the like.

[0097] The term "haloalkoxy" refers to an alkoxy group substituted by one or more halogens, wherein alkoxy and halogen have the same meanings as those defined herein. In some embodiments, haloalkoxy refers to a haloalkoxy group containing 1 to 6 carbon atoms, i.e., C 1-6 In other embodiments, haloalkoxy represents a haloalkoxy group containing 1 to 4 carbon atoms, i.e., C 1-4 In other embodiments, haloalkoxy represents a haloalkoxy group containing 1 to 3 carbon atoms, i.e., C 1-3 Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy (—OCF 3 ), monofluoromethoxy (—OCH 2 F), 2-fluoroethoxy (—OCH 2 CH 2 F), and the like.

[0098] The term "cycloalkyl" refers to a monovalent saturated monocyclic or bicyclic carbon ring system of 3 to 12 carbon atoms, in which the -CH2- group may be optionally replaced by -C(=O)- (or -(CO)-). In one embodiment, the cycloalkyl group contains 3 to 10 carbon atoms, i.e., C 3-10 In another embodiment, the cycloalkyl group contains 3 to 7 carbon atoms, i.e., C 3-7 In another embodiment, the cycloalkyl group contains 3 to 6 carbon atoms, i.e., C 3-6In another embodiment, the cycloalkyl group contains 3-5 carbon atoms, i.e., C 3-5 In another embodiment, the cycloalkyl group is a monocyclic cycloalkyl group containing 3 to 7 carbon atoms, i.e., C 3-7 Monocyclic cycloalkyl. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydro-1H-indenyl, octahydropentalenyl, and the like. Examples of carbocyclic rings in which the -CH2- group may be replaced by -C(=O)- include, but are not limited to, cyclopentanone, cyclobutanone, and the like.

[0099] The term "heterocycle" or "heterocyclyl" refers to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms; wherein the heterocycle or heterocyclyl is non-aromatic and does not contain any aromatic rings. When the heterocycle is attached to the rest of the molecule through a single attachment point, the heterocycle represents a monovalent heterocyclyl. Unless otherwise specified, the heterocyclyl group can be carbon or nitrogen, and the -CH2- group can be optionally replaced by -C(=O)-. The sulfur atom of the ring can be optionally oxidized to an S-oxide. The nitrogen atom of the ring can be optionally oxidized to an N-oxide. In some embodiments, the heterocycle or heterocyclyl consists of 3-10 atoms, representing a 3-10-membered heterocycle or a 3-10-membered heterocyclyl; in other embodiments, the heterocycle or heterocyclyl consists of 3-9 atoms, representing a 3-9-membered heterocycle or a 3-9-membered heterocyclyl; in other embodiments, the heterocycle or heterocyclyl consists of 5-9 atoms, representing a 5-9-membered heterocycle or a 5-9-membered heterocyclyl; in other embodiments, the heterocycle or heterocyclyl consists of 3-6 atoms, representing a 3-6-membered heterocycle or a 3-6-membered heterocyclyl; in other embodiments, the heterocycle or heterocyclyl consists of 5-6 atoms, representing a 5-6-membered heterocycle or a 5-6-membered heterocyclyl. In other embodiments, the heterocycle or heterocyclyl consists of a monocyclic ring consisting of 3-7 atoms, representing a 3-7-membered monocyclic heterocycle or a 3-7-membered monocyclic heterocyclyl. Examples of the heterocycle include, but are not limited to, oxirane, aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, thiazolidine, pyrazolidine, pyrazoline, oxazolidine, imidazolidine, piperidine, piperazine, morpholine, 3,8-diazabicyclo[3.2.1]octane, 3,6-diazabicyclo[3.1.1]heptane, 2,5-diazabicyclo[2.2.2]octane. The heterocyclic group includes, but is not limited to, oxirane, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophene, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl.

[0100] The term "aryl" refers to a monovalent carbon ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system comprises a ring of 3-7 atoms. In some embodiments, the aryl group contains 6-12 ring atoms and is represented by C 6-12 In some embodiments, the aryl group contains 6-10 ring atoms and is represented by C 6-10 Aryl or 6-10 membered aryl. Examples of the aryl group may include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl and anthracene.

[0101] The term "heteroaryl" or "heteroaromatic ring" refers to a monovalent monocyclic, bicyclic or tricyclic ring system containing 5-14 ring atoms, or 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring is aromatic and at least one ring contains one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. The heteroaryl group is usually, but not necessarily, attached to the parent molecule through the aromatic ring of the heteroaryl group. When a -CH2- group is present in the heteroaryl group, the -CH2- group can be optionally replaced by -C(=O)-. Unless otherwise specified, the heteroaryl group can be attached to the rest of the molecule (e.g., the main structure in the general formula) through any reasonable position (which can be C or N). The term "heteroaryl" can be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, the heteroaryl group is a heteroaryl group containing 5-12 ring atoms, represented by a 5-12-membered heteroaryl group; in other embodiments, the heteroaryl group is a heteroaryl group containing 5-10 ring atoms, represented by a 5-10-membered heteroaryl group; in other embodiments, the heteroaryl group is a heteroaryl group containing 5-6 ring atoms, represented by a 5-6-membered heteroaryl group. Examples of heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, triazolyl, tetrazolyl, benzopyridinyl, benzimidazolyl, benzopyrrolyl, benzopyrazolyl, benzopyrrolidinyl, and the like.

[0102] The term "alkylthio" refers to an alkyl group attached to the rest of the molecule through a sulfur atom, wherein alkyl has the definition as described herein. In some embodiments, alkylthio is C 1-6 Alkylthio refers to an alkylthio group containing 1 to 6 carbon atoms; in other embodiments, the alkylthio group is C 1-4 Alkylthio, refers to an alkylthio group containing 1 to 4 carbon atoms; in other embodiments, the alkylthio group is C 1-3Alkylthio refers to an alkylthio group containing 1 to 3 carbon atoms. Examples of alkylthio groups include, but are not limited to, methylthio (-SCH3), ethylthio (-SCH2CH3), and the like.

[0103] The term "haloalkylthio" refers to an alkylthio group substituted by one or more halogen atoms, wherein the alkylthio group has the definition as described herein. In some embodiments, the haloalkylthio group is C 1-6 Halogenated alkylthio refers to a C 1-6 In other embodiments, the haloalkylthio group is C 1-4 Halogenated alkylthio refers to a C 1-4 In other embodiments, the haloalkylthio group is C 1-3 Halogenated alkylthio refers to a C 1-3 Alkylthio. The definition of haloalkylthio includes, but is not limited to, trifluoromethylthio (-SCF3), 2,2,2-trifluoroethylthio (-SCH2CF3), monofluoromethylthio (-SCH2F), and the like.

[0104] The term "arylalkyl" refers to an alkyl group substituted with an aryl group, wherein aryl and alkyl have the definitions described herein. In some embodiments, arylalkyl is C 6-10 Aryl C 1-6 Alkyl or (6-10 membered aryl)-C 1-6 Alkyl; in other embodiments, arylalkyl is C 6-10 Aryl C 1-4 Alkyl or (6-10 membered aryl)-C 1-4 Alkyl; in other embodiments, arylalkyl is C 6-10 Aryl C 1-3 Alkyl or (6-10 membered aryl)-C 1-3 In other embodiments, arylalkyl is phenyl C 1-6 In other embodiments, arylalkyl is phenyl C 1-4 In other embodiments, arylalkyl is phenyl C 1-3 Examples of arylalkyl groups include, but are not limited to, phenylmethyl, phenylethyl, naphthylmethyl, and the like.

[0105] The term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group, wherein heteroaryl and alkyl have the definitions described herein. In some embodiments, heteroarylalkyl is (5-12 membered heteroaryl)-C 1-6 In other embodiments, heteroarylalkyl is (5-12 membered heteroaryl)-C 1-4In other embodiments, heteroarylalkyl is (5-12 membered heteroaryl)-C 1-3 In other embodiments, heteroarylalkyl is (5-6 membered heteroaryl)-C 1-6 In other embodiments, heteroarylalkyl is (5-6 membered heteroaryl)-C 1-4 In other embodiments, heteroarylalkyl is (5-6 membered heteroaryl)-C 1-3 Examples of heteroarylalkyl groups include, but are not limited to, pyrimidinylmethyl, pyridinylmethyl, pyridinylethyl, pyrazolylmethyl, and the like.

[0106] The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl group, wherein heterocyclyl and alkyl are as defined herein. In some embodiments, heterocyclylalkyl is (3-6 membered heterocyclyl)-C 1-6 In other embodiments, heterocyclylalkyl is (3-6 membered heterocyclyl)-C 1-4 In other embodiments, heterocyclylalkyl is (3-6 membered heterocyclyl)-C 1-3 Examples of heterocyclylalkyl groups include, but are not limited to, piperidinylmethyl, piperidinylethyl, pyrrolidinylmethyl, and the like.

[0107] The term "cycloalkylalkyl" refers to an alkyl group substituted with a cycloalkyl group. In some embodiments, the cycloalkylalkyl group is C 3-6 Cycloalkyl C 1-6 Alkyl; in other embodiments, cycloalkylalkyl is C 3-6 Cycloalkyl C 1-4 Alkyl; in other embodiments, cycloalkylalkyl is C 3-6 Cycloalkyl C 1-3 Examples of cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, and the like.

[0108] The term "halogen" refers to F (fluorine), Cl (chlorine), Br (bromine) or I (iodine).

[0109] The term "oxo" means =0.

[0110] The term "cyano" refers to -CN or -C≡N.

[0111] The term "mercapto" refers to -SH.

[0112] The term "hydroxy" refers to -OH.

[0113] The term "carboxy" refers to -C(=O)OH.

[0114] The term "amino" refers to -NH2.

[0115] The term "composed of jk atoms" or "jk-membered" means that the cyclic group is composed of jk ring atoms, and the ring atoms include carbon atoms and / or heteroatoms such as O, N, S, and P; j and k are each independently any non-zero natural number, and k>j; "jk" includes j, k and any natural number in between. For example, “consisting of 3-8 atoms” or “3-8-membered”, “consisting of 3-6 atoms” or “3-6-membered”, “consisting of 5-10 atoms” or “5-10-membered”, or “consisting of 5-6 atoms” or “5-6-membered” means that the cyclic group is composed of 3-8 (i.e., 3, 4, 5, 6, 7 or 8), 3-6 (i.e., 3, 4, 5 or 6), 5-10 (i.e., 5, 6, 7, 8, 9 or 10) or 5-6 (i.e., 5 or 6) ring atoms, and the ring atoms include carbon atoms and / or heteroatoms such as O, N, S, and P.

[0116] As described in the present invention, the substituent (R A1 )q1 The ring system formed by a bond connected to the central ring represents q substituents R A1 Substitution can be made at any substitutable position or any reasonable position on the ring. For example, formula a represents a hexahydro-1H-pyrrolopyrrole ring which can be substituted with q1 R A1 Substitution is performed at any substitutable position or any reasonable position on the ring, when q1 is greater than 1, each R 8 can be independently selected from the same or different substituent groups.

[0117] In the present invention in They respectively represent that the alkenyl group can be in cis, trans or a mixture thereof.

[0118] The term "prodrug" as used herein refers to a compound that is converted in vivo into a compound represented by Formula (I), (I-1), (I-2), (I-3), (I-1a), or (I-1b). Such conversion is affected by hydrolysis of the prodrug in the blood or by enzymatic conversion of the prodrug into the parent structure in the blood or tissues. The prodrug compound of the present invention may be an ester. In the prior art, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound of the present invention containing a hydroxyl group can be acylated to produce a prodrug form of the compound. Other prodrug forms include phosphate esters, such as these phosphate ester compounds, which are obtained by phosphorylating a hydroxyl group on the parent compound.

[0119] "Metabolite" refers to a product resulting from the in vivo metabolism of a specific compound or salt thereof. Metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized using assays such as those described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention encompasses metabolites of the compound, including metabolites produced by contacting the compound of the invention with a mammal for a sufficient period of time.

[0120] As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable salts formed by non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups. The present invention also contemplates quaternary ammonium salts formed by any compound containing a N group. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter-counterions.

[0121] The term "solvate" as used herein refers to an association formed between one or more solvent molecules and a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term "hydrate" refers to an association formed when the solvent molecule is water.

[0122] When the solvent is water, the term "hydrate" may be used. In one embodiment, one molecule of the compound of the present invention may be associated with one water molecule, such as a monohydrate; in another embodiment, one molecule of the compound of the present invention may be associated with more than one water molecule, such as a dihydrate; and in yet another embodiment, one molecule of the compound of the present invention may be associated with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the biological effectiveness of the non-hydrated form of the compound.

[0123] As used herein, the term "treating" any disease or condition, in some embodiments, refers to ameliorating the disease or condition (i.e., slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to regulating the disease or condition physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a physical parameter), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.

[0124] The terms "prevent" or "prevention" refer to a reduction in the risk of acquiring a disease or disorder (i.e., halting the development of at least one clinical symptom of a disease in a subject who may be at risk or predisposed to the disease but has not yet experienced or displayed symptoms of the disease).

[0125] The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect treatment of the disease. The "therapeutically effective amount" may vary depending on the compound, the disease and its severity, and the condition, age, weight, sex, etc. of the subject to be treated.

[0126] Unless otherwise stated, all suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, pharmaceutically acceptable salts and prodrugs thereof of the compounds of the present invention are encompassed within the scope of the invention.

[0127] In structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, all stereoisomers of the structure are contemplated and included as compounds disclosed herein. When stereochemistry is indicated by a solid wedge or dashed line representing a specific configuration, the stereoisomers of the structure are unambiguous and defined.

[0128] Nitrogen oxides of the compounds of the present invention are also included within the scope of the present invention. Nitrogen oxides of the compounds of the present invention can be prepared by oxidation of the corresponding nitrogen-containing basic substance using a conventional oxidizing agent (e.g., hydrogen peroxide) in the presence of an acid such as acetic acid at elevated temperatures, or by reaction with a peracid in a suitable solvent, such as peracetic acid in dichloromethane, ethyl acetate, or methyl acetate, or with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.

[0129] The compound represented by formula (I), (I-1), (I-2), (I-3), (I-1a) or (I-1b) may exist in the form of a salt.

[0130] Any structural formula given herein also encompasses non-isotopically enriched as well as isotopically enriched forms of these compounds. Isotopically enriched compounds have structures depicted by the formula given herein except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 18 F. 31 P. 32 P. 35 S. 36 Cl and 125 I.

[0131] Description of the compounds of the present invention

[0132] The present invention provides a compound, or a pharmaceutical composition thereof, which can be used as a KRAS inhibitor, particularly a KRAS12D inhibitor. The present invention further relates to the use of the compound or the pharmaceutical composition thereof for preparing a medicament for treating a disease and / or condition by inhibiting KRAS activity.

[0133] The excellent properties of the compounds of the present invention, such as half-life, clearance rate, selectivity, bioavailability, chemical stability, metabolic stability, membrane permeability, solubility, etc., can contribute to the reduction of side effects, the expansion of therapeutic index or the improvement of tolerability.

[0134] In one aspect, the present invention provides a compound represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I),

[0135] Among them, ring A, R 1 , Y, R 2 、R 3 、R 4 、R 5 and n each have the meanings as described in the present invention.

[0136] In some embodiments, R 1 is -H, -D, -CN, -NH2, -C(=O)H, -C(=O)OH, -C(=O)OR 6a 、-C(=O)NR 6 R 7 、-NR6 C(=O)R 7 、-NR 6a C(=O)NR 6 R 7 、-C(=O)R 6a 、-NR 6 S(=O)2R 7 、-S(=O)2NR 6 R 7 、-NR 6a S(=O)2NR 6 R 7 、-NR 6 R 7 、-C 1-6 Alkyl-NR 6 C(=O)R 7 、-C 1-6 Alkyl-NR 6 R 7 、-C 1-6 Alkyl-C(=O)OR 6 、-C 1-6 Alkyl-C(=O)NR 6 R 7 、C 1-6 Alkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, (C 3-12 Cycloalkyl)-C 1-6 Alkyl, (3-12 membered heterocyclic)-C 1-6 Alkyl, (C 6-10 Aryl)-C 1-6 Alkyl, (5-12 membered heteroaryl)-C 1-6 Alkyl, (C 3-12 Cycloalkyl)-OC 1-6 Alkyl, (3-12 membered heterocyclic)-OC 1-6 Alkyl, C 1-6 Mercaptoalkyl, C 6-12 Aryl, 5-12 membered heteroaryl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group; wherein the C 1-6 Alkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, (C 3-12Cycloalkyl)-C 1-6 Alkyl, (3-12 membered heterocyclic)-C 1-6 Alkyl, (C 6-10 Aryl)-C 1-6 Alkyl, (5-12 membered heteroaryl)-C 1-6 Alkyl, (C 3-12 Cycloalkyl)-OC 1-6 Alkyl, (3-12 membered heterocyclic)-OC 1-6 Alkyl, C 1-6 Mercaptoalkyl, C 6-12 Aryl, 5-12 membered heteroaryl, C 3-12 Cycloalkyl and 3-12 membered heterocyclyl are each independently optionally substituted by 1, 2, 3 or 4 groups selected from D, -OH, -F, -Cl, -Br, -I, CN, -C(=O)OR 6e 、-NR 6e R 7e 、-C(=O)NR 6e R 7e 、-NR 6e C(=O)R 7e and C 1-6 substituted by an alkyl substituent; wherein R 6 、R 7 、R 6a 、R 6e and R 7e Each has the definition as described in the present invention.

[0137] In some embodiments, R 1 is -H, -D, -CN, -NH2, -C(=O)H, -C(=O)OH, -C(=O)OR 6a 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 、-NR 6a C(=O)NR 6 R 7 、-C(=O)R 6a 、-NR 6 S(=O)2R 7 、-S(=O)2NR 6 R 7 、-NR 6a S(=O)2NR 6 R 7 、-NR 6 R 7 、-C 1-4 Alkyl-NR 6 C(=O)R 7 、-C1-4 Alkyl-NR 6 R 7 、-C 1-4 Alkyl-C(=O)OR 6 、-C 1-4 Alkyl-C(=O)NR 6 R 7 、C 1-4 Alkyl, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, (C 3-6 Cycloalkyl)-C 1-4 Alkyl, (C 7-12 Cycloalkyl)-C 1-4 Alkyl, (3-6 membered heterocyclic)-C 1-4 Alkyl, (7-12 membered heterocyclyl)-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, (5-6 membered heteroaryl)-C 1-4 Alkyl, (C 3-6 Cycloalkyl)-OC 1-4 Alkyl, (C 7-12 Cycloalkyl)-OC 1-4 Alkyl, (3-7 membered heterocyclic)-OC 1-6 Alkyl, (7-12 membered heterocyclic)-OC 1-4 Alkyl, C 1-4 Mercaptoalkyl, C 6-10 Aryl, 5-12 membered heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; wherein the C 1-4 Alkyl, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, (C 3-6 Cycloalkyl)-C 1-4 Alkyl, (C 7-12 Cycloalkyl)-C 1-4 Alkyl, (3-6 membered heterocyclic)-C 1-4 Alkyl, (7-12 membered heterocyclyl)-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, (5-6 membered heteroaryl)-C 1-4 Alkyl, (C 3-6 Cycloalkyl)-OC 1-4 Alkyl, (C7-12 Cycloalkyl)-OC 1-4 Alkyl, (3-7 membered heterocyclic)-OC 1-6 Alkyl, (7-12 membered heterocyclyl)-OC 1-4 Alkyl, C 1-4 Mercaptoalkyl, C 6-10 Aryl, 5-12 membered heteroaryl, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl are each independently optionally substituted by 1, 2, 3 or 4 groups selected from D, -OH, -F, -Cl, -Br, -I, CN, -C(=O)OR 6e 、-NR 6e R 7e 、-C(=O)NR 6e R 7e 、-NR 6e C(=O)R 7e and C 1-4 substituted by an alkyl substituent; wherein R 6 、R 7 、R 6a 、R 6e and R 7e Each has the definition as described in the present invention.

[0138] In some embodiments, R 1 is -H, -D, -CN, -NH2, -C(=O)H, -C(=O)OH, -C(=O)OR 6a 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 、-NR 6a C(=O)NR 6 R 7 、-C(=O)R 6a 、-NR 6 S(=O)2R 7 、-S(=O)2NR 6 R 7 、-NR 6a S(=O)2NR 6 R 7 、-NR 6 R 7 、-CH2NR 6 C(=O)R 7 、-CH2NR 6 R 7 、-(CH2)2NR 6 R 7 、-CH2C(=O)OR 6 、-(CH2)2C(=O)OR6 、-(CH2)3C(=O)OR 6 、-CH2C(=O)NR 6 R 7 、-(CH2)2C(=O)NR 6 R 7 、-(CH2)3C(=O)NR 6 R 7, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CN, -(CH2) 2CN, -(CH2)3CN, -CH(CH3)CN, -C(CH3)2CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -(CH2)2C HF2, -(CH2)2CF(CF3)2, -CF3, -CHF2, -CH2F, -(CH2)2F, -(CH2)2Cl, -CH2CF3, -OCH3, -OCH2CH3, -O (CH2)2CH3, -O(CH2)3CH3, -OC(CH3)3, -OCH(CH3)2, -CH2OCH3, -(CH2)2OCH3, -(CH2)2OCH2CH3, -CH 2OCH2CH3, -CH2OC(CH3)3, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -(CH2)2-cyclopentyl, -(CH2)3-cyclopentyl, -(CH2)2-cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -(CH2)2-cyclobutyl, -CH2-cyclopentyl, -(CH2)2-cyclopentyl, -CH2-azetidinyl, -CH2-pyrrolidine yl, -CH2-piperidinyl, -CH2-morpholinyl, -CH2-phenyl, -CH2-imidazolyl, -CH2-pyrazolyl, -CH2O-cyclopropyl, -CH2O-cyclobutyl, -(CH2)2O-cyclobutyl, -CH2O-cyclopentyl, -(CH2)2O-cyclopentyl, -CH2O-azetidinyl, -CH2O-oxetanyl, -CH2O-tetrahydrofuranyl, -CH2O-spiro[2.3]hexane, -CH2O-spiro[3.3] heptyl-, -CH2SH, -(CH2)2SH, phenyl, naphthyl, pyridyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydropyranyl, azetidinyl or pyrrolidinyl; wherein -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH(CH3)CN, -C(CH3)2CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -(CH2)2CHF2, -(CH2)2CF(CF3)2, -CHF2, -CH2F, -(CH2) 2F, -(CH2)2Cl, -CH2CF3, -OCH3, -OCH2CH3, -O(CH2)2CH3, -O(CH2)3CH3, -OC(CH3)3, -OCH(CH3)2, -CH2OCH3, -(CH2)2OCH3, -(CH2)2OCH2CH3, -CH2OCH2CH3, -CH2OC(CH3)3, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -(CH2)2-cyclo Pentyl, -(CH2)3-cyclopentyl, -(CH2)2-cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -(CH2)2-cyclobutyl, -CH2-cyclopentyl, -(CH2)2-cyclopentyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-morpholinyl, -CH2-phenyl, -CH2-imidazolyl, -CH2-pyrazolyl, -CH2O-cyclopropyl, -CH2O-cyclobutyl, -(CH2)2O-cyclobutyl, -CH2O-cyclopentyl, -(CH2)2 -C(=O)OR, -C(=O)- ... 6e 、-NR 6e R 7e 、-C(=O)NR 6e R 7e 、-NR 6e C(=O)R 7e, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl; wherein, R 6 、R 7 、R 6a 、R 6e and R 7e Each has the same definition as in the present invention.

[0139] In some embodiments, Y is a bond, O, or S.

[0140] In some embodiments, R 2 for Among them, ring B1, ring C1, ring B2, ring C2, ring B3, ring D1, ring D2, ring D3, L 1 , L 2 , L 3 、R A1 、R A2 、R A3 、R A4 、R A1a 、R A1b 、 R A2a 、R A2b 、R A3a 、R A3b , q1, q2, q3 and q4 each have the definition as described in the present invention.

[0141] In some embodiments, L 1 , L 2 and L 3 Each independently is C 1-6 Alkylene or C 1-6 Heteroalkylene, wherein the C 1-6 Alkylene and C 1-6 Each heteroalkylene group is independently optionally substituted by 1, 2, 3 or 4 R a replace.

[0142] In some preferred embodiments, L 1 , L 2 and L 3 Each is independently -CH2-, -(CH2)2-, -(CH2)3- or -(CH2)4-, wherein said -CH2-, -(CH2)2-, -(CH2)3- and -(CH2)4- are each independently optionally replaced by 1, 2, 3 or 4 R a replace.

[0143] In some more preferred embodiments, L 1 , L 2 and L 3 Each is independently -CH2-.

[0144] In some embodiments, R a is -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, C 1-6 Alkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; or two R attached to the same carbon atom a Together they form C 3-6 Cycloalkyl.

[0145] In some embodiments, R a is -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, C 1-4 Alkyl, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; or two R attached to the same carbon atom a Together they form C 3-6 Cycloalkyl.

[0146] In some embodiments, Ring B1 and Ring C1 are each independently a 3-7 membered monocyclic heterocyclyl.

[0147] In some embodiments, Ring B2, Ring B3, and Ring C2 are each independently C 3-7 a monocyclic cycloalkyl group or a 3-7 membered monocyclic heterocyclic group.

[0148] Ring D1, ring D2 and ring D3 are each independently C 3-7 a monocyclic cycloalkyl group or a 3-7 membered monocyclic heterocyclic group.

[0149] In some embodiments, R A1 、R A2 、R A3 and R A4 Each independently represents -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6d R 7d 、-C(=O)NR 6d R 7d 、-CH2NR 6d R 7d 、-CH2OC(=O)NR 6d R7d 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, (C 6-10 Aryl)-C 1-6 Alkyl, (5-12 membered heteroaryl)-C 1-6 Alkyl, (3-6 membered heterocyclic)-C 1-6 Alkyl, (C 3-6 Cycloalkyl)-C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; wherein, R 6d and R 7d Each has the definition as described in the present invention.

[0150] In some embodiments, R A1 、R A2 、R A3 and R A4 Each independently represents -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6d R 7d 、-C(=O)NR 6d R 7d 、-CH2NR 6d R 7d 、-CH2OC(=O)NR 6d R 7d 、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, phenyl-C 1-4 Alkyl, (5-6 membered heteroaryl)-C 1-4 Alkyl, (3-6 membered heterocyclic)-C 1-4 Alkyl, (C 3-6 Cycloalkyl)-C 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; wherein, R 6d and R 7d Each has the definition as described in the present invention.

[0151] In some embodiments, R A1 、R A2 、R A3 and R A4 Each independently represents -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6d R 7d 、-C(=O)NR 6d R7d 、-CH2NR 6d R 7d 、-CH2OC(=O)NR 6d R 7d , -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, -OCH3 , -OCH2CH3, -OCH2CH3, -OC(CH3)3, -(CH2)2CHF2, -(CH2)2CF(CF3)2, -CF3, -CHF2, -CH2F, -(CH2)2F, -(CH2)2Cl, -CH2CF3, -OCF3, -OCHF2, -CH2-phenyl, -CH2-pyridyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-cyclopropyl, -CH2-cyclopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydropyranyl, morpholinyl, azetidinyl and pyrrolidinyl; wherein R 6d and R 7d Each has the definition as described in the present invention.

[0152] In some embodiments, two R A1 Together Among them, R A1a* and R A1b* Each has the definition as described in the present invention.

[0153] In some embodiments, two R A1 Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 3-6 The cycloalkyl and 3-6 membered heterocyclic groups are each independently optionally substituted by 1, 2, 3 or 4 R 8a Replaced by, where R 8a Has the definition as described in the present invention.

[0154] In some preferred embodiments, two R A1and the carbon atom to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl, wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholinyl are each independently optionally substituted by 1, 2, 3 or 4 R 8a Replaced by, where R 8a Has the definition as described in the present invention.

[0155] In some embodiments, two R attached to two adjacent atoms A1 Together with the two adjacent atoms it is connected to form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 3-6 The cycloalkyl and 3-6 membered heterocyclic groups are each independently optionally substituted by 1, 2, 3 or 4 R 8a* Replaced by, where R 8a* Has the definition as described in the present invention.

[0156] In some preferred embodiments, two R A1 and the two adjacent atoms to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl, wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholinyl are each independently optionally substituted by 1, 2, 3 or 4 R 8a* Replaced by, where R 8a* Has the definition as described in the present invention.

[0157] In some embodiments, two R A2 Together Among them, R A2a* and R A2b* Each has the definition as described in the present invention.

[0158] In some embodiments, two R A2Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 3-6 The cycloalkyl and 3-6 membered heterocyclic groups are each independently optionally substituted by 1, 2, 3 or 4 R 9a Replaced by, where R 9a Has the definition as described in the present invention.

[0159] In some preferred embodiments, two R A2 and the carbon atom to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl, wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholinyl are each independently optionally substituted by 1, 2, 3 or 4 R 9a Replaced by, where R 9a Has the definition as described in the present invention.

[0160] In some embodiments, two R attached to two adjacent atoms A2 Together with the two adjacent atoms it is connected to form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 3-6 The cycloalkyl and 3-6 membered heterocyclic groups are each independently optionally substituted by 1, 2, 3 or 4 R 9a* Replaced by, where R 9a* Has the definition as described in the present invention.

[0161] In some preferred embodiments, two R A2 and the two adjacent atoms to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl, wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholinyl are each independently optionally substituted by 1, 2, 3 or 4 R 9a* Replaced by, where R 9a* Has the definition as described in the present invention.

[0162] In some embodiments, two R A3 Together Among them, R A3a* and R A3b* Each has the definition as described in the present invention.

[0163] In some embodiments, two R A3 Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 3-6 The cycloalkyl and 3-6 membered heterocyclic groups are each independently optionally substituted by 1, 2, 3 or 4 R 10a Replaced by, where R 10a Has the definition as described in the present invention.

[0164] In some preferred embodiments, two R A3 and the carbon atom to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl, wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholinyl are each independently optionally substituted by 1, 2, 3 or 4 R 10a Replaced by, where R 10a Has the definition as described in the present invention.

[0165] In some embodiments, two R attached to two adjacent atoms A3 Together with the two adjacent atoms it is connected to form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 3-6 The cycloalkyl and 3-6 membered heterocyclic groups are each independently optionally substituted by 1, 2, 3 or 4 R 10a* Replaced by, where R 10a* Has the definition as described in the present invention.

[0166] Two R's connected to two adjacent atoms A3and the two adjacent atoms to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl, wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholinyl are each independently optionally substituted by 1, 2, 3 or 4 R 10a* Replaced by, where R 10a* Has the definition as described in the present invention.

[0167] In some embodiments, R A1a 、R A1b 、R A2a 、R A2b 、R A3a 、R A3b 、R A1a* 、R A1b* 、R A2a* 、R A2b* 、R A3a* and R A3b* Each is independently -H, -D, -F, -Cl, -Br, -I, -CN, -C 1-6 Alkyl-NR 6 C(=O)R 7 、-C 1-6 Alkyl-NR 6 R 7 、-C 1-6 Alkyl-C(=O)OR 6 、-C 1-6 Alkyl-C(=O)NR 6 R 7 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, (C 3-12 Cycloalkyl)-C 1-6 Alkyl, (3-12 membered heterocyclic)-C 1-6 Alkyl, (C 3-12 Cycloalkyl)-OC 1-6 Alkyl, (3-12 membered heterocyclic)-OC 1-6 Alkyl, C 6-12 Aryl, 5-12 membered heteroaryl, C 3-12Cycloalkyl or 3-12 membered heterocyclic group; wherein, R 6 and R 7 Each has the definition as described in the present invention.

[0168] In some embodiments, R A1a 、R A1b 、R A2a 、R A2b 、R A3a 、R A3b 、R A1a* 、R A1b* 、R A2a* 、R A2b* 、R A3a* and R A3b* Each is independently -H, -D, -F, -Cl, -Br, -I, -CN, -C 1-4 Alkyl-NR 6 C(=O)R 7 、-C 1-4 Alkyl-NR 6 R 7 、-C 1-4 Alkyl-C(=O)OR 6 、-C 1-4 Alkyl-C(=O)NR 6 R 7 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, (C 3-6 Cycloalkyl)-C 1-4 Alkyl, (3-6 membered heterocyclic)-C 1-4 Alkyl, (C 3-6 Cycloalkyl)-OC 1-4 Alkyl, (3-6 membered heterocyclic)-OC 1-4 Alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein R 6 and R 7 Each has the definition as described in the present invention.

[0169] In some embodiments, R A1a 、R A1b 、R A2a 、R A2b 、R A3a 、R A3b 、R A1a* 、R A1b* 、R A2a* 、R A2b*、R A3a* and R A3b* Each is independently -H, -D, -F, -Cl, -Br, -I, -CN, -CH2NR 6 C(=O)R 7 、-CH2NR 6 R 7 、-CH2C(=O)OR 6 、-(CH2)2C(=O)OR 6 、-(CH2)3C(=O)OR 6 、-CH2C(=O)NR 6 R 7 、(CH2)2C(=O)NR 6 R 7 、-(CH2)3C(=O)NR 6 R 7 , -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, -(CH 2)2CHF2, -(CH2)2CF(CF3)2, -CF3, -CHF2, -CH2F, -(CH2)2F, -(CH2)2Cl, -CH2CF3, -CH2 CN, -(CH2)2CN, -(CH2)3CN, -CH(CH3)CN, -C(CH3)2CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -CH2OCH3, -(CH2)2OCH3, -(CH2)2OCH2CH3, -CH2OCH2CH3, -CH2OC(CH3)3, - -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -(CH2)2-cyclopentyl, -(CH2)3-cyclopentyl, -(CH2)2-cyclohexyl, -CH2-cyclopentyl, -CH2-azetidinyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, -CH2-morpholinyl, -CH2O-cyclopropyl, -CH2O-cyclobutyl, -(CH2)3-cyclopentyl, -(CH2)2-cyclohexyl, -CH2-cyclopentyl, -CH2-azetidinyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, -CH2-morpholinyl, -CH2O-cyclopropyl, -CH2O-cyclobutyl, -( wherein R 6 and R 7 Each has the definition as described in the present invention.

[0170] In some embodiments, R8a 、R 8a* 、R 9a 、R 9a* 、R 10a and R 10a* Each is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)OH, -C(=O)NH2, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(=O)OC 1-6 Alkyl, -C(=O)NHC 1-6 Alkyl or -C(=O)N(C 1-6 Alkyl)2.

[0171] In some embodiments, R 8a 、R 8a* 、R 9a 、R 9a* 、R 10a and R 10a* Each is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)OH, -C(=O)NH2, oxo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, phenyl, 5-6 membered heteroaryl, -C(=O)OC 1-4 Alkyl, -C(=O)NHC 1-4 Alkyl, -C(=O)N(C 1-4 Alkyl)2.

[0172] In some embodiments, R 8a 、R 8a* 、R 9a 、R 9a* 、R 10a and R 10a*each independently represents -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)OH, -C(=O)NH2, oxo, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, -(CH2)2CHF2, -(CH2)2CF(CF3)2, -CF3, -CHF2, -CH2F, -(CH2)2F, -(CH2)2Cl, -CH2CF3, -OCH3, -OCH2CH3, -OCH2CH3, -OC(CH3)3, -CH2OH, -(CH2)2OH, -(CH2)3OH, phenyl, pyridyl, pyrimidinyl, -C(=O)OCH3, -C(=O)NH CH3, -C(=O)N(CH3)2.

[0173] In some embodiments, R 2 for Among them, ring B1, ring C1, L 1 、R A1 、R A1a 、R A1b 、R A2a 、R A2b and q1 each have the definition as described in the present invention.

[0174] In some embodiments, R 2 for Among them, ring B1, ring C1, R A1 、R A1a 、R A1b 、R A2a 、R A2b and q1 each have the definition as described in the present invention.

[0175] In some embodiments,

[0176] R 3 for Among them, R 11a 、R 11b 、R 11c and R 11d Each has the definition as described in the present invention.

[0177] In some embodiments, R 11a 、R 11b 、R 11c and R 11d Each independently represents -H, -D, -OH, -SH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OR 6a 、-C(=O)NR 6R 7 、C 1-6 Alkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy or 5-6 membered heteroaryl; wherein R 6 、R 7 and R 6a Each has the definition as described in the present invention.

[0178] In some embodiments, R 11a 、R 11b 、R 11c and R 11d Each is independently -H, -D, -OH, -SH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OCH3, -C(=O)NH2, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)4CH3, -CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -CH2OH, -(CH2)2OH, -CH2CN, -(CH2)2CN, -CF3, -CHF2, -CH2F, -OCF3, -OCH3 or -OCH2CH3.

[0179] In some embodiments, R 4 is -H, -D, -OH, -SH, -F, -Cl, -Br, -I, -CN, methyl, ethyl, n-propyl, isopropyl, n-butyl or C 1-4 Halogenated alkyl.

[0180] In some embodiments, Ring A is C 6-12 aryl or 5-12 membered heteroaryl.

[0181] In some embodiments, Ring A is one of the following substructures,

[0182] In some embodiments, each R 5 are independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH2C(=O)NR 6b R 7b 、-C(=O)R 6c 、-C(=O)OR 6c 、-C(=O)NR 6b R 7b 、-NR 6b C(=O)R 7b 、-NR 6b R7b 、C 1-6 Alkyl, C 1-6 Alkylthio, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Hydroxyalkynyl, C 1-6 Alkoxy, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 2-6 Halogenated alkenyl, C 2-6 Haloalkynyl, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkylthio, 6-12 membered aryl, 5-12 membered heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Alkylthio, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Hydroxyalkynyl, C 1-6 Alkoxy, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 2-6 Halogenated alkenyl, C 2-6 Haloalkynyl, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkylthio, 6-12 membered aryl, 5-12 membered heteroaryl, C 3-6 The cycloalkyl and 3-6 membered heterocyclyl groups are each independently optionally substituted by 1, 2, 3 or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Substituted by a cycloalkyl or 3-6 membered heterocyclic group, wherein R 6b 、R 7b and R 6c Each has the definition as described in the present invention.

[0183] In some embodiments, each R 5 are independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH2C(=O)NR 6b R 7b 、-C(=O)R 6c 、-C(=O)OR 6c 、-C(=O)NR 6b R 7b 、-NR 6b C(=O)R7b 、-NR 6b R 7b 、C 1-4 Alkyl, C 1-4 Alkylthio, C 2-4 Alkenyl, C 2-4 Alkynyl, C 2-4 Hydroxyalkynyl, C 1-4 Alkoxy, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl, C 2-4 Halogenated alkenyl, C 2-4 Haloalkynyl, C 1-4 Halogenated alkoxy, C 1-4 Halogenated alkylthio, 6-12 membered aryl, 5-12 membered heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 1-4 Alkyl, C 1-4 Alkylthio, C 2-4 Alkenyl, C 2-4 Alkynyl, C 2-4 Hydroxyalkynyl, C 1-4 Alkoxy, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl, C 2-4 Halogenated alkenyl, C 2-4 Haloalkynyl, C 1-4 Halogenated alkoxy, C 1-4 Halogenated alkylthio, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 The cycloalkyl and 3-6 membered heterocyclyl groups are each independently optionally substituted by 1, 2, 3 or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 substituted by a cycloalkyl or 3-6 membered heterocyclic group; wherein, R 6b 、R 7b and R 6c Each has the definition as described in the present invention.

[0184] In some embodiments, each R 5 are independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH2C(=O)NR 6b R 7b 、-C(=O)R 6c 、-C(=O)OR 6c 、-C(=O)NR6b R 7b 、-NR 6b C(=O)R 7b 、-NR 6b R 7b, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡ CH, -C≡CCH2OH, -C≡C(CH2)2OH, -OCH3, -OCH2CH3, -O(CH2)2CH3, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -( -(CH2)2Cl, -CH=CHF, -CH=CHCl, -CH=CHCH2F, -C≡CCH2F, -C≡C(CH2)2F, -C≡CF, -OCF3, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCHClCHCl2, -OCH2CH2F, -SCF3, -SCH2CF3, -SCH2CHF2, phenyl, naphthyl, pyridyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl or piperazinyl,wherein said -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, -C≡CCH2OH, -C≡C(CH2)2OH, -O CH3, -OCH2CH3, -O(CH2)2CH3, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2)2OH, -(CH2)3 OH, -CH(OH)CH3, -(CH2)2F, -CH2CHF2, -CH2CF3, -CHF2, -CH2F, -(CH2)2Cl, -CH=CHF, -CH=CH Cl, -CH=CHCH2F, -C≡CCH2F, -C≡C(CH2)2F, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCHClCHCl2, -OCH2CH2F, -SCH2CF3, -SCH2CHF2, phenyl, naphthyl, pyridyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl, and Each piperazinyl group is independently optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl and piperazinyl; wherein R, 6b 、R 7b and R 6c Each has the definition as described in the present invention.

[0185] In some embodiments, R 6 、R 7 、R 6a 、R 6b 、R 6c 、R 7b 、R 6d 、R 7d 、R 6e and R 7e Each is independently -H, -D or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted by 1, 2, 3 or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NH2, C 1-6 Alkoxy, C 6-12 Aryl, C3-6 The cycloalkyl group and the 3- to 6-membered heterocyclic group are substituted.

[0186] In some embodiments, R 6 、R 7 、R 6a 、R 6b 、R 6c 、R 7b 、R 6d 、R 7d 、R 6e and R 7e Each is independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NH2, methoxy, ethoxy, n-propoxy, isopropoxy, isobutoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, oxiranyl, oxetanyl, azetidinyl and pyrrolidinyl.

[0187] In some embodiments, The structural formula is:

[0188] In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7.

[0189] In some embodiments, q1, q2, and q3 are each independently 0, 1, 2, 3, 4, 5, or 6.

[0190] In some embodiments, each q4 is independently 0, 1, 2, 3, or 4.

[0191] In some embodiments, R 2 for Among them, R A1a 、R A1b 、R A2a 、R A2b 、R A1 、R A2 , q1 and q2 each have the definition as described in the present invention.

[0192] In some embodiments, R 2 for wherein ring D1, ring D2 and ring D3 are each independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxetanyl, azetidinyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl and piperazinyl, wherein R A1 、R A2 、R A3 、R A4 , q1, q2, q3 and q4 each have the definition as described in the present invention.

[0193] In some embodiments, R 2 for Among them, R A1a 、R A1b 、R A2a 、R A2b 、R A1 、R A2 、R A1a* and R A1b* Each has the definition as described in the present invention.

[0194] In some embodiments, R 2 for

[0195] In some embodiments, R 2 for

[0196] In some embodiments, the compound of the present invention is a compound represented by formula (I-1), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I-1).

[0197] Among them, R 1 、R 4 、R 5 、R A1 、R A1a 、R A1b 、R 11a , n and q1 each have the meanings as described in the present invention.

[0198] In some embodiments, the compound of the present invention is a compound represented by formula (I-2), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I-2).

[0199] Among them, R 1 、R4 、R 5 、R A1 、R A1a 、R A1b 、R 11a , n and q1 each have the meanings as described in the present invention.

[0200] In some embodiments, the compound of the present invention is a compound represented by formula (I-3), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I-3).

[0201] Among them, R 1 、R 4 、R 5 、R A1 、R A1a 、R A1b 、R 11a , n and q1 each have the meanings as described in the present invention.

[0202] In some embodiments, the compound of the present invention is a compound represented by formula (I-1a), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I-1a).

[0203] Among them, R 1 、R 4 、R 5 、R A1 、R A1a 、R A1b 、R 11a and n each have the meanings as described in the present invention.

[0204] In some embodiments, the compound of the present invention is a compound represented by formula (I-1b), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I-1b).

[0205] Among them, R 1 、R 4 、R 5 、R A1a 、R A1b 、R A1a* 、R A1b* 、R 11a and n each have the meanings as described in the present invention.

[0206] In some embodiments, the compound of the present invention is a compound represented by formula (I-1c), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I-1c).

[0207] Among them, R 1 、R 4 、R 5 、R A1 、R A1a 、R A1b 、R A1a* 、R A1b* 、R 11a 、R A4 , q4 and n each have the meanings as described in the present invention.

[0208] In some embodiments, the compound of the present invention is a compound represented by formula (IB), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (IB).

[0209] Wherein, n2 is 1, 2, 3, 4 or 5; R 1 、R 4 、R 5 、R A1a 、R A1b 、R A1 and q1 each have the definition as described in the present invention.

[0210] In some embodiments, the compound of the present invention is a compound represented by formula (IC), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (IC).

[0211] Wherein, n2 is 1, 2, 3, 4 or 5; R 1 、R 4 、R 5 、R A1a 、R A1b 、R A1 and q1 each have the definition as described in the present invention.

[0212] In some embodiments, the compounds described herein have the following structure, or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof,

[0213] In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention.

[0214] In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable adjuvant.

[0215] In some embodiments, the adjuvants of the present invention include, but are not limited to, carriers, excipients, diluents, solvents, or combinations thereof. In some embodiments, the pharmaceutical composition can be in liquid, solid, semi-solid, gel or spray form.

[0216] In another aspect, the present invention provides use of the pharmaceutical composition of the present invention in the preparation of a medicament for preventing, treating or alleviating KRAS G12D-related diseases.

[0217] In some embodiments, the KRAS G12D-related disease described herein is cancer.

[0218] In some embodiments, the compounds of the present invention or their pharmaceutical compositions can be effectively used to prevent, treat or alleviate the symptoms of cancer in patients, including, but not limited to: cardiac cancer: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma; lung cancer: bronchial cancer (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), non-small cell lung cancer, small cell lung cancer, alveolar (bronchiolar) cancer, bronchial adenoma, sarcoma, lymphoma, chondroma, hamartoma, mesothelioma; gastrointestinal cancer: esophageal (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma) cancer, stomach (carcinoma, lymphoma, leiomyosarcoma) cancer, pancreatic (ductal adenocarcinoma, insulinoma) cancer. Cancers of the genitourinary tract: kidney (adenocarcinoma, Wilms' tumor (Nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testicular (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma), and liver: hepatocellular carcinoma. Cancers of the bile duct: gallbladder cancer, ampullary carcinoma, and bile duct cancer; bone cancer: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell chordoma, osteochronfroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; cancers of the nervous system: neuroma, skull (osteoma, hemangioma, granuloma, xanthomas, and osteitis deformans), and meningeal cancer (meningioma, meningeal sarcoma, and glioma). Disease), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma); gynecological cancer: uterus (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified) cancer), granulosa cell tumor, interstitial cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma), fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (carcinoma), ovarian cancer, breast cancer;Hematologic cancers: leukemias (myeloid leukemias (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative leukemia, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin cancers: melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland cancers: neuroblastoma.

[0219] In some embodiments, the cancer described herein is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, colon cancer, small intestine cancer, pancreatic cancer, uterine cancer, gastric cancer, esophageal cancer, prostate cancer, ovarian cancer, breast cancer, leukemia, melanoma, lymphoma, or neuroma.

[0220] In another aspect, the present invention further provides a method for preventing or treating a KRAS G12D-related disease, comprising administering to a patient a therapeutically effective amount of the compound of the present invention or a pharmaceutical composition thereof.

[0221] On the other hand, the present invention relates to methods for preparing, separating and purifying compounds represented by formula (I), (I-1), (I-2), (I-3), (I-1a), (I-1b), (IB) or (IC).

[0222] Unless otherwise indicated, all stereoisomers, tautomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs of the compounds of the present invention are within the scope of the present invention.

[0223] The term "pharmaceutically acceptable" includes that the substance or composition must be suitable chemically and toxicologically with respect to the other ingredients that make up the formulation and the mammal to be treated.

[0224] The salts of the compounds of the present invention also include intermediates used to prepare or purify compounds represented by formula (I), (I-1), (I-2), (I-3), (I-1a), (I-1b), (IB) or (IC) or salts of separated enantiomers of compounds represented by formula (I), (I-1), (I-2), (I-3), (I-1a), (I-1b), (IB) or (IC), but are not necessarily pharmaceutically acceptable salts.

[0225] Pharmaceutical compositions, preparations, administration and uses of the compounds of the present invention

[0226] The pharmaceutical compositions of the present invention feature compounds represented by Formula (I), (I-1), (I-2), (I-3), (I-1a), (I-1b), (IB), or (IC), compounds listed herein, or compounds of the Examples, and a pharmaceutically acceptable carrier. The amount of the compound in the pharmaceutical compositions of the present invention is effective to treat or alleviate a KRAS G12D-mediated disease in a patient.

[0227] The compounds of the present invention exist in free form or, where appropriate, as pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adducts or derivatives that can be administered directly or indirectly to a patient in need, the compounds described in other aspects of the present invention, their metabolites, or their residues.

[0228] As described herein, the pharmaceutically acceptable compositions of the present invention further comprise pharmaceutically acceptable adjuvants, such as those used in the present invention, including any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for the specific target dosage form. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of these literatures indicate that various adjuvants can be used in the preparation of pharmaceutically acceptable compositions and their known preparation methods. Except to the extent that any conventional adjuvants are incompatible with the compounds of the present invention, for example by producing any adverse biological effects or interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition, their use is contemplated by the present invention.

[0229] Examples of pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl cellulose. sodium cellulose, ethylcellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol, phosphate buffered solution, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and fragrances, preservatives and antioxidants.

[0230] When preparing pharmaceutical composition provided by the invention, active ingredient is usually mixed with excipient, diluted by excipient or encapsulated in this vehicle in the form of for example capsule, sachet, paper or other container.If excipient is used as diluent, it can be solid, semisolid or liquid material, it is used as the vehicle, carrier or medium of active ingredient.Suitable carrier includes but is not limited to magnesium carbonate, magnesium stearate, talcum powder, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethyl cellulose, low melting point wax, cocoa butter etc.Therefore, composition can be tablet, pill, powder, lozenge, capsule, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (solid form or in liquid medium), ointment, soft and hard gelatin capsule, suppository, sterile injection solution and aseptically packaged powder.In one embodiment, composition is formulated for oral administration.In one embodiment, composition is formulated into tablet or capsule.

[0231] The compounds or pharmaceutical compositions of the present invention can be administered in the form of oral dosage forms such as tablets, capsules (each of which includes sustained-release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They can also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously, or intramuscularly, all of which are well known to those of ordinary skill in the pharmaceutical field. They can be administered alone, but will generally be administered together with a pharmaceutical carrier selected based on the selected mode of administration and standard pharmaceutical practice.

[0232] The compounds or pharmaceutical compositions of the present invention can be administered intranasally via topical use of a suitable intranasal vehicle, or transdermally via the use of a transdermal patch. When administered in the form of a transdermal delivery system, the dosage administered is continuous rather than intermittent throughout the duration of administration.

[0233] The compounds or pharmaceutical compositions of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from different phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine.

[0234] The compounds of the present invention or pharmaceutical compositions are also coupled to soluble polymers as targeted drug carriers. Such polymers include polyvinyl pyrrolidone, pyran copolymer, polyhydroxypropyl methacrylate-phenol, polyhydroxyethyl aspartamide phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention can be coupled to a class of biodegradable polymers for controlled drug release, for example, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly-ε caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphiphilic blocking copolymers of hydrogels.

[0235] The dosage regimen of the compounds or pharmaceutical compositions of the present invention will vary depending on various known factors, such as the pharmacokinetic characteristics of the specific agent and its mode and route of administration; the race, age, sex, health condition, medical condition and weight of the recipient; the nature and extent of symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration, the patient's renal and hepatic function, and the desired effect. A physician or veterinarian can determine and prescribe an effective amount of the drug to prevent, counteract or arrest the development of cancer.

[0236] As a general guideline, to achieve the intended effect, the dosage of each active ingredient used is in the range of about 0.001 to 1000 mg / kg body weight per day, preferably about 0.01 to 100 mg / kg body weight per day. The compounds of the present invention can be administered once daily, or in divided doses of two, three, or four times daily.

[0237] Each unit dose of a dosage form (pharmaceutical composition) suitable for administration may contain about 1 mg to about 100 mg of active ingredient. In these pharmaceutical compositions, the weight of the active ingredient will generally account for about 0.5-95% of the total weight of the composition.

[0238] The compounds and compositions of the present invention can be administered alone or in combination with other compounds or other therapeutic agents. The compounds or compositions of the present invention can be administered simultaneously or sequentially with other therapeutic agents via the same or different routes of administration. The compounds of the present invention can be included in a single formulation or in a separate formulation together with other therapeutic agents.

[0239] When the compounds of the invention are administered with other therapeutic agents, the amount of each component in a typical daily dose and typical dosage form may generally be reduced relative to the usual dose when administered alone, in view of the additive or synergistic effects of the therapeutic agents when administered in combination.

[0240] The compound or pharmaceutically acceptable salt or hydrate thereof or pharmaceutical composition thereof according to the present invention can be effectively used for preventing, treating or alleviating KRAS-mediated diseases, especially KRAS G12D-mediated diseases, particularly cancer, in patients.

[0241] In some embodiments, the compounds of the present invention or their pharmaceutical compositions can be effectively used to prevent, treat or alleviate the symptoms of cancer in patients, including, but not limited to: cardiac cancer: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma; lung cancer: bronchial cancer (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), non-small cell lung cancer, small cell lung cancer, alveolar (bronchiolar) cancer, bronchial adenoma, sarcoma, lymphoma, chondroma, hamartoma, mesothelioma; gastrointestinal cancer: esophageal (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma) cancer, stomach (carcinoma, lymphoma, leiomyosarcoma) cancer, pancreatic (ductal adenocarcinoma, insulinoma) cancer. Cancers of the genitourinary tract: kidney (adenocarcinoma, Wilms' tumor (Nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testicular (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma), and liver: hepatocellular carcinoma. Cancers of the bile duct: gallbladder cancer, ampullary carcinoma, and bile duct cancer; bone cancer: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell chordoma, osteochronfroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; cancers of the nervous system: neuroma, skull (osteoma, hemangioma, granuloma, xanthomas, and osteitis deformans), and meningeal cancer (meningioma, meningeal sarcoma, and glioma). Disease), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma); gynecological cancer: uterus (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified) cancer), granulosa cell tumor, interstitial cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma), fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (carcinoma), ovarian cancer, breast cancer;Hematologic cancers: leukemias (myeloid leukemias (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative leukemia, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin cancers: melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland cancers: neuroblastoma.

[0242] In particular, the compounds of the present invention or their pharmaceutical compositions can be effectively used to prevent, treat or alleviate cancer conditions in patients including non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, colon cancer, small intestine cancer, pancreatic cancer, uterine cancer, gastric cancer, esophageal cancer, prostate cancer, ovarian cancer, breast cancer, leukemia, melanoma, lymphoma or neuroma.

[0243] General synthesis process

[0244] To illustrate the present invention, the following examples are used to further illustrate the technical solutions of the present invention. The following examples are only used to illustrate the specific implementation methods of the present invention so that those skilled in the art can understand the present invention, but are not intended to limit the scope of protection of the present invention. In the specific implementation methods of the present invention, technical means or methods not specifically described are conventional technical means or methods in the art.

[0245] Unless otherwise specified, the substituents are as defined herein. The following reaction schemes and examples are provided to further illustrate the present invention.

[0246] Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare other compounds of the present invention, and that other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art through modifications, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also generally applicable to the preparation of other compounds of the present invention.

[0247] In the examples described below, all temperatures are in degrees Celsius (°C) unless otherwise indicated. Room temperature in the examples refers to 15°C–30°C; in some examples, room temperature is 20°C–30°C. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company, and Alfa Chemical Company and used without further purification. Unless otherwise indicated, common reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Factory, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.

[0248] Anhydrous tetrahydrofuran, dioxane, toluene, and diethyl ether were dried over sodium reflux. Anhydrous dichloromethane and chloroform were dried over calcium hydride reflux. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.

[0249] The following reactions were generally carried out under a positive pressure of nitrogen or argon or with a drying tube over anhydrous solvents (unless otherwise indicated), reaction flasks were plugged with suitable rubber stoppers, and substrates were introduced via syringe. All glassware was dried.

[0250] The chromatographic column used was a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.

[0251] 1 H NMR spectra were recorded using a Bruker 400 MHz, 600 MHz, or 599 MHz nuclear magnetic resonance spectrometer. 1 H NMR spectra were obtained using CDC13, DMSO-d6, CD3OD, or acetone-d6 as solvents (in ppm) and referenced to TMS (0 ppm) or chloroform (7.26 ppm). When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), br s (broadened singlet, br.s), dd (doublet of doublets), dt (doublet of triplets), and qt (quartet of triplets). Coupling constants, J, are expressed in Hertz (Hz).

[0252] Low-resolution mass spectrometry (MS) data were collected using an Agilent 6120 quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1×30 mm, 3.5 μm, 6 min, flow rate: 0.6 mL / min). Mobile phase: 5%-95% (CH3CN containing 0.1% formic acid) in (H2O containing 0.1% formic acid). Electrospray ionization (ESI) was used with UV detection at 210 nm / 254 nm.

[0253] The pure compounds were analyzed using Agilent 1260 pre-HPLC or Calesep pump 250 pre-HPLC (column model: NOVASEP 50 / 80 mm DAC) at 210 nm / 254 nm with UV detection.

[0254] The following abbreviations or English words are used throughout the present invention: EtOAc, EA, ethyl acetate, DIPEA, N,N-diisopropylethylamine, PdCl2(PPh3)2, Pd(PPh3)2Cl2, bis(triphenylphosphine)palladium dichloride, POCl3, phosphorus oxychloride, TEA, Et3N, triethylamine, toluene, toluene, PE, petroleum ether, OMOM, methoxymethyloxy, -OCH2OCH3, THF, tetrahydrofuran, TIPS, triisopropylsilyl, DMSO, dimethyl sulfoxide, K3PO4·7H2O, potassium phosphate heptahydrate, DMSO-d6, deuterated dimethyl sulfoxide, ice-bath, DCM, dichloromethane, C SCesium fluoride (F), TFA, CF3COOH, trifluoroacetic acid, DMF, N,N-dimethylformamide, dioxane, 1,4-dioxane, 1,4-dioxane, Pre-TLC, preparative thin-layer chromatography (TLC), CS2CO3, cesium carbonate (h), HCl / dioxane, hydrogen chloride in 1,4-dioxane (min), MeCN, ACN, acetonitrile, NaH, sodium hydride, PTSA, p-toluenesulfonic acid (°C), Na2SO3, sodium sulfite (g), NaHCO3, sodium bicarbonate (mmol), MeOH, methanol (mL), NH3, ammonia (mg), NH3 / MeOH, NH 3·MeOH ammonia in methanol rt room temperature M, mol / L mole / liter HTRF homogeneous time-resolved fluorescence NH2Boc tert-butyl carbamate TMS trimethylsilyl THF / H2O mixed solution of tetrahydrofuran and water TMSOTf trimethylsilyl trifluoromethanesulfonate Boc tert-butyloxycarbonyl TMP MgCl-LiCl 2,2,6,6-tetramethylpiperidinyl magnesium chloride lithium chloride complex Boc2O di-tert-butyl carbonic anhydride K3PO4 potassium phosphate CuI cuprous iodide TBAF tetrabutylammonium fluoride XPhos Pd G3 methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'- HRMS High-resolution mass spectrometry, high-resolution tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium mass spectrometry (II) DAST, diethylaminosulfur trifluoride, LiHMDS, lithium hexamethyldisilazane, LiAlH4, lithium aluminum tetrahydride, PMB, tetramethoxybenzyl, PMBCl, tetramethoxybenzyl chloride, NIS, N-iodosuccinimide, Pd(dppf)Cl2·CH2Cl2, B2Pin2, bis(diphenylphosphino)ferrocene, Pd(dppf)Cl2, [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride, DIBAL-H, diisobutylaluminum hydride dichloromethane complex, HMPT, tris(dimethylamino)phosphine, cataCXium A, Pd G3, [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate

[0255] Synthesis Scheme 1

[0256] Compound (IA) can be synthesized by referring to the method of Synthesis Scheme 1. Wherein ring B1, ring C1, R 1 、R 4 、R 5 、R 11a 、R A1a 、R A1b 、R A1 , q1 and n each have the meanings as described in the present invention; Hal is a halogen, preferably Cl or Br; R a C 1-4 Alkyl, preferably methyl or ethyl. Compound (IA-1) reacts with 2,2,2-trichloroacetyl isocyanate in a suitable solvent (e.g., tetrahydrofuran) to obtain compound (IA-2); compound (IA-2) reacts in a methanolic ammonia solution to obtain compound (IA-3); compound (IA-3) reacts with POCl3 under suitable conditions (e.g., heating, in the presence of DIPEA) to obtain compound (IA-4); compound (IA-4) reacts with compound (IA-5) under suitable conditions (e.g., in the presence of DIPEA) to obtain compound (IA-6); compound (IA-6) reacts with compound (IA-7) under suitable conditions (e.g., low temperature, in the presence of NaH) to obtain compound (IA-8); compound (IA-8) reacts with compound (IA-9) in the presence of a suitable catalyst (e.g., XPhos Pd G3) to obtain compound (IA-10); compound (IA-10) reacts under acidic conditions (e.g., TMSOTf) to obtain compound (IA).

[0257] Synthesis Scheme 2

[0258] Compound (IB) can be synthesized by referring to the method of Synthesis Scheme 2. Wherein ring B1, ring C1, R 1 、R 4 、R 5 、R 11a 、R A1a 、R A1b 、R A1 q1 has the definition as described in the present invention; n2 is a natural number of 1-5, preferably 1 or 2; Hal is a halogen, preferably Cl or Br. Compound (IA-8) reacts with compound (IB-1) in the presence of a suitable catalyst (e.g., XPhos Pd G3) to produce compound (IB-2); compound (IB-2) reacts under acidic conditions (e.g., TMSOTf) to produce compound (IB-3); compound (IB-3) removes the TIPS group under suitable conditions (e.g., CsF in DMF solvent) to produce compound (IB).

[0259] Synthesis Scheme 3

[0260] Compound (IC) can be synthesized by referring to the method of Synthesis Scheme 3. 1 、R 4 、R 5 、R 11a 、R A1a 、R A1b 、R A1 , q1 has the definition as described in the present invention; n2 is a natural number of 1-5, preferably 1 or 2; Hal is a halogen, preferably Cl or Br;. Compound (IA-6) reacts with compound (IC-1) under suitable conditions (e.g., low temperature, in the presence of NaH) to produce compound (IC-2); compound (IC-2) reacts with compound (IC-3) in the presence of a suitable catalyst (e.g., XPhos Pd G3) to produce compound (IC-4); compound (IC-4) reacts under acidic conditions (e.g., TMSOTf) to produce compound (IC-5); compound (IC-5) removes the TIPS group under suitable conditions (e.g., in the presence of CsF in DMF solvent) to produce compound (IC).

[0261] Synthesis Scheme 4

[0262] Compound (ID) can be synthesized by referring to the method of Synthesis Scheme 4. Wherein ring B1, ring C1, R 1 、R 4 、R 5 、R 11a 、R A1a 、R A1b 、R A1 , q1, and n are each defined as described herein; Hal is a halogen, preferably Cl or Br. Compound (IA-8) reacts with compound (ID-1) in the presence of a suitable catalyst (e.g., XPhos Pd G3) to produce compound (ID-2); compound (ID-2) reacts under acidic conditions (e.g., TMSOTf) to produce compound (ID).

[0263] The compounds, pharmaceutical compositions and applications of the present invention are further described below with reference to the examples. Example

[0264] Synthesis of intermediate compound M1

[0265] Step 1: Synthesis of Compound M1-2

[0266] M1-1 (10 g, 45.74 mmol), DMAP (1.12 g, 9.15 mmol), and DCM (200 mL) were added to a 1000 mL single-necked flask and stirred at room temperature. Di-tert-butyl dicarbonate (21.96 g, 100.63 mmol) was added dropwise to the reaction solution and stirred at room temperature for 18 h. The reaction was stopped and imidazole (3.11 g, 45.74 mmol) was added to the reaction solution. After stirring for half an hour, the solution was washed with saturated ammonium chloride solution (100 mL × 3). The organic phase was separated and washed with saturated sodium chloride solution (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain 17.4 g of the yellow solid product M1-2 with a yield of 90.8%, which was used directly in the next step. 1 H NMR (599MHz, CDCl3): δ8.79 (s, 1H), 4.37 (q, J = 7.1Hz, 2H), 1.41 (s, 18H), 1.38 (t, J = 7.1Hz, 3H).

[0267] Step 2: Synthesis of Compound M1-3

[0268] To a 500 mL three-necked flask, M1-2 (10 g, 23.88 mmol) was added. Anhydrous THF (100 mL) was added under nitrogen, and the mixture was stirred and cooled to -40°C. A solution of TMPMgCl-LiCl in tetrahydrofuran (35.82 mL, 35.82 mmol, 1 M) was added dropwise at -40°C. Stirring was continued at -40°C for 4 h, followed by the dropwise addition of a solution of dibromotetrachloroethane (9.33 g, 28.66 mmol) in THF (30 mL). Stirring was continued at -40°C for 4 h. The reaction was stopped and quenched with saturated ammonium chloride solution (100 mL). The mixture was then extracted with EA (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using PE / DCM (v / v = 100 / 1 to 1 / 1) as the eluent to afford 8.5 g of M1-3 as a yellow solid in a 71.5% yield. 1 H NMR (599MHz, CDCl3): δ4.40 (q, J=7.2Hz, 2H), 1.42 (s, 18H), 1.37 (t, J=7.2Hz, 3H).

[0269] Step 3: Synthesis of Compound M1

[0270] To a 250 mL three-necked flask, M1-3 (5 g, 10.05 mmol), DCM (50 mL), and TFA (14.97 mL, 200.1 mmol) were added and stirred at 30°C for 5 h. The reaction was stopped, and the pH was adjusted to neutral by adding saturated sodium carbonate. The mixture was then extracted with DCM (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford 2.9 g of M1 as a light brown solid in a 97% yield.1 H NMR (599MHz, CDCl3): δ6.07 (s, 2H), 4.41 (q, J = 7.1Hz, 2H), 1.41 (t, J = 7.1Hz, 3H); LC-MS (ESI, pos.ion) m / z: 297.1 [M+H] + .

[0271] Synthesis of intermediate compound M2

[0272] Step 1: Synthesis of compound M2-1

[0273] M1 (1.0 g, 3.36 mmol), Pd(PPh3)2Cl2 (0.472 g, 0.67 mmol) and CuI (0.128 g, 0.67 mmol) were added to a 50 mL two-necked flask and the atmosphere was replaced with nitrogen three times. 1-(Trimethylsilyl)propyne (0.566 g, 5.04 mmol), TEA (2.33 mL, 16.8 mmol) and anhydrous THF (10 mL) were added and the atmosphere was replaced with nitrogen three times. A tetrahydrofuran solution of TBAF (5.04 mL, 5.04 mmol, 1.0 M) was added dropwise with stirring. After completion of the addition, the mixture was stirred at room temperature at 25 ° C for 6 h to stop the reaction, filtered through celite, and the filtrate was spin-dried and purified by column chromatography with PE / DCM (v / v = 100 / 1-2 / 1) eluent to obtain 0.523 g of yellow solid M2-1 with a yield of 60.6%. LC-MS(ESI,pos.ion)m / z:257.3[M+H] + .

[0274] Step 2: Synthesis of compound M2-2

[0275] M2-1 (0.52 g, 2.03 mmol) and anhydrous THF (6 mL) were added to a 50 mL single-necked flask under nitrogen atmosphere. Stirring was continued until dissolved. 2,2,2-trichloroacetyl isocyanate (0.497 g, 2.64 mmol) was then added. Stirring was continued at room temperature (25°C) for 1 h. The reaction was stopped, dried, and directly used in the next step. The yield was calculated as 100%. LC-MS (ESI, pos. ion) m / z: 445.9 [M+H] + .

[0276] Step 3: Synthesis of Compound M2

[0277] Methanol (6 mL) was added to M2-2 (0.885 g, 1.99 mmol) obtained in the previous step, and the mixture was stirred to dissolve. Ammonia in methanol (2.84 mL, 19.99 mmol, 7 M) was then added and stirred at room temperature (25°C) for 2 h. The reaction was terminated and the crude product obtained after concentration was slurried with MTBE (10 mL) for 0.5 h and filtered to obtain 0.48 g of M2 as a white solid. The yield of steps 2 and 3 was 95%. LC-MS (ESI, pos. ion) m / z: 254.1 [M+H] + .

[0278] Synthesis of intermediate compound M3

[0279] Step 1: Synthesis of Compound M3-1

[0280] To a 500 mL two-necked flask were added M1 (10 g, 33.61 mmol), 4-formyl-1-butyne (3.78 g, 43.69 mmol), Pd(PPh3)2Cl2 (2.36 g, 3.36 mmol), CuI (0.64 g, 3.36 mmol), TEA (10.20 g, 100.83 mmol), and anhydrous THF (200 mL). The atmosphere was replaced with nitrogen three times and stirred at 25°C for 4 h. The reaction was terminated, filtered over Celite, and the filtrate was dried over anhydrous sodium sulfate and spin-dried. Purification by column chromatography using PE / EA (v / v = 5 / 1-3 / 1) as the eluent afforded 4.74 g of M3-1 as a yellow solid in a 47.2% yield. LC-MS (ESI, pos. ion) m / z: 299.30 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ9.83 (d, J = 1.0Hz, 1H), 6.26 (s, 2H), 4.41 (q, J = 7.1Hz, 2H), 2.84–2.73 (m, 4H), 1.42 (t, J = 7.1Hz, 3H).

[0281] Step 2: Synthesis of compound M3-2

[0282] M3-1 (4.74 g, 15.87 mmol) and dichloromethane (90 mL) were added to a 250 mL single-necked bottle. Diethylaminosulfur trifluoride (DAST, 12.79 g, 79.35 mmol) was added dropwise at 0°C. The mixture was stirred at 0°C for 2 h and quenched with saturated sodium bicarbonate (100 mL). The layers were separated, and the aqueous phase was extracted with dichloromethane (100 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using PE / EA (v / v = 5 / 1) as the eluent to obtain 2.12 g of M3-2 as a yellow solid in a 41.7% yield. LC-MS (ESI, pos. ion) m / z: 321.1 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ6.27(s,2H),6.00(tt,J=56.4,4.5Hz,1H),4.41(q,J=7.1Hz,2 H), 2.63 (t, J = 7.3Hz, 2H), 2.16 (ttd, J = 16.7, 7.3, 4.4Hz, 2H), 1.41 (t, J = 7.1Hz, 3H).

[0283] Step 3: Synthesis of Compound M3-3

[0284] M3-2 (2.1 g, 6.55 mmol) and anhydrous THF (40 mL) were added to a 50 mL single-necked flask and stirred to dissolve. 2,2,2-trichloroacetyl isocyanate (1.95 g, 9.82 mmol) was then slowly added. Stir at 25°C for 40 minutes. The reaction was stopped and dried to obtain a yellow solid, which was directly used in the next step. The yield was calculated as 100%. LC-MS (ESI, pos. ion) m / z: 508.0 [M+H] + .

[0285] Step 4: Synthesis of Compound M3

[0286] Methanol (45 mL) was added to M3-3 obtained in the previous step and stirred to dissolve. Ammonia in methanol (4.67 mL, 32.7 mmol, 7 M) was then added and stirred at room temperature (25°C) for 2.5 h. The reaction was terminated and the crude product obtained after concentration was slurried with MTBE (15 mL) for 0.5 h, filtered, and dried to obtain 1.98 g of a yellow solid M3. The combined yield of steps 3 and 4 was 95.2%. LC-MS (ESI, pos. ion) m / z: 318.1 [M+H] + .

[0287] Synthesis of intermediate compound M4

[0288] Step 1: Synthesis of compound M4-2

[0289] In a 500 mL three-necked flask, M4-1 (10 g, 40.44 mmol) and anhydrous THF (100 mL) were added, the atmosphere was replaced with nitrogen three times, the temperature was lowered to -78 °C, and LiHMDS (80.88 mL, 80.88 mmol, 1 M THF solution), stirred at -78 ° C for 15 minutes, 3-chloro-2-chloromethylpropene (7.58 g, 60.66 mmol) was added at -78 ° C, the reaction solution was transferred to room temperature 25 ° C and stirred for 15 hours, cooled to 0 ° C, adjusted to pH 7 with 1 M hydrochloric acid, added water (200 mL), extracted with EA (100 mL), separated, EA (100 mL) and saturated sodium chloride aqueous solution (100 mL) were added to the aqueous phase, separated, the organic phases were combined, the organic phase was washed with saturated sodium chloride aqueous solution (150 mL), the organic phase was dried over anhydrous sodium sulfate, and purified by column chromatography with PE / EA (v / v = 9 / 1) eluent to obtain 7.5 g of yellow liquid M4-2 with a yield of 55.2%.

[0290] Step 2: Synthesis of Compound M4-3

[0291] M4-2 (7.5 g, 22.33 mmol) and dichloromethane (70 mL) were added to a 250 mL single-necked flask. The temperature was lowered to 0°C, and trifluoroacetic acid (30.7 g, 269.2 mmol) was added dropwise. The mixture was transferred to room temperature (25°C) and stirred for 4 h. The reaction was stopped and concentrated under reduced pressure at 45°C. Methanol (30 mL) was added at 0°C. The pH was adjusted to 8 with 7 M ammonia in methanol (7 M) at 0°C. The mixture was evaporated to dryness and purified by column chromatography using PE / EA (v / v = 1 / 1) as the eluent to obtain 4.1 g of a yellow liquid, M4-3, in a 92.1% yield. LC-MS (ESI, pos. ion) m / z: 200.2 [M+H] + .

[0292] Step 3: Synthesis of Compound M4

[0293] LiAlH4 (1.56 g, 41.16 mmol) and anhydrous THF (40 mL) were added to a 250 mL single-necked flask at room temperature. The atmosphere was replaced with nitrogen three times. A solution of M4-3 (4.1 g, 20.58 mmol) in THF (40 mL) was added dropwise at -10°C. After the addition was complete, the mixture was stirred for 15 minutes and then allowed to react at 25°C for 2 hours. Once the reaction was complete, sodium sulfate decahydrate (3.32 g, 10.29 mmol) was added at 0°C and stirred at room temperature for 1 hour to quench the reaction. After quenching, the reaction mixture was filtered through Celite, and the filtrate was dried to give 2.15 g of the yellow oily product M4 in a 61% yield. LC-MS (ESI, pos.ion) m / z: 172.2 [M+H] + .

[0294] Synthesis of intermediate compound M5

[0295] Step 1: Synthesis of compound M5-2

[0296] In a 500 mL three-necked flask, M5-1 (5 g, 20.72 mmol) and anhydrous THF (30 mL) were added, the atmosphere was replaced with nitrogen three times, the temperature was lowered to -78 ° C, a tetrahydrofuran solution of LiHMDS (41.44 mL, 41.44 mmol) was added dropwise, and the mixture was stirred at -78 ° C for 60 min. 3-Chloro-2-chloromethylpropene (3.84 mL, 41.44 mmol) was slowly added dropwise at -78 ° C, and stirred at -78 ° C for 3 h. Stirring was stopped, and the mixture was transferred to room temperature. Saturated ammonium chloride solution (100 mL) was added to quench the mixture. The liquids were separated, and the aqueous phase was extracted with EA (80 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography with PE / EA (v / v = 20 / 1) as the eluent to obtain 6.25 g of light yellow liquid M5-2 with a yield of 91.4%.

[0297] Step 2: Synthesis of compound M5-3

[0298] In a 250 mL single-necked flask, M5-2 (6.25 g, 18.95 mmol) and acetonitrile (50 mL) were added, the temperature was lowered to 0 ° C and stirred for 5 minutes, a solution of hydrochloric acid in 1,4-dioxane (47.73 mL, 189.5 mmol, 4 M) was added dropwise, the temperature was transferred to 25 ° C and stirred for 1 h, the reaction was stopped, the reaction solution was concentrated and dried, acetonitrile (50 mL) was added for dissolution, and then sodium bicarbonate (7.77 g, 92.5 mmol) and potassium iodide (0.31 g, 1.85 mmol) were added. The reaction solution was stirred at room temperature for 1.5 h, the stirring was stopped, the reaction solution was filtered, washed with acetonitrile (50 mL), the filtrate was concentrated, and purified by column chromatography with PE / EA (v / v = 4 / 1-3 / 2) eluent to obtain 3.05 g of yellow liquid M5-3 with a yield of 85.31%. LC-MS(ESI,pos.ion)m / z:194.2[M+H] + .

[0299] Step 3: Synthesis of Compound M5

[0300] LiAlH4 (1.2 g, 31.56 mmol) was added to a 250 mL single-necked flask at room temperature. The atmosphere was replaced with nitrogen three times. Anhydrous THF (31 mL) was added at -10°C and stirred for 5 minutes. A solution of M5-3 (3.05 g, 15.78 mmol) in THF (20 mL) was slowly added dropwise. After the addition was complete, the temperature was raised to 0°C and the reaction was allowed to react for 1 hour. Once the starting materials had reacted completely, sodium sulfate decahydrate (2.54 g, 7.89 mmol) was slowly added to quench the reaction. After quenching, the reaction solution was filtered through Celite, and the filtrate was dried to give 1.59 g of the yellow oily product M5 in a 60.8% yield. LC-MS (ESI, pos.ion) m / z: 166.2 [M+H]. + .

[0301] Synthesis of intermediate compound M8

[0302] Step 1: Synthesis of compound M8-1

[0303] 2-Fluoro-3-nitrotoluene (10 g, 64.46 mmol), concentrated sulfuric acid (60 mL) and NBS (13.19 g, 74.13 mmol) were added to a 100 mL single-necked bottle and stirred at 50°C for 2 h. The reaction was stopped and the reaction solution was poured into ice water and extracted with EA (100 mL). The organic phase was dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography using PE / EA (v / v = 10 / 1) as the eluent to obtain 14 g of compound M8-1 as an orange-red oil with a yield of 90.15%. Step 2: Synthesis of compound M8-2

[0304] To a 500 mL three-necked flask were added M8-1 (16 g, 68.37 mmol), ethanol (100 mL), iron powder (19.09 g, 341.85 mmol), and ammonium chloride (56.98 mL, 341.85 mmol, 6 M aqueous solution). The mixture was heated to 80°C and stirred for 2 h. The reaction mixture was filtered and the filtrate concentrated. The resulting residue was diluted with ethyl acetate (500 mL) and washed with water (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and purified by column chromatography using PE / EA (v / v = 20 / 1-5 / 1) as the eluent to obtain 10 g of compound M8-2 as a yellow oil in a yield of 71.68%. LC-MS (ESI, pos. ion) m / z: 204.0 [M+H] + .

[0305] Step 3: Synthesis of compound M8-3

[0306] M8-2 (10 g, 49.01 mmol) and anhydrous DMF (60 mL) were added to a 250 mL three-necked flask. The mixture was cooled to 0°C and stirred. NaH (5.88 g, 147.03 mmol, 60% by mass) was added and stirred at room temperature for 20 min. 4-Methoxybenzyl chloride (15.35 g, 98.02 mmol) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched by the addition of saturated ammonium chloride solution (40 mL), diluted with water (40 mL), and extracted with ethyl acetate (100 mL). The organic phase was concentrated, dried over anhydrous sodium sulfate, and then purified by column chromatography using PE / EA (v / v = 20 / 1) as the eluent to obtain 18.4 g of compound M8-3 as a white solid in an 84.5% yield. LC-MS (ESI, pos. ion) m / z: 444.1 [M+H] + .

[0307] Step 4: Synthesis of Compound M8-4

[0308] M8-3 (7 g, 15.75 mmol) and acetic acid (20 mL) were added to a 50 mL single-necked flask under nitrogen atmosphere and stirred for 2 minutes. NIS (5.32 g, 23.63 mmol) was then added and stirred at room temperature for 15 hours. The reaction was quenched by adding saturated sodium thiosulfate solution (10 mL). The mixture was extracted with EA (20 mL), dried over anhydrous sodium sulfate, and purified by column chromatography using PE / EA (v / v = 10 / 1) as the eluent to obtain 8.7 g of M8-4 as a colorless oil in a 96.8% yield. LC-MS (ESI, pos. ion) m / z: 570.0 [M+H] + .

[0309] Step 5: Synthesis of Compound M8-5

[0310] In a 50 mL single-necked flask, M8-4 (8.7 g, 15.26 mmol), methyl fluorosulfonyldifluoroacetate (27.85 g, 144.97 mmol), cuprous iodide (29.06 g, 152.6 mmol) and DMF (90 mL) were added, and the atmosphere was replaced with nitrogen three times. The mixture was heated to 75 ° C and stirred for 15 h. The reaction was stopped, and the mixture was returned to room temperature and filtered. EA (60 mL) was added, and the organic phase was washed with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography with PE / EA (v / v = 10 / 1) eluent to obtain 2 g of orange oily compound M8-5 with a yield of 25.6%.

[0311] Step 6: Synthesis of Compound M8

[0312] To a 50 mL single-necked flask were added M8-5 (2 g, 1.95 mmol), pinacol diboron (1.49 g, 5.85 mmol), Pd(dppf)Cl2·CH2Cl2 (0.16 g, 0.20 mmol), potassium acetate (0.58 g, 5.95 mmol), and 1,4-dioxane (20 mL). After nitrogen displacement three times, the mixture was heated to 100°C and stirred for 3 h. The silica gel was then dried and the sample was purified by column chromatography using PE / EA (v / v = 10 / 1) as the eluent to obtain 0.93 g of compound M8 as a white solid in an 85.2% yield. LC-MS (ESI, pos. ion) m / z: 560.3 [M+H] + .

[0313] Synthesis of intermediate compound M9

[0314] Step 1: Synthesis of Compound M9

[0315] To a 100 mL single-necked flask were added 3-bromo-5-chloro-4-(trifluoromethyl)aniline (5 g, 18.22 mmol, purchased from Beijing LeYan Technology), pinacol diboron (5.55 g, 21.86 mmol), Pd(dppf)Cl2 (1.19 g, 1.82 mmol), potassium acetate (5.36 g, 54.66 mmol), and 1,4-dioxane (200 mL). After nitrogen substitution three times, the mixture was heated to 80°C and stirred for 18 h to terminate the reaction. The reaction solution was filtered through celite and concentrated. The crude product was purified by column chromatography using PE / EA (v / v = 4 / 1-1 / 1) as the eluent to obtain 2.535 g of Compound M9 as a white solid in a 43.3% yield. LC-MS (ESI, pos. ion) m / z: 322.0 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ6.73 (d, J = 1.9 Hz, 1H), 6.55 (d, J = 1.9 Hz, 1H), 3.97 (s, 2H), 1.35 (s, 12H). 19 F NMR(376MHz,CD3Cl3)δ-56.70(3F).

[0316] Example 1: Synthesis of Compound 1

[0317] Step 1: Synthesis of compound 1-1

[0318] In a 100 mL single-necked flask, M2 (2.00 g, 7.89 mmol) and anhydrous toluene (20 mL) were added, followed by phosphorus oxychloride (2.16 mL, 23.67 mmol) and DIPEA (6.52 mL, 39.45 mmol). The mixture was heated to 70 °C and stirred for 1 h. The reaction was stopped, cooled, concentrated, and used directly in the next step. The yield was calculated as 100%.

[0319] Step 2: Synthesis of compound 1-2

[0320] Anhydrous dichloromethane (20 mL) was added to 1-1 obtained in the previous step, and the atmosphere was replaced with nitrogen three times. The mixture was stirred and dissolved, cooled to -40 °C and stirred for 5 minutes, and DIPEA (6.51 mL, 39.4 mmol) was added. Then, 8-B was added. OC -3,8-diazabicyclo[3.2.1]octane (1.67 g, 7.88 mmol). After stirring at -40°C for 0.5 h, the reaction was stopped and quenched with saturated ammonium chloride solution (50 mL). The mixture was returned to room temperature and extracted with DCM (50 mL x 2). The organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using PE / EA (v / v = 9 / 1) as the eluent to obtain 787 mg of compound 1-2 as a yellow solid. The combined yield of steps 1 and 2 was 21.4%. LC-MS (ESI, pos. ion) m / z: 466.2 [M+H]. + .

[0321] Step 3: Synthesis of Compound 1-3

[0322] Sodium hydride (0.13 g, 3.28 mmol, 60%) was added to a 100 mL two-necked flask. The atmosphere was purged with nitrogen and anhydrous THF (8 mL) was added. The mixture was stirred at 0°C for 5 minutes. A solution of M4 (0.28 g, 1.64 mmol) in THF (2 mL) was slowly added dropwise. The mixture was stirred at 0°C for 1 hour. A solution of compound 1-2 (383 mg, 0.82 mmol) in THF (5 mL) was slowly added dropwise. The mixture was stirred at 0°C for 2.5 hours. Stirring was stopped, and the mixture was diluted with 15 mL of EA. The mixture was washed with saturated ammonium chloride solution (15 mL). The layers were separated and the aqueous phase was extracted with EA (10 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v = 50 / 1) as the eluent to afford 312 mg of compound 1-3 as a yellow solid in a 63.2% yield. LC-MS (ESI, pos. ion) m / z: 601.3 [M+H] + .

[0323] Step 4: Synthesis of Compound 1-4

[0324] In a 25 mL two-necked flask, 1-3 (200 mg, 0.33 mmol, 1 equiv.), M6 (0.25 g, 0.49 mmol), Xphos Pd G3 (56 mg, 0.066 mmol), K3PO4·7H2O (280 mg, 0.83 mmol) and THF / H2O (v / v = 4.8 mL / 1.6 mL) were added. The atmosphere was replaced with nitrogen three times and stirred at room temperature at 25 ° C for 13 h. The reaction was monitored by TLC. Half of the raw material 1-3 remained. M6 (0.25 g, 0.49 mmol, 1.5 equiv.), Xphos Pd G3 (56 mg, 0.066 mmol), K3PO4·7H2O (280 mg, 0.83 mmol) and THF / H2O (v / v = 4.8 mL / 1.6 mL) were added. G3 (56 mg, 0.066 mmol, 0.2 equiv.), K3PO4·7H2O (280 mg, 0.83 mmol, 2.5 equiv.), and THF / H2O (0.5 mL / 0.5 mL) were added. After nitrogen substitution, stirring was continued for 1.5 h. If the reaction was still incomplete, the additional addition process was repeated. The reaction of starting material 1-3 was essentially complete. Saturated ammonium chloride solution (20 mL) was added, and the mixture was extracted with EA (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v = 50 / 1) as the eluent to afford 296 mg of compound 1-4 as a red solid in a 93.5% yield. LC-MS (ESI, pos. ion) m / z: 951.4 [M+H] + .

[0325] Step 5: Synthesis of Compounds 1-5

[0326] 1-4 (296 mg, 0.31 mmol) and acetonitrile (7 mL) were added to a 50 mL single-necked bottle, cooled to -20 ° C and stirred for 5 minutes, TMSOTf (0.14 mL, 0.78 mmol) was added dropwise, and stirred for 60 minutes to stop the reaction. Saturated aqueous sodium bicarbonate solution (20 mL) was added to quench the reaction, and the mixture was extracted with DCM (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v = 9 / 1) as the eluent to obtain 82 mg of yellow solid compound 1-5 with a yield of 32.6%. LC-MS (ESI, pos. ion) m / z: 807.5 [M+H] + .

[0327] Step 6: Synthesis of Compound 1

[0328] 1-5 (82 mg, 0.10 mmol), cesium fluoride (230 mg, 1.5 mmol) and DMF (0.5 mL) were added to a 25 mL single-necked bottle, and the atmosphere was replaced with nitrogen three times. The mixture was stirred at room temperature for 5 h, and the reaction was stopped. Water (10 mL) was added to precipitate a solid, which was filtered to obtain a crude solid product. The crude product was purified by thin-layer chromatography using DCM / MeOH (v / v=8 / 1) as the eluent to obtain 36 mg of compound 1 as a yellow solid. The yield was 54.4%. LC-MS (ESI, pos.ion) m / z: 651.5 [M+H] + ; HRMS (ESI): 651.2709 [M+H] + ; 1 H NMR (400MHz, CD3OD) δ7.86(dd,J=9.1,5.7Hz,1H),7.37–7.27(m,2H),7.20(s,1H),5.33(d,J=53.3Hz,1H),5.02(s,2H),4.71–4.20(m ,5H),4.08–3.68(m,5H),3.52–3.36(m,1H),3.05–2.80(m,2H),2.61–2.38(m,2H),2.19(s,3H),2.25–2.05(m,1H),1.96–1.59(m,4H). 19 F NMR (376MHz, CD3OD) δ-111.52(1F),-139.92(1F),-174.11(1F).

[0329] Example 2: Synthesis of Compound 2

[0330] Step 1: Synthesis of compound 2-1

[0331] Sodium hydride (0.13 g, 3.28 mmol, 60% content) was added to a 100 mL two-necked flask. The atmosphere was replaced with nitrogen, and anhydrous THF (7 mL) was added. The mixture was stirred at 0°C for 5 minutes. A solution of M5 (0.24 g, 1.48 mmol) in THF (2 mL) was slowly added dropwise. The mixture was stirred at 0°C for 1 hour. A solution of 1-2 (383 mg, 0.82 mmol) in THF (5 mL) was slowly added dropwise. The mixture was stirred at 0°C for 3 hours. Stirring was stopped, and the reaction was quenched by the addition of saturated ammonium chloride solution (30 mL). The layers were separated, and the aqueous phase was extracted with EA (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v = 50 / 1) as the eluent to afford 271 mg of compound 2-1 as a yellow solid in a 55.4% yield. LC-MS (ESI, pos. ion) m / z: 595.5 [M+H] + .

[0332] Step 2: Synthesis of compound 2-2

[0333] In a 25 mL two-necked flask, 2-1 (200 mg, 0.34 mmol, 1.0 eq), M6 (0.26 g, 0.51 mmol), Xphos Pd G3 (58 mg, 0.068 mmol), K3PO4·7H2O (290 mg, 0.85 mmol) and THF / H2O (5.1 mL / 1.7 mL) were added. The atmosphere was replaced with nitrogen three times and stirred at room temperature at 25 °C for 1 h. The reaction was monitored by TLC. If half of the raw material 2-1 remained, M6 (0.26 g, 0.51 mmol, 1.5 equiv.), Xphos Pd G3 (58 mg, 0.068 mmol) and K3PO4·7H2O (290 mg, 0.85 mmol) were added. The mixture was stirred at room temperature at 25 °C for 1 h. The reaction was monitored by TLC. If half of the raw material 2-1 remained, M6 (0.26 g, 0.51 mmol, 1.5 equiv.) and Xphos Pd G3 (58 mg, 0.068 mmol) were added. G3 (58 mg, 0.068 mmol, 0.2 equiv.), K3PO4·7H2O (290 mg, 0.85 mmol, 2.5 equiv.), and THF / H2O (0.5 mL / 0.5 mL) were added. After nitrogen substitution, stirring was continued for 0.5 h. If the reaction was still incomplete, the additional addition procedure was repeated. The reaction of the starting material 2-1 was essentially complete. Saturated ammonium chloride solution (20 mL) was added, and the mixture was extracted with EA (20 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v = 30 / 1) as the eluent to afford 227 mg of compound 2-2 as a red solid in a 71.5% yield. LC-MS (ESI, pos. ion) m / z: 473.5 [M+2H]. 2+ .

[0334] Step 3: Synthesis of compound 2-3

[0335] 2-2 (227 mg, 0.24 mmol) and acetonitrile (6 mL) were added to a 50 mL single-necked flask, cooled to -15 ° C and stirred for 5 minutes, and TMSOTf (0.12 mL, 0.65 mmol) was slowly added dropwise and stirred for 30 minutes to stop the reaction. Saturated aqueous sodium bicarbonate solution (20 mL) was added to quench the reaction, and the mixture was extracted with DCM (15 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v = 9 / 1) as the eluent to obtain 110 mg of yellow solid compound 2-3 with a yield of 57.2%. LC-MS (ESI, pos. ion) m / z: 801.4 [M+H] + .

[0336] Step 4: Synthesis of compound 2

[0337] 1-5 (110 mg, 0.14 mmol), cesium fluoride (320 mg, 2.1 mmol) and DMF (0.8 mL) were added to a 25 mL single-necked bottle, and the atmosphere was replaced with nitrogen three times. The mixture was stirred at room temperature at 25 ° C for 17.5 h, and the reaction was stopped. 15 mL of water was added to precipitate a solid, which was filtered to obtain a crude solid product. The crude product was purified by thin-layer chromatography using DCM / MeOH (v / v=8 / 1) as the eluent to obtain 67 mg of compound 2 as a yellow solid. The yield was 75.7%. LC-MS (ESI, pos.ion) m / z: 645.5 [M+H] + ; HRMS (ESI): 645.2802[M+H] + ; 1 H NMR (400MHz, CD3OD): δ7.86(dd,J=9.1,5.7Hz,1H),7.38–7.27(m,2H),7.24–7.16(m,1H),5.13–5.00(m,4H),4.64–4.27(m,4 H),4.09–3.72(m,6H),3.54–3.39(m,2H),3.33(s,1H),2.93–2.76(m,2H),2.71–2.56(m,2H),2.20(s,3H),1.99–1.62(m,4H). 19 F NMR(376MHz,CD3OD)δ-111.51(1F),-139.85(1F).

[0338] Example 3: Synthesis of Compound 3

[0339] Step 1: Synthesis of compound 3-1

[0340] In a 100 mL single-necked flask, M3 (1.88 g, 5.92 mmol) and anhydrous toluene (38 mL) were added, followed by phosphorus oxychloride (3.63 g, 23.68 mmol) and DIPEA (3.06 g, 23.68 mmol). The mixture was heated to 70 °C and stirred for 1.5 h. The reaction was stopped, cooled, concentrated, and used directly in the next step. The yield was calculated as 100%.

[0341] Step 2: Synthesis of compound 3-2

[0342] Anhydrous dichloromethane (40 mL) was added to 3-1 obtained in the previous step. The atmosphere was replaced with nitrogen three times, and the mixture was stirred to dissolve. The mixture was cooled to -40°C and stirred for 5 minutes. DIPEA (2.28 g, 17.67 mmol) was added, followed by a solution of 8-BOC-3,8-diazabicyclo[3.2.1]octane (1.25 g, 5.89 mmol) in DCM (10 mL) dropwise. After stirring at -40°C for 0.5 h, the reaction was stopped and quenched with saturated ammonium chloride solution (50 mL). The mixture was returned to room temperature and extracted with DCM (30 mL x 2). The organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using PE / EA (v / v = 10 / 1-2 / 1) as the eluent to afford 2.01 g of compound 3-2 as a yellow solid. The combined yield for Steps 1 and 2 was 64.3%. LC-MS (ESI, pos. ion) m / z: 531.5 [M+H] + .

[0343] Step 3: Synthesis of compound 3-3

[0344] To a 100 mL two-necked flask were added 3-2 (1.65 g, 3.105 mmol), M4 (798 mg, 4.65 mmol), DIPEA (2.56 mL, 15.52 mmol), and anhydrous 1,4-dioxane (18 mL). After nitrogen purge three times, the mixture was heated to 90°C and stirred for 12 h. Stirring was stopped, the mixture was concentrated, and the mixture was purified by column chromatography using DCM / MeOH (v / v = 100 / 1-30 / 1) as the eluent to obtain 450 mg of compound 3-3 as a yellow oil in a 21.8% yield. LC-MS (ESI, pos. ion) m / z: 666.0 [M+H] + .

[0345] Step 4: Synthesis of compound 3-4

[0346] To a 25 mL two-necked flask were added 3-3 (450 mg, 0.68 mmol), M6 (0.697 g, 1.36 mmol), Xphos Pd G3 (172.7 mg, 0.20 mmol), K3PO4·7H2O (1.15 g, 3.40 mmol), and THF / H2O (10 mL / 2 mL). The atmosphere was purged with nitrogen three times and stirred at 30°C for 6 h. The reaction was terminated by adding saturated ammonium chloride solution (20 mL) and extracting with DCM (50 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v = 100 / 1 to 30 / 1) as the eluent to afford 323 mg of compound 3-4 as a brown oil in a 47.0% yield. LC-MS (ESI, pos. ion) m / z: 508.4 [M+2H] 2+ .

[0347] Step 5: Synthesis of compound 3-5

[0348] 3-4 (270 mg, 0.27 mmol) and acetonitrile (10 mL) were added to a 50 mL single-necked flask, cooled to 0°C and stirred for 5 minutes, TMSOTf (0.24 mL, 1.35 mmol) was added dropwise, and stirred at 0°C for 30 minutes to stop the reaction. Saturated aqueous sodium bicarbonate solution (20 mL) was added to quench the reaction, and the mixture was extracted with DCM (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by thin-layer chromatography using DCM / MeOH (v / v = 10 / 1) as the eluent to obtain 65 mg of compound 3-5 as a yellow solid in a yield of 28.1%. LC-MS (ESI, pos. ion) m / z: 871.4 [M+H] + .

[0349] Step 6: Synthesis of compound 3

[0350] 3-5 (80 mg, 0.092 mmol), cesium fluoride (140 mg, 0.92 mmol) and DMF (2 mL) were added to a 25 mL single-necked bottle, and the atmosphere was replaced with nitrogen three times. The mixture was stirred at room temperature at 25 ° C for 4 h, and the reaction was stopped. 8 mL of water was added to precipitate the solid, which was filtered to obtain a solid crude product. The crude product was purified by thin-layer chromatography using DCM / MeOH / TEA (v / v = 10 / 1 / 0.1) as the eluent to obtain 27 mg of brown solid compound 3. The yield was 41.1%. LC-MS (ESI, pos. ion) m / z: 715.2 [M+H] + ; HRMS (ESI): 715.2836 [M+H] + ; 1 H NMR (400MHz, CD3OD): δ7.86 (dd, J=9.1, 5.7Hz, 1H), 7.38–7.29 (m, 2H), 7.21 (s, 1 H),6.05(tt,J=56.4,4.3Hz,1H),5.34(d,J=53.2Hz,1H),5.02(s,2H),4.72–4.2 6(m,4H),4.05–3.75(m,5H),3.50–3.39(m,1H),3.34(s,1H),3.03–2.84(m,2H), 2.77(t,J=7.4Hz,2H),2.60–2.39(m,2H),2.29–2.04(m,4H),1.95–1.64(m,4H). 19 F NMR (376MHz, CD3OD): δ-111.44(1F),-119.49(2F),-139.27(1F),-174.25(1F).

[0351] Example 4: Synthesis of Compound 4

[0352] Step 1: Synthesis of compound 4-1

[0353] To a 50 mL two-necked flask were added 3-2 (450 mg, 0.85 mmol), M5 (280.9 mg, 1.7 mmol), DIPEA (0.70 mL, 4.25 mmol), and anhydrous 1,4-dioxane (6 mL). After nitrogen replacement three times, the mixture was heated to 95°C and stirred for 12 h. Stirring was stopped, the mixture was concentrated, and the mixture was purified by column chromatography using DCM / MeOH (v / v = 100 / 1-30 / 1) as the eluent to obtain 220 mg of compound 4-1 as a yellow oil in a 39.3% yield. LC-MS (ESI, pos. ion) m / z: 659.3 [M+H] + .

[0354] Step 2: Synthesis of compound 4-2

[0355] To a 25 mL two-necked flask were added 4-1 (220 mg, 0.33 mmol), M6 (338 mg, 0.66 mmol), Xphos Pd G3 (139.7 mg, 0.17 mmol), K3PO4·7H2O (0.56 g, 1.65 mmol), and THF / H2O (5 mL / 1 mL). The atmosphere was purged with nitrogen three times and stirred at 30°C for 6 h. The reaction was terminated, and saturated ammonium chloride solution (20 mL) was added. The mixture was extracted with EA (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v = 100 / 1 to 30 / 1) as the eluent to afford 200 mg of compound 4-2 as a brown oil in a 59.4% yield. LC-MS (ESI, pos. ion) m / z: 1009.5 [M+H] + .

[0356] Step 3: Synthesis of compound 4-3

[0357] 4-2 (180 mg, 0.18 mmol) and acetonitrile (6 mL) were added to a 50 mL single-necked bottle, cooled to 0°C and stirred for 5 minutes, TMSOTf (0.16 mL, 0.90 mmol) was added dropwise, and stirred at 0°C for 30 minutes to stop the reaction. Saturated aqueous sodium bicarbonate solution (20 mL) was added to quench the reaction, and the mixture was extracted with DCM (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 140 mg of brown solid compound 4-3 with a yield of 90.7%. LC-MS (ESI, pos.ion) m / z: 865.4 [M+H] + .

[0358] Step 4: Synthesis of compound 4

[0359] 4-3 (140 mg, 0.16 mmol), cesium fluoride (240 mg, 1.6 mmol) and DMF (2 mL) were added to a 25 mL single-necked bottle, and the atmosphere was replaced with nitrogen three times. The mixture was stirred at room temperature for 5 h, and the reaction was stopped. 10 mL of water was added to precipitate a solid, which was filtered to obtain a crude solid product. The crude product was purified by thin-layer chromatography using DCM / MeOH / TEA (v / v = 100 / 10 / 0.5) as the eluent to obtain 35 mg of brown solid compound 4 in a yield of 30.5%. LC-MS (ESI, pos. ion) m / z: 709.3 [M+H] + ; HRMS (ESI): 709.2906[M+H] + ; 1 H NMR(400MHz,CD3OD)δ7.87(dd,J=9.1,5.7Hz,1H),7.42–7.27(m,2H),7.22( s,1H),6.05(tt,J=56.4,4.3Hz,1H),5.13–5.01(m,4H),4.69–4.28(m,4H), 4.09–3.78(m,6H),3.54–3.43(m,2H),3.34(s,1H),2.91–2.81(m,2H),2.77 (t,J=7.4Hz,2H),2.69–2.57(m,2H),2.30–2.13(m,2H),1.97–1.63(m,4H). 19 F NMR (376MHz, CD3OD): δ-111.43(1F),-119.46(2F),-139.26(1F).

[0360] Example 5: Synthesis of Compound 5

[0361] Step 1: Synthesis of compound 5-1

[0362] At room temperature, ethyl 5-oxopyrrolidine-2-carboxylate (10 g, 63.63 mmol), 3-chloro-2-chloromethylpropene (11.93 g, 95.45 mmol), and anhydrous THF (20 mL) were added to a 250 mL two-necked flask. The atmosphere was purged with nitrogen three times, and the temperature was cooled to -40°C. LiHMDS (100 mL, 100 mmol, 1.0 M THF solution) was added dropwise. After completion of the addition, the mixture was allowed to react at -40°C for 30 min, then moved to room temperature and stirred for 16 h. The reaction was stopped and quenched with saturated ammonium chloride (50 mL). The mixture was extracted with EA (50 mL × 2). The organic phases were combined and washed twice with saturated brine (50 mL × 2). The organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using PE / DCM (v / v = 0 / 100) as the eluent to obtain 5.3 g of compound 5-1 as a yellow oil in a 40% yield. LC-MS(ESI,pos.ion)m / z:210.1[M+H] + .

[0363] Step 2: Synthesis of compound 5-2

[0364] At room temperature, 5-1 (1.3 g, 5.30 mmol) was added to a 250 mL single-necked flask. The temperature was lowered to 0°C, and a toluene solution of diisobutylaluminum hydride (1.5 M, 67.55 mL, 101.32 mmol) was added dropwise. The mixture was stirred at room temperature overnight. The reaction mixture was added to 250 mL of ice water with stirring for 15 min, filtered through celite, and the filter cake was rinsed with ethyl acetate (200 mL). The filtrate was separated, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v = 4 / 1) as the eluent to obtain 1.2 g of compound 5-2 as a yellow solid in a 31% yield. LC-MS (ESI, pos. ion) m / z: 154.2 [M+H] + .

[0365] Step 3: Synthesis of compound 5-3

[0366] At room temperature, a 100 mL single-necked flask was charged with 1-2 (1 g, 2.14 mmol), 5-2 (0.66 g, 4.28 mmol), potassium carbonate (1.18 g, 8.56 mmol), and 1,4-dioxane (15 mL). The atmosphere was replaced with nitrogen three times, and the temperature was raised to 100°C and refluxed for 16 h. The reaction was stopped, filtered, and the filter cake was washed with EA (60 mL). The combined filtrate was added with saturated ammonium chloride (60 mL) and separated. The aqueous phase was extracted with EA (50 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v = 100 / 0-20 / 1) as the eluent to obtain 0.43 g of compound 5-3 as a dark solid in a 34% yield. LC-MS (ESI, pos. ion) m / z: 583.3 [M+H] + .

[0367] Step 4: Synthesis of compound 5-4

[0368] To a 50 mL two-necked flask were added 5-3 (430 mg, 0.74 mmol), M6 (0.57 g, 1.11 mmol), K3PO4·7H2O (880 mg, 2.59 mmol), and THF / H2O (10 mL / 1 mL). The atmosphere was purged with nitrogen three times, and Xphos Pd G3 (190 mg, 0.22 mmol) was added portionwise. The mixture was stirred at 35°C for 5 h. Saturated ammonium chloride solution (20 mL) was added, and the mixture was extracted with EA (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v = 20 / 1) as the eluent to afford 320 mg of compound 5-4 as a yellow solid in a 46% yield. LC-MS (ESI, pos. ion) m / z: 933.3 [M+H] + .

[0369] Step 5: Synthesis of compound 5-5

[0370] 5-4 (320 mg, 0.34 mmol) and acetonitrile (3 mL) were added to a 50 mL single-necked bottle, cooled to 0°C and stirred for 5 minutes, TMSOTf (0.23 g, 1.02 mmol) was slowly added dropwise, and stirred for 60 minutes to stop the reaction. Saturated aqueous sodium bicarbonate solution (20 mL) was added to quench the reaction, and the mixture was extracted with EA (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by thin-layer chromatography using DCM / MeOH (v / v = 8 / 1) as the eluent to obtain 270 mg of yellow solid compound 5-5 in a yield of 99%. LC-MS (ESI, pos. ion) m / z: 789.3 [M+H] + .

[0371] Step 6: Synthesis of compound 5

[0372] 5-5 (110 mg, 0.34 mmol), cesium fluoride (260 mg, 1.7 mmol) and DMF (2 mL) were added to a 25 mL single-necked bottle, and the atmosphere was replaced with nitrogen three times. The mixture was stirred at room temperature at 25 ° C for 16 h, and the reaction was stopped. Water (80 mL) was added to precipitate a solid, which was filtered to obtain a solid crude product. The crude product was purified by thin-layer chromatography using DCM / MeOH / TEA (v / v = 7 / 1 / 0.05) as the eluent to obtain 28 mg of yellow solid compound 5 in a yield of 13%. LC-MS (ESI, pos.ion) m / z: 633.3 [M+H] + ; 1H NMR(400MHz,CD3OD)δ7.92–7.82(m,1H),7.40–7.29(m,2H),7.27–7.19(m,1H),5 .20(s,2H),4.66–4.47(m,4H),4.22–4.10(m,1H),3.91–3.66(m,4H),3.62–3.48 (m,1H),3.13–3.02(m,1H),3.01–2.91(m,1H),2.76–2.62(m,1H),2.38–2.26(m,2H),2.20(s,3H),2.18–1.95(m,4H),1.94–1.71(m,4H). 19 F NMR (376MHz, CD3OD) δ-111.48(1F),-140.34(1F).

[0373] Example 6: Synthesis of Compound 6

[0374] Step 1: Synthesis of compound 6-1

[0375] Sodium hydride (0.13 g, 3.28 mmol, 60% content) was added to a 100 mL two-necked flask, replaced with nitrogen, anhydrous THF (5 mL) was added, and stirred at 0°C for 5 minutes. A solution of M5 (0.27 g, 1.64 mmol) in THF (1.5 mL) was slowly added dropwise, and stirred at 0°C for 1 h. A solution of 6-0 (500 mg, 0.82 mmol, the synthesis method of compound 6-0 was synthesized by referring to the synthesis method of M8-5 on page 56 of patent WO2023061463) in THF (2 mL) was slowly added dropwise, and stirred at 0°C for 3 h. Stirring was stopped, and a saturated ammonium chloride solution (50 mL) was added to quench the reaction. The layers were separated, and the aqueous phase was extracted with EA (20 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v = 50 / 1) as the eluent to obtain 220 mg of compound 6-1 as a yellow solid in a yield of 36.3%. LC-MS (ESI, pos. ion) m / z: 737.4 [M+H] + .

[0376] Step 2: Synthesis of compound 6-2

[0377] In a 25 mL two-necked flask, 6-1 (140 mg, 0.19 mmol, 1.0 eq), M6 (0.19 g, 0.38 mmol, purchased from Shanghai Lingkai Pharmaceutical), Xphos Pd G3 (32 mg, 0.038 mmol), K3PO4·7H2O (160 mg, 0.47 mmol) and THF / H2O (3 mL / 1 mL) were added. The atmosphere was purged with nitrogen three times and stirred at room temperature at 25°C for 2 h. Xphos Pd G3 (0.2 equiv.) was added. After nitrogen purging, stirring was continued for 1 h. If the reaction was still not complete, the addition step was repeated until the reaction of the raw material 6-1 was substantially complete. Saturated ammonium chloride solution (20 mL) was added and the mixture was extracted with DCM (20 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=50 / 1) as the eluent to obtain 188 mg of red solid compound 6-2 in a yield of 91%. LC-MS(ESI,pos.ion)m / z:544.5[M+2H] 2+ .

[0378] Step 3: Synthesis of compound 6-3

[0379] To a 25 mL single-necked flask, 6-2 (188 mg, 0.17 mmol) and acetonitrile (4 mL) were added. The mixture was cooled to 0°C and stirred for 5 minutes. TMSOTf (0.092 mL, 0.51 mmol) was slowly added dropwise and stirred for 30 minutes to terminate the reaction. Saturated aqueous sodium bicarbonate solution (15 mL) was added to quench the reaction. The mixture was extracted with DCM (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by thin-layer chromatography using DCM / MeOH (v / v = 10 / 1) as the eluent to obtain 68 mg of compound 6-3 as a yellow solid in a 42% yield. LC-MS (ESI, pos. ion) m / z: 943.9 [M+H] + .

[0380] Step 4: Synthesis of compound 6

[0381] 6-5 (68 mg, 0.072 mmol), cesium fluoride (160 mg, 1.08 mmol) and DMF (0.6 mL) were added to a 25 mL single-necked bottle, and the atmosphere was replaced with nitrogen three times. The mixture was stirred at room temperature for 3 h, and the reaction was stopped. 14 mL of water was added to precipitate a solid, which was filtered to obtain a crude solid product. The crude product was purified by thin-layer chromatography using DCM / MeOH (v / v=8 / 1) as the eluent to obtain 8 mg of compound 6 as a yellow solid in an 18% yield. LC-MS (ESI, pos.ion) m / z: 631.3 [M+H] + ; HRMS (ESI): 631.2658 [M+H] + ; 1H NMR (400MHz, CD3OD) δ7.88(dd,J=9.1,5.7Hz,1H),7.42–7.30(m,2H),7.29–7.18(m,1H),5.12–4.98(m,4H),4.74–4.46(m,3H),4.42–4.24(m ,3H),3.88–3.75(m,3H),3.73–3.61(m,2H),3.60–3.47(m,1H),3.43– 3.35(m,2H),2.89–2.73(m,2H),2.68–2.54(m,2H),1.84–1.56(m,4H). 19 F NMR(376MHz,CD3OD)δ-111.47(1F),-138.25(1F).

[0382] Example 7: Synthesis of Compound 7

[0383] Step 1: Synthesis of compound 7-1

[0384] To a 50 mL single-necked flask were added 6-1 (80 mg, 0.11 mmol, 1.0 eq), M7 (79 mg, 0.22 mmol, purchased from Shaoyuan Technology), Xphos Pd G4 (19 mg, 0.022 mmol), K3PO4·7H2O (93 mg, 0.28 mmol), and THF / H2O (3 mL / 0.56 mL). The atmosphere was purged with nitrogen three times and stirred at room temperature at 25°C for 1 h. This process of adding Xphos Pd G4 was repeated until the reaction of the starting material 6-1 was complete. Saturated ammonium chloride solution (15 mL) was added, and the mixture was extracted with DCM (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v = 50 / 1) as the eluent to afford 83 mg of compound 7-1 as a yellow oil in an 82% yield. LC-MS (ESI, pos. ion) m / z: 468.4 [M+2H]. 2+ .

[0385] Step 2: Synthesis of compound 7-2

[0386] 7-1 (83 mg, 0.089 mmol) and acetonitrile (3 mL) were added to a 25 mL single-necked bottle, cooled to 0 ° C and stirred for 5 minutes, TMSOTf (0.048 mL, 0.27 mmol) was slowly added dropwise, stirred for 30 minutes, and the reaction was stopped. Saturated aqueous sodium bicarbonate solution (15 mL) was added to quench the reaction, and the mixture was extracted with DCM (20 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and purified by thin-layer chromatography using DCM / MeOH (v / v = 10 / 1) as the eluent to obtain 37 mg of yellow solid compound 7-2 in a yield of 53%. LC-MS (ESI, pos.ion) m / z: 791.4 [M+H] + .

[0387] Step 3: Synthesis of compound 7

[0388] 7-2 (37 mg, 0.047 mmol), cesium fluoride (71 mg, 0.47 mmol) and DMF (0.4 mL) were added to a 25 mL single-necked bottle, and the atmosphere was replaced with nitrogen three times. The mixture was stirred at room temperature for 3 h, and the reaction was stopped. 10 mL of water was added to precipitate a solid, which was filtered to obtain a crude solid product. The crude product was purified by thin-layer chromatography using DCM / MeOH (v / v = 9 / 1) as the eluent to obtain 27 mg of compound 7 as a yellow solid in a yield of 91%. LC-MS (ESI, pos. ion) m / z: 635.3 [M+H] + ; HRMS (ESI): 635.2973 [M+H] + ; 1 H NMR(400MHz,CD3OD)δ7.69(dd,J=9.0,5.9Hz,1H),7.35–7.19(m,2H),7.16–7.06(m, 1H),5.10–4.97(m,4H),4.69–4.45(m,3H),4.43–4.26(m,2H),4.21–3.88(m,2H),3. 84–3.65(m,3H),3.63–3.46(m,2H),3.37(s,1H),2.88–2.71(m,2H),2.67–2.53(m,2 H),2.50–2.36(m,1H),2.28–2.16(m,2H),1.85–1.63(m,3H),0.85(t,J=7.4Hz,3H). 19 F NMR (376MHz, CD3OD) δ-120.83(1F),-138.10(1F).

[0389] Example 8: Synthesis of Compound 8

[0390] Step 1: Synthesis of compound 8-1

[0391] To a 25 mL two-necked flask were added 2-1 (180 mg, 0.30 mmol, 1.0 eq), M8 (0.25 g, 0.45 mmol), Xphos Pd G4 (52 mg, 0.060 mmol), K3PO4·7H2O (305 mg, 0.90 mmol), and THF / H2O (6 mL / 2 mL). The atmosphere was replaced with nitrogen three times and stirred at room temperature at 25°C for 7 h. The reaction was terminated, and saturated ammonium chloride solution (10 mL) was added. The mixture was extracted with EA (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v = 30 / 1) as the eluent to afford 230 mg of compound 8-1 as a brownish-yellow solid in a 65% yield. LC-MS (ESI, pos. ion) m / z: 992.3 [M+H] + .

[0392] Step 2: Synthesis of compound 8

[0393] 8-1 (230 mg, 0.23 mmol) and trifluoroacetic acid (20 mL) were added to a 25 mL single-necked bottle and stirred at room temperature for 1 h. The reaction was stopped and dried, dissolved in DCM (10 mL), and washed with saturated sodium bicarbonate solution (20 mL). The organic phase was concentrated and dried, then dried, and the crude product was purified by thin-layer chromatography using DCM / MeOH (v / v = 15 / 1) as the eluent to obtain 73 mg of compound 8 as a yellow solid in a 48% yield. LC-MS (ESI, pos. ion) m / z: 652.3 [M+H] + ; 1 H NMR(400MHz,CD3OD)δ6.64(d,J=8.6Hz,1H),5.08–5.00(m,4H),4.99–4.93(m,2H),4.40–4.26(m,2H),3.99–3.63(m,5H), 3.63–3.44(m,3H),3.38–3.34(m,2H),2.86–2.71(m,2H),2.64–2.55(m,2H),2.41(s,3H),2.21(s,3H),1.80–1.54(m,4H). 19 F NMR (376MHz, CD3OD) δ-54.95(3F),-137.80(1F),-141.73(1F).

[0394] Example 9: Synthesis of Compound 9

[0395] Step 1: Synthesis of compound 9-1

[0396] To a 25 mL two-necked flask were added 2-1 (150 mg, 0.25 mmol), M7 (180 mg, 0.50 mmol), Xphos Pd G4 (43 mg, 0.050 mmol, purchased from Shaoyuan Technology), K3PO4·7H2O (338 mg, 1 mmol), and THF / H2O (6 mL / 2 mL). The atmosphere was replaced with nitrogen three times and stirred at room temperature for 10 h. The reaction was terminated and saturated ammonium chloride solution (10 mL) was added. The mixture was extracted with EA (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v = 30 / 1) as the eluent to afford 145 mg of compound 9-1 as a reddish-brown solid in a 72% yield. LC-MS (ESI, pos. ion) m / z: 793.3 [M+H] + .

[0397] Step 2: Synthesis of compound 9

[0398] 9-1 (145 mg, 0.18 mmol) and acetonitrile (3 mL) were added to a 25 mL single-necked flask, cooled to -20°C and stirred for 5 minutes. TMSOTf (0.098 mL, 0.54 mmol) was slowly added dropwise and stirred for 60 minutes to terminate the reaction. Saturated aqueous sodium bicarbonate solution (15 mL) was added to quench the reaction, and the mixture was extracted with DCM (20 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by preparative thin-layer chromatography using DCM / MeOH (v / v = 10 / 1) as the eluent to afford 60 mg of compound 9 as a yellow solid in a 51% yield. LC-MS (ESI, pos. ion) m / z: 649.3 [M+H] + ; HRMS (ESI): 649.3098 [M+H] + ; 1 H NMR(400MHz,CD3OD)δ7.73–7.57(m,1H),7.36–7.18(m,2H),7.10(s,1H),5.09 –4.97(m,4H),4.44–4.28(m,3H),4.06–3.86(m,1H),3.80(d,J=14.7Hz,3H),3 .69–3.52(m,3H),3.41–3.34(m,2H),2.87–2.71(m,2H),2.66–2.53(m,2H),2. 51–2.36(m,1H),2.29–2.11(m,4H),1.86–1.48(m,4H),0.84(t,J=7.3Hz,3H). 19 F NMR (376MHz, CD3OD) δ-120.85(1F),-139.75(1F).

[0399] Example 10: Synthesis of Compound 10

[0400] Step 1: Synthesis of compound 10-1

[0401] To a 25 mL two-necked flask were added 2-1 (78 mg, 0.131 mmol), M9 (64 mg, 0.2 mmol), Pd(PPh3)4 (30 mg, 0.026 mmol), cesium carbonate (130 mg, 0.4 mmol), and 1,4-dioxane / H2O (3 mL / 0.8 mL). The atmosphere was purged with nitrogen three times and stirred at 100°C for 6 h. The reaction was terminated, and saturated ammonium chloride solution (10 mL) was added. The mixture was extracted with EA (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by preparative thin-layer chromatography using DCM / MeOH (v / v = 40 / 1) as the eluent to afford 54 mg of compound 10-1 as a reddish-brown solid in a 55% yield. LC-MS (ESI, pos. ion) m / z: 754.2 [M+H] + .

[0402] Step 2: Synthesis of compound 10

[0403] 10-1 (54 mg, 0.072 mmol) and acetonitrile (3 mL) were added to a 25 mL single-necked flask, cooled to 0°C and stirred for 5 minutes, TMSOTf (0.033 mL, 0.18 mmol) was slowly added dropwise, and stirred for 60 minutes to stop the reaction. Saturated aqueous sodium bicarbonate solution (15 mL) was added to quench the reaction, and the mixture was extracted with DCM (15 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by thin-layer chromatography using DCM / MeOH (v / v = 10 / 1) as the eluent to obtain 31 mg of compound 10 as a yellow solid in a yield of 66%. LC-MS (ESI, pos. ion) m / z: 654.2 [M+H] + ; 1 H NMR (400MHz, CD3OD) δ6.95–6.87(m,1H),6.52(s,1H),5.09–4.98(m,4H),4.83–4.71(m,2H),4.68–4.48(m,2H),4.39–4.26(m,2H) ,3.94–3.69(m,4H),3.65–3.52(m,2H),3.42–3.34(m,2H),2.86–2.73(m,2H),2.65–2.55(m,2H),2.21(s,3H),1.83–1.51(m,4H). 19 F NMR (376MHz, CD3OD): δ-55.72(3F),-141.83(1F).

[0404] Example 11: Synthesis of Compound 11

[0405] Step 1: Synthesis of compound 11-1

[0406] In a 250 mL single-necked bottle, ethyl 2,5-dioxohexahydro-1H-pyrrolizine-7a-carboxylate (11 g, 52.08 mmol) and THF (100 mL) were added at room temperature, cooled to -10 ° C, HMPT (34.0 g, 208.32 mmol) was added dropwise, and stirred for 5 minutes after the addition was completed. Dibromodifluoromethane (54.64 g, 260.4 mmol) was introduced into the gaseous solution, and stirred at -10 ° C for 1.5 hours, and then transferred to room temperature for reaction for 60 minutes. Zinc powder 1 was added. The mixture was heated to 80°C for 6 hours, then cooled to room temperature and filtered through celite. The filtrate was added with water (50 mL) and saturated sodium chloride (100 mL), and extracted with EA (100 mL × 3). The layers were separated, and the organic phase was washed twice with saturated brine (100 mL × 2) and evaporated to dryness. The crude product was purified by column chromatography using PE / EA (v / v = 1 / 1) as the eluent to obtain 4.95 g of compound 11-1 as a yellow oil, with a yield of 39%. LC-MS (ESI, pos. ion) m / z: 246.1 [M+H] + Step 2: Synthesis of compound 11-2

[0407] Lithium aluminum tetrahydride (0.46 g, 12.24 mmol) was added to a 100 mL two-necked flask at room temperature. After nitrogen substitution three times, the temperature was lowered to 0°C, anhydrous THF (10 mL) was added, and 11-1 (1 g, 4.08 mmol, 10 mL of THF solution) was added dropwise. After the addition was complete, the temperature was raised to 65°C for reaction. The reaction was stopped, the temperature was lowered to 0°C, and water (0.5 mL) was slowly added. 15% sodium hydroxide solution (0.5 mL) was slowly added dropwise, followed by water (1.5 mL). The mixture was dried over anhydrous sodium sulfate and filtered. The filter cake was rinsed with DCM (50 mL), and the combined filtrates were evaporated to dryness to obtain 0.65 g of compound 11-2 as a yellow oil in a 93% yield. LC-MS (ESI, pos.ion) m / z: 172.1 [M+H] + .

[0408] Step 3: Synthesis of compound 11-3

[0409] At room temperature, a 100 mL single-necked flask was charged with 1-2 (1.77 g, 3.8 mmol), 11-2 (0.65 g, 3.80 mmol), potassium carbonate (1.58 g, 11.40 mmol), and 1,4-dioxane (16 mL). The atmosphere was replaced with nitrogen three times, and the temperature was raised to 100°C and refluxed for 12 h. The reaction was stopped, filtered, and the filter cake was washed with EA (30 mL). The combined filtrates were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v = 100 / 0-20 / 1) as the eluent to afford 0.45 g of compound 11-3 as a yellow-brown solid in a 20% yield. LC-MS (ESI, pos. ion) m / z: 601.3 [M+H] + .

[0410] Step 4: Synthesis of compound 11-4

[0411] To a 50 mL two-necked flask were added 11-3 (270 mg, 0.45 mmol), M6 (0.47 g, 0.90 mmol), K3PO4·7H2O (450 mg, 1.35 mmol), and THF / H2O (7 mL / 0.5 mL). The atmosphere was purged with nitrogen three times, and Xphos Pd G3 (114 mg, 0.135 mmol) was added portionwise. The reaction was stirred at 35°C for 4 h to terminate the reaction. Saturated ammonium chloride solution (20 mL) was added, and the mixture was extracted with EA (30 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / EA (v / v = 1 / 1) as the eluent to afford 135 mg of compound 11-4 as a yellow solid in a 32% yield. LC-MS (ESI, pos. ion) m / z: 951.4 [M+H] + .

[0412] Step 5: Synthesis of compound 11-5

[0413] 11-4 (135 mg, 0.14 mmol) and acetonitrile (3 mL) were added to a 50 mL single-necked bottle, cooled to 0°C and stirred for 5 minutes, TMSOTf (0.16 g, 0.70 mmol) was slowly added dropwise, stirred for 3 h, and the reaction was stopped. Saturated aqueous sodium bicarbonate solution (20 mL) was added to quench the reaction, and the mixture was extracted with EA (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give a yellow solid compound 11-5. The yield was calculated as 100%. LC-MS (ESI, pos. ion) m / z: 807.3 [M+H] + .

[0414] Step 6: Synthesis of compound 11

[0415] 11-5 (110 mg, 0.14 mmol), cesium fluoride (210 mg, 1.4 mmol) and DMF (1 mL) were added to a 25 mL single-necked bottle, and the atmosphere was replaced with nitrogen three times. The mixture was stirred at room temperature for 16 h, and the reaction was stopped. Water (80 mL) was added to precipitate a solid, which was filtered to obtain a crude solid product. The crude product was purified by thin-layer chromatography using DCM / MeOH (v / v=8 / 1) as the eluent to obtain 35 mg of compound 11 as an off-white solid in a yield of 38%. LC-MS (ESI, pos. ion) m / z: 651.3 [M+H] + ; 1 H NMR (400MHz, CD3OD) δ7.93–7.81(m,1H),7.44–7.29(m,2H),7.23(s,1H),6.98–6.52(m,1H),4.49–4.33(m,2H),4.07–3.72 (m,5H),3.69–3.51(m,2H),2.94–2.76(m,2H),2.64–2.47(m,1H),2.43–2.29(m,1H),2.26–2.11(m,5H),2.10–1.73(m,8H). 19 F NMR (376MHz, CD3OD): δ-111.50(1F),-131.02(1F),-140.03(1F).

[0416] Example 12: Synthesis of Compound 12-A and Compound 12-B

[0417] Step 1: Synthesis of compound 12-1

[0418] To a 25 mL two-necked flask were added 11-3 (180 mg, 0.30 mmol, 1.0 eq), M9 (140 mg, 0.45 mmol), potassium phosphate heptahydrate (410 mg, 1.2 mmol), and THF / H2O (4 mL / 0.3 mL). The atmosphere was purged with nitrogen three times, and Xphos Pd G3 (76 mg, 0.090 mmol) was added portionwise. The mixture was stirred at 35°C for 16 h under nitrogen protection. The reaction was terminated, and saturated ammonium chloride solution (10 mL) was added. The mixture was extracted with EA (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by preparative thin-layer chromatography using DCM / MeOH (v / v = 20 / 1) as the eluent to afford 160 mg of compound 12-1 as a yellow solid in a 70% yield. LC-MS (ESI, pos. ion) m / z: 760.2 [M+H] + .

[0419] Step 2: Synthesis of compound 12

[0420] 12-1 (160 mg, 0.21 mmol) and acetonitrile (3 mL) were added to a 25 mL single-necked flask, cooled to 0°C and stirred for 5 minutes, TMSOTf (0.23 g, 1.05 mmol) was slowly added dropwise, and stirred for 1.5 h to stop the reaction. Saturated aqueous sodium bicarbonate solution (15 mL) was added to quench the reaction, and the mixture was extracted with DCM (15 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and purified by thin-layer chromatography using DCM / MeOH (v / v = 8 / 1) as the eluent to obtain 20 mg of off-white solid compound 12-A (the least polar spot on the TLC plate) and 17 mg of yellow solid compound 12-B (the most polar spot on the TLC plate), with a yield of 27%. LC-MS (ESI, pos. ion) m / z: 660.3 [M+H] + Compound 12-A: 1 H NMR(599MHz,CD3OD)δ6.93(s,1H),6.77–6.59(m,1H),6.53(s,1H),4.67–4.56(m,4H),4.37–4.27(m,2H),3.91–3.86(m,1H),3.66–3.59(m, 2H),3.55–3.48(m,1H),3.23–3.16(m,1H),2.79–2.71(m,2H),2.52–2 .45(m,1H),2.25–2.11(m,5H),2.06–1.86(m,4H),1.82–1.60(m,4H). 19 F NMR (376MHz, CD3OD): δ-55.73 (3F), -131.93 (1F), -141.85 (1F). Compound 12-B: 1 H NMR(599MHz,CD3OD)δ6.96–6.89(m,1H),6.84–6.66(m,1H),6.52(s,1H),4.70–4 .52(m,2H),4.40–4.26(m,2H),4.16–4.08(m,1H),3.79–3.70(m,1H),3.65–3.54 (m,2H),3.40–3.33(m,2H),3.20–3.13(m,1H),2.88–2.81(m,1H),2.76–2.67(m, 1H),2.63–2.54(m,1H),2.26–2.11(m,4H),2.06–1.85(m,5H),1.80–1.52(m,4H). 19 F NMR (376MHz, CD3OD): δ-55.73(3F),-133.28(1F),-141.84(1F).

[0421] Example 13: Synthesis of Compound 13

[0422] Step 1: Synthesis of compound 13-1

[0423] Lithium aluminum tetrahydride (1.24 g, 32.64 mmol) was added to a 100 mL two-necked flask at room temperature. After nitrogen substitution three times, anhydrous THF (20 mL) was added, the temperature was lowered to 0°C, and 11-1 (2 g, 8.16 mmol, in a 20 mL THF solution) was added dropwise. After completion of the addition, the reaction was allowed to proceed at 0°C for 6 h. The reaction was stopped, the temperature was lowered to 0°C, and water (1.3 mL) was slowly added. 15% sodium hydroxide solution (1.3 mL) was then slowly added dropwise, followed by water (1.3 mL). A small amount of anhydrous sodium sulfate was added to dry the mixture, and the mixture was filtered. The filter cake was rinsed with EA (20 mL), and the filtrate was evaporated to dryness to obtain 1.4 g of compound 13-1 as a yellow oil, with a yield of 45%. LC-MS (ESI, pos.ion) m / z: 190.0 [M+H] + .

[0424] Step 2: Synthesis of compound 13-2

[0425] At room temperature, a 100 mL single-necked flask was charged with 1-2 (1.0 g, 2.14 mmol), 13-1 (1.4 g, 3.70 mmol), cesium carbonate (3.49 g, 10.70 mmol), triethylamine (0.06 g, 0.54 mmol), anhydrous THF (5 mL), and anhydrous DMF (5 mL). The atmosphere was purged with nitrogen three times and the reaction was allowed to proceed at room temperature for 1.5 h. The reaction was stopped, and water (30 mL) and EA (30 mL) were added, followed by saturated sodium chloride (20 mL). The organic phase was separated and washed with saturated sodium chloride (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / EA (v / v = 1 / 1) as the eluent to obtain a yellow-white solid compound. The solid was slurried with EA (4 mL) for 10 minutes, the solid was removed by filtration, and the filtrate was spin-dried to obtain 0.15 g of a brown solid compound 13-2 in an 11% yield. LC-MS(ESI,pos.ion)m / z:619.3[M+H] + .

[0426] Step 3: Synthesis of compound 13-3

[0427] To a 50 mL two-necked flask were added 11-3 (150 mg, 0.24 mmol), M6 (0.25 g, 0.48 mmol), K3PO4·7H2O (320 mg, 0.96 mmol), and THF / H2O (4 mL / 0.3 mL). The atmosphere was purged with nitrogen three times, and Xphos Pd G3 (61 mg, 0.072 mmol) was added. The reaction was stirred at 35°C for 6 h to terminate the reaction. Saturated ammonium chloride solution (10 mL) was added, and the mixture was extracted with EA (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / EA (v / v = 1 / 1) as the eluent to afford 100 mg of compound 13-3 as a tan solid in a 42% yield. LC-MS (ESI, pos. ion) m / z: 969.4 [M+H] + .

[0428] Step 4: Synthesis of compound 13-4

[0429] 13-3 (100 mg, 0.10 mmol) and acetonitrile (2 mL) were added to a 50 mL single-necked bottle, cooled to 0°C and stirred for 5 minutes, TMSOTf (0.11 g, 0.50 mmol) was slowly added dropwise, stirred for 1.5 h, and the reaction was stopped. Saturated aqueous sodium bicarbonate solution (10 mL) was added to quench the reaction, and the mixture was extracted with EA (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give a yellow solid compound 13-4. The yield was calculated as 100%. LC-MS (ESI, pos. ion) m / z: 825.3 [M+H] + .

[0430] Step 5: Synthesis of compound 13

[0431] To a 25 mL single-necked flask were added 13-4 (85 mg, 0.10 mmol), cesium fluoride (91 mg, 0.60 mmol) and DMF (1 mL). The atmosphere was replaced with nitrogen three times and stirred at room temperature for 16 h. The reaction was stopped and water (80 mL) was added to precipitate a solid. The solid was filtered to obtain a crude solid product. The crude product was purified by thin-layer chromatography using DCM / MeOH (v / v = 9 / 1) as the eluent to obtain 10 mg of compound 11 as an off-white solid in a yield of 13%. LC-MS (ESI, pos. ion) m / z: 669.2 [M+H] + ; 1H NMR(400MHz,MeOD)δ7.92–7.83(m,1H),7.39–7.31(m,2H),7.26–7.19(m,1H),4.42–4.27(m,2H),3.89–3.74(m,2H),3.71–3.55(m,3H),3. 50–3.41(m,1H),3.30(s,1H),3.21–3.13(m,1H),2.87–2.67(m,2H),2 .60–2.47(m,1H),2.22(s,3H),2.16–1.87(m,5H),1.86–1.56(m,5H). 19 F NMR (376MHz, CD3OD): δ-92.80(2F),-111.50(1F),-140.14(1F).

[0432] Example 14: Synthesis of Compound 14

[0433] The synthesis of compound 14 was carried out according to the synthesis steps of compound 13, and M6 was replaced by M9 to obtain 12 mg of light yellow solid compound 14. LC-MS (ESI, pos.ion) m / z: 678.3 [M+H] + .

[0434] Example 15: Synthesis of Compound 15

[0435] Step 1: Synthesis of compound 15-1

[0436] A 50 mL single-necked bottle was added with 2-1 (150 mg, 0.25 mmol), M10 (190 mg, 0.30 mmol, synthesized according to the synthesis method of 001-5D on pages 30-31 of patent WO2023138662), Xphos Pd G4 (22 mg, 0.025 mmol), K3PO4·7H2O (250 mg, 0.75 mmol) and THF / H2O (6 mL / 2 mL). The atmosphere was replaced with nitrogen three times and stirred at room temperature for 16 h. Saturated ammonium chloride solution (20 mL) was added and extracted with EA (10 mL×2). The organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography with DCM / MeOH (v / v=50 / 1-30 / 1) as the eluent to obtain 60 mg of orange solid compound 15-1 in a yield of 22%. LC-MS(ESI,pos.ion)m / z:1065.4[M+H] + .

[0437] Step 2: Synthesis of compound 15-2

[0438] 15-1 (60 mg, 0.056 mmol) and acetonitrile (2 mL) were added to a 50 mL single-necked bottle, cooled to 0°C and stirred for 5 minutes, and concentrated sulfuric acid (0.054 g, 0.56 mmol) was slowly added dropwise. The mixture was stirred for 120 minutes to stop the reaction. Saturated aqueous sodium bicarbonate solution (10 mL) was added to quench the reaction, and the mixture was extracted with DCM (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude brown solid compound 15-2, which was used directly in the next step. The yield was calculated as 100%. LC-MS (ESI, pos. ion) m / z: 800.3 [M+H] + .

[0439] Step 3: Synthesis of compound 15

[0440] 15-2 (45 mg, 0.056 mmol), cesium fluoride (68 mg, 0.45 mmol) and DMF (1 mL) were added to a 25 mL single-necked bottle. The atmosphere was replaced with nitrogen three times and stirred at room temperature for 14 h. The reaction was stopped and water (10 mL) was added to precipitate a solid. The solid was filtered to obtain a crude solid product. The crude product was purified by thin-layer chromatography using DCM / MeOH (v / v = 12 / 1) as the eluent to obtain 10 mg of compound 15 as a brown solid in a yield of 28%. LC-MS (ESI, pos. ion) m / z: 644.4 [M+H] + ; 1 H NMR (400MHz, CD3OD) δ7.83–7.68(m,1H),7.33–7.08(m,3H),5.12–4.98(m,4H),4.64–4.52(m,6H),4.38(s,2H),3.88–3.77(m, 2H),3.74–3.64(m,2H),3.43–3.35(m,2H),3.25(s,1H),2.89–2.75(m,2H),2.67–2.53(m,2H),2.22(s,3H),2.12–1.82(m,4H). 19 F NMR(376MHz,CD3OD)δ-113.31(1F),-140.06(1F).

[0441] Example 16: Synthesis of Compound 16

[0442] Step 1: Synthesis of compound 16-1

[0443] To a 100 mL single-necked flask were added M11 (3 g, 8.08 mmol, purchased from Shaoyuan Technology), bipyraclostrobin (3.08 g, 12.12 mmol), Pd(dppf)Cl2·DCM·(0.79 g, 0.97 mmol), potassium acetate (2.38 g, 24.24 mmol), and 1,4-dioxane (100 mL). After nitrogen substitution three times, the mixture was heated to 85°C and stirred for 16 h. The reaction was terminated, filtered through celite, and concentrated. The crude product was purified by column chromatography using PE / DCM (v / v = 10 / 1-2 / 1) as the eluent to obtain 2.83 g of compound 16-1 as a white solid in an 84% yield. LC-MS (ESI, pos. ion) m / z: 417.2 [M+H] + .

[0444] Step 2: Synthesis of compound 16-2

[0445] To a 50 mL two-necked flask were added 2-1 (110 mg, 0.18 mmol), 16-1 (110 mg, 0.27 mmol), potassium phosphate heptahydrate (180 mg, 0.54 mmol), 1,4-dioxane / H2O (4 mL / 1 mL), and cataCXium A Pd G3 (13 mg, 0.018 mmol). The mixture was stirred at 60°C for 14 h under nitrogen atmosphere to terminate the reaction. Saturated ammonium chloride solution (10 mL) was added and the mixture was extracted with EA (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by preparative thin-layer chromatography using DCM / MeOH (v / v = 40 / 1) as the eluent to afford 115 mg of compound 16-2 as a yellow solid in a 73% yield. LC-MS (ESI, pos. ion) m / z: 851.3 [M+H] + .

[0446] Step 3: Synthesis of compound 16

[0447] 16-2 (100 mg, 0.118 mmol) and DCM (1 mL) were added to a 50 mL single-necked bottle, cooled to 0°C and stirred for 5 minutes, trifluoroacetic acid (1 mL) was slowly added dropwise, and stirred at room temperature for 4 h to stop the reaction. Saturated aqueous sodium bicarbonate solution (15 mL) was slowly added to quench the reaction, and the mixture was extracted with DCM / MeOH (15 / 1 mL). The organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by thin-layer chromatography using DCM / MeOH (v / v = 9 / 1) as the eluent to obtain 10 mg of compound 16 as a gray solid in a 13% yield. LC-MS (ESI, pos. ion) m / z: 651.3 [M+H] + ; 1H NMR (400MHz, CD3OD) δ7.47(dd,J=8.4,5.1Hz,1H),7.06(dd,J=9.5,8.4Hz,1H),5.09–5.01(m,4H),4.65–4.53(m,4H),4.36(s,2H) ,3.97–3.69(m,4H),3.66–3.54(m,2H),3.43–3.35(m,2H),2.87–2.74(m,2H),2.67–2.55(m,2H),2.21(s,3H),1.80–1.56(m,4H). 19 F NMR (376MHz, CD3OD): δ-118.00(1F),-141.85(1F).

[0448] Example 17: Synthesis of Compound 17

[0449] Step 1: Synthesis of compound 17-1

[0450] In a 250 mL three-necked flask, N-BOC-trans-4-fluoro-L-proline methyl ester (5.00 g, 20.2 mmol, Shanghai Bid Pharmaceutical) was added, cooled to -45 °C and stirred for 10 minutes, and LiHMDS (30.33 mL, 30.33 mmol, 1 M The mixture was stirred at -45°C for 60 min, and 3-chloro-2-(chloromethyl)prop-1-ene (3.03 g, 24.26 mmol, dissolved in 15 mL of anhydrous THF) was slowly added dropwise. After the addition was complete, the temperature was slowly raised to room temperature (approximately 1 h). Stirring was stopped, and saturated ammonium chloride solution (20 mL) was slowly added to quench the reaction. The layers were separated, and the aqueous phase was extracted with EA (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using PE / EA (v / v = 20 / 1-5 / 1) as the eluent to obtain 6.06 g of compound 17-1 as a yellow oil in an 89% yield. LC-MS (ESI, pos. ion) m / z: 236.0 [M-Boc+H+H] + .

[0451] Step 2: Synthesis of compound 17-2

[0452] To a 250 mL single-necked flask, 17-1 (6.06 g, 18.05 mmol) and DCM (100 mL) were added. The mixture was cooled to 0°C and stirred for 5 minutes. A solution of hydrogen chloride in dioxane (22.56 mL, 90.25 mmol, 4 M) was then added dropwise. After the addition was complete, the mixture was transferred to room temperature and stirred for 14.5 hours. Stirring was stopped, and the reaction solution was concentrated and drained to obtain 17-2, which was used directly in the next step. The yield was calculated as 100%. LC-MS (ESI, pos. ion) m / z: 236.0 [M+H] + Step 3: Synthesis of compound 17-3

[0453] To a 250 mL single-necked flask, 17-2 (4.25 g, 18.03 mmol), acetonitrile (50 mL), sodium bicarbonate (7.57 g, 90.15 mmol), and potassium iodide (0.30 g, 1.80 mmol) were added and stirred at room temperature for 2 h. Stirring was stopped, and the reaction mixture was filtered, washed with acetonitrile (50 mL), concentrated, and purified by column chromatography using PE / EA (v / v = 4 / 1-3 / 2) as the eluent to obtain 3.00 g of compound 17-3 as a yellow oil in an 83.5% yield. LC-MS (ESI, pos. ion) m / z: 200.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ5.29–5.12(m,1H),4.95(d,J=13.7Hz,2H),3.87(d,J=14.8Hz,1H),3.75(s,3H),3.59– 3.40(m,1H),3.27–3.16(m,1H),2.98–2.86(m,2H),2.85–2.73(m,1H),2.57–2.48(m,1H),2.21–1.93(m,1H).

[0454] Step 4: Synthesis of compound 17-4

[0455] To a 100 mL single-necked flask, 17-3 (400 mg, 2.01 mmol) was added. The atmosphere was purged with nitrogen three times, and anhydrous DCM (12 mL) was added. The mixture was cooled to -20°C and stirred for 10 minutes. Diethylzinc reagent (10.05 mL, 10.05 mmol, 1 M solution in n-hexane) was slowly added dropwise and stirred for 30 minutes. Diiodomethane (1.62 mL, 20.10 mmol) was slowly added dropwise, and the mixture was transferred to 0°C and stirred for 3 hours. Saturated ammonium chloride (20 mL) was added to quench the reaction. The aqueous phase was extracted with EA (20 mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using PE / EA (v / v = 7 / 3) as the eluent to obtain 223 mg of compound 17-4 as a yellow oil in a 52% yield. LC-MS (ESI, pos. ion) m / z: 214.4 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ5.37–5.16(m,1H),3.77(s,3H),3.68–3.52(m,1H),3.19(d,J=10.6Hz,1H),3.10–2.92(m ,1H),2.91–2.76(m,1H),2.63(d,J=10.6Hz,1H),2.25–2.02(m,2H),1.89(d,J=12.9Hz,1H),0.66–0.42(m,4H).

[0456] Step 5: Synthesis of compound 17-5

[0457] LiAlH4 (0.79 g, 2.08 mmol) was added to a 100 mL two-necked flask. The atmosphere was replaced with nitrogen three times, and the mixture was brought to -10°C. THF (2 mL) was added and stirred for 5 min. 17-4 (221 mg, 1.04 mmol) dissolved in THF (3 mL) was slowly added dropwise. After the addition was complete, the temperature was raised to 0°C and stirred for 3.5 h. The reaction was quenched by slowly adding sodium sulfate decahydrate, filtered through celite, concentrated, and drained to afford 162 mg of a yellow oil, 17-5, in an 84% yield. LC-MS (ESI, pos. ion) m / z: 186.2 [M+H]. + .

[0458] Step 6: Synthesis of compound 17-6

[0459] Compound 1-2 (950 mg, 2.04 mmol), 17-5 (302.3 mg, 1.63 mmol), potassium carbonate (0.85 g, 6.12 mmol), and anhydrous 1,4-dioxane (15 mL) were added to a 50 mL single-necked flask. The atmosphere was purged with nitrogen three times, and the mixture was heated to 100°C and stirred for 8 h. The reaction was stopped and cooled to room temperature. The reaction solution was concentrated, diluted with EA (20 mL), filtered, concentrated, and purified by column chromatography using DCM / MeOH (v / v = 50 / 1) as the eluent to obtain 160 mg of compound 17-6 as a red solid in a 13% yield. LC-MS (ESI, pos. ion) m / z: 615.3 [M+H] + .

[0460] Step 7: Synthesis of compound 17-7

[0461] Compound 17-6 (80 mg, 0.13 mmol), M9 (63 mg, 0.20 mmol), Xphos Pd G3 (22 mg, 0.026 mmol), K3PO4·7H2O (130 mg, 0.39 mmol) and THF / H2O (v / v = 2.5 mL / 0.8 mL) were added to a 25 mL single-necked flask. The atmosphere was replaced with nitrogen three times and stirred at room temperature for 1 h. Xphos Pd G3 (22 mg, 0.026 mmol) was added and stirred at room temperature for 8 h. The reaction was stopped and diluted with DCM (15 mL). The mixture was washed with saturated ammonium chloride (15 mL) and extracted with DCM (15 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by thin-layer chromatography using DCM / MeOH (v / v = 40 / 1) as the eluent to obtain 51 mg of compound 17-7 as a red solid in a yield of 51%. LC-MS(ESI,pos.ion)m / z:774.2[M+H] + .

[0462] Step 8: Synthesis of compound 17

[0463] Compound 17-7 (51 mg, 0.066 mmol) and acetonitrile (2 mL) were added to a 25 mL single-necked flask, cooled to 0°C and stirred for 5 minutes. TMSOTf (0.024 mL, 0.13 mmol) was then added dropwise and stirred at 0°C for 60 minutes to terminate the reaction. Saturated aqueous sodium bicarbonate solution (15 mL) was added to quench the reaction, and the mixture was extracted with DCM (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and drained. The crude product was purified by thin-layer chromatography using DCM / MeOH (v / v = 10 / 1) as the eluent to afford 28 mg of compound 17 as a yellow solid in a 63% yield. LC-MS (ESI, pos. ion) m / z: 674.2 [M+H] +; HRMS (ESI): 674.2425[M+H] + ; 1 H NMR (400MHz, CD3OD) δ6.96–6.84(m,1H),6.53(s,1H),5.50–5.32(m,1H),4.66–4.54(m,5H),4.47(s,2H),3.65–3.42(m,3H),3.20–3.00 (m,2H),2.77–2.65(m,1H),2.67–2.47(m,1H),2.22(s,3H),2.19–2.02(m,2H),1.93–1.80(m,2H),1.79–1.49(m,4H),0.71–0.49(m,4H). 19 F NMR (376MHz, CD3OD) δ-55.73(3F),-141.87(1F),-175.37(1F).

[0464] Example 18: Synthesis of Compound 18

[0465] Step 1: Synthesis of compound 18-1

[0466] In a 25 mL single-necked flask, compound 17-6 (80 mg, 0.13 mmol), M6 (0.13 g, 0.26 mmol), Xphos Pd G3 (22 mg, 0.026 mmol), K3PO4·7H2O (130 mg, 0.39 mmol) and THF / H2O (v / v = 2.5 mL / 0.8 mL) were added. The atmosphere was replaced with nitrogen three times and stirred at room temperature for 1 h. Xphos Pd G3 (0.2 equiv.) was added and stirring was continued at room temperature for 2 h. The reaction was stopped and diluted with DCM (15 mL). The mixture was washed with saturated ammonium chloride (15 mL) and extracted with DCM (15 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by thin-layer chromatography using DCM / MeOH (v / v = 50 / 1) as the eluent to give 56 mg of compound 18-1 as a red oil in a yield of 45%. LC-MS(ESI,pos.ion)m / z:965.4[M+H] + .

[0467] Step 2: Synthesis of compound 18-2

[0468] Compound 18-1 (56 mg, 0.058 mmol) and acetonitrile (3 mL) were added to a 25 mL single-necked bottle, cooled to 0°C and stirred for 5 minutes, TMSOTf (0.031 mL, 0.17 mmol) was added dropwise, and stirred at 0°C for 2 h to stop the reaction. Saturated aqueous sodium bicarbonate solution (20 mL) was added to quench the reaction, and the mixture was extracted with DCM (20 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and drained. The crude product was purified by thin-layer chromatography using DCM / MeOH (v / v = 9 / 1) as the eluent to obtain 25 mg of compound 18-2 as a red solid in a yield of 52%. LC-MS (ESI, pos. ion) m / z: 821.3 [M+H] + .

[0469] Step 3: Synthesis of compound 18

[0470] Compound 18-2 (25 mg, 0.076 mmol), cesium fluoride (36 mg, 0.24 mmol) and DMF (0.5 mL) were added to a 25 mL single-necked flask. The atmosphere was replaced with nitrogen three times and stirred at room temperature for 13 h. The reaction was stopped and 10 mL of water was added to precipitate a solid. The solid was filtered to obtain a crude solid product. The crude product was purified by thin-layer chromatography using DCM / MeOH (v / v = 8 / 1) as the eluent to obtain 18 mg of compound 18 as a yellow solid in an 89% yield. LC-MS (ESI, pos. ion) m / z: 665.3 [M+H] + ; HRMS (ESI): 665.2824 [M+H] + ; 1 H NMR(400MHz,CD3OD)δ7.92–7.82(m,1H),7.40–7.29(m,2H),7.23(s,1H),5 .53–5.33(m,1H),4.70–4.54(m,4H),4.53–4.42(m,2H),3.67–3.56(m,2H) ,3.55–3.45(m,1H),3.21–3.01(m,2H),2.78–2.69(m,1H),2.67–2.47(m,1 H),2.21(s,3H),2.20–2.01(m,2H),1.92–1.55(m,6H),0.70–0.56(m,4H). 19 F NMR (376MHz, CD3OD): δ-111.53(1F),-140.24(1F),-175.34(1F).

[0471] Examples 19-24 (i.e., compounds 19-24) were prepared with reference to the method for constructing the core in Example 2 and WO2023061463; Examples 25-37 and Examples 40-42 (i.e., compounds 25-37, 40-42) were prepared with reference to the synthesis method of the right fragment in M4 and Example 11; Examples 38 and 39 were prepared with reference to the synthesis method of Example 18; It should be noted that in the synthesis process of Examples 19-42, while referring to the synthesis method of the target compound, it also includes the process of appropriate or necessary adjustment of the synthesis method by technicians based on the conventional technical knowledge in the field. The structures and characterization data of Examples 19-42 are shown in the following table.

[0472] Biologically active examples

[0473] 1. KRAS G12D / cRAF Binding Assay

[0474] Experimental steps:

[0475] (1) Compounds were prepared with DMSO and diluted 3-fold in series with DMSO.

[0476] (2) Add 0.1 μl of serially diluted compounds to a 384-well plate.

[0477] (3) Add 5 μl of specific concentration of Tag2-KRASG12D>P to the 384-well plate and centrifuge at 1000 rpm for 1 minute.

[0478] (4) Add 5 μl of Tag1-cRAF at a specific concentration to the 384-well plate and centrifuge at 1000 rpm for 1 minute.

[0479] (5) Incubate at 25°C for 15 minutes.

[0480] (6) Add 10 μl of the mixture of anti-Tag1-Eu and anti-Tag2-XL665 to the 384-well plate.

[0481] (7) Centrifuge at 1000 rpm for 1 minute and incubate at 4°C for 3 hours.

[0482] (8) Read the 665 / 615 nm ratio using a microplate reader.

[0483] (9) Data analysis: The log value of the compound concentration was used as the horizontal axis, and the 665 / 615 nm ratio was used as the vertical axis. GraphPad Prism 8.0 software was used to analyze the data and calculate the IC 50 value.

[0484] Conclusion: The compounds of the present invention can effectively bind to KRAS G12D-GTP and inhibit the binding of KRAS to cRAF protein. 50 are all less than 50 nM; preferably, the IC of the compounds of the present invention for KRAS G12D-GTP / cRAF 50 Less than 20nM.

[0485] 2. KRAS G12D / SOS1 Binding Experiment

[0486] Experimental steps:

[0487] (1) Compounds were prepared with DMSO and diluted 3-fold in series with DMSO.

[0488] (2) Add 0.1 μl of serially diluted compounds to a 384-well plate.

[0489] (3) Add 5 μl of specific concentration of Tag2-KRASG12D>P to the 384-well plate and centrifuge at 1000 rpm for 1 minute.

[0490] (4) Add 5 μl of Tag1-SOS1 of a specific concentration to the 384-well plate and centrifuge at 1000 rpm for 1 minute.

[0491] (5) Incubate at 25°C for 15 minutes.

[0492] (6) Add 10 μl of anti-Tag1-Tb to the 384-well plate 3+ and a mixture of anti-Tag2-XL665.

[0493] (7) Centrifuge at 1000 rpm for 1 minute and incubate at 4°C for 3 hours.

[0494] (8) Read the 665 / 615 nm ratio using a microplate reader.

[0495] (9) Data analysis: The log value of the compound concentration was plotted as the horizontal axis and the 665 / 615 nm ratio was plotted as the vertical axis. GraphPad Prism 8.0 software was used to analyze the data and calculate the IC 50 value.

[0496] Conclusion: The compounds of the present invention can effectively bind to KRAS G12D-GTP and inhibit the binding of KRAS to SOS1 protein. 50 are all less than 50 nM; preferably, the IC of the compounds of the present invention for KRAS G12D-GTP / SOS1 50Less than 20nM.

[0497] 3. In-cell Western blotting to detect the inhibitory effect of compounds on intracellular pERK

[0498] Reagents used

[0499] Experimental steps:

[0500] (1) On the first day, revive the following cells with the corresponding culture medium and incubate them in a 37°C 5% CO2 incubator until confluent:

[0501] (2) On the third day, the culture medium was removed and the cells were rinsed once with DPBS. 2 mL of TrypLE™ trypsin was added for digestion and the cells were placed at room temperature until the cells fell off.

[0502] (3) Add 5 mL of new culture medium to resuspend the cells to terminate digestion, gently pipette the cells, and centrifuge at 1000 rpm at room temperature for 5 minutes.

[0503] (4) Remove the supernatant, add 5 mL of new culture medium to resuspend the cells, and count them.

[0504] (5) The appropriate cell concentration was adjusted with the corresponding cell culture medium, and the cells were plated in a 384-well plate and incubated in a 37°C 5% CO2 incubator overnight.

[0505] (6) Add 200 nL of the prepared gradient dilution compound (final DMSO concentration is 0.5%) and place in a 37°C 5% CO2 incubator for incubation for 3 h (HPAC cell lines only need to be incubated in the incubator for 1 h).

[0506] (7) Fix the cells.

[0507] (8) Wash twice with PBS.

[0508] (9) Add blocking solution and incubate at room temperature for 1 hour.

[0509] (10) Remove the blocking solution, add the primary antibody (phospho-ERK Rabbit mAb + GAPDH (D4C6R) Mouse mAb), and incubate at 4°C overnight.

[0510] (11) Wash twice with PBST (PBS + 0.05% Tween 20), 2 minutes each time.

[0511] (12) Remove PBST and add secondary antibodies (IRDye 800CW Goat anti-Rabbit IgG (H+L) + IRDye 680RD Goat anti-Mouse IgG (H+L)) at room temperature in the dark.

[0512] (14) Discard the secondary antibody and wash twice with PBST for 2 minutes each time.

[0513] (15) Invert the 384-well plate, centrifuge at 1000 rpm for 1 minute at room temperature, and scan the 384-well plate using the Odyssey CLx.

[0514] (16) Data Analysis

[0515] a) Perform assay stability checks using DMSO and reference control data:

[0516] Relative signal value = pERK (signal value of 800 channel) / GAPDH (signal value of 700 channel)

[0517] Inhibition rate % = 100 - (Signal value of each sample - relative signal value of quality control) / (Signal value of DMSO well - relative signal value of quality control) × 100

[0518] b) Compound IC 50 Nonlinear fitting:

[0519] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)×HillSlope)).

[0520] Experimental conclusion: The compounds of the present invention can effectively inhibit the phosphorylation of ERK protein in the KRAS G12D mutant cell line AGS cell line. The experimental test results of some compounds of the present invention are shown in Table A.

[0521] Table A Inhibitory effects of the compounds of the present invention on pERK in KRAS G12D mutant cell line AGS

[0522] 4. In-cell Western blotting to detect the inhibitory effect of compounds on intracellular pERK

[0523] Reagents used

[0524] Experimental steps:

[0525] (2) On the first day, revive the following cells with the corresponding culture medium and incubate them in a 37°C 5% CO2 incubator until confluent:

[0526] (2) On the third day, the culture medium was removed, 2 mL of trypsin was added for digestion, and the cells were placed in an incubator until the cells fell off.

[0527] (3) Add 5 mL of new culture medium to resuspend the cells to terminate digestion, gently pipette the cells, and centrifuge at 1000 rpm at room temperature for 5 minutes.

[0528] (4) Remove the supernatant, add 5 mL of new culture medium to resuspend the cells, and count them.

[0529] (5) Adjust the cell concentration to an appropriate level with complete culture medium, plate the cells in a 96-well plate, add 90 μL per well, and incubate in a 37°C 5% CO2 incubator overnight.

[0530] (6) Add 10 μL of the prepared gradient dilution compound (final DMSO concentration is 0.5%) and incubate in a 37°C 5% CO2 incubator for 2 h.

[0531] (7) Discard the supernatant and add 200 μL of 4% paraformaldehyde fixative to each cell.

[0532] (8) Wash with TBST three times.

[0533] (9) Add blocking solution and incubate at room temperature for 1 hour.

[0534] (10) Remove the blocking solution, add the primary antibody (phospho-ERK Rabbit mAb + α-Tubulin (DM1A) Mouse mAb), and incubate at 4°C overnight.

[0535] (11) Wash three times with 1×PBST, 5 minutes each time.

[0536] (12) Remove PBST and add secondary antibodies (IRDye 800CW Goat anti-Rabbit IgG (H+L) + IRDye 680RD Goat anti-Mouse IgG (H+L)) at room temperature in the dark.

[0537] (14) Discard the secondary antibody and wash with PBST three times, 5 minutes each time.

[0538] (15) Invert the 96-well plate, centrifuge at 1000 rpm for 1 minute at room temperature, and scan the 96-well plate with Odyssey CLx.

[0539] (16) Data Analysis

[0540] c) Perform assay stability checks using DMSO and reference control data:

[0541] Relative signal value = pERK (signal value of 800 channel) / GAPDH (signal value of 700 channel)

[0542] Inhibition rate % = 100 - (Signal value of each sample - relative signal value of quality control) / (Signal value of DMSO well - relative signal value of quality control) × 100

[0543] d) Compound IC 50 Nonlinear fitting:

[0544] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)×HillSlope)).

[0545] Conclusion: The compounds of the present invention can effectively inhibit the phosphorylation of ERK protein in the KRAS G12D mutant cell line ASPC-1 cell line. The experimental test results of some compounds of the present invention are shown in Table B.

[0546] Table B Inhibitory effects of the compounds of the present invention on pERK in KRAS G12D mutant cell lines

[0547] 5. 3D-CTG method to detect the effect of compounds on the proliferation inhibition of KRAS G12D mutant cells:

[0548] Reagents used

[0549] Experimental steps:

[0550] (1) On the first day, revive the following cells with the corresponding culture medium and incubate them in a 37°C 5% CO2 incubator until confluent:

[0551] (2) On the second day, rinse the cells with PBS, add preheated trypsin, and place in a 37°C 5% CO2 incubator for digestion for 3 to 5 minutes; add an appropriate amount of complete culture medium (containing 10% fetal bovine serum) to terminate the digestion, transfer the cells to a centrifuge tube, and centrifuge at 1000 rpm for 5 minutes.

[0552] (3) Resuspend the cells in complete culture medium, count the cells, and adjust the cell concentration to an appropriate level using complete culture medium.

[0553] (4) Add 90 μl / well of cell suspension to a 96-well plate and incubate in a 5% CO2 incubator at 37°C overnight.

[0554] (5) Add 10 μl of the prepared 10× gradient dilution compound (final DMSO concentration is 0.5%) to each well and incubate in a 37°C 5% CO2 incubator.

[0555] (6) After the 7th day of incubation, 50 μl of 3D CTG detection reagent was added to each well and the cells were shaken at 350 rpm for 20 minutes.

[0556] (7) Read the signal value using an enzyme analyzer.

[0557] (8) Data analysis:

[0558] The IC50 values ​​of the compounds were fitted using the nonlinear regression equation of Graphpad software.

[0559] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0560] X: log value of compound concentration

[0561] Y: inhibition rate (%inh)

[0562] Conclusion: The compounds of the present invention have good inhibitory activity against the proliferation of KRAS-G12D mutant cell lines. See Table C for the activity of some compounds of the present invention against KRAS-G12D mutant cell lines.

[0563] Table C Inhibitory effect of the compounds of the present invention on cell proliferation of KRAS G12D mutant cell lines

[0564] 6. 3D-CTG method to detect the effects of compounds on GP2D and HPAC cell proliferation inhibition:

[0565] Experimental steps:

[0566] (1) Resuscitate GP2D and HPAC cells with DMEM medium containing 10% fetal bovine serum and use them for experiments after the cells have recovered.

[0567] (2) On the first day, rinse the cells once with PBS, add preheated trypsin, and place in a 37°C 5% CO2 incubator for digestion for 3 to 5 minutes; add an appropriate amount of complete culture medium (containing 10% fetal bovine serum) to terminate the digestion, transfer the cells to a centrifuge tube, and centrifuge at 1000 rpm for 5 minutes.

[0568] (3) Resuspend the cells in complete culture medium, count the cells, and adjust the cell concentration to an appropriate level using complete culture medium.

[0569] (4) Using the ECHO 655 acoustic liquid handling system, 0.2 μl of the prepared 200× gradient dilution compound (final DMSO concentration of 0.5%) was added to a 384-well plate. Then, 40 μl of the cell suspension counted in step (3) was added to each well, and the plate was incubated in a 37°C 5% CO2 incubator.

[0570] (6) After the 8th day of incubation, 3D CTG detection reagent was added to each well.

[0571] (7) Use Envision to read the signal value.

[0572] (8) Data analysis:

[0573] a) Use DMSO and culture medium to test the stability of the experimental method:

[0574] H = DMSO wells

[0575] L = culture medium well

[0576] H, CV% (DMSO well) = 100 × (DMSO well SD value / DMSO well average value)

[0577] L, CV% (corresponding culture medium well) = 100 × (culture medium well SD value / corresponding culture medium well average value)

[0578] Z' = 1-3 × (SD value of DMSO well + SD value of culture medium well) / (average value of DMSO well - average value of corresponding culture medium well)

[0579] Inhibition rate, % = (average value of DMSO wells – average value of sample wells) / (average value of DMSO wells – average value of corresponding culture medium wells) x 100

[0580] b) IC50 values ​​of the compounds were fitted using the nonlinear regression equation of XLfit 5.5.0 software.

[0581] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0582] X: log value of compound concentration

[0583] Y: inhibition rate (%inh)

[0584] Conclusion: The IC values ​​of the compounds of the present invention for the inhibition of GP2D and HPAC cell proliferation are 50 <1 μM, IC of most compounds on the inhibition of cell proliferation mentioned above 50 <100nM; IC values ​​of most compounds for the inhibition of cell proliferation mentioned above 50 <10 nM. Therefore, the compounds of the present invention have a good inhibitory effect on the proliferation of GP2D and HPAC cells. The partial inhibitory activity of some compounds of the present invention is shown in Table D-1 and Table D-2.

[0585] Table D-1 Inhibitory effect of the compounds of the present invention on cell proliferation of KRAS G12D mutant cell line GP2D

[0586] Table D-2 Inhibitory effect of the compounds of the present invention on KRAS G12D mutant cell line HPAC

[0587] VII. Pharmacokinetic Evaluation of the Compounds of the Invention in Mice, Rats, and Dogs by Intravenous Injection or Oral Gavage

[0588] The inventors conducted pharmacokinetic evaluations of the compounds of the present invention in mice, rats, and dogs. Detailed animal information is shown in Table 2.

[0589] Table 2: Information of the test animals of the present invention

[0590] Experimental methods

[0591] The compounds of the present invention were administered to the test animals in the form of 5% DMSO + 30% PEG400 + 65% saline, 10% DMSO + 10% Kolliphor HS15 + 80% Saline, 10% DMSO + 89% (25% SBE-B-CD) + (2% HCl), 20% PEG400 + 80% sterile water for injection, or 10% DMA + 10% HS15 + 30% PEG400 + 50% sterile aqueous solution for injection. The animals were fasted for 12 hours before administration and had free access to water. For the intravenous injection group, the dosage was 1 mg / kg, and blood was collected venously at the following time points after administration (blood volume was approximately 0.15 mL): 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h (dog), 0.083, 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24 h (mice and rats) or 0.083, 0.25, 0.5, 1.0, 2.0, 6.0, 8.0 and 24 h (monkeys). EDTA-K2 was pre-added to the blood collection tube as an anticoagulant. The blood samples were centrifuged at 12,000 rpm for 2 minutes, and the plasma was collected and stored at -20°C or -70°C. For the oral gavage administration group, the dosage was 1 mg / kg (mice, dogs and monkeys) or 5 mg / kg (rats), and venous blood was collected at the following time points after administration (blood volume was approximately 0.15 mL): 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h (dogs), 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24 h (mice and rats) or 0.25, 0.5, 1.0, 2.0, 6.0, 8.0 and 24 h (monkeys). EDTA-K2 was pre-added to the blood collection tube as an anticoagulant. The blood samples were centrifuged at 12,000 rpm for 2 minutes, and the plasma was collected and stored at -20°C or -70°C.

[0592] The collected plasma samples were processed (frozen plasma was thawed at room temperature and vortexed for 15 seconds, 10-20 μL of plasma was taken, 120-150 μL of acetonitrile solution containing the internal standard was added, vortexed for 5 minutes, centrifuged at 4,000 rpm for 5 minutes, 100 μL of the supernatant was taken, and 120-150 μL of methanol / water (v / v = 1 / 1) was added and mixed), and then the concentration of the compound in the plasma was analyzed by LC-MS / MS.

[0593] The analysis results show that the compound of the present invention has good pharmacokinetic properties in mice, rats and dogs, indicating that the compound of the present invention has better drugability and better clinical application prospects.

[0594] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "some implementation plans", "example", "specific example" or "some examples" means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine different embodiments, implementation plans or examples described in this specification and features of different embodiments, implementation plans or examples, unless they are mutually inconsistent.

[0595] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention without departing from the principles and purpose of the present invention. The scope of the present invention is defined by the claims and their equivalents.

Claims

1. A compound, which is a compound represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I), in, R 1 is -H, -D, -CN, -NH2, -C(=O)H, -C(=O)OH, -C(=O)OR 6a 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 、-NR 6a C(=O)NR 6 R 7 、-C(=O)R 6a 、-NR 6 S(=O)2R 7 、-S(=O)2NR 6 R 7 、-NR 6a S(=O)2NR 6 R 7 、-NR 6 R 7 , -C 1-6 Alkyl-NR 6 C(=O)R 7 , -C 1-6 Alkyl-NR 6 R 7 , -C 1-6 Alkyl-C(=O)OR 6 , -C 1-6 Alkyl-C(=O)NR 6 R 7 , C 1-6 Alkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, (C 3-12 Cycloalkyl)-C 1-6 Alkyl, (3-12 membered heterocyclic)-C 1-6 Alkyl, (C 6-10 Aryl)-C 1-6 Alkyl, (5-12 membered heteroaryl)-C 1-6 Alkyl, (C 3-12 Cycloalkyl)-OC 1-6 Alkyl, (3-12 membered heterocyclic)-OC 1-6 Alkyl, C 1-6 Mercaptoalkyl, C 6-12 Aryl, 5-12 membered heteroaryl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group; wherein the C 1-6 Alkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, (C 3-12 Cycloalkyl)-C 1-6 Alkyl, (3-12 membered heterocyclic)-C 1-6 Alkyl, (C 6-10 Aryl)-C 1-6 Alkyl, (5-12 membered heteroaryl)-C 1-6 Alkyl, (C 3-12 Cycloalkyl)-OC 1-6 Alkyl, (3-12 membered heterocyclic)-OC 1-6 Alkyl, C 1-6 Mercaptoalkyl, C 6-12 Aryl, 5-12 membered heteroaryl, C 3-12 The cycloalkyl and 3-12 membered heterocyclyl groups are each independently optionally substituted by 1, 2, 3 or 4 groups selected from D, -OH, -F, -Cl, -Br, -I, CN, -C(=O)OR 6e 、-NR 6e R 7e 、-C(=O)NR 6e R 7e 、-NR 6e C(=O)R 7e and C 1-6 substituted by an alkyl substituent; Y is a bond, O or S; R 2 for L 1 , L 2 and L 3 Each independently is C 1-6 Alkylene or C 1-6 Heteroalkylene, wherein the C 1-6 Alkylene and C 1-6 Each heteroalkylene group is independently optionally substituted by 1, 2, 3 or 4 R a replace; R a is -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, C 1-6 Alkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; or two R attached to the same carbon atom a Together they form C 3-6 Cycloalkyl; Ring B1 and Ring C1 are each independently a 3-7 membered monocyclic heterocyclic group; Ring B2, Ring B3 and Ring C2 are each independently C 3-7 Monocyclic cycloalkyl or 3-7 membered monocyclic heterocyclyl; Ring D1, ring D2 and ring D3 are each independently C 3-7 Monocyclic cycloalkyl or 3-7 membered monocyclic heterocyclyl; R A1 , R A2 , R A3 and R A4 Each is independently -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6d R 7d 、-C(=O)NR 6d R 7d 、-CH2NR 6d R 7d 、-CH2OC(=O)NR 6d R 7d , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, (C 6-10 Aryl)-C 1-6 Alkyl, (5-12 membered heteroaryl)-C 1-6 Alkyl, (3-6 membered heterocyclic)-C 1-6 Alkyl, (C 3-6 Cycloalkyl)-C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; Or, two R attached to the same carbon atom A1 Together we form Or, two R attached to the same carbon atom A1 Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 3-6 The cycloalkyl and 3-6 membered heterocyclic groups are each independently optionally substituted by 1, 2, 3 or 4 R 8a or, two R connected to two adjacent atoms A1 Together with the two adjacent atoms it is connected to, it forms C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 3-6 The cycloalkyl and 3-6 membered heterocyclic groups are each independently optionally substituted by 1, 2, 3 or 4 R 8a* replaced by; Or, two R attached to the same carbon atom A2 Together we form Or, two R attached to the same carbon atom A2 Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 3-6 The cycloalkyl and 3-6 membered heterocyclic groups are each independently optionally substituted by 1, 2, 3 or 4 R 9a or, two R connected to two adjacent atoms A2 Together with the two adjacent atoms it is connected to, it forms C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 3-6 The cycloalkyl and 3-6 membered heterocyclic groups are each independently optionally substituted by 1, 2, 3 or 4 R 9a* replaced by; Or, two R attached to the same carbon atom A3 Together we form Or, two R attached to the same carbon atom A3 Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 3-6 The cycloalkyl and 3-6 membered heterocyclic groups are each independently optionally substituted by 1, 2, 3 or 4 R 10a or, two R connected to two adjacent atoms A3 Together with the two adjacent atoms it is connected to, it forms C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 3-6 The cycloalkyl and 3-6 membered heterocyclic groups are each independently optionally substituted by 1, 2, 3 or 4 R 10a* replaced by; R A1a , R A1b , R A2a , R A2b , R A3a , R A3b , R A1a* , R A1b* , R A2a* , R A2b* , R A3a* and R A3b* are independently -H, -D, -F, -Cl, -Br, -I, -CN, -C 1-6 Alkyl-NR 6 C(=O)R 7 , -C 1-6 Alkyl-NR 6 R 7 , -C 1-6 Alkyl-C(=O)OR 6 , -C 1-6 Alkyl-C(=O)NR 6 R 7 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, (C 3-12 Cycloalkyl)-C 1-6 Alkyl, (3-12 membered heterocyclic)-C 1-6 Alkyl, (C 3-12 Cycloalkyl)-OC 1-6 Alkyl, (3-12 membered heterocyclic)-OC 1-6 Alkyl, C 6-12 Aryl, 5-12 membered heteroaryl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group; R 8a , R 8a* , R 9a , R 9a* , R 10a and R 10a* Each is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)OH, -C(=O)NH2, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(=O)OC 1-6 Alkyl, -C(=O)NHC 1-6 Alkyl or -C(=O)N(C 1-6 Alkyl)2; R 3 for R 11a , R 11b , R 11c and R 11d each independently represents -H, -D, -OH, -SH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OR 6a 、-C(=O)NR 6 R 7 , C 1-6 Alkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or 5-6 membered heteroaryl; R 4 is -H, -D, -OH, -SH, -F, -Cl, -Br, -I, -CN, methyl, ethyl, n-propyl, isopropyl, n-butyl or C 1-4 Haloalkyl; Ring A is C 6-12 Aryl or 5-12 membered heteroaryl; Each R 5 are independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH2C(=O)NR 6b R 7b 、-C(=O)R 6c 、-C(=O)OR 6c 、-C(=O)NR 6b R 7b 、-NR 6b C(=O)R 7b 、-NR 6b R 7b , C 1-6 Alkyl, C 1-6 Alkylthio, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Hydroxyalkynyl, C 1-6 Alkoxy, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 2-6 Halogenated alkenyl, C 2-6 Haloalkynyl, C 1-6 Haloalkoxy, C 1-6 alkylthio halide, 6-12 membered aryl, 5-12 membered heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Alkylthio, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Hydroxyalkynyl, C 1-6 Alkoxy, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 2-6 Halogenated alkenyl, C 2-6 Haloalkynyl, C 1-6 Haloalkoxy, C 1-6 alkylthio halide, 6-12 membered aryl, 5-12 membered heteroaryl, C 3-6 The cycloalkyl and 3-6 membered heterocyclyl groups are each independently optionally substituted by 1, 2, 3 or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Substituted by cycloalkyl and 3-6 membered heterocyclic substituents; R 6 , R 7 , R 6a , R 6b , R 6c , R 7b , R 6d , R 7d , R 6e and R 7e Each is independently -H, -D or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1, 2, 3 or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NH2, C 1-6 Alkoxy, C 6-12 Aryl, C 3-6 Substituted by cycloalkyl and 3-6 membered heterocyclic substituents; n is 0, 1, 2, 3, 4, 5, 6 or 7; and q1, q2 and q3 are each independently 0, 1, 2, 3, 4, 5 or 6; Each q4 is independently 0, 1, 2, 3 or 4; Wherein, the compound of formula (I) is not 2. The compound according to claim 1, wherein R 1 is -H, -D, -CN, -NH2, -C(=O)H, -C(=O)OH, -C(=O)OR 6a 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 、-NR 6a C(=O)NR 6 R 7 、-C(=O)R 6a 、-NR 6 S(=O)2R 7 、-S(=O)2NR 6 R 7 、-NR 6a S(=O)2NR 6 R 7 、-NR 6 R 7 , -C 1-4 Alkyl-NR 6 C(=O)R 7 , -C 1-4 Alkyl-NR 6 R 7 , -C 1-4 Alkyl-C(=O)OR 6 , -C 1-4 Alkyl-C(=O)NR 6 R 7 , C 1-4 Alkyl, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, (C 3-6 Cycloalkyl)-C 1-4 Alkyl, (C 7-12 Cycloalkyl)-C 1-4 Alkyl, (3-6 membered heterocyclic)-C 1-4 Alkyl, (7-12 membered heterocyclic)-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, (5-6 membered heteroaryl)-C 1-4 Alkyl, (C 3-6 Cycloalkyl)-OC 1-4 Alkyl, (C 7-12 Cycloalkyl)-OC 1-4 Alkyl, (3-7 membered heterocyclic)-OC 1-6 Alkyl, (7-12 membered heterocyclic)-OC 1-4 Alkyl, C 1-4 Mercaptoalkyl, C 6-10 Aryl, 5-12 membered heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; wherein the C 1-4 Alkyl, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, (C 3-6 Cycloalkyl)-C 1-4 Alkyl, (C 7-12 Cycloalkyl)-C 1-4 Alkyl, (3-6 membered heterocyclic)-C 1-4 Alkyl, (7-12 membered heterocyclic)-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, (5-6 membered heteroaryl)-C 1-4 Alkyl, (C 3-6 Cycloalkyl)-OC 1-4 Alkyl, (C 7-12 Cycloalkyl)-OC 1-4 Alkyl, (3-7 membered heterocyclic)-OC 1-6 Alkyl, (7-12 membered heterocyclic)-OC 1-4 Alkyl, C 1-4 Mercaptoalkyl, C 6-10 Aryl, 5-12 membered heteroaryl, C 3-6 The cycloalkyl and 3-6 membered heterocyclyl groups are each independently optionally substituted by 1, 2, 3 or 4 groups selected from D, -OH, -F, -Cl, -Br, -I, CN, -C(=O)OR 6e 、-NR 6e R 7e 、-C(=O)NR 6e R 7e 、-NR 6e C(=O)R 7e and C 1-4 The alkyl group is substituted with an alkyl substituent.

3. The compound according to any one of claims 1 to 2, wherein R 1 is -H, -D, -CN, -NH2, -C(=O)H, -C(=O)OH, -C(=O)OR 6a 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 、-NR 6a C(=O)NR 6 R 7 、-C(=O)R 6a 、-NR 6 S(=O)2R 7 、-S(=O)2NR 6 R 7 、-NR 6a S(=O)2NR 6 R 7 、-NR 6 R 7 、-CH2NR 6 C(=O)R 7 、-CH2NR 6 R 7 、-(CH2)2NR 6 R 7 、-CH2C(=O)OR 6 、-(CH2)2C(=O)OR 6 、-(CH2)3C(=O)OR 6 、-CH2C(=O)NR 6 R 7 、-(CH2)2C(=O)NR 6 R 7 、-(CH2)3C(=O)NR 6 R 7 , -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CN, -(CH2)2CN, -(CH2) 3CN, -CH(CH3)CN, -C(CH3)2CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -(CH2)2CHF2, -(CH2)2CF(CF3)2, -CF3, -CHF2, -CH2F, -(CH2)2F, -(CH2)2Cl, -CH2CF3, -OCH3, -OCH2CH3, -O(CH2)2CH3, -O(CH2)3CH3, -OC(CH3)3, -OCH(CH3)2, -CH2OCH3, -(CH2)2OCH3, -(CH2)2OCH2CH3, -CH2OCH2CH3, -CH2OC(CH3)3, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -(CH2)2-cyclopentyl, -(CH2)3-cyclopentyl, -(CH2)2-cyclohexyl yl, -CH2-cyclopropyl, -CH2-cyclobutyl, -(CH2)2-cyclobutyl, -CH2-cyclopentyl, -(CH2)2-cyclopentyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-morpholinyl, -CH2-phenyl, -CH2-imidazolyl, -CH2-pyrazolyl, -CH2O-cyclopropyl, -CH2O-cyclobutyl, -(CH2)2O-cyclobutyl, -CH2O-cyclopentyl, -(CH2)2O-cyclopentyl, -CH2O-azetidinyl, -CH2O-oxetanyl, -CH2O-tetrahydrofuranyl, -CH2O-spiro[2.3]hexanyl, -CH2O-spiro[3.3] heptyl-, -CH2SH, -(CH2)2SH, phenyl, naphthyl, pyridyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydropyranyl, azetidinyl or pyrrolidinyl; wherein -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH(CH3)CN, -C(CH3)2CN, -CH2OH, - (CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -(CH2)2CHF2, -(CH2)2CF(CF3)2, -CHF2, -CH2F, -(CH2)2F, -(CH2)2Cl, -CH2CF3, -OCH3, -OC H2CH3, -O(CH2)2CH3, -O(CH2)3CH3, -OC(CH3)3, -OCH(CH3)2, -CH2OCH3, -(CH2)2OCH3, -(CH2)2OCH2CH3, -CH2OCH2CH3, -CH2OC(C H3)3, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -(CH2)2-cyclopentyl, -(CH2)3-cyclopentyl, -(CH2)2-cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -(CH2)2-cyclobutyl, -CH2-cyclopentyl, -(CH2)2-cyclopentyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-morpholinyl, -CH2-phenyl, -CH2-imidazolyl, -CH2-pyrazolyl, -CH2O-cyclopropyl, -CH2O-cyclobutyl, -(CH2)2O-cyclobutyl, -CH2O-cyclopentyl, -(CH2)2O-cyclopentyl, -CH2O-azetidinyl, -CH2O-oxetanyl, -CH2O-tetrahydrofuranyl, -CH2O-spiro[2.3]hexanyl, -CH2O-spiro[3.3]heptyl-, phenyl, naphthyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydropyranyl, azetidinyl and pyrrolidinyl are each independently optionally substituted by 1, 2, 3 or 4 groups selected from D, -OH, -F, -Cl, -Br, -I, CN, -C(=O)OR. 6e 、-NR 6e R 7e 、-C(=O)NR 6e R 7e 、-NR 6e C(=O)R 7e , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl substituents.

4. The compound according to any one of claims 1 to 3, wherein R A1 , R A2 , R A3 and R A4 Each is independently -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6d R 7d 、-C(=O)NR 6d R 7d 、-CH2NR 6d R 7d 、-CH2OC(=O)NR 6d R 7d , C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy, phenyl-C 1-4 Alkyl, (5-6 membered heteroaryl)-C 1-4 Alkyl, (3-6 membered heterocyclic)-C 1-4 Alkyl, (C 3-6 Cycloalkyl)-C 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; or, R A1 , R A2 , R A3 and R A4 Each is independently -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6d R 7d 、-C(=O)NR 6d R 7d 、-CH2NR 6d R 7d 、-CH2OC(=O)NR 6d R 7d , -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH3, -OC(CH3)3, -(CH2)2CHF2, -(CH2)2CF(CF3)2, -CF3, -CHF2, -CH2F, -(CH2)2F, -(CH2)2Cl, -CH2CF3, -OCF3, -OCHF2, -CH2-phenyl, -CH2-pyridyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-cyclopropyl, -CH2-cyclopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydropyranyl, morpholinyl, azetidinyl or pyrrolidinyl; Or, two R attached to the same carbon atom A1 Together we form Or, two R attached to the same carbon atom A1 and the carbon atom to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholinyl are each independently and optionally substituted by 1, 2, 3 or 4 R 8a or, two R connected to two adjacent atoms A1 and the two adjacent atoms to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholinyl are each independently and optionally substituted by 1, 2, 3 or 4 R 8a* replaced by; Or, two R attached to the same carbon atom A2 Together we form Or, two R attached to the same carbon atom A2 and the carbon atom to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholinyl are each independently and optionally substituted by 1, 2, 3 or 4 R 9a or, two R connected to two adjacent atoms A2 and the two adjacent atoms to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholinyl are each independently and optionally substituted by 1, 2, 3 or 4 R 9a* replaced by; Or, two R attached to the same carbon atom A3 Together we form Or, two R attached to the same carbon atom A3 Together with the carbon atom to which it is attached, it forms a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, Oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholinyl are each independently and optionally substituted by 1, 2, 3 or 4 R 10a or, two R connected to two adjacent atoms A3 and the two adjacent atoms to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholinyl are each independently and optionally substituted by 1, 2, 3 or 4 R 10a* replaced by; R A1a , R A1b , R A2a , R A2b , R A3a , R A3b , R A1a* , R A1b* , R A2a* , R A2b* , R A3a* and R A3b* are independently -H, -D, -F, -Cl, -Br, -I, -CN, -C 1-4 Alkyl-NR 6 C(=O)R 7 , -C 1-4 Alkyl-NR 6 R 7 , -C 1-4 Alkyl-C(=O)OR 6 , -C 1-4 Alkyl-C(=O)NR 6 R 7 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, (C 3-6 Cycloalkyl)-C 1-4 Alkyl, (3-6 membered heterocyclic)-C 1-4 Alkyl, (C 3-6 Cycloalkyl)-OC 1-4 Alkyl, (3-6 membered heterocyclic)-OC 1-4 Alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; R 8a , R 8a* , R 9a , R 9a* , R 10a and R 10a* Each is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)OH, -C(=O)NH2, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, phenyl, 5-6 membered heteroaryl, -C(=O)OC 1-4 Alkyl, -C(=O)NHC 1-4 Alkyl or -C(=O)N(C 1-4 Alkyl)2.

5. The compound according to any one of claims 1 to 4, wherein R A1a , R A1b , R A2a , R A2b , R A3a , R A3b , R A1a* , R A1b* , R A2a* , R A2b* , R A3a* and R A3b* Each is independently -H, -D, -F, -Cl, -Br, -I, -CN, -CH2NR 6 C(=O)R 7 、-CH2NR 6 R 7 、-CH2C(=O)OR 6 、-(CH2)2C(=O)OR 6 、-(CH2)3C(=O)OR 6 、-CH2C(=O)NR 6 R 7 、(CH2)2C(=O)NR 6 R 7 、-(CH2)3C(=O)NR 6 R 7 , -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, -(C H2)2CHF2, -(CH2)2CF(CF3)2, -CF3, -CHF2, -CH2F, -(CH2)2F, -(CH2)2Cl, -CH2CF3, -CH 2CN, -(CH2)2CN, -(CH2)3CN, -CH(CH3)CN, -C(CH3)2CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -CH2OCH3, -(CH2)2OCH3, -(CH2)2OCH2CH3, -CH2OCH2CH3, -CH2OC(CH3)3 , -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -(CH2)2-cyclopentyl, -(CH2)3-cyclopentyl, -(CH2)2-cyclohexyl, -CH2-cyclopentyl, -CH2-azetidinyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, -CH2-morpholinyl, -CH2O-cyclopropyl, -CH2O-cyclobutyl , -(CH2)2O-cyclobutyl, -CH2O-cyclopentyl, -(CH2)2O-cyclopentyl, -CH2O-azetidinyl, -CH2O-oxetanyl, -CH2O-tetrahydrofuranyl, -CH2-O-morpholinyl, phenyl, pyridyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydropyranyl, morpholinyl, azetidinyl, or pyrrolidinyl; R 8a , R 8a* , R 9a , R 9a* , R 10a and R 10a* Each is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)OH, -C(=O)NH2, oxo, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, -(CH2)2CHF2, -(CH2)2CF(CF3)2, -CF3, -CHF2, -CH2F, -(CH2)2F, -(CH2)2Cl, -CH2CF3, -OCH3, -OCH2CH3, -OCH2CH3, -OC(CH3)3, -CH2OH, -(CH2)2OH, -(CH2)3OH, phenyl, pyridinyl, pyrimidinyl, -C(=O)OCH3, -C(=O)NHCH3 or -C(=O)N(CH3)2.

6. The compound according to any one of claims 1 to 5, wherein Ring A is one of the following substructures, Each R 5 are independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH2C(=O)NR 6b R 7b 、-C(=O)R 6c 、-C(=O)OR 6c 、-C(=O)NR 6b R 7b 、-NR 6b C(=O)R 7b 、-NR 6b R 7b , C 1-4 Alkyl, C 1-4 Alkylthio, C 2-4 Alkenyl, C 2-4 Alkynyl, C 2-4 Hydroxyalkynyl, C 1-4 Alkoxy, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 2-4 Halogenated alkenyl, C 2-4 Haloalkynyl, C 1-4 Halogenated alkoxy, C 1-4 Halogenated alkylthio, 6-12 membered aryl, 5-12 membered heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 1-4 Alkyl, C 1-4 Alkylthio, C 2-4 Alkenyl, C 2-4 Alkynyl, C 2-4 Hydroxyalkynyl, C 1-4 Alkoxy, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 2-4 Halogenated alkenyl, C 2-4 Haloalkynyl, C 1-4 Halogenated alkoxy, C 1-4 Halogenated alkylthio, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 The cycloalkyl and 3-6 membered heterocyclyl groups are each independently optionally substituted by 1, 2, 3 or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl group is substituted by a substituent of a 3- to 6-membered heterocyclic group.

7. The compound according to any one of claims 1 to 6, wherein Each R 5 is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH2C(=O)NR 6b R 7b , -C(=O)R 6c , -C(=O)OR 6c , -C(=O)NR 6b R 7b , -NR 6b C(=O)R 7b , -NR 6b R 7b , -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, -C≡CCH2OH, -C≡C(CH2)2OH, -OCH3, -OCH2CH3, -O(CH2)2CH3, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -(CH2)2F, -CH2CHF2, -CF3, -CH2CF3, -CHF2, -CH2F, -(CH2)2Cl, -CH=CHF, -CH=CHCl, -CH=CHCH2F, -C≡CCH2F, -C≡C(CH2)2F, -C≡CF, -OCF3, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCHClCHCl2, -OCH2CH2F, -SCF3, -SCH2CF3, -SCH2CHF2, phenyl, naphthyl, pyridyl, pyrimidyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl or piperazinyl, wherein the -CH3, -CH2C H3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡C CH3, -CH2C≡CH, -C≡CCH2OH, -C≡C(CH2)2OH, -OCH3, -OCH2CH3, -O(CH2)2CH3, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, - (CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -(CH2)2F, -CH2CHF2, -CH2CF3, -CHF2, -CH2F, -(CH2)2Cl, -CH=CHF, -CH=CHCl, -C H=CHCH2F, -C≡CCH2F, -C≡C(CH2)2F, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCHClCHCl2, -OCH2CH2F, -SCH2CF3, -SCH2CHF2, benzene The invention also provides that the present invention relates to an alkyl, alkyl, alkyl, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, alkylene, 8. The compound according to any one of claims 1 to 7, wherein R 6 , R 7 , R 6a , R 6b , R 6c , R 7b , R 6d , R 7d , R 6e and R 7e Each is independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl is each independently optionally substituted by 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NH2, methoxy, ethoxy, n-propoxy, isopropoxy, isobutoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, oxiranyl, oxetanyl, azetidinyl and pyrrolidinyl.

9. The compound according to any one of claims 1 to 8, wherein R 2 for 10. The compound according to any one of claims 1 to 8, wherein R 2 for Wherein, ring D1, ring D2 and ring D3 are each independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetanyl, azetidinyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl and piperazinyl.

11. The compound according to any one of claims 1 to 9, wherein R 2 for 12. A compound according to any one of claims 1 to 11, which is a compound of formula (I-1a), (I-1b) or (I-1c), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I-1a), (I-1b) or (I-1c), in, R 1 , R 4 , R 5 , R A1 , R A1a , R A1b , R A1a* , R A1b* , R 11a , R A4 , q4 and n each have the definition as described in any one of claims 1-11.

13. A compound having the following structure, or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, 14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13; optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant.

15. Use of the compound according to any one of claims 1 to 13 or the pharmaceutical composition according to claim 14 in the preparation of a drug for preventing, treating or alleviating KRAS G12D-related diseases; wherein, The KRAS G12D-related disease is cancer; optionally, the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, colon cancer, small intestine cancer, pancreatic cancer, uterine cancer, gastric cancer, esophageal cancer, prostate cancer, ovarian cancer, breast cancer, leukemia, melanoma, lymphoma or neuroma.

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