Pyrimidopyridine compounds, pharmaceutical compositions and uses thereof

Abstract

The invention belongs to the field of medicines, and relates to pyrimidopyridine compounds as well as a pharmaceutical composition and application thereof. Specifically, the invention relates to a compound as shown in a formula (I), or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound as shown in the formula (I). As a KRAS G12D inhibitor, the compound and the pharmaceutical composition thereof can be used for preparing drugs for preventing or treating KRAS G12D related diseases, and especially can be used for preparing drugs for preventing or treating cancers. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and 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] The RAS gene is one of the most commonly mutated genes in cancer (20%-25%). The currently known members of the RAS gene family include KRAS, NRAS and HRAS, among which KRAS mutation is the most common, accounting for about 85%. The mutation rate of KRAS in pancreatic ductal adenocarcinoma (PDAC) is the highest, reaching 97%, followed by colorectal cancer, multiple myeloma and lung cancer, which are 52%, 42% and 32% respectively. The most common way for the KRAS gene to mutate is point mutation, and common mutation forms include KRAS G12D mutation (41%), KRAS G12V (28%) and KRAS G12C (14%) mutation. 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). The 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 combination of many targets.

[0003] In recent years, people have made some progress in drug development using the allosteric sites of KRAS G12C mutants. For example, in 2013, a research team reported the discovery of KRAS G12C small molecule inhibitors (Nature, 2013, 503, 548-551); but people have done less research on KRAS G12D. Compared with KRAS G12C mutations, other mutation types such as KRAS G12D and KRAS G12V have a higher proportion in pancreatic cancer. Therefore, inhibiting KRAS G12D mutations to treat pancreatic cancer is a potentially effective means. Among them, Mirati announced a series of KRAS G12D inhibitors in patent application WO20211041671, which showed specificity for KRAS G12D mutants and had 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 urgent. Summary of the invention

[0005] The present invention provides a compound, or a pharmaceutical composition thereof, which can be used as an inhibitor of KRAS, especially as a KRAS G12D inhibitor. The present invention also relates to the use of the compound or the pharmaceutical composition thereof for preparing a drug for treating a disease and / or condition, especially cancer, by inhibiting KRAS activity.

[0006] As a class of non-covalent KRAS G12D specific inhibitors, the compounds of the present invention can effectively bind to KRAS G12D-GTP and inhibit the phosphorylation of ERK downstream of KRAS G12D.

[0007] 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),

[0008]

[0009] in,

[0010] R 1 -H, -D, -CN, -NH 2 , -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) 2 R 7 、-S(=O) 2 NR 6 R 7 、-NR 6a S(=O) 2 NR 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 6R 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;

[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, -NH 2 , -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;

[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 Monocyclic cycloalkyl or 3-7 membered monocyclic heterocyclyl;

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

[0018] 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 、-CH 2 NR 6d R 7d 、-CH 2OC(=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;

[0019] 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;

[0020] 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;

[0021] 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;

[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* 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;

[0023] R 8a , R 8a* , R 9a , R 9a* , R 10a and R 10a* Each is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , -C(=O)OH, -C(=O)NH 2 , 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 ;

[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 Haloalkyl, 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 Haloalkyl;

[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, -CH 2C(=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, -NH 2 , -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;

[0029] R 6 , R 7 , R 6a , R 6b , R 6c , R7b , 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, -NH 2 , C 1-6 Alkoxy, C 6-12 Aryl, C 3-6 Substituted by cycloalkyl and 3-6 membered heterocyclic substituents;

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

[0031] q 1 ,q 2 and q 3 Each independently is 0, 1, 2, 3, 4, 5 or 6;

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

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

[0034] In some embodiments, R 1 -H, -D, -CN, -NH 2 , -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) 2 R 7 、-S(=O) 2 NR 6 R 7 、-NR 6a S(=O) 2 NR 6 R 7 、-NR 6 R 7 , -C 1-4 Alkyl-NR 6 C(=O)R7 , -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)-OC1-4 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 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 -H, -D, -CN, -NH 2 , -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) 2 R 7 、-S(=O) 2 NR 6 R 7 、-NR 6a S(=O) 2 NR 6 R 7 、-NR 6 R 7 、-CH 2 NR 6 C(=O)R 7 、-CH 2 NR 6 R7 、-(CH 2 ) 2 NR 6 R 7 、-CH 2 C(=O)OR 6 、-(CH 2 ) 2 C(=O)OR 6 、-(CH 2 ) 3 C(=O)OR 6 、-CH 2 C(=O)NR 6 R 7 、-(CH 2 ) 2 C(=O)NR 6 R 7 、-(CH 2 ) 3 C(=O)NR 6 R 7 、-CH 3 、-CH 2 CH 3 、-(CH 2 ) 2 CH 3 、-(CH 2 ) 3 CH 3 、-C(CH 3 ) 3 、-CH(CH 3 ) 2 、-CH 2 CH(CH 3 ) 2 、-CH 2 CN、-(CH 2 ) 2 CN、-(CH 2 ) 3 CN、-CH(CH 3 )CN、-C(CH 3 ) 2 CN、-CH 2 OH、-(CH 2 ) 2 OH、-(CH 2 ) 3 OH、-CH(OH)CH 3 、-(CH 2 ) 2 CHF 2 、-(CH 2 ) 2 CF(CF3 ) 2 , -CF 3 , -CHF 2 、-CH 2 F, -(CH 2 ) 2 F, -(CH 2 ) 2 Cl, -CH 2 CF 3 、-OCH 3 、-OCH 2 CH 3 、-O(CH 2 ) 2 CH 3 、-O(CH 2 ) 3 CH 3 、-OC(CH 3 ) 3 、-OCH(CH 3 ) 2 、-CH 2 OCH 3 、-(CH 2 ) 2 OCH 3 、-(CH 2 ) 2 OCH 2 CH 3 、-CH 2 OCH 2 CH 3 、-CH 2 OC(CH 3 ) 3 、-CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -(CH 2 ) 2 -cyclopentyl, -(CH 2 ) 3 -cyclopentyl, -(CH 2 ) 2 -cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -(CH 2 ) 2 -cyclobutyl, -CH 2 -cyclopentyl, -(CH 2 ) 2 Cyclopentyl, -CH 2 -azetidinyl, -CH 2-pyrrolidinyl, -CH 2 -piperidinyl, -CH 2 -morpholinyl, -CH 2 -phenyl, -CH 2 -Imidazole, -CH 2 -pyrazolyl, -CH 2 O-cyclopropyl, -CH 2 O-cyclobutyl, -(CH 2 ) 2 O-cyclobutyl, -CH 2 O-cyclopentyl, -(CH 2 ) 2 O-cyclopentyl, -CH 2 O-azetidinyl, -CH 2 O-oxetane, -CH 2 O-tetrahydrofuranyl, -CH 2 O-spiro[2.3]hexane, -CH 2 O-Spiro[3.3]heptyl-, -CH 2 SH, -(CH 2 ) 2 SH, phenyl, naphthyl, pyridyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydropyranyl, azetidinyl or pyrrolidinyl; wherein the -CH 3 、-CH 2 CH 3 、-(CH 2 ) 2 CH 3 、-(CH 2 ) 3 CH 3 、-C(CH 3 ) 3 、-CH(CH 3 ) 2 、-CH 2 CH(CH 3 ) 2 、-CH 2 CN, -(CH 2 ) 2 CN, -(CH 2 ) 3 CN, -CH(CH 3 )CN、-C(CH 3 ) 2 CN、-CH 2 OH, -(CH 2 ) 2 OH, -(CH 2 ) 3 OH, -CH(OH)CH3 、-(CH 2 ) 2 CHF 2 、-(CH 2 ) 2 CF(CF 3 ) 2 , -CHF 2 、-CH 2 F, -(CH 2 ) 2 F, -(CH 2 ) 2 Cl, -CH 2 CF 3 、-OCH 3 、-OCH 2 CH 3 、-O(CH 2 ) 2 CH 3 、-O(CH 2 ) 3 CH 3 、-OC(CH 3 ) 3 、-OCH(CH 3 ) 2 、-CH 2 OCH 3 、-(CH 2 ) 2 OCH 3 、-(CH 2 ) 2 OCH 2 CH 3 、-CH 2 OCH 2 CH 3 、-CH 2 OC(CH 3 ) 3 、-CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -(CH 2 ) 2 -cyclopentyl, -(CH 2 ) 3 -cyclopentyl, -(CH 2 ) 2 -cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -(CH 2 ) 2 -cyclobutyl, -CH 2-cyclopentyl, -(CH 2 ) 2 Cyclopentyl, -CH 2 -azetidinyl, -CH 2 -pyrrolidinyl, -CH 2 -piperidinyl, -CH 2 -morpholinyl, -CH 2 -phenyl, -CH 2 -Imidazole, -CH 2 -pyrazolyl, -CH 2 O-cyclopropyl, -CH 2 O-cyclobutyl, -(CH 2 ) 2 O-cyclobutyl, -CH 2 O-cyclopentyl, -(CH 2 ) 2 O-cyclopentyl, -CH 2 O-azetidinyl, -CH 2 O-oxetane, -CH 2 O-tetrahydrofuranyl, -CH 2 O-spiro[2.3]hexane, -CH 2 O-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 radicals 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 definition as defined in the present invention.

[0036] In some embodiments, 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、-CH 2 NR 6d R 7d 、-CH 2 OC(=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 、-CH 2 NR 6d R 7d 、-CH 2 OC(=O)NR 6d R 7d 、-CH 3 、-CH 2 CH 3 、-(CH 2 ) 2 CH 3 、-(CH 2 ) 3 CH 3 、-C(CH 3 ) 3 、-CH(CH 3 ) 2 、-CH 2 CH(CH 3 ) 2 、-OCH 3 、-OCH 2 CH 3 、-OCH 2 CH 3 、-OC(CH 3 ) 3 、-(CH 2 ) 2 CHF 2 、-(CH2 ) 2 CF(CF 3 ) 2 , -CF 3 , -CHF 2 、-CH 2 F, -(CH 2 ) 2 F, -(CH 2 ) 2 Cl, -CH 2 CF 3 、-OCF 3 、-OCHF 2 、-CH 2 -phenyl, -CH 2 -pyridyl, -CH 2 -pyrrolidinyl, -CH 2 -piperidinyl, -CH 2 -cyclopropyl, -CH 2 -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 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 A1and 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;

[0038] 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;

[0039] Or, two R attached to the same carbon atom A3 Together we form Or, two R attached to the same carbon atom A3and 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 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;

[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* 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, C1-4 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, -NH 2 , -C(=O)OH, -C(=O)NH 2 , 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 .

[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, -CH 2 NR 6 C(=O)R 7 、-CH 2 NR 6 R 7 、-CH 2 C(=O)OR6 、-(CH 2 ) 2 C(=O)OR 6 、-(CH 2 ) 3 C(=O)OR 6 、-CH 2 C(=O)NR 6 R 7 、(CH 2 ) 2 C(=O)NR 6 R 7 、-(CH 2 ) 3 C(=O)NR 6 R 7 、-CH 3 、-CH 2 CH 3 、-(CH 2 ) 2 CH 3 、-(CH 2 ) 3 CH 3 、-C(CH 3 ) 3 、-CH(CH 3 ) 2 、-CH 2 CH(CH 3 ) 2 、-(CH 2 ) 2 CHF 2 、-(CH 2 ) 2 CF(CF 3 ) 2 、-CF 3 、-CHF 2 、-CH 2 F、-(CH 2 ) 2 F、-(CH 2 ) 2 Cl、-CH 2 CF 3 、-CH 2 CN、-(CH 2 ) 2 CN、-(CH 2 ) 3 CN、-CH(CH 3 )CN、-C(CH 3 ) 2 CN、-CH 2 OH、-(CH 2) 2 OH, -(CH 2 ) 3 OH, -CH(OH)CH 3 、-CH 2 OCH 3 、-(CH 2 ) 2 OCH 3 、-(CH 2 ) 2 OCH 2 CH 3 、-CH 2 OCH 2 CH 3 、-CH 2 OC(CH 3 ) 3 、-CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -(CH 2 ) 2 -cyclopentyl, -(CH 2 ) 3 -cyclopentyl, -(CH 2 ) 2 -cyclohexyl, -CH 2 -cyclopentyl, -CH 2 -azetidinyl, -CH 2 -Oxetane, -CH 2 -tetrahydrofuranyl, -CH 2 -morpholinyl, -CH 2 O-cyclopropyl, -CH 2 O-cyclobutyl, -(CH 2 ) 2 O-cyclobutyl, -CH 2 O-cyclopentyl, -(CH 2 ) 2 O-cyclopentyl, -CH 2 O-azetidinyl, -CH 2 O-oxetane, -CH 2 O-tetrahydrofuranyl, -CH 2 -O-morpholinyl, phenyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydropyranyl, morpholinyl, azetidinyl or pyrrolidinyl; wherein R 6 and R 7 Each has the definition as described in the present invention;

[0043] R 8a , R8a* , R 9a , R 9a* , R 10a and R 10a* Each is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , -C(=O)OH, -C(=O)NH 2 , oxo, -CH 3 、-CH 2 CH 3 、-(CH 2 ) 2 CH 3 、-(CH 2 ) 3 CH 3 、-C(CH 3 ) 3 、-CH(CH 3 ) 2 、-CH 2 CH(CH 3 ) 2 、-(CH 2 ) 2 CHF 2 、-(CH 2 ) 2 CF(CF 3 ) 2 , -CF 3 , -CHF 2 、-CH 2 F, -(CH 2 ) 2 F, -(CH 2 ) 2 Cl, -CH 2 CF 3 、-OCH 3 、-OCH 2 CH 3 、-OCH 2 CH 3 、-OC(CH 3 ) 3 、-CH 2 OH, -(CH 2 ) 2 OH, -(CH 2 ) 3 OH, phenyl, pyridyl, pyrimidyl, -C(=O)OCH 3 、-C(=O)NHCH 3 or -C(=O)N(CH 3 ) 2 .

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

[0045]

[0046] Each R 5 are independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH 2 C(=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 Haloalkoxy, C 1-4 alkylthio halide, 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 Haloalkoxy, 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, -NH 2 , -C(=O)H, -C(=O)OH, C1-4 Alkyl, C 1-4 Alkoxy, C 3-6 substituted by a cycloalkyl group or a 3-6-membered heterocyclic group; wherein R 6b , R 7b and R 6c Each has the definition as described in the present invention.

[0047] In some embodiments, each R 5 are independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH 2 C(=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 、-CH 3 、-CH 2 CH 3 、-(CH 2 ) 2 CH 3 、-(CH 2 ) 3 CH 3 、-C(CH 3 ) 3 、-CH(CH 3 ) 2 、-SCH 3 、-SCH 2 CH 3 、-CH=CH 2 、-CH=CHCH 3 、-CH 2 CH=CH 2 、-C≡CH、-C≡CCH 3 、-CH 2 C≡CH, -C≡CCH 2 OH, -C≡C(CH 2 ) 2 OH, -OCH 3 、-OCH 2 CH 3 、-O(CH 2 ) 2 CH 3 、-CH 2 CN, -(CH 2 ) 2CN, -(CH 2 ) 3 CN、-CH 2 OH, -(CH 2 ) 2 OH, -(CH 2 ) 3 OH, -CH(OH)CH 3 、-(CH 2 ) 2 F, -CH 2 CHF 2 , -CF 3 、-CH 2 CF 3 , -CHF 2 、-CH 2 F, -(CH 2 ) 2 Cl, -CH=CHF, -CH=CHCl, -CH=CHCH 2 F, -C≡CCH 2 F, -C≡C(CH 2 ) 2 F, -C≡CF, -OCF 3 、-OCHF 2 、-OCH 2 CHF 2 、-OCH 2 CF 3 、-OCHClCHCl 2 、-OCH 2 CH 2 F, -SCF 3 、-SCH 2 CF 3 、-SCH 2 CHF 2 , phenyl, naphthyl, pyridyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl or piperazinyl, wherein the -CH 3 、-CH 2 CH 3 、-(CH 2 ) 2 CH 3 、-(CH 2 ) 3 CH 3 、-C(CH 3 ) 3 、-CH(CH 3 ) 2 、-SCH 3 、-SCH 2 CH 3、-CH=CH 2 、-CH=CHCH 3 、-CH 2 CH=CH 2 、-C≡CH、-C≡CCH 3 、-CH 2 C≡CH、-C≡CCH 2 OH、-C≡C(CH 2 ) 2 OH 3 、 - OUCH 2 CH 3 、-O(CH 2 ) 2 CH 3 、-CH 2 CN、-(CH 2 ) 2 CN、-(CH 2 ) 3 CN、-CH 2 OH、-(CH 2 ) 2 OH、-(CH 2 ) 3 OH、-CH(OH)CH 3 、-(CH 2 ) 2 F、-CH 2 CHF 2 、-CH 2 CF 3 、-CHF 2 、-CH 2 F、-(CH 2 ) 2 Cl、-CH=CHF、-CH=CHCl、-CH=CHCH 2 F、-C≡CCH 2 F、-C≡C(CH 2 ) 2 F、-OCHF 2 、 - OUCH 2 CHF 2 、 - OUCH 2 CF 3 、-OCHClCHCl 2 、 - OUCH 2 CH 2 F、-SCH 2 CF 3 、-SCH 2 CHF 2, phenyl, naphthyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl and piperazinyl are each independently optionally substituted by 1, 2, 3 or 4 moieties selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , -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.

[0048] 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 independently is -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 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NH 2 , methoxy, ethoxy, n-propoxy, isopropoxy, isobutoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, oxiranyl, oxetanyl, azetidinyl and pyrrolidinyl substituents.

[0049] In some embodiments, R 2 for Among them, R A1a , R A1b , R A2a , R A2b , R A1 , R A2 ,q 1 and q 2 Each has the definition as described in the present invention.

[0050] In some embodiments, R 2 for wherein ring D1, ring D2 and ring D3 are each independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclopropyl, oxetanyl, azetidinyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl and piperazinyl, wherein R A1 , R A2 , R A3 , R A4 ,q 1 ,q 2 ,q 3 and q 4 Each has the definition as described in the present invention.

[0051] In some embodiments, R 2 for

[0052] 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.

[0053] In some embodiments, R 2 for

[0054] 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 the compound represented by formula (I-1), (I-2) or (I-3).

[0055]

[0056] Among them, R 1 , R 4 , R 5 , R A1 , R A1a , R A1b , R 11a , n and q 1 Each has the definition as described in the present invention.

[0057] 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).

[0058]

[0059] Among them, R 1 , R 4 , R 5 , R A1 , R A1a , R A1b , R A1a* , R A1b* , R 11a , R A4 ,q 4 , n each have the definition as described in the present invention.

[0060] In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention.

[0061] In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable adjuvant.

[0062] In some embodiments, the adjuvants described in 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.

[0063] 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.

[0064] In some embodiments, the KRAS G12D-related disease described herein is cancer.

[0065] 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.

[0066] On the other hand, the present invention also provides a method for preventing or treating a KRAS G12D-related disease, comprising administering a therapeutically effective amount of the compound of the present invention or a pharmaceutical composition thereof to a patient.

[0067] 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).

[0068] Unless otherwise indicated, all stereoisomers, tautomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs of the compounds of the invention are within the scope of the invention.

[0069] 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 with the mammal to be treated.

[0070] 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.

[0071] The foregoing description only summarizes certain aspects of the present invention, but is not limited to these aspects. These aspects and other aspects will be described in more detail and complete below.

[0072] Detailed description of the invention

[0073] Definitions and general terms

[0074] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formula and chemical formula. The present invention is intended to cover all substitutions, modifications and equivalent technical solutions, which are all included in the scope of the present invention as defined in the claims. It should be appreciated by those skilled in the art that many methods and materials similar or equivalent to those described in the present invention can be used to practice the present invention. The present invention is by no means limited to the methods and materials described in the present invention. In the event that one or more of the combined documents, patents and similar materials are different from or contradictory to the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0075] It should be further appreciated that certain features of the invention, which for clarity are described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which for brevity are described in a single embodiment, may also be provided separately or in any suitable sub-combination.

[0076] 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.

[0077] The term "subject" as used in the present invention refers to an animal. Typically, the animal is a mammal. Subjects, for example, also refer to primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0078] 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.

[0079] The term "comprising" is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

[0080] "Stereoisomers" refer to compounds with the same chemical structure but 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 formula described in the present invention are within the scope of the present invention. In addition, unless otherwise indicated, the structural formula of the compounds described in the present invention includes one or more enriched isotopes of different atoms.

[0081] The 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.

[0082] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0083] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be mutually converted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be reached. For example, proton tautomers (protontautomers) (also known as prototropic tautomers) include mutual conversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include mutual conversions 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 stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0084] As described herein, the compounds of the present invention may be independently optionally substituted with one or more substituents, such as the general formula compounds above, or as specific examples in the embodiments, subclasses, and classes of compounds encompassed by the present invention. It should be understood that the terms "independently optionally substituted" or "optionally substituted" are used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specific 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 structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted the same or differently at each position.

[0085] In addition, it should be noted that, unless explicitly stated otherwise, the description methods used in the present invention, "each... is independently" and "... are each independently" and "... are independently" can be interchanged and should be understood in a broad sense, which 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.

[0086] In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to group types or ranges. It is particularly pointed out that the present invention includes each independent subcombination of the individual members of these group types and ranges. For example, the term "C 1-6 "Alkyl" refers specifically to methyl, ethyl, C 3 Alkyl, C 4Alkyl, C 5 Alkyl and C 6 alkyl.

[0087] 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 as 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 an alkylene group or an arylene group, respectively, that is linked.

[0088] The term "alkyl" refers to a saturated, straight-chain 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 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 1-3 Alkyl. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), n-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 )2 ), 2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2 ), 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 ), n-heptyl, n-octyl, and the like.

[0089] The term "alkylene" refers to a saturated divalent hydrocarbon group derived from a saturated straight or branched hydrocarbon by removing two hydrogen atoms. In some embodiments, the alkylene group contains 1-6 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: -CH 2 -、-CH 2 CH 2 -、-CH(CH 3 )CH 2 -,etc.

[0090] The term "alkenyl" refers to a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms and having 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 Examples of alkenyl groups include, but are not limited to, vinyl (—CH═CH 2 ), allyl (-CH 2 CH=CH 2 ), 1-propenyl (i.e., propenyl, -CH=CH-CH 3 ),etc.

[0091] The term "alkynyl" refers to a straight or branched monovalent hydrocarbon group containing 2 to 12 carbon atoms, wherein at least one unsaturated site, i.e., a carbon-carbon sp triple bond, wherein the alkynyl group may be optionally substituted with one or more substituents described herein. In one embodiment, the alkynyl group contains 2 to 6 carbon atoms, represented by C 2-6 In another embodiment, the alkynyl group contains 2-4 carbon atoms and is represented by C 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (—C≡CH), propargyl (—CH 2 C≡CH), 1-propynyl (-C≡C-CH 3 )etc.

[0092] The term "cyanoalkyl" refers to an alkyl group substituted by one or more cyano groups, wherein cyano and alkyl groups have the definitions described herein. In some embodiments, "cyanoalkyl" refers to an alkyl group substituted by one cyano group. In some embodiments, "cyanoalkyl" is C 1-6 Cyanoalkyl, i.e., 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, i.e., C substituted by one or more cyano groups 1-4 Examples of cyanoalkyl groups include, but are not limited to, -CH 2 CN、-CH 2 CH 2 CH 2 CH 2 CN、-CH 2 CH 2 CN、-CH 2 CH(CN)CH 2 CH 2 CN、-CH 2 CH(CN)CH 2 CH(CH 3 )CN, etc.

[0093] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein the alkyl and hydroxyl groups have the definitions as described herein. In some embodiments, hydroxyalkyl refers to an alkyl group substituted with 1, 2, 3 or 4 hydroxyl groups. In some embodiments, hydroxyalkyl refers to an alkyl group substituted with one or two hydroxyl 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. 1-6Hydroxyalkyl represents C 1-6 In some embodiments, hydroxyalkyl represents C 1-4 In some embodiments, hydroxyalkyl represents C 1-3 Examples of hydroxyalkyl groups include, but are not limited to, -CH 2 OH, -CH 2 CH 2 CH 2 CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH(OH)CH 2 CH 2 OH, -CH 2 CH(OH)CH 2 CH(CH 3 )OH, etc.

[0094] The term "haloalkyl" means an alkyl group substituted with one or more halogen atoms, wherein alkyl and halogen have the definitions as described herein. 1-6 Haloalkyl, 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 Haloalkyl, 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 Haloalkyl, 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.

[0095] The term "haloalkenyl" refers to an alkenyl group substituted with one or more halogen atoms, wherein alkenyl has the definition as described herein. 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 2-4 Alkenyl groups are substituted with one or more halogen atoms. Examples include, but are not limited to, 1-chloroethenyl (-CCl=CH2 ), 2-fluorovinyl (-CH=CHF), 1-fluoroallyl (-CHFCH=CH 2 ), 3-fluoropropenyl (i.e., -CH=CH-CH 2 F), 3,3-difluoropropenyl (i.e., -CH=CH-CHF 2 ).

[0096] The term "haloalkynyl" refers to an alkynyl group substituted with one or more halogen atoms, wherein alkynyl has the definition as described herein. 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-CH 2 Cl), etc.

[0097] The term "hydroxyalkynyl" refers to an alkynyl group substituted with one or more hydroxyl groups, wherein hydroxyl and alkynyl are as defined herein. 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-CH 2 OH), 4-hydroxybutynyl (-C≡C-(CH 2 ) 2 OH), etc.

[0098] 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.

[0099] 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 with 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 Examples of mercaptoalkyl groups 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)), etc.

[0100] 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 In another embodiment, the alkoxy group contains 1-4 carbon atoms, indicating C 1-4 In another embodiment, the alkoxy group contains 1-3 carbon atoms, indicating C 1-3 Alkoxy. The alkoxy group may be optionally substituted with one or more substituents described herein. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n-propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy(i-PrO, i-propoxy, -OCH(CH3 ) 2 ), 1-butoxy (n-BuO, n-butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butoxy(s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy(t-BuO, t-butoxy, -OC(CH 3 ) 3 ), 1-pentyloxy (n-pentyloxy, -OCH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyloxy(-OCH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyloxy(-OCH(CH 2 CH 3 ) 2 ), 2-methyl-2-butoxy(-OC(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butoxy(-OCH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butoxy (-OCH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butoxy (-OCH 2 CH(CH 3 )CH 2 CH 3 ),etc.

[0101] 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, the haloalkoxy group refers to a haloalkoxy group containing 1 to 6 carbon atoms, i.e., C 1-6 In other embodiments, the haloalkoxy group represents a haloalkoxy group containing 1 to 4 carbon atoms, i.e., C1-4 In other embodiments, the haloalkoxy group 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), etc.

[0102] The term "cycloalkyl" refers to a monovalent saturated monocyclic or bicyclic carbon ring system of 3 to 12 carbon atoms, wherein -CH 2 The -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 3-7 carbon atoms, i.e., C 3-7 In another embodiment, the cycloalkyl group contains 3-6 carbon atoms, i.e., C 3-6 In 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. 2 Examples of the - group which may be replaced by -C(=O)- include, but are not limited to, cyclopentanone, cyclobutanone, and the like.

[0103] 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 ring. When the heterocycle is attached to the rest of the molecule through one attachment point, the heterocycle represents a monovalent heterocyclyl. Unless otherwise specified, the heterocyclyl may be a carbonyl or nitrogenyl group, and -CH 2-group may be optionally replaced by -C(=O)-. The sulfur atom of the ring may be optionally oxidized to an S-oxide. The nitrogen atom of the ring may be optionally oxidized to an N-oxide. In some embodiments, the heterocycle or heterocyclic radical consists of 3-10 atoms, represented by a 3-10-membered heterocycle or a 3-10-membered heterocyclic radical; in other embodiments, the heterocycle or heterocyclic radical consists of 3-9 atoms, represented by a 3-9-membered heterocycle or a 3-9-membered heterocyclic radical; in other embodiments, the heterocycle or heterocyclic radical consists of 5-9 atoms, represented by a 5-9-membered heterocycle or a 5-9-membered heterocyclic radical; in other embodiments, the heterocycle or heterocyclic radical consists of 3-6 atoms, represented by a 3-6-membered heterocycle or a 3-6-membered heterocyclic radical; in other embodiments, the heterocycle or heterocyclic radical consists of 5-6 atoms, represented by a 5-6-membered heterocycle or a 5-6-membered heterocyclic radical. In other embodiments, the heterocycle or heterocyclic group is a monocyclic ring consisting of 3-7 atoms, represented by a 3-7-membered monocyclic heterocycle or a 3-7-membered monocyclic heterocyclic group. 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, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl, etc.

[0104] 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, and each ring system contains 3-7 ring 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.

[0105] 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 the -CH 2 - group, the -CH 2 -group can be optionally replaced by -C(=O)-. Unless otherwise specified, the heteroaryl group can be connected to the rest of the molecule (e.g., the main structure in the general formula) through any reasonable site (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, expressed as a 5-12-membered heteroaryl group; in other embodiments, the heteroaryl group is a heteroaryl group containing 5-10 ring atoms, expressed as a 5-10-membered heteroaryl group; in other embodiments, the heteroaryl group is a heteroaryl group containing 5-6 ring atoms, expressed as 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.

[0106] 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. 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 1-3 Alkylthio refers to an alkylthio group containing 1 to 3 carbon atoms. Examples of alkylthio groups include, but are not limited to, methylthio (-SCH 3 ), ethylthio (-SCH 2 CH 3 ),wait.

[0107] 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 Haloalkylthio refers to a C 1-6 In other embodiments, the haloalkylthio group is C 1-4Haloalkylthio refers to a C 1-4 In other embodiments, the haloalkylthio group is C 1-3 Haloalkylthio refers to a C 1-3 The definition of haloalkylthio includes, but is not limited to, trifluoromethylthio (-SCF 3 )、2,2,2-trifluoroethylthio (-SCH 2 CF 3 ), monofluoromethylthio (-SCH 2 F), etc.

[0108] 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 In other embodiments, arylalkyl is C 6-10 Aryl C 1-4 Alkyl or (6-10 membered aryl)-C 1-4 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 phenylC 1-6 In other embodiments, arylalkyl is phenylC 1-4 In other embodiments, arylalkyl is phenylC 1-3 Examples of arylalkyl include, but are not limited to, phenylmethyl, phenylethyl, naphthylmethyl, and the like.

[0109] 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 1-4 In 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 1-3Examples of heteroarylalkyl include, but are not limited to, pyrimidinylmethyl, pyridinylmethyl, pyridinylethyl, pyrazolylmethyl, and the like.

[0110] The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl group, wherein the heterocyclyl group and the alkyl group are as defined herein. In some embodiments, the heterocyclylalkyl group 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 include, but are not limited to, piperidinylmethyl, piperidinylethyl, pyrrolidinylmethyl, and the like.

[0111] 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 In other embodiments, cycloalkylalkyl is C 3-6 Cycloalkyl C 1-4 In other embodiments, cycloalkylalkyl is C 3-6 Cycloalkyl C 1-3 Examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, and the like.

[0112] The term "halogen" means F (fluorine), Cl (chlorine), Br (bromine) or I (iodine).

[0113] The term "oxo" means =0.

[0114] The term "cyano" means -CN or -C≡N.

[0115] The term "mercapto" refers to -SH.

[0116] The term "hydroxy" refers to -OH.

[0117] The term "carboxy" refers to -C(=O)OH.

[0118] The term "amino" refers to -NH 2 .

[0119] 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, P, etc.; 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 members”, “consisting of 3-6 atoms” or “3-6 members”, “consisting of 5-10 atoms” or “5-10 members”, or “consisting of 5-6 atoms” or “5-6 members” 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, P, etc.

[0120] As described in the present invention, the substituent (R A1 )q 1 The ring system formed by a bond 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 by q 1 R A1 Substitution is performed at any substitutable position or any reasonable position on the ring, when q 1 When R 8 The substituent groups may be independently selected from the same or different substituent groups.

[0121]

[0122] In the present invention In They respectively represent that the alkenyl group can be in cis, trans or a mixture thereof.

[0123] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound represented by formula (I), (I-1), (I-2), (I-3), (I-1a) or (I-1b) in vivo. Such conversion is affected by the prodrug being hydrolyzed in the blood or being converted into the parent structure by enzymes 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 contains a hydroxyl group, which can be acylated to obtain a prodrug form of the compound. Other prodrug forms include phosphates, such as these phosphate compounds obtained by phosphorylation of the hydroxyl group on the parent.

[0124] "Metabolite" refers to a product obtained by the metabolism of a specific compound or salt thereof in vivo. The metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by experimental methods as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time.

[0125] The "pharmaceutically acceptable salt" used in the present invention refers to the organic salt and inorganic salt of the compound of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describepharmaceutically 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 N groups. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter-balancing ions.

[0126] The "solvate" of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvents forming solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine or a mixture thereof. The term "hydrate" refers to an association formed by a solvent molecule being water.

[0127] 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 combined with one water molecule, such as a monohydrate; in another embodiment, one molecule of the compound of the present invention may be combined with more than one water molecule, such as a dihydrate; in yet another embodiment, one molecule of the compound of the present invention may be combined 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.

[0128] As used herein, the term "treating" any disease or condition, in some embodiments, refers to ameliorating the disease or condition (i.e., slowing or preventing 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 perceptible symptoms) or physiologically (e.g., stabilizing physical parameters), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.

[0129] 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 exposed or predisposed to the disease but does not yet experience or display symptoms of the disease).

[0130] The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a subject to treat a disease, is sufficient to be effective in treating the disease."Therapeutically effective amount" may vary with the compound, the disease and its severity, and the condition, age, weight, sex, etc. of the subject to be treated.

[0131] 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 present invention.

[0132] In structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, all stereoisomers of the structure are contemplated within the present invention and are included as compounds disclosed herein. When stereochemistry is indicated by a solid wedge or dashed line representing a particular configuration, the stereoisomers of the structure are thus unambiguous and defined.

[0133] Nitrogen oxides of the compounds of the invention are also included within the scope of the invention. Nitrogen oxides of the compounds of the invention can be prepared by oxidation of the corresponding nitrogen-containing basic substance using a conventional oxidizing agent (e.g., hydrogen peroxide) at elevated temperatures in the presence of an acid such as acetic acid, or by reaction with a peracid in a suitable solvent, such as peracetic acid in methylene chloride, ethyl acetate or methyl acetate, or with 3-chloroperoxybenzoic acid in chloroform or methylene chloride.

[0134] 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.

[0135] Any structural formula given herein also encompasses non-isotopically enriched forms of these compounds as well as isotopically enriched forms. Isotopically enriched compounds have structures depicted by the general 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 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.

[0136] Description of the compounds of the present invention

[0137] The present invention provides a compound, or a pharmaceutical composition thereof, which can be used as a KRAS inhibitor, especially as a KRAS12D inhibitor. The present invention further relates to the use of the compound or the pharmaceutical composition thereof for preparing a drug for treating a disease and / or a condition by inhibiting KRAS activity by the compound.

[0138] 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.

[0139] 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),

[0140]

[0141] 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.

[0142] In some embodiments, R 1 -H, -D, -CN, -NH 2 , -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) 2 R 7 、-S(=O) 2 NR 6 R 7 、-NR 6a S(=O) 2 NR 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 1-6Haloalkyl, 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; wherein R 6 , R 7 , R 6a , R 6e and R 7e Each has the definition as described in the present invention.

[0143] In some embodiments, R 1 -H, -D, -CN, -NH 2 , -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) 2 R 7 、-S(=O) 2 NR 6 R 7 、-NR 6a S(=O) 2 NR6 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 1-4Alkyl, (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 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.

[0144] In some embodiments, R 1 -H, -D, -CN, -NH 2 , -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) 2 R 7 、-S(=O) 2 NR 6 R 7 、-NR 6a S(=O) 2 NR 6 R 7 、-NR6 R 7 、-CH 2 NR 6 C(=O)R 7 、-CH 2 NR 6 R 7 、-(CH 2 ) 2 NR 6 R 7 、-CH 2 C(=O)OR 6 、-(CH 2 ) 2 C(=O)OR 6 、-(CH 2 ) 3 C(=O)OR 6 、-CH 2 C(=O)NR 6 R 7 、-(CH 2 ) 2 C(=O)NR 6 R 7 、-(CH 2 ) 3 C(=O)NR 6 R 7 、-CH 3 、-CH 2 CH 3 、-(CH 2 ) 2 CH 3 、-(CH 2 ) 3 CH 3 、-C(CH 3 ) 3 、-CH(CH 3 ) 2 、-CH 2 CH(CH 3 ) 2 、-CH 2 CN、-(CH 2 ) 2 CN、-(CH 2 ) 3 CN、-CH(CH 3 )CN、-C(CH 3 ) 2 CN、-CH 2 OH、-(CH 2 ) 2 OH、-(CH 2 ) 3OH, -CH(OH)CH 3 、-(CH 2 ) 2 CHF 2 、-(CH 2 ) 2 CF(CF 3 ) 2 , -CF 3 , -CHF 2 、-CH 2 F, -(CH 2 ) 2 F, -(CH 2 ) 2 Cl, -CH 2 CF 3 、-OCH 3 、-OCH 2 CH 3 、-O(CH 2 ) 2 CH 3 、-O(CH 2 ) 3 CH 3 、-OC(CH 3 ) 3 、-OCH(CH 3 ) 2 、-CH 2 OCH 3 、-(CH 2 ) 2 OCH 3 、-(CH 2 ) 2 OCH 2 CH 3 、-CH 2 OCH 2 CH 3 、-CH 2 OC(CH 3 ) 3 、-CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -(CH 2 ) 2 -cyclopentyl, -(CH 2 ) 3 -cyclopentyl, -(CH 2 ) 2 -cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -(CH 2 )2 -cyclobutyl, -CH 2 -cyclopentyl, -(CH 2 ) 2 Cyclopentyl, -CH 2 -azetidinyl, -CH 2 -pyrrolidinyl, -CH 2 -piperidinyl, -CH 2 -morpholinyl, -CH 2 -phenyl, -CH 2 -Imidazole, -CH 2 -pyrazolyl, -CH 2 O-cyclopropyl, -CH 2 O-cyclobutyl, -(CH 2 ) 2 O-cyclobutyl, -CH 2 O-cyclopentyl, -(CH 2 ) 2 O-cyclopentyl, -CH 2 O-azetidinyl, -CH 2 O-oxetane, -CH 2 O-tetrahydrofuranyl, -CH 2 O-spiro[2.3]hexane, -CH 2 O-Spiro[3.3]heptyl-, -CH 2 SH, -(CH 2 ) 2 SH, phenyl, naphthyl, pyridyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydropyranyl, azetidinyl or pyrrolidinyl; wherein the -CH 3 、-CH 2 CH 3 、-(CH 2 ) 2 CH 3 、-(CH 2 ) 3 CH 3 、-C(CH 3 ) 3 、-CH(CH 3 ) 2 、-CH 2 CH(CH 3 ) 2 、-CH 2 CN, -(CH 2 ) 2 CN, -(CH 2 ) 3 CN, -CH(CH 3 )CN、-C(CH 3 )2 CN, -CH 2 OH, -(CH 2 ) 2 OH, -(CH 2 ) 3 OH, -CH(OH)CH 3 , -(CH 2 ) 2 CHF 2 , -(CH 2 ) 2 CF(CF 3 ) 2 , -CHF 2 , -CH 2 F, -(CH 2 ) 2 F, -(CH 2 ) 2 Cl, -CH 2 CF 3 , -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -O(CH 2 ) 3 CH 3 , -OC(CH 3 ) 3 , -OCH(CH 3 ) 2 , -CH 2 OCH 3 , -(CH 2 ) 2 OCH 3 , -(CH 2 ) 2 OCH 2 CH 3 , -CH 2 OCH 2 CH 3 , -CH 2 OC(CH 3 ) 3 , -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -(CH 2 ) 2 -cyclopentyl, -(CH 2 ) 3 -cyclopentyl, -(CH 2) 2 -cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -(CH 2 ) 2 -cyclobutyl, -CH 2 -cyclopentyl, -(CH 2 ) 2 Cyclopentyl, -CH 2 -azetidinyl, -CH 2 -pyrrolidinyl, -CH 2 -piperidinyl, -CH 2 -morpholinyl, -CH 2 -phenyl, -CH 2 -Imidazole, -CH 2 -pyrazolyl, -CH 2 O-cyclopropyl, -CH 2 O-cyclobutyl, -(CH 2 ) 2 O-cyclobutyl, -CH 2 O-cyclopentyl, -(CH 2 ) 2 O-cyclopentyl, -CH 2 O-azetidinyl, -CH 2 O-oxetane, -CH 2 O-tetrahydrofuranyl, -CH 2 O-spiro[2.3]hexane, -CH 2 O-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 radicals 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; wherein R 6 , R 7 , R 6a , R 6e and R 7e Each has the definition as defined in the present invention.

[0145] In some embodiments, Y is a bond, O, or S.

[0146] In some embodiments, R2 for

[0147] 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.

[0148] 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.

[0149] In some preferred embodiments, L 1 , L 2 and L 3 Each is independently -CH 2 -、-(CH 2 ) 2 -、-(CH 2 ) 3 -or-(CH 2 ) 4 -, wherein the -CH 2 -、-(CH 2 ) 2 -、-(CH 2 ) 3 - and - (CH 2 ) 4 - each independently optionally substituted by 1, 2, 3 or 4 R a replace.

[0150] In some more preferred embodiments, L 1 , L 2 and L 3 Each is independently -CH 2 -.

[0151] In some embodiments, R a is -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , -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.

[0152] In some embodiments, R a is -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , -C(=O)H, -C(=O)OH, C 1-4 Alkyl, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, 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.

[0153] In some embodiments, Ring B1 and Ring C1 are each independently a 3-7 membered monocyclic heterocyclyl.

[0154] In some embodiments, Ring B2, Ring B3, and Ring C2 are each independently C 3-7 Monocyclic cycloalkyl or 3-7 membered monocyclic heterocyclic group.

[0155] Ring D1, ring D2 and ring D3 are each independently C 3-7 Monocyclic cycloalkyl or 3-7 membered monocyclic heterocyclic group.

[0156] In some embodiments, 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 、-CH 2 NR 6d R 7d、-CH 2 OC(=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; wherein R 6d and R 7d Each has the definition as described in the present invention.

[0157] In some embodiments, 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 、-CH 2 NR 6d R 7d 、-CH 2 OC(=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; wherein R 6d and R 7d Each has the definition as described in the present invention.

[0158] In some embodiments, R A1 , R A2 , R A3 and R A4Each is independently -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6d R 7d 、-C(=O)NR 6d R 7d 、-CH 2 NR 6d R 7d 、-CH 2 OC(=O)NR 6d R 7d 、-CH 3 、-CH 2 CH 3 、-(CH 2 ) 2 CH 3 、-(CH 2 ) 3 CH 3 、-C(CH 3 ) 3 、-CH(CH 3 ) 2 、-CH 2 CH(CH 3 ) 2 、-OCH 3 、-OCH 2 CH 3 、-OCH 2 CH 3 、-OC(CH 3 ) 3 、-(CH 2 ) 2 CHF 2 、-(CH 2 ) 2 CF(CF 3 ) 2 , -CF 3 , -CHF 2 、-CH 2 F, -(CH 2 ) 2 F, -(CH 2 ) 2 Cl, -CH 2 CF 3 、-OCF 3 、-OCHF 2 、-CH 2 -phenyl, -CH 2 -pyridyl, -CH 2 -pyrrolidinyl, -CH 2 -piperidinyl, -CH 2 -cyclopropyl, -CH 2-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.

[0159] In some embodiments, two R A1 Together we form Among them, R A1a* and R A1b* Each has the definition as described in the present invention.

[0160] 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.

[0161] In some preferred embodiments, the two R 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 replaced by, where R 8a Has the definition as described in the present invention.

[0162] In some embodiments, two R attached 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, where R 8a* Has the definition as described in the present invention.

[0163] In some preferred embodiments, the two RA1 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, where R 8a* Has the definition as described in the present invention.

[0164] In some embodiments, two R A2 Together we form Among them, R A2a* and R A2b* Each has the definition as described in the present invention.

[0165] In some embodiments, two R 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 replaced by, where R 9a Has the definition as described in the present invention.

[0166] In some preferred embodiments, the 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 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 replaced by, where R 9a Has the definition as described in the present invention.

[0167] In some embodiments, two R attached to two adjacent atoms A2Together 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, where R 9a* Has the definition as described in the present invention.

[0168] In some preferred embodiments, the 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, 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, where R 9a* Has the definition as described in the present invention.

[0169] In some embodiments, two R A3 Together we form Among them, R A3a* and R A3b* Each has the definition as described in the present invention.

[0170] 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.

[0171] In some preferred embodiments, the two R A3and 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 10a replaced by, where R 10a Has the definition as described in the present invention.

[0172] In some embodiments, two R attached 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, where R 10a* Has the definition as described in the present invention.

[0173] Two R's 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, where R 10a* Has the definition as described in the present invention.

[0174] 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*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; wherein R 6 and R 7 Each has the definition as described in the present invention.

[0175] 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* 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, wherein R 6 and R 7 Each has the definition as described in the present invention.

[0176] 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, -CH 2 NR 6 C(=O)R 7 、-CH 2 NR 6 R 7 、-CH 2 C(=O)OR 6 、-(CH 2 ) 2 C(=O)OR 6 、-(CH 2 ) 3 C(=O)OR 6 、-CH 2 C(=O)NR 6 R 7 , (CH 2 ) 2 C(=O)NR 6 R 7 、-(CH 2 ) 3 C(=O)NR 6 R 7 、-CH3 、-CH 2 CH 3 、-(CH 2 ) 2 CH 3 、-(CH 2 ) 3 CH 3 、-C(CH 3 ) 3 、-CH(CH 3 ) 2 、-CH 2 CH(CH 3 ) 2 、-(CH 2 ) 2 CHF 2 、-(CH 2 ) 2 CF(CF 3 ) 2 、-CF 3 、-CHF 2 、-CH 2 F、-(CH 2 ) 2 F、-(CH 2 ) 2 Cl、-CH 2 CF 3 、-CH 2 CN、-(CH 2 ) 2 CN、-(CH 2 ) 3 CN、-CH(CH 3 )CN、-C(CH 3 ) 2 CN、-CH 2 OH、-(CH 2 ) 2 OH、-(CH 2 ) 3 OH、-CH(OH)CH 3 、-CH 2 OCH 3 、-(CH 2 ) 2 OCH 3 、-(CH 2 ) 2 OCH 2 CH 3 、-CH 2 OCH 2 CH 3 、-CH 2 OC(CH 3 )3 、-CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -(CH 2 ) 2 -cyclopentyl, -(CH 2 ) 3 -cyclopentyl, -(CH 2 ) 2 -cyclohexyl, -CH 2 -cyclopentyl, -CH 2 -azetidinyl, -CH 2 -Oxetane, -CH 2 -tetrahydrofuranyl, -CH 2 -morpholinyl, -CH 2 O-cyclopropyl, -CH 2 O-cyclobutyl, -(CH 2 ) 2 O-cyclobutyl, -CH 2 O-cyclopentyl, -(CH 2 ) 2 O-cyclopentyl, -CH 2 O-azetidinyl, -CH 2 O-oxetane, -CH 2 O-tetrahydrofuranyl, -CH 2 -O-morpholinyl, phenyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydropyranyl, morpholinyl, azetidinyl or pyrrolidinyl; wherein R 6 and R 7 Each has the definition as described in the present invention.

[0177] 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, -NH 2 , -C(=O)OH, -C(=O)NH 2 , 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)NHC1-6 Alkyl or -C(=O)N(C 1-6 alkyl) 2 .

[0178] 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, -NH 2 , -C(=O)OH, -C(=O)NH 2 , 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, -C(=O)N(C 1-4 alkyl) 2 .

[0179] 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, -NH 2 , -C(=O)OH, -C(=O)NH 2 , oxo, -CH 3 、-CH 2 CH 3 、-(CH 2 ) 2 CH 3 、-(CH 2 ) 3 CH 3 、-C(CH 3 ) 3 、-CH(CH 3 ) 2 、-CH 2 CH(CH 3 ) 2 、-(CH 2 ) 2 CHF 2 、-(CH 2 ) 2 CF(CF 3 )2 , -CF 3 , -CHF 2 、-CH 2 F, -(CH 2 ) 2 F, -(CH 2 ) 2 Cl, -CH 2 CF 3 、-OCH 3 、-OCH 2 CH 3 、-OCH 2 CH 3 、-OC(CH 3 ) 3 、-CH 2 OH, -(CH 2 ) 2 OH, -(CH 2 ) 3 OH, phenyl, pyridyl, pyrimidyl, -C(=O)OCH 3 、-C(=O)NHCH 3 、-C(=O)N(CH 3 ) 2 .

[0180] 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 q 1 Each has the definition as described in the present invention.

[0181] In some embodiments, R 2 for Among them, ring B1, ring C1, R A1 , R A1a , R A1b , R A2a , R A2b and q 1 Each has the definition as described in the present invention.

[0182] In some embodiments,

[0183] R 3 for Among them, R 11a , R 11b , R 11c and R 11d Each has the definition as described in the present invention.

[0184] 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 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; wherein R 6 , R 7 and R 6a Each has the definition as described in the present invention.

[0185] 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)OCH 3 、-C(=O)NH 2 、-CH 3 、-CH 2 CH 3 、-(CH 2 ) 2 CH 3 、-(CH 2 ) 4 CH 3 、-CH(CH 3 ) 2 、-CH 2 CH(CH 3 ) 2 、-C(CH 3 ) 3 、-CH 2 OH, -(CH 2 ) 2 OH, -CH 2 CN, -(CH 2 ) 2 CN, -CF 3 , -CHF 2 、-CH 2 F, -OCF 3、-OCH 3 or -OCH 2 CH 3 .

[0186] 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.

[0187] In some embodiments, Ring A is C 6-12 Aryl or 5-12 membered heteroaryl.

[0188] In some embodiments, Ring A is one of the following substructures,

[0189]

[0190] In some embodiments, each R 5 are independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH 2 C(=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, C1-6 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, -NH 2 , -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.

[0191] In some embodiments, each R 5 are independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH 2 C(=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 Haloalkoxy, C 1-4 alkylthio halide, 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 2-4Alkenyl, 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 Haloalkoxy, 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, -NH 2 , -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.

[0192] In some embodiments, each R 5 are independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH 2 C(=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 、-CH 3 、-CH 2 CH 3 、-(CH 2 ) 2 CH 3 、-(CH 2 ) 3 CH 3 、-C(CH 3 ) 3 、-CH(CH 3 ) 2 、-SCH 3 、-SCH 2 CH 3 、-CH=CH2 、-CH=CHCH 3 、-CH 2 CH=CH 2 、-C≡CH、-C≡CCH 3 、-CH 2 C≡CH、-C≡CCH 2 OH、-C≡C(CH 2 ) 2 OH 3 、 - OUCH 2 CH 3 、-O(CH 2 ) 2 CH 3 、-CH 2 CN、-(CH 2 ) 2 CN、-(CH 2 ) 3 CN、-CH 2 OH、-(CH 2 ) 2 OH、-(CH 2 ) 3 OH、-CH(OH)CH 3 、-(CH 2 ) 2 F、-CH 2 CHF 2 、-CF 3 、-CH 2 CF 3 、-CHF 2 、-CH 2 F、-(CH 2 ) 2 Cl、-CH=CHF、-CH=CHCl、-CH=CHCH 2 F、-C≡CCH 2 F、-C≡C(CH 2 ) 2 F、-C≡CF、-OCF 3 、-OCHF 2 、 - OUCH 2 CHF 2 、 - OUCH 2 CF 3 、-OCHClCHCl 2 、 - OUCH 2 CH 2 F、-SCF 3 、-SCH 2 CF 3 、-SCH 2 CHF2 , phenyl, naphthyl, pyridyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl or piperazinyl, wherein the -CH 3 、-CH 2 CH 3 、-(CH 2 ) 2 CH 3 、-(CH 2 ) 3 CH 3 、-C(CH 3 ) 3 、-CH(CH 3 ) 2 、-SCH 3 、-SCH 2 CH 3 、-CH=CH 2 、-CH=CHCH 3 、-CH 2 CH=CH 2 、-C≡CH、-C≡CCH 3 、-CH 2 C≡CH, -C≡CCH 2 OH, -C≡C(CH 2 ) 2 OH, -OCH 3 、-OCH 2 CH 3 、-O(CH 2 ) 2 CH 3 、-CH 2 CN, -(CH 2 ) 2 CN, -(CH 2 ) 3 CN、-CH 2 OH, -(CH 2 ) 2 OH, -(CH 2 ) 3 OH, -CH(OH)CH 3 、-(CH 2 ) 2 F, -CH 2 CHF 2 、-CH 2 CF 3 , -CHF 2 、-CH 2 F, -(CH 2 ) 2Cl, -CH=CHF, -CH=CHCl, -CH=CHCH 2 F, -C≡CCH 2 F, -C≡C(CH 2 ) 2 F, -OCHF 2 、-OCH 2 CHF 2 、-OCH 2 CF 3 、-OCHClCHCl 2 、-OCH 2 CH 2 F, -SCH 2 CF 3 、-SCH 2 CHF 2 , phenyl, naphthyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl and piperazinyl are each independently optionally substituted by 1, 2, 3 or 4 moieties selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , -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.

[0193] 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 with 1, 2, 3 or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NH 2 , C 1-6 Alkoxy, C 6-12 Aryl, C 3-6 The cycloalkyl group is substituted by a substituent of a 3- to 6-membered heterocyclic group.

[0194] In some embodiments, R6 , R 7 , R 6a , R 6b , R 6c , R 7b , R 6d , R 7d , R 6e and R 7e each independently is -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 by 1, 2, 3 or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NH 2 , methoxy, ethoxy, n-propoxy, isopropoxy, isobutoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, oxiranyl, oxetanyl, azetidinyl and pyrrolidinyl substituents.

[0195] In some embodiments, The structural formula is:

[0196] In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7.

[0197] In some embodiments, q 1 ,q 2 and q 3 Each independently is 0, 1, 2, 3, 4, 5 or 6.

[0198] In some embodiments, each q 4 is independently 0, 1, 2, 3 or 4.

[0199] In some embodiments, R 2 for Among them, R A1a , R A1b , R A2a , R A2b , R A1 , R A2 ,q 1 and q 2 Each has the definition as described in the present invention.

[0200] In some embodiments, R 2 for wherein ring D1, ring D2 and ring D3 are each independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclopropyl, oxetanyl, azetidinyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl and piperazinyl, wherein R A1 , R A2 , R A3 , R A4 ,q 1 ,q 2 ,q 3 and q 4 Each has the definition as described in the present invention.

[0201] In some embodiments, R 2 for

[0202] 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.

[0203] In some embodiments, R 2 for

[0204] In some embodiments, R 2 for

[0205] 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).

[0206]

[0207] Among them, R 1 , R 4 , R 5 , R A1 , R A1a , R A1b , R 11a , n and q 1 Each has the definition as described in the present invention.

[0208] 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).

[0209]

[0210] Among them, R 1 , R 4 , R 5 , R A1 , R A1a , R A1b , R 11a , n and q 1 Each has the definition as described in the present invention.

[0211] 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).

[0212]

[0213] Among them, R 1 , R 4 , R 5 , R A1 , R A1a , R A1b , R 11a , n and q 1 Each has the definition as described in the present invention.

[0214] 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).

[0215]

[0216] 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.

[0217] 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).

[0218]

[0219] 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.

[0220] 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).

[0221]

[0222] Among them, R 1 , R 4 , R 5 , R A1 , R A1a , R A1b , R A1a* , R A1b* , R 11a , R A4 ,q 4 and n each have the meanings as described in the present invention.

[0223] 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).

[0224]

[0225] Among them, n 2 is 1, 2, 3, 4 or 5; R 1 , R 4 , R 5 , R A1a , R A1b , R A1 and q 1 Each has the definition as described in the present invention.

[0226] 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 (IC).

[0227]

[0228] Among them, n 2 is 1, 2, 3, 4 or 5; R 1 , R 4 , R 5 , R A1a , R A1b , R A1 and q 1 Each has the definition as described in the present invention.

[0229] 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,

[0230]

[0231]

[0232]

[0233]

[0234] In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention.

[0235] In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable adjuvant.

[0236] In some embodiments, the adjuvants described in 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.

[0237] 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.

[0238] In some embodiments, the KRAS G12D-related disease described herein is cancer.

[0239] 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 (cancer, lymphoma, leiomyosarcoma) cancer, pancreatic (ductal adenocarcinoma, insulinoma) cancer Cancer of the genitourinary tract: kidney (adenocarcinoma, nephroblastoma (Wilms tumor), lymphoma, leukemia) cancer, bladder and urethra cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma) cancer, testicular (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma) cancer; cancer of the liver: liver Cancer (hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract cancer: gallbladder cancer, ampullary cancer, bile duct cancer; Bone cancer: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor; Nervous system cancer: neuroma, skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meningeal cancer (meningioma, meningeal sarcoma, glioma Disease), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, neurothecoma, 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) cancer, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, grape-like sarcoma (embryo rhabdomyosarcoma), fallopian tube (cancer), 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, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal gland cancers: neuroblastoma.

[0240] 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.

[0241] On the other hand, the present invention also provides a method for preventing or treating a KRAS G12D-related disease, comprising administering a therapeutically effective amount of the compound of the present invention or a pharmaceutical composition thereof to a patient.

[0242] 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).

[0243] Unless otherwise indicated, all stereoisomers, tautomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs of the compounds of the invention are within the scope of the invention.

[0244] The term "pharmaceutically acceptable" includes substances or compositions that are suitable for chemical or toxicological

[0245] physiology, with respect to the other ingredients making up the formulation and to the mammal to be treated.

[0246] The salts of the compounds of the present invention also include intermediates used in the preparation or purification of 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.

[0247] Pharmaceutical compositions, preparations, administration and uses of the compounds of the present invention

[0248] The pharmaceutical composition of the present invention is characterized by comprising a compound represented by formula (I), (I-1), (I-2), (I-3), (I-1a), (I-1b), (IB) or (IC), a compound listed in the present invention, or a compound of the embodiments, and a pharmaceutically acceptable carrier. The amount of the compound in the pharmaceutical composition of the present invention is effective to treat or alleviate a KRAS G12D-mediated disease in a patient.

[0249] The compounds of the present invention exist in free form, or are suitable 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 directly or indirectly administered according to the needs of patients, compounds described in other aspects of the present invention, their metabolites or their residues.

[0250] As described in the present invention, the pharmaceutically acceptable composition of the present invention further comprises a pharmaceutically acceptable adjuvant, which, as used in the present invention, includes any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for a specific target dosage form. As described in the following documents: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York, the contents of the documents herein are combined to show that different adjuvants can be applied to the preparation of pharmaceutically acceptable compositions and their known preparation methods. Except insofar as any conventional adjuvant is incompatible with the compounds of the present invention, for example by producing any undesirable biological effect or interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition, their use is contemplated by the present invention.

[0251] Substances that can be used as 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, polyvinyl pyrrolidone, 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.

[0252] When preparing pharmaceutical composition provided by the invention, active ingredient is usually mixed with excipient, diluted by excipient or encapsulated in such carrier in the form of capsule, pouch, paper or other container for example. If excipient is used as diluent, it can be solid, semisolid or liquid material, which is used as carrier, 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 carboxymethylcellulose, 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.

[0253] 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, and all dosage forms used 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.

[0254] The compounds or pharmaceutical compositions of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or transdermally by use of transdermal patches. When administered in the form of a transdermal delivery system, the dosage administered is continuous rather than intermittent throughout the medication period.

[0255] 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.

[0256] The compounds of the present invention or pharmaceutical compositions are also coupled with soluble polymers, which serve as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Moreover, the compounds of the present invention can be coupled with 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 crosslinked or amphiphilic blocking copolymers of hydrogels.

[0257] The dosage regimen of the compounds or pharmaceutical compositions of the present invention will vary with known factors, such as the pharmacokinetic characteristics of the specific agent and its mode and route of administration; the race, age, sex, health status, medical condition and weight of the recipient; the nature and extent of the symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration, the patient's renal and liver function, and the desired effect. A physician or veterinarian can make a decision and prescribe an effective amount of the drug to prevent, counteract or arrest the development of cancer.

[0258] According to general guidelines, in order to achieve the specified effect, the dosage of each active ingredient used is between about 0.001 and 1000 mg / kg body weight per day, preferably, between about 0.01 and 100 mg / kg body weight. The compound of the present invention can be administered once a day, or can be administered twice, three times or four times a day.

[0259] 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.

[0260] The compounds and compositions of the present invention can be used alone or in combination with other compounds or other therapeutic agents. The compounds or compositions of the present invention can be used simultaneously or successively with other therapeutic agents by the same or different routes of administration. The compounds of the present invention can be included in a single preparation or in a separate preparation together with other therapeutic agents.

[0261] When the compounds of the invention are administered with other therapeutic agents, generally the amount of each component in a typical daily dose and typical dosage form may be reduced relative to the usual dose when administered alone, taking into account the additive or synergistic effects of the therapeutic agents when administered in combination.

[0262] The compound or its pharmaceutically acceptable salt or hydrate or its pharmaceutical composition involved in the present invention can be effectively used for preventing, treating or alleviating KRAS-mediated diseases, especially KRAS G12D-mediated diseases, especially cancer, in patients.

[0263] 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 (cancer, lymphoma, leiomyosarcoma) cancer, pancreatic (ductal adenocarcinoma, insulinoma) cancer Cancer of the genitourinary tract: kidney (adenocarcinoma, nephroblastoma (Wilms tumor), lymphoma, leukemia) cancer, bladder and urethra cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma) cancer, testicular (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma) cancer; cancer of the liver: liver Cancer (hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract cancer: gallbladder cancer, ampullary cancer, bile duct cancer; Bone cancer: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor; Nervous system cancer: neuroma, skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meningeal cancer (meningioma, meningeal sarcoma, glioma Disease), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, neurothecoma, 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) cancer, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, grape-like sarcoma (embryo rhabdomyosarcoma), fallopian tube (cancer), 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, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal gland cancers: neuroblastoma.

[0264] In particular, the compounds of the present invention or their pharmaceutical compositions can be effectively used to prevent, treat or alleviate cancer symptoms 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.

[0265] General synthesis process

[0266] To describe the present invention, the present invention will further illustrate the technical scheme of the present invention with the following examples. The following examples are only used to illustrate the specific implementation method of the present invention so that those skilled in the art can understand the present invention, but are not used to limit the scope of protection of the present invention. In the specific implementation method of the present invention, the technical means or methods not specifically described are conventional technical means or methods in the art.

[0267] Unless otherwise specified, the substituents are as defined herein. The following reaction schemes and examples are provided to further illustrate the present invention.

[0268] Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of non-exemplified compounds according to the invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making some conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized to be applicable to the preparation of other compounds of the invention.

[0269] In the examples described below, unless otherwise indicated, all temperatures are set in degrees Celsius (°C), and room temperature in the examples means 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 were used without further purification. Unless otherwise indicated, general 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.

[0270] Anhydrous tetrahydrofuran, dioxane, toluene, and ether were obtained by drying under reflux with sodium metal. Anhydrous dichloromethane and chloroform were obtained by drying under reflux with calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.

[0271] The following reactions were generally carried out under positive pressure of nitrogen or argon or with a drying tube over anhydrous solvents (unless otherwise indicated), reaction bottles were plugged with appropriate rubber stoppers, and substrates were injected via syringes. All glassware was dried.

[0272] The chromatographic column used was a silica gel column, and the silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.

[0273] 1 H NMR spectra were recorded using a Bruker 400 MHz, 600 MHz or 599 MHz nuclear magnetic resonance spectrometer. 1 H NMR spectrum of CDC1 3 DMSO-d 6 , CD 3 OD or acetone-d 6is the solvent (in ppm), TMS (0 ppm) or chloroform (7.26 ppm) is used as the reference standard. When multiple peaks appear, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), brs (broadened singlet, br.s, broad singlet), dd (doublet of doublets), dt (doublet of triplets), qt (quartet of triplets). The coupling constant J is expressed in Hertz (Hz).

[0274] The low-resolution mass spectrometry (MS) data were measured under the following conditions: 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% (CH 3 CN) in (H 2 O) using electrospray ionization (ESI) at 210 nm / 254 nm with UV detection.

[0275] 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.

[0276] The following abbreviations or English words are used throughout this invention:

[0277] EtOAc, EA, ethyl acetate, DIPEAN, N-diisopropylethylamine

[0278] PdCl 2 (PPh 3 ) 2 ,Pd(PPh 3 ) 2 Cl 2 Bis(triphenylphosphine)palladium(II) chloridePOCl 3 Phosphorus oxychloride

[0279] TEA,Et 3 N-Triethylamine toluene

[0280] PE petroleum ether OMOM methoxymethyloxy, -OCH 2 OCH 3

[0281] THF Tetrahydrofuran TIPS Triisopropylsilyl

[0282] DMSO Dimethyl Sulfoxide K 3 PO 4 7H 2 O Potassium phosphate heptahydrate

[0283] DMSO-d 6 Deuterated dimethyl sulfoxide ice-bath

[0284] DCM dichloromethane S Cesium fluoride

[0285] TFA,CF 3 COOHTrifluoroacetic acidDMF N,N-dimethylformamide

[0286] dioxane,1,4-dioxane 1,4-dioxane Pre-TLC Preparative Thin Layer Chromatography

[0287] CS 2 CO 3 Cesium carbonate h hours

[0288] HCl / dioxane Hydrogen chloride in 1,4-dioxane min

[0289] MeCN,ACN,Acetonitrile,NaH,Sodium hydride

[0290] PTSA p-Toluenesulfonic acid ℃ Celsius

[0291] Na 2 SO 3 Sodium sulfite g

[0292] NaHCO 3 Sodium bicarbonate mmol

[0293] MeOH mL

[0294] NH 3 Ammonia mg

[0295] NH 3 / MeOH,NH 3· MeOH ammonia methanol solution rt

[0296] M, mol / L HTRF homogeneous time-resolved fluorescence

[0297] NH 2 Boc tert-butyl carbamate TMS trimethylsilyl

[0298] THF / H 2 O Tetrahydrofuran and water mixed solution TMSOTf trimethylsilyl trifluoromethanesulfonate Boc tert-ButyloxycarbonylTMPMMgCl-LiCl 2,2,6,6-Tetramethyl Piperidinyl magnesium chloride lithium chloride complex

[0300] Boc 2 O Di-tert-butyl carbonate K 3 PO 4 Potassium Phosphate

[0301] CuI Cuprous iodide TBAF Tetrabutylammonium fluoride

[0302] XPhos Pd G3 methanesulfonic acid (2-dicyclohexylphosphino-2', HRMS High-resolution mass 4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino) spectrometry, high resolution mass spectrometry -1,1'-biphenyl-2-yl)palladium(II)

[0303] DASTDiethylaminosulfur trifluorideLiHMDSLithium hexamethyldisilazide

[0304] LiAlH 4 PMB tetramethoxybenzyl

[0305] PMBClTetramethoxybenzyl chloride NIS N-iodosuccinimide

[0306] Pd(dppf)Cl 2 ·CH 2 Cl 2 B 2 Pin 2 Pinacol borate

[0307] Pd(dppf)Cl 2 [1,1'-Bis(diphenylphosphino)ferrocene] dichloropalladium DIBAL-H diisobutylaluminum hydride

[0308] Dichloromethane complex

[0309] HMPT tris(dimethylamino)phosphine cataCXium A Pd G3 methanesulfonic acid [normal Butyldi(1-adamantyl)phosphine](2-amino

[0310] 1,1'-biphenyl-2-yl)palladium(II)

[0311] Synthesis Scheme 1

[0312]

[0313]

[0314] 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 ,q 1 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 (such as tetrahydrofuran) to obtain compound (IA-2); compound (IA-2) reacts in a methanol solution of ammonia to obtain compound (IA-3); compound (IA-3) reacts with POCl 3 The reaction is carried out under appropriate conditions (such as heating, under the action of DIPEA) to obtain compound (IA-4); compound (IA-4) and compound (IA-5) are reacted under appropriate conditions (such as in the presence of DIPEA) to obtain compound (IA-6); compound (IA-6) and compound (IA-7) are reacted under appropriate conditions (such as low temperature, under the action of NaH) to obtain compound (IA-8); compound (IA-8) and compound (IA-9) are reacted under the action of a suitable catalyst (such as XPhos Pd G3) to obtain compound (IA-10); compound (IA-10) is reacted under acidic conditions (such as TMSOTf) to obtain compound (IA).

[0315] Synthesis Scheme 2

[0316]

[0317] 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 , RA1a , R A1b , R A1 ,q 1 Having the definition as described in the present invention; n 2 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) under the action of a suitable catalyst (such as XPhos Pd G3) to obtain compound (IB-2); compound (IB-2) reacts under acidic conditions (such as TMSOTf) to obtain compound (IB-3); compound (IB-3) removes the TIPS group under suitable conditions (such as CsF in DMF solvent) to obtain compound (IB).

[0318] Synthesis Scheme 3

[0319]

[0320] 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 ,q 1 Having the definition as described in the present invention; n 2 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 (such as low temperature, under the action of NaH) to obtain compound (IC-2); compound (IC-2) reacts with compound (IC-3) under the action of a suitable catalyst (such as XPhos Pd G3) to obtain compound (IC-4); compound (IC-4) reacts under acidic conditions (such as TMSOTf) to obtain compound (IC-5); compound (IC-5) removes the TIPS group under suitable conditions (such as under the action of CsF, in DMF solvent) to obtain compound (IC).

[0321] Synthesis Scheme 4

[0322]

[0323] 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 ,q 1and n each have the meanings as described in the present invention; Hal is a halogen, preferably Cl or Br. Compound (IA-8) reacts with compound (ID-1) in the presence of a suitable catalyst (such as XPhos Pd G3) to obtain compound (ID-2); compound (ID-2) reacts under acidic conditions (such as TMSOTf) to obtain compound (ID).

[0324] The compounds, pharmaceutical compositions and applications of the present invention are further described below in conjunction with the examples. Example

[0325] Synthesis of intermediate compound M1

[0326]

[0327] Step 1: Synthesis of compound M1-2

[0328] 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-mouth bottle, stirred at room temperature, and di-tert-butyl dicarbonate (21.96 g, 100.63 mmol) was added dropwise to the reaction solution. After the addition, the mixture was 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, a saturated ammonium chloride solution was added for washing (100 mL × 3), and the organic phase was separated. The organic phase was then washed with a 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 a yellow solid product M1-2 with a yield of 90.8%, which was directly used in the next step. 1 HNMR (599MHz, CDCl 3 ): δ8.79(s,1H),4.37(q,J=7.1Hz,2H),1.41(s,18H),1.38(t,J=7.1Hz,3H).

[0329] Step 2: Synthesis of Compound M1-3

[0330] In a 500mL three-necked flask, add M1-2 (10g, 23.88mmol), add anhydrous THF (100mL) under nitrogen protection, stir and cool to -40℃, add TMPMgCl-LiCl tetrahydrofuran solution (35.82mL, 35.82mmol, 1M) dropwise at -40℃. Continue stirring at -40℃ for 4h, then add dibromotetrachloroethane (9.33g, 28.66mmol) in THF (30mL) dropwise. Continue stirring at -40℃ for 4h. Stop the reaction, add saturated ammonium chloride solution (100mL) to quench, and then extract with EA (100mL×2). The organic phases are combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography with PE / DCM (v / v=100 / 1-1 / 1) eluent to obtain 8.5g of yellow solid M1-3, with a yield of 71.5%. 1 H NMR (599 MHz, CDCl 3 ): δ4.40(q,J=7.2Hz,2H),1.42(s,18H),1.37(t,J=7.2Hz,3H).

[0331] Step 3: Synthesis of Compound M1

[0332] In a 250 mL three-necked flask, add M1-3 (5 g, 10.05 mmol), DCM (50 mL) and TFA (14.97 mL, 200.1 mmol), and stir at 30°C for 5 h. Stop the reaction, add saturated sodium carbonate to adjust the pH to neutral, and then extract with DCM (30 mL×3). The organic phases are combined, dried over anhydrous sodium sulfate, and concentrated to obtain 2.9 g of light brown solid M1 with a yield of 97%. 1 H NMR (599 MHz, CDCl 3 ): 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] + .

[0333] Synthesis of intermediate compound M2

[0334]

[0335] Step 1: Synthesis of compound M2-1

[0336] M1 (1.0 g, 3.36 mmol), Pd (PPh 3 ) 2 Cl 2(0.472g, 0.67mmol) and CuI (0.128g, 0.67mmol), nitrogen replacement three times, then add 1-(trimethylsilyl) propyne (0.566g, 5.04mmol), TEA (2.33mL, 16.8mmol) and anhydrous THF (10mL), nitrogen replacement three times, TBAF tetrahydrofuran solution (5.04mL, 5.04mmol, 1.0M) dropwise while stirring, after the dropwise addition, stir at room temperature 25℃ for 6h, stop the reaction, filter with diatomaceous earth, spin dry the filtrate, and purify it by column chromatography with PE / DCM (v / v=100 / 1-2 / 1) eluent to obtain 0.523g yellow solid M2-1, with a yield of 60.6%. LC-MS (ESI, pos.ion) m / z: 257.3[M+H] + .

[0337] Step 2: Synthesis of compound M2-2

[0338] Add M2-1 (0.52 g, 2.03 mmol) and anhydrous THF (6 mL) to a 50 mL single-mouth bottle, protect with nitrogen, stir to dissolve, then add 2,2,2-trichloroacetyl isocyanate (0.497 g, 2.64 mmol), stir at room temperature 25°C for 1 h, stop the reaction, spin dry and directly use in the next step, the yield is calculated as 100%. LC-MS (ESI, pos.ion) m / z: 445.9 [M+H] + .

[0339] Step 3: Synthesis of Compound M2

[0340] 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 methanol solution (2.84 mL, 19.99 mmol, 7 M) was then added, and the mixture was stirred at room temperature for 2 h at 25 °C. The reaction was stopped, 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 white solid M2. The yield of step 2 and step 3 was 95%. LC-MS (ESI, pos.ion) m / z: 254.1 [M+H] + .

[0341] Synthesis of intermediate compound M3

[0342]

[0343] Step 1: Synthesis of compound M3-1

[0344] In a 500 mL two-necked bottle, add M1 (10 g, 33.61 mmol), 4-formyl-1-butyne (3.78 g, 43.69 mmol), Pd (PPh3 ) 2 Cl 2 (2.36g, 3.36mmol), CuI (0.64g, 3.36mmol), TEA (10.20g, 100.83mmol) and anhydrous THF (200mL), nitrogen replacement three times, stirring at room temperature 25℃ for 4h. Stop the reaction, filter with celite, dry the filtrate with anhydrous sodium sulfate, spin dry, and purify with PE / EA (v / v=5 / 1-3 / 1) eluent column chromatography to obtain 4.74g yellow solid M3-1, with a yield of 47.2%. LC-MS (ESI, pos.ion) m / z: 299.30[M+H] + ; 1 H NMR (400 MHz, CDCl 3 )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).

[0345] Step 2: Synthesis of compound M3-2

[0346] In a 250 mL single-mouth bottle, add M3-1 (4.74 g, 15.87 mmol) and dichloromethane (90 mL), add diethylaminosulfur trifluoride (DAST, 12.79 g, 79.35 mmol) dropwise at 0°C, stir at 0°C for 2 h, add saturated sodium bicarbonate (100 mL) to quench, separate, extract the aqueous phase with dichloromethane (100 mL), combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography with PE / EA (v / v=5 / 1) eluent to obtain 2.12 g of yellow solid M3-2, with a yield of 41.7%. LC-MS (ESI, pos.ion) m / z: 321.1 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 )δ6.27(s,2H),6.00(tt,J=56.4,4.5Hz,1H),4.41(q,J=7.1Hz,2H),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).

[0347] Step 3: Synthesis of compound M3-3

[0348] Add M3-2 (2.1 g, 6.55 mmol) and anhydrous THF (40 mL) to a 50 mL single-mouth bottle, stir to dissolve, then slowly add 2,2,2-trichloroacetyl isocyanate (1.95 g, 9.82 mmol), stir at room temperature 25°C for 40 minutes, stop the reaction, spin dry to obtain a yellow solid, directly use it for the next step, the yield is calculated as 100%. LC-MS (ESI, pos.ion) m / z: 508.0 [M+H] + .

[0349] Step 4: Synthesis of Compound M3

[0350] Methanol (45 mL) was added to M3-3 obtained in the previous step, stirred to dissolve, and then ammonia methanol solution (4.67 mL, 32.7 mmol, 7 M) was added, stirred at room temperature 25°C for 2.5 h, the reaction was stopped, 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 yellow solid M3. The combined yield of step 3 and step 4 was 95.2%. LC-MS (ESI, pos.ion) m / z: 318.1 [M+H] + .

[0351] Synthesis of intermediate compound M4

[0352]

[0353] Step 1: Synthesis of compound M4-2

[0354] In a 500 mL three-necked flask, add M4-1 (10 g, 40.44 mmol) and anhydrous THF (100 mL), replace with nitrogen three times, cool to -78 ° C, and dropwise add LiHMDS (80.88 mL, 80.88 mmol, 1M THF solution), stirred at -78 ° C for 15 minutes, 3-chloro-2-chloromethyl propylene (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 h, 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%.

[0355] Step 2: Synthesis of compound M4-3

[0356] In a 250mL single-mouth bottle, add M4-2 (7.5g, 22.33mmol) and dichloromethane (70mL), cool to 0℃, add trifluoroacetic acid (30.7g, 269.2mmol) dropwise, transfer to room temperature 25℃ and stir for 4h, stop the reaction, concentrate under reduced pressure at 45℃, add methanol (30mL) at 0℃, adjust pH to 8 with 7M ammonia methanol solution (7M) at 0℃, evaporate to dryness and purify by column chromatography with PE / EA (v / v=1 / 1) eluent to obtain 4.1g yellow liquid M4-3, with a yield of 92.1%. LC-MS (ESI, pos.ion) m / z: 200.2[M+H] + .

[0357] Step 3: Synthesis of Compound M4

[0358] Add LiAlH into a 250 mL single-necked bottle at room temperature. 4 (1.56g, 41.16mmol) and anhydrous THF (40mL), nitrogen replacement three times, M4-3 (4.1g, 20.58mmol) THF (40mL) solution was added dropwise at -10℃, stirred for 15 minutes after the addition was completed, and then transferred to room temperature 25℃ for reaction for 2h. The raw materials reacted completely, and then transferred to 0℃, sodium sulfate decahydrate (3.32g, 10.29mmol) was added, and then transferred to room temperature for stirring for 1h to quench. After quenching, the reaction solution was filtered with diatomaceous earth, and the filtrate was dried to obtain 2.15g of yellow oily product M4, with a yield of 61%. LC-MS (ESI, pos.ion) m / z: 172.2 [M+H] + .

[0359] Synthesis of intermediate compound M5

[0360]

[0361] Step 1: Synthesis of compound M5-2

[0362] In a 500mL three-necked flask, M5-1 (5g, 20.72mmol) and anhydrous THF (30mL) were added, and the atmosphere was replaced with nitrogen three times. The temperature was cooled to -78°C, and a tetrahydrofuran solution of LiHMDS (41.44mL, 41.44mmol) was added dropwise. The mixture was stirred at -78°C for 60 minutes. 3-Chloro-2-chloromethylpropene (3.84mL, 41.44mmol) was slowly added dropwise at -78°C, and the mixture was stirred at -78°C for 3h. Stirring was stopped, and the mixture was transferred to room temperature. A saturated ammonium chloride solution (100mL) was added to quench the mixture. The mixture was separated, and the aqueous phase was extracted with EA (80mL×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 6.25g of light yellow liquid M5-2 with a yield of 91.4%.

[0363] Step 2: Synthesis of compound M5-3

[0364] In a 250mL single-mouth bottle, add M5-2 (6.25g, 18.95mmol) and acetonitrile (50mL), cool to 0℃ and stir for 5 minutes, add dropwise a solution of hydrochloric acid in 1,4-dioxane (47.73mL, 189.5mmol, 4M), transfer to 25℃ and stir for 1h, stop the reaction, concentrate the reaction solution and spin dry, add acetonitrile (50mL) to dissolve, then add sodium bicarbonate (7.77g, 92.5mmol) and potassium iodide (0.31g, 1.85mmol), stir the reaction solution at room temperature for 1.5h, stop stirring, filter the reaction solution, wash with acetonitrile (50mL), concentrate the filtrate, and purify it by column chromatography with PE / EA (v / v=4 / 1-3 / 2) eluent to obtain 3.05g of yellow liquid M5-3 with a yield of 85.31%. LC-MS(ESI,pos.ion)m / z:194.2[M+H] + .

[0365] Step 3: Synthesis of Compound M5

[0366] Add LiAlH into a 250 mL single-necked bottle at room temperature. 4 (1.2g, 31.56mmol), nitrogen replacement three times, add anhydrous THF (31mL) at -10℃ and stir for 5 minutes, slowly drop M5-3 (3.05g, 15.78mmol) THF (20mL) solution, after the dropwise addition, turn to 0℃ for reaction for 1h, the raw material reaction is complete, slowly add sodium sulfate decahydrate (2.54g, 7.89mmol) to quench the reaction. After quenching, the reaction solution is filtered with diatomaceous earth, and the filtrate is dried to obtain 1.59g yellow oil product M5, with a yield of 60.8%. LC-MS (ESI, pos.ion) m / z: 166.2 [M+H] + .

[0367] Synthesis of intermediate compound M8

[0368]

[0369]

[0370] Step 1: Synthesis of compound M8-1

[0371] Add 2-fluoro-3-nitrotoluene (10 g, 64.46 mmol), concentrated sulfuric acid (60 mL) and NBS (13.19 g, 74.13 mmol) to a 100 mL single-mouth bottle, stir at 50 ° C for 2 h, stop the reaction, pour the reaction solution into ice water, extract with EA (100 mL), dry the organic phase with anhydrous sodium sulfate, spin dry, and purify with PE / EA (v / v=10 / 1) eluent column chromatography to obtain 14 g of orange-red oily compound M8-1, with a yield of 90.15%. Step 2: Synthesis of compound M8-2

[0372] In a 500mL three-necked flask, add M8-1 (16g, 68.37mmol), ethanol (100mL), iron powder (19.09g, 341.85mmol) and ammonium chloride (56.98mL, 341.85mmol, 6M aqueous solution), heat to 80°C and stir for 2h, filter the reaction solution, concentrate the filtrate, dilute the residue with ethyl acetate (500mL), wash with water (50mL), separate the organic phase, dry with anhydrous sodium sulfate, and purify with PE / EA (v / v=20 / 1-5 / 1) eluent column chromatography to obtain 10g of yellow oily compound M8-2, with a yield of 71.68%. LC-MS (ESI, pos.ion) m / z: 204.0 [M+H] + .

[0373] Step 3: Synthesis of compound M8-3

[0374] In a 250mL three-necked flask, add M8-2 (10g, 49.01mmol) and anhydrous DMF (60mL), cool to 0℃ and stir, add NaH (5.88g, 147.03mmol, mass fraction 60%), transfer to room temperature and stir for 20min, add 4-methoxybenzyl chloride (15.35g, 98.02mmol) to the reaction solution, stir the resulting mixture at room temperature for 1h, add saturated ammonium chloride solution (40mL) to quench the reaction, add water (40mL) to dilute, extract with ethyl acetate (100mL), concentrate the organic phase, dry over anhydrous sodium sulfate, spin dry and purify with PE / EA (v / v=20 / 1) eluent column chromatography to obtain 18.4g of white solid compound M8-3, yield 84.5%. LC-MS (ESI, pos.ion) m / z: 444.1 [M+H] + .

[0375] Step 4: Synthesis of Compound M8-4

[0376] In a 50 mL single-mouth bottle, add M8-3 (7 g, 15.75 mmol) and acetic acid (20 mL), protect with nitrogen, stir for 2 minutes, then add NIS (5.32 g, 23.63 mmol), stir at room temperature for 15 h, add saturated sodium thiosulfate solution (10 mL) to quench the reaction, extract with EA (20 mL), dry with anhydrous sodium sulfate, spin dry and purify with PE / EA (v / v=10 / 1) eluent column chromatography to obtain 8.7 g of colorless oily compound M8-4, with a yield of 96.8%. LC-MS (ESI, pos.ion) m / z: 570.0 [M+H] + .

[0377] Step 5: Synthesis of Compound M8-5

[0378] In a 50 mL single-mouth bottle, add 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), replace with nitrogen three times, heat to 75 ° C and stir for 15 h, stop the reaction, return to room temperature and filter, add EA (60 mL), wash the organic phase with saturated brine (20 mL × 3), dry the organic phase with anhydrous sodium sulfate, spin dry and purify with PE / EA (v / v = 10 / 1) eluent column chromatography to obtain 2 g of orange oily compound M8-5 with a yield of 25.6%.

[0379] Step 6: Synthesis of Compound M8

[0380] In a 50 mL single-necked bottle, add M8-5 (2 g, 1.95 mmol), biboric acid pinacol ester (1.49 g, 5.85 mmol), Pd(dppf)Cl 2 ·CH 2 Cl 2 (0.16g, 0.20mmol), potassium acetate (0.58g, 5.95mmol) and 1,4-dioxane (20mL), after nitrogen replacement three times, heated to 100℃ and stirred for 3h, spin-dried with silica gel, mixed with sample, and purified by column chromatography with PE / EA (v / v=10 / 1) eluent to obtain 0.93g of white solid compound M8, with a yield of 85.2%. LC-MS (ESI, pos.ion) m / z: 560.3[M+H] + .

[0381] Synthesis of intermediate compound M9

[0382]

[0383] Step 1: Synthesis of Compound M9

[0384] In a 100 mL single-mouth bottle, add 3-bromo-5-chloro-4-(trifluoromethyl)aniline (5 g, 18.22 mmol, purchased from Beijing LeYan Technology), bipyraclostrobin (5.55 g, 21.86 mmol), Pd(dppf)Cl 2 ·(1.19 g, 1.82 mmol), potassium acetate (5.36 g, 54.66 mmol) and 1,4-dioxane (200 mL), after nitrogen replacement three times, heated to 80 ° C and stirred for 18 hours, the reaction was stopped, the reaction solution was filtered with diatomaceous earth, concentrated, and the crude product was purified by column chromatography with PE / EA (v / v=4 / 1-1 / 1) eluent to obtain 2.535 g of white solid compound M9, with a yield of 43.3%. LC-MS (ESI, pos.ion) m / z: 322.0 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 )δ6.73(d,J=1.9Hz,1H),6.55(d,J=1.9Hz,1H),3.97(s,2H),1.35(s,12H). 19 F NMR (376MHz, CD 3 Cl 3 )δ-56.70(3F).

[0385] Example 1: Synthesis of Compound 1

[0386]

[0387]

[0388] Step 1: Synthesis of compound 1-1

[0389] In a 100mL single-necked bottle, add M2 (2.00g, 7.89mmol) and anhydrous toluene (20mL), then add phosphorus oxychloride (2.16mL, 23.67mmol) and DIPEA (6.52mL, 39.45mmol), heat to 70℃ and stir for 1h, stop the reaction, cool, concentrate and use directly in the next step. The yield is calculated as 100%.

[0390] Step 2: Synthesis of compound 1-2

[0391] 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 to dissolve, 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 by adding saturated ammonium chloride solution (50 mL). The mixture was returned to room temperature and extracted by adding DCM (50 mL × 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 yellow solid compound 1-2. The total yield of step 1 and step 2 was 21.4%. LC-MS (ESI, pos.ion) m / z: 466.2 [M+H] + .

[0392] Step 3: Synthesis of Compound 1-3

[0393] Sodium hydride (0.13 g, 3.28 mmol, 60%) was added to a 100 mL two-necked flask, replaced with nitrogen, anhydrous THF (8 mL) was added, 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, stirred at 0°C for 1 h, a solution of compound 1-2 (383 mg, 0.82 mmol) in THF (5 mL) was slowly added dropwise, and stirred at 0°C for 2.5 h. Stirring was stopped, 15 mL of EA was added for dilution, washed with saturated ammonium chloride solution (15 mL), separated, the aqueous phase was 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) as eluent to obtain 312 mg of yellow solid compound 1-3 with a yield of 63.2%. LC-MS (ESI, pos.ion) m / z: 601.3 [M+H] + .

[0394] Step 4: Synthesis of Compound 1-4

[0395] 1-3 (200 mg, 0.33 mmol, 1 equiv.), M6 (0.25 g, 0.49 mmol), Xphos Pd G3 (56 mg, 0.066 mmol), K 3 PO 4 7H 2 O (280 mg, 0.83 mmol) and THF / H 2 O (v / v = 4.8mL / 1.6mL), replaced with nitrogen three times, stirred at room temperature at 25°C for 13h, and the reaction was detected by TLC. Half of the raw material 1-3 was still left. M6 (0.25g, 0.49mmol, 1.5equiv.), Xphos Pd G3 (56mg, 0.066mmol, 0.2equiv.), and K 3 PO 4 7H2 O (280 mg, 0.83 mmol, 2.5 equiv) and THF / H 2 O (0.5mL / 0.5mL), after nitrogen replacement, stirring was continued for 1.5h. The reaction was still not complete, and the step of adding materials was repeated. The raw material 1-3 was basically reacted, and a saturated ammonium chloride solution (20mL) was added, and extracted with EA (20mL×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) eluent to obtain 296mg of red solid compound 1-4, with a yield of 93.5%. LC-MS (ESI, pos.ion) m / z: 951.4[M+H] + .

[0396] Step 5: Synthesis of Compound 1-5

[0397] 1-4 (296 mg, 0.31 mmol) and acetonitrile (7 mL) were added to a 50 mL single-mouth bottle, cooled to -20 ° C and stirred for 5 minutes, TMSOTf (0.14 mL, 0.78 mmol) was added dropwise, stirred for 60 minutes, the reaction was stopped, saturated sodium bicarbonate aqueous solution (20 mL) was added to quench, and extracted with DCM (20 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography with DCM / MeOH (v / v = 9 / 1) 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] + .

[0398] Step 6: Synthesis of compound 1

[0399] 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-mouth bottle, replaced with nitrogen three times, stirred at room temperature for 5 h, the reaction was stopped, water (10 mL) was added, a solid was precipitated, and a solid crude product was obtained by filtration. The crude product was purified by TLC preparative plate with DCM / MeOH (v / v=8 / 1) eluent to obtain 36 mg of yellow solid compound 1, with a yield of 54.4%, LC-MS (ESI, pos.ion) m / z: 651.5 [M+H] + ; HRMS (ESI): 651.2709 [M+H] + ; 1 H NMR (400MHz, CD 3OD)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 FNMR (376MHz, CD 3 OD)δ-111.52(1F),-139.92(1F),-174.11(1F).

[0400] Example 2: Synthesis of Compound 2

[0401]

[0402] Step 1: Synthesis of compound 2-1

[0403] Sodium hydride (0.13 g, 3.28 mmol, 60% content) was added to a 100 mL two-necked flask, replaced with nitrogen, anhydrous THF (7 mL) was added, 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, stirred at 0°C for 1 h, a solution of 1-2 (383 mg, 0.82 mmol) in THF (5 mL) was slowly added dropwise, and stirred at 0°C for 3 h. Stirring was stopped, saturated ammonium chloride solution (30 mL) was added to quench the reaction, the liquids were separated, the aqueous phase was extracted with EA (20 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) eluent to obtain 271 mg of yellow solid compound 2-1 with a yield of 55.4%. LC-MS (ESI, pos.ion) m / z: 595.5 [M+H] + .

[0404] Step 2: Synthesis of compound 2-2

[0405] 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), K 3 PO 4 7H 2 O (290 mg, 0.85 mmol) and THF / H 2O (5.1 mL / 1.7 mL), replaced with nitrogen three times, stirred at room temperature at 25 ° C for 1 h, and the reaction was detected by TLC. Half of the raw material 2-1 was still left. M6 (0.26 g, 0.51 mmol, 1.5 equiv.), Xphos Pd G3 (58 mg, 0.068 mmol, 0.2 equiv.), and K 3 PO 4 7H 2 O (290 mg, 0.85 mmol, 2.5 equiv) and THF / H 2 O (0.5mL / 0.5mL), after nitrogen replacement, continue stirring for 0.5h, the reaction is still not complete, repeat the step of adding materials, the raw material 2-1 is basically reacted, add saturated ammonium chloride solution (20mL), extract with EA (20mL×2), combine the organic phases, dry with anhydrous sodium sulfate, concentrate, and purify with DCM / MeOH (v / v=30 / 1) eluent column chromatography to obtain 227mg red solid compound 2-2, yield 71.5%. LC-MS (ESI, pos.ion) m / z: 473.5[M+2H] 2+ .

[0406] Step 3: Synthesis of compound 2-3

[0407] 2-2 (227 mg, 0.24 mmol) and acetonitrile (6 mL) were added to a 50 mL single-mouth bottle, cooled to -15 ° C and stirred for 5 minutes, TMSOTf (0.12 mL, 0.65 mmol) was slowly added dropwise, stirred for 30 minutes, the reaction was stopped, saturated sodium bicarbonate aqueous solution (20 mL) was added to quench, and extracted with DCM (15 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography with DCM / MeOH (v / v = 9 / 1) 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] + .

[0408] Step 4: Synthesis of compound 2

[0409] 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-mouth bottle, replaced with nitrogen three times, stirred at room temperature at 25 ° C for 17.5 h, the reaction was stopped, 15 mL of water was added, a solid was precipitated, and a solid crude product was obtained by filtration. The crude product was purified by TLC preparation plate with DCM / MeOH (v / v=8 / 1) eluent to obtain 67 mg of yellow solid compound 2, with a yield of 75.7%, LC-MS (ESI, pos.ion) m / z: 645.5 [M+H]+ ; HRMS (ESI): 645.2802 [M+H] + ; 1 H NMR (400MHz, CD 3 OD): 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,4H),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, CD 3 OD)δ-111.51(1F),-139.85(1F).

[0410] Example 3: Synthesis of Compound 3

[0411]

[0412]

[0413] Step 1: Synthesis of compound 3-1

[0414] In a 100mL single-necked bottle, add M3 (1.88g, 5.92mmol) and anhydrous toluene (38mL), then add phosphorus oxychloride (3.63g, 23.68mmol) and DIPEA (3.06g, 23.68mmol), heat to 70℃ and stir for 1.5h, stop the reaction, cool, concentrate and use directly in the next step. The yield is calculated as 100%.

[0415] Step 2: Synthesis of compound 3-2

[0416] Anhydrous dichloromethane (40 mL) was added to 3-1 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, DIPEA (2.28 g, 17.67 mmol) was added, and then a solution of 8-BOC-3,8-diazabicyclo[3.2.1]octane (1.25 g, 5.89 mmol) in DCM (10 mL) was added dropwise. After stirring at -40°C for 0.5 h, the reaction was stopped, saturated ammonium chloride solution (50 mL) was added to quench, the mixture returned to room temperature, and DCM (30 mL×2) was added to extract the mixture. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography with PE / EA (v / v=10 / 1-2 / 1) eluent to obtain 2.01 g of yellow solid compound 3-2. The total yield of step 1 and step 2 was 64.3%. LC-MS (ESI, pos.ion) m / z: 531.5 [M+H] + .

[0417] Step 3: Synthesis of compound 3-3

[0418] 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) were added to a 100 mL two-necked bottle. After nitrogen replacement three times, the temperature was raised to 90 ° C. and stirred for 12 h. Stirring was stopped, concentrated, and purified by column chromatography with DCM / MeOH (v / v=100 / 1-30 / 1) eluent to obtain 450 mg of yellow oily compound 3-3 with a yield of 21.8%. LC-MS (ESI, pos.ion) m / z: 666.0 [M+H] + .

[0419] Step 4: Synthesis of compound 3-4

[0420] 3-3 (450 mg, 0.68 mmol), M6 (0.697 g, 1.36 mmol), Xphos PdG3 (172.7 mg, 0.20 mmol), K 3 PO 4 7H 2 O (1.15 g, 3.40 mmol) and THF / H 2O (10mL / 2mL), nitrogen replacement three times, stirring at 30°C for 6h, stopping the reaction, adding saturated ammonium chloride solution (20mL), extracting with DCM (50mL), drying the organic phase with anhydrous sodium sulfate, concentrating, and purifying by column chromatography with DCM / MeOH (v / v=100 / 1-30 / 1) eluent to obtain 323mg brown oily compound 3-4, with a yield of 47.0%. LC-MS (ESI, pos.ion) m / z: 508.4 [M+2H] 2+ .

[0421] Step 5: Synthesis of compound 3-5

[0422] 3-4 (270 mg, 0.27 mmol) and acetonitrile (10 mL) were added to a 50 mL single-mouth bottle, cooled to 0 ° C and stirred for 5 minutes, TMSOTf (0.24 mL, 1.35 mmol) was added dropwise, stirred at 0 ° C for 30 minutes, the reaction was stopped, saturated sodium bicarbonate aqueous solution (20 mL) was added to quench, and extracted with DCM (30 mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and purified by TLC preparation plate with DCM / MeOH (v / v=10 / 1) eluent to obtain 65 mg of yellow solid compound 3-5, with a yield of 28.1%, LC-MS (ESI, pos.ion) m / z: 871.4 [M+H] + .

[0423] Step 6: Synthesis of compound 3

[0424] 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-mouth bottle, replaced with nitrogen three times, stirred at room temperature at 25 ° C for 4 h, the reaction was stopped, 8 mL of water was added, a solid was precipitated, and a solid crude product was obtained by filtration. The crude product was purified by thin layer chromatography with DCM / MeOH / TEA (v / v=10 / 1 / 0.1) eluent to obtain 27 mg of brown solid compound 3, with a yield of 41.1%, LC-MS (ESI, pos.ion) m / z: 715.2 [M+H] + ; HRMS(ESI):715.2836[M+H] + ; 1 H NMR (400MHz, CD 3OD): δ7.86(dd,J=9.1,5.7Hz,1H),7.38–7.29(m,2H),7.21(s,1H),6.05(tt ,J=56.4,4.3Hz,1H),5.34(d,J=53.2Hz,1H),5.02(s,2H),4.72–4.26(m,4H) ,4.05–3.75(m,5H),3.50–3.39(m,1H),3.34(s,1H),3.03–2.84(m,2H),2.7 7(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, CD 3 OD): δ-111.44(1F),-119.49(2F),-139.27(1F),-174.25(1F).

[0425] Example 4: Synthesis of Compound 4

[0426]

[0427] Step 1: Synthesis of compound 4-1

[0428] 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) were added to a 50 mL two-necked bottle. After nitrogen replacement three times, the temperature was raised to 95 ° C. and stirred for 12 h. Stirring was stopped, concentrated, and purified by column chromatography with DCM / MeOH (v / v=100 / 1-30 / 1) eluent to obtain 220 mg of yellow oily compound 4-1 with a yield of 39.3%. LC-MS (ESI, pos.ion) m / z: 659.3 [M+H] + .

[0429] Step 2: Synthesis of compound 4-2

[0430] 4-1 (220 mg, 0.33 mmol), M6 (338 mg, 0.66 mmol), Xphos PdG3 (139.7 mg, 0.17 mmol), K 3 PO 4 7H 2 O (0.56 g, 1.65 mmol) and THF / H 2O (5mL / 1mL), nitrogen replacement three times, stirring at 30°C for 6h, stopping the reaction, adding saturated ammonium chloride solution (20mL), extracting with EA (30mL×3), combining the organic phases, drying over anhydrous sodium sulfate, concentrating, and purifying by column chromatography with DCM / MeOH (v / v=100 / 1-30 / 1) eluent to obtain 200mg brown oily compound 4-2, with a yield of 59.4%. LC-MS (ESI, pos.ion) m / z: 1009.5[M+H] + .

[0431] Step 3: Synthesis of compound 4-3

[0432] 4-2 (180 mg, 0.18 mmol) and acetonitrile (6 mL) were added to a 50 mL single-mouth bottle, cooled to 0 ° C and stirred for 5 minutes, TMSOTf (0.16 mL, 0.90 mmol) was added dropwise, stirred at 0 ° C for 30 minutes, the reaction was stopped, saturated sodium bicarbonate aqueous solution (20 mL) was added to quench, and extracted with DCM (30 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate and concentrated to obtain 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] + .

[0433] Step 4: Synthesis of compound 4

[0434] 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-mouth bottle, replaced with nitrogen three times, stirred at room temperature for 5 h, the reaction was stopped, 10 mL of water was added, a solid was precipitated, and a solid crude product was obtained by filtration. The crude product was purified by TLC preparation plate with DCM / MeOH / TEA (v / v=100 / 10 / 0.5) eluent to obtain 35 mg of brown solid compound 4, with 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, CD 3OD)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, CD 3 OD): δ-111.43(1F),-119.46(2F),-139.26(1F).

[0435] Example 5: Synthesis of Compound 5

[0436]

[0437] Step 1: Synthesis of compound 5-1

[0438] 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, replaced with nitrogen three times, cooled to -40 ° C, and LiHMDS (100 mL, 100 mmol, 1.0 M THF solution) was added dropwise. After the addition was complete, the mixture was reacted at -40 ° C for 30 min, and then moved to room temperature and stirred for 16 h. The reaction was stopped, saturated ammonium chloride (50 mL) was added to quench, and extracted with EA (50 mL × 2). The organic phases were combined and washed twice with saturated brine (50 mL × 2), and the organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography with PE / DCM (v / v = 0 / 100) eluent to obtain 5.3 g of yellow oily compound 5-1 with a yield of 40%. LC-MS(ESI,pos.ion)m / z:210.1[M+H] + .

[0439] Step 2: Synthesis of compound 5-2

[0440] At room temperature, 5-1 (1.3 g, 5.30 mmol) was added to a 250 mL single-mouth bottle, cooled to 0 °C, and a toluene solution of diisobutylaluminum hydride (1.5 M, 67.55 mL, 101.32 mmol) was added dropwise, and stirred at room temperature overnight. The reaction solution was stirred and added to 250 mL of ice water, stirred for 15 min, filtered through diatomaceous earth, and the filter cake was rinsed with ethyl acetate (200 mL). The filtrate was separated, the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography with DCM / MeOH (v / v=4 / 1) as the eluent to obtain 1.2 g of yellow solid compound 5-2, with a yield of 31%. LC-MS (ESI, pos.ion) m / z: 154.2 [M+H] + .

[0441] Step 3: Synthesis of compound 5-3

[0442] At room temperature, 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) were added to a 100 mL single-mouth bottle, replaced with nitrogen three times, and heated to 100 ° C for reflux reaction for 16 h. Stop the reaction, filter, wash the filter cake with EA (60 mL), add saturated ammonium chloride (60 mL) to the combined filtrate, extract and separate, extract the aqueous phase with EA (50 mL), combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography with DCM / MeOH (v / v=100 / 0-20 / 1) eluent to obtain 0.43 g of dark solid compound 5-3, with a yield of 34%. LC-MS (ESI, pos.ion) m / z: 583.3 [M+H] + .

[0443] Step 4: Synthesis of compound 5-4

[0444] 5-3 (430 mg, 0.74 mmol), M6 (0.57 g, 1.11 mmol), K 3 PO 4 7H 2 O (880 mg, 2.59 mmol) and THF / H 2 O (10mL / 1mL), nitrogen replacement three times, Xphos Pd G3 (190mg, 0.22mmol) was added in batches, stirred at 35°C for 5h, saturated ammonium chloride solution (20mL) was added, extracted with EA (20mL×2), the organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography with DCM / MeOH (v / v=20 / 1) eluent to obtain 320mg yellow solid compound 5-4, with a yield of 46%. LC-MS (ESI, pos.ion) m / z: 933.3[M+H] + .

[0445] Step 5: Synthesis of compound 5-5

[0446] 5-4 (320 mg, 0.34 mmol) and acetonitrile (3 mL) were added to a 50 mL single-mouth bottle, cooled to 0 ° C and stirred for 5 minutes, TMSOTf (0.23 g, 1.02 mmol) was slowly added dropwise, stirred for 60 minutes, the reaction was stopped, saturated sodium bicarbonate aqueous solution (20 mL) was added to quench, and extracted with EA (10 mL × 2), the organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and purified by TLC preparation plate with DCM / MeOH (v / v=8 / 1) eluent to obtain 270 mg of yellow solid compound 5-5, yield 99%, LC-MS (ESI, pos.ion) m / z: 789.3 [M+H] + .

[0447] Step 6: Synthesis of compound 5

[0448] 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-mouth bottle, replaced with nitrogen three times, stirred at room temperature at 25 ° C for 16 h, the reaction was stopped, water (80 mL) was added, a solid was precipitated, and a solid crude product was obtained by filtration. The crude product was purified by TLC preparation plate with DCM / MeOH / TEA (v / v=7 / 1 / 0.05) eluent to obtain 28 mg of yellow solid compound 5, with a yield of 13%, LC-MS (ESI, pos.ion) m / z: 633.3 [M+H] + ; 1 H NMR (400MHz, CD 3 OD)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, CD 3 OD)δ-111.48(1F),-140.34(1F).

[0449] Example 6: Synthesis of Compound 6

[0450]

[0451] Step 1: Synthesis of compound 6-1

[0452] Sodium hydride (0.13 g, 3.28 mmol, content 60%) was added to a 100 mL two-necked flask, replaced with nitrogen, anhydrous THF (5 mL) was added, stirred at 0°C for 5 minutes, M5 (0.27 g, 1.64 mmol) in THF (1.5 mL) was slowly added dropwise, stirred at 0°C for 1 h, 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, saturated ammonium chloride solution (50 mL) was added to quench the reaction, the liquids were separated, the aqueous phase was extracted with EA (20 mL × 2), the organic phases were combined and 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 yellow solid compound 6-1, with a yield of 36.3%. LC-MS (ESI, pos.ion) m / z: 737.4 [M+H] + .

[0453] Step 2: Synthesis of compound 6-2

[0454] 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), K 3 PO 4 7H 2 O (160 mg, 0.47 mmol) and THF / H 2 O (3mL / 1mL), nitrogen replacement three times, stirring at room temperature at 25°C for 2h, adding Xphos Pd G3 (0.2equiv.), after nitrogen replacement, stirring for 1h, the reaction is still not complete, repeat the step of adding materials until the raw material 6-1 is basically reacted, add saturated ammonium chloride solution (20mL), extract with DCM (20mL×2), combine the organic phases, dry with anhydrous sodium sulfate, concentrate, and purify with DCM / MeOH (v / v=50 / 1) eluent column chromatography to obtain 188mg of red solid compound 6-2, yield 91%. LC-MS (ESI, pos.ion) m / z: 544.5[M+2H] 2+ .

[0455] Step 3: Synthesis of compound 6-3

[0456] 6-2 (188 mg, 0.17 mmol) and acetonitrile (4 mL) were added to a 25 mL single-mouth bottle, cooled to 0 ° C and stirred for 5 minutes, TMSOTf (0.092 mL, 0.51 mmol) was slowly added dropwise, stirred for 30 minutes, the reaction was stopped, saturated sodium bicarbonate aqueous solution (15 mL) was added to quench, extracted with DCM (15 mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and purified by TLC preparation plate with DCM / MeOH (v / v = 10 / 1) eluent to obtain 68 mg of yellow solid compound 6-3, with a yield of 42%. LC-MS (ESI, pos.ion) m / z: 943.9 [M+H] + .

[0457] Step 4: Synthesis of compound 6

[0458] 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-mouth bottle, replaced with nitrogen three times, stirred at room temperature for 3 h, the reaction was stopped, 14 mL of water was added, a solid was precipitated, and a solid crude product was obtained by filtration. The crude product was purified by TLC preparation plate with DCM / MeOH (v / v=8 / 1) eluent to obtain 8 mg of yellow solid compound 6, with a yield of 18%, LC-MS (ESI, pos.ion) m / z: 631.3 [M+H] + ; HRMS (ESI): 631.2658 [M+H] + ; 1 H NMR (400MHz, CD 3 OD)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, CD 3 OD)δ-111.47(1F),-138.25(1F).

[0459] Example 7: Synthesis of Compound 7

[0460]

[0461] Step 1: Synthesis of compound 7-1

[0462] 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), K 3 PO 4 7H 2 O (93 mg, 0.28 mmol) and THF / H 2 O (3mL / 0.56mL), nitrogen replacement three times, stirring at room temperature at 25°C for 1h, repeating the process of adding Xphos Pd G4 until the reaction of raw material 6-1 is complete, adding saturated ammonium chloride solution (15mL), extracting with DCM (20mL×2), combining the organic phases, drying with anhydrous sodium sulfate, concentrating, and purifying with DCM / MeOH (v / v=50 / 1) eluent column chromatography to obtain 83mg of yellow oily compound 7-1, with a yield of 82%. LC-MS (ESI, pos.ion) m / z: 468.4[M+2H] 2+ .

[0463] Step 2: Synthesis of compound 7-2

[0464] 7-1 (83 mg, 0.089 mmol) and acetonitrile (3 mL) were added to a 25 mL single-mouth 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, the reaction was stopped, saturated sodium bicarbonate aqueous solution (15 mL) was added to quench, and extracted with DCM (20 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and purified by thin layer chromatography preparation plate with DCM / MeOH (v / v=10 / 1) eluent to obtain 37 mg of yellow solid compound 7-2, with a yield of 53%, LC-MS (ESI, pos.ion) m / z: 791.4 [M+H] + .

[0465] Step 3: Synthesis of compound 7

[0466] 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-mouth bottle, replaced with nitrogen three times, stirred at room temperature for 3 h, the reaction was stopped, 10 mL of water was added, a solid was precipitated, and a solid crude product was obtained by filtration. The crude product was purified by TLC preparation plate with DCM / MeOH (v / v=9 / 1) eluent to obtain 27 mg of yellow solid compound 7, with 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, CD 3 OD)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,2H), 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, CD 3 OD)δ-120.83(1F),-138.10(1F).

[0467] Example 8: Synthesis of Compound 8

[0468]

[0469] Step 1: Synthesis of compound 8-1

[0470] 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), K 3 PO 4 7H 2 O (305 mg, 0.90 mmol) and THF / H 2 O (6mL / 2mL), nitrogen replacement three times, stirring at room temperature 25°C for 7h, stopping the reaction, adding saturated ammonium chloride solution (10mL), extracting with EA (20mL×2), combining the organic phases, drying with anhydrous sodium sulfate, concentrating, and purifying with DCM / MeOH (v / v=30 / 1) eluent column chromatography to obtain 230mg brown solid compound 8-1, with a yield of 65%. LC-MS (ESI, pos.ion) m / z: 992.3[M+H] + .

[0471] Step 2: Synthesis of compound 8

[0472] 8-1 (230 mg, 0.23 mmol) and trifluoroacetic acid (20 mL) were added to a 25 mL single-mouth bottle, stirred at room temperature for 1 h, the reaction was stopped, the mixture was spin-dried, dissolved in DCM (10 mL), washed with saturated sodium bicarbonate solution (20 mL), the organic phase was concentrated and dried, and then spin-dried. The crude product was purified by TLC preparation using DCM / MeOH (v / v=15 / 1) as the eluent to obtain 73 mg of yellow solid compound 8, with a yield of 48%. LC-MS (ESI, pos.ion) m / z: 652.3 [M+H] + ; 1 H NMR (400MHz, CD 3 OD)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, CD 3 OD)δ-54.95(3F),-137.80(1F),-141.73(1F).

[0473] Example 9: Synthesis of Compound 9

[0474]

[0475] Step 1: Synthesis of compound 9-1

[0476] 2-1 (150 mg, 0.25 mmol), M7 (180 mg, 0.50 mmol), Xphos PdG4 (43 mg, 0.050 mmol, purchased from Shaoyuan Technology), K 3 PO 4 7H 2 O (338 mg, 1 mmol) and THF / H 2 O (6mL / 2mL), nitrogen replacement three times, stirring at room temperature for 10h, stopping the reaction, adding saturated ammonium chloride solution (10mL), extracting with EA (20mL×2), combining the organic phases, drying with anhydrous sodium sulfate, concentrating, and purifying with DCM / MeOH (v / v=30 / 1) eluent column chromatography to obtain 145mg red-brown solid compound 9-1, with a yield of 72%. LC-MS (ESI, pos.ion) m / z: 793.3[M+H] + .

[0477] Step 2: Synthesis of compound 9

[0478] 9-1 (145 mg, 0.18 mmol) and acetonitrile (3 mL) were added to a 25 mL single-mouth bottle, cooled to -20 °C and stirred for 5 minutes, TMSOTf (0.098 mL, 0.54 mmol) was slowly added dropwise, stirred for 60 minutes, the reaction was stopped, saturated sodium bicarbonate aqueous solution (15 mL) was added to quench, extracted with DCM (20 mL × 2), the organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and purified by TLC preparative plate with DCM / MeOH (v / v = 10 / 1) eluent to obtain 60 mg of yellow solid compound 9, with a yield of 51%. LC-MS (ESI, pos.ion) m / z: 649.3 [M+H] + ; HRMS(ESI):649.3098[M+H] + ; 1 H NMR (400MHz, CD 3 OD)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),3.69–3.5 2(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, CD 3 OD)δ-120.85(1F),-139.75(1F).

[0479] Example 10: Synthesis of Compound 10

[0480]

[0481] Step 1: Synthesis of compound 10-1

[0482] 2-1 (78 mg, 0.131 mmol), M9 (64 mg, 0.2 mmol), Pd(PPh 3 ) 4 (30 mg, 0.026 mmol), cesium carbonate (130 mg, 0.4 mmol) and 1,4-dioxane / H 2O (3mL / 0.8mL), nitrogen replacement three times, stirring at 100°C for 6h, stopping the reaction, adding saturated ammonium chloride solution (10mL), extracting with EA (20mL×2), combining the organic phases, drying with anhydrous sodium sulfate, concentrating, and purifying with DCM / MeOH (v / v=40 / 1) eluent thin layer chromatography preparation plate to obtain 54mg red brown solid compound 10-1, yield 55%. LC-MS (ESI, pos.ion) m / z: 754.2[M+H] + .

[0483] Step 2: Synthesis of compound 10

[0484] 10-1 (54 mg, 0.072 mmol) and acetonitrile (3 mL) were added to a 25 mL single-mouth bottle, cooled to 0 ° C and stirred for 5 minutes, TMSOTf (0.033 mL, 0.18 mmol) was slowly added dropwise, stirred for 60 minutes, the reaction was stopped, saturated sodium bicarbonate aqueous solution (15 mL) was added to quench, and extracted with DCM (15 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and purified by TLC preparation using DCM / MeOH (v / v = 10 / 1) eluent to obtain 31 mg of yellow solid compound 10, with a yield of 66%, LC-MS (ESI, pos.ion) m / z: 654.2 [M+H] + ; 1 H NMR (400MHz, CD 3 OD)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, CD 3 OD):δ-55.72(3F),-141.83(1F). Example 11: Synthesis of Compound 11

[0485]

[0486]

[0487] Step 1: Synthesis of compound 11-1

[0488] 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, stirred for 5 minutes after the addition, dibromodifluoromethane (54.64 g, 260.4 mmol) was introduced, stirred at -10 °C for 1.5 h, then transferred to room temperature for reaction for 60 min, and zinc powder 1 was added. 3.63g, 208.32mmol), heated to 80℃ for 6 hours, stopped the reaction, cooled to room temperature, filtered through diatomaceous earth, added water (50mL) and saturated sodium chloride (100mL) to the filtrate, extracted with EA (100mL×3), separated, the organic phase was washed twice with saturated brine (100mL×2), evaporated to dryness, and the crude product was purified by column chromatography with PE / EA (v / v=1 / 1) eluent to obtain 4.95g of yellow oily compound 11-1, with a yield of 39%. LC-MS (ESI, pos.ion) m / z: 246.1[M+H] + Step 2: Synthesis of compound 11-2

[0489] At room temperature, lithium aluminum tetrahydride (0.46 g, 12.24 mmol) was added to a 100 mL two-necked flask. After nitrogen replacement 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, water (0.5 mL) was slowly added, and 15% sodium hydroxide solution (0.5 mL) was slowly added dropwise, and then water (1.5 mL) was added. The mixture was dried over anhydrous sodium sulfate, filtered, and the filter cake was rinsed with DCM (50 mL). The combined filtrate was evaporated to dryness to obtain 0.65 g of yellow oily compound 11-2 with a yield of 93%. LC-MS (ESI, pos.ion) m / z: 172.1 [M+H] + .

[0490] Step 3: Synthesis of compound 11-3

[0491] At room temperature, 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) were added to a 100 mL single-mouth bottle, and the atmosphere was replaced with nitrogen three times. 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 filtrate was combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography with DCM / MeOH (v / v=100 / 0-20 / 1) eluent to obtain 0.45 g of yellow-brown solid compound 11-3, with a yield of 20%. LC-MS (ESI, pos.ion) m / z: 601.3 [M+H]+ .

[0492] Step 4: Synthesis of compound 11-4

[0493] 11-3 (270 mg, 0.45 mmol), M6 (0.47 g, 0.90 mmol), K 3 PO 4 7H 2 O (450 mg, 1.35 mmol) and THF / H 2 O (7mL / 0.5mL), nitrogen replacement three times, Xphos Pd G3 (114mg, 0.135mmol) was added in batches, stirred at 35℃ for 4h, the reaction was stopped, saturated ammonium chloride solution (20mL) was added, and extracted with EA (30mL×2), the organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography with DCM / EA (v / v=1 / 1) eluent to obtain 135mg yellow solid compound 11-4, with a yield of 32%. LC-MS (ESI, pos.ion) m / z: 951.4[M+H] + .

[0494] Step 5: Synthesis of compound 11-5

[0495] 11-4 (135 mg, 0.14 mmol) and acetonitrile (3 mL) were added to a 50 mL single-mouth 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, the reaction was stopped, saturated sodium bicarbonate aqueous solution (20 mL) was added to quench, and extracted with EA (10 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate and concentrated to obtain a yellow solid compound 11-5. The yield was calculated as 100%. LC-MS (ESI, pos.ion) m / z: 807.3 [M+H] + .

[0496] Step 6: Synthesis of compound 11

[0497] 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-mouth bottle, replaced with nitrogen three times, stirred at room temperature for 16 h, the reaction was stopped, water (80 mL) was added, a solid was precipitated, and a solid crude product was obtained by filtration. The crude product was purified by TLC preparation plate with DCM / MeOH (v / v=8 / 1) eluent to obtain 35 mg of off-white solid compound 11, with a yield of 38%, LC-MS (ESI, pos.ion) m / z: 651.3 [M+H] + ; 1 H NMR (400MHz, CD3 OD)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, CD 3 OD): δ-111.50(1F),-131.02(1F),-140.03(1F).

[0498] Example 12: Synthesis of Compound 12-A and Compound 12-B

[0499]

[0500] Step 1: Synthesis of compound 12-1

[0501] 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 / H were added to a 25 mL two-necked bottle. 2 O (4mL / 0.3mL), nitrogen replacement three times, Xphos Pd G3 (76mg, 0.090mmol) was added in batches, nitrogen protection, stirring at 35°C for 16h, stopping the reaction, adding saturated ammonium chloride solution (10mL), extracting with EA (20mL×2), combining the organic phases, drying with anhydrous sodium sulfate, concentrating, and purifying with DCM / MeOH (v / v=20 / 1) eluent thin layer chromatography preparation plate to obtain 160mg yellow solid compound 12-1, yield 70%. LC-MS (ESI, pos.ion) m / z: 760.2[M+H] + .

[0502] Step 2: Synthesis of compound 12

[0503] 12-1 (160 mg, 0.21 mmol) and acetonitrile (3 mL) were added to a 25 mL single-mouth bottle, cooled to 0 ° C and stirred for 5 minutes, TMSOTf (0.23 g, 1.05 mmol) was slowly added dropwise, stirred for 1.5 h, the reaction was stopped, saturated sodium bicarbonate aqueous solution (15 mL) was added to quench, extracted with DCM (15 mL × 2), the organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and purified by thin layer chromatography preparation using DCM / MeOH (v / v = 8 / 1) eluent to obtain 20 mg of off-white solid compound 12-A (the spot with less polarity on the TLC plate), 17 mg of yellow solid compound 12-B (the spot with more polarity on the TLC plate), the yield was 27%, LC-MS (ESI, pos.ion) m / z: 660.3 [M+H] + Compound 12-A: 1 H NMR (599 MHz, CD 3 OD)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),3.5 5–3.48(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, CD 3 OD):δ-55.73(3F),-131.93(1F),-141.85(1F).Compound 12-B: 1 H NMR (599 MHz, CD 3 OD)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, CD 3OD): δ-55.73(3F),-133.28(1F),-141.84(1F).

[0504] Example 13: Synthesis of Compound 13

[0505]

[0506] Step 1: Synthesis of compound 13-1

[0507] At room temperature, lithium aluminum tetrahydride (1.24 g, 32.64 mmol) was added to a 100 mL two-necked flask. After nitrogen replacement three times, anhydrous THF (20 mL) was added, the temperature was lowered to 0°C, and 11-1 (2 g, 8.16 mmol, 20 mL of THF solution) was added dropwise. After the addition was completed, the reaction was allowed to proceed at 0°C for 6 h. The reaction was stopped, the temperature was lowered to 0°C, water (1.3 mL) was slowly added, and then 15% sodium hydroxide solution (1.3 mL) was slowly added dropwise, and then water (1.3 mL) was slowly added. A small amount of anhydrous sodium sulfate was added for drying, and the filter cake was rinsed with EA (20 mL). The filtrate was evaporated to dryness to obtain 1.4 g of yellow oily compound 13-1, with a yield of 45%. LC-MS (ESI, pos.ion) m / z: 190.0 [M+H] + .

[0508] Step 2: Synthesis of compound 13-2

[0509] At room temperature, 100 mL single-mouth bottle was added 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), nitrogen was replaced 3 times, and the reaction was carried out at room temperature for 1.5 h. The reaction was stopped, water (30 mL) and EA (30 mL) were added, and then saturated sodium chloride (20 mL) was added, the organic phase was separated, washed with saturated sodium chloride (20 mL × 2), the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography with DCM / EA (v / v = 1 / 1) eluent to obtain a yellow-white solid compound, the solid was slurried with EA (4 mL) for 10 minutes, the solid was filtered to remove the solid, and the filtrate was spin-dried to obtain 0.15 g of brown solid compound 13-2, with a yield of 11%. LC-MS(ESI,pos.ion)m / z:619.3[M+H] + .

[0510] Step 3: Synthesis of compound 13-3

[0511] 11-3 (150 mg, 0.24 mmol), M6 (0.25 g, 0.48 mmol), K 3 PO4 7H 2 O (320 mg, 0.96 mmol) and THF / H 2 O (4mL / 0.3mL), nitrogen replacement three times, add Xphos Pd G3 (61mg, 0.072mmol), stir at 35℃ for 6h, stop the reaction, add saturated ammonium chloride solution (10mL), extract with EA (20mL×2), combine the organic phases and dry with anhydrous sodium sulfate, concentrate, and purify with DCM / EA (v / v=1 / 1) eluent column chromatography to obtain 100mg brown solid compound 13-3, with a yield of 42%. LC-MS (ESI, pos.ion) m / z: 969.4[M+H] + .

[0512] Step 4: Synthesis of compound 13-4

[0513] 13-3 (100 mg, 0.10 mmol) and acetonitrile (2 mL) were added to a 50 mL single-mouth 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, the reaction was stopped, saturated sodium bicarbonate aqueous solution (10 mL) was added to quench, and extracted with EA (10 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate and concentrated to obtain a yellow solid compound 13-4. The yield was calculated as 100%. LC-MS (ESI, pos.ion) m / z: 825.3 [M+H] + .

[0514] Step 5: Synthesis of compound 13

[0515] 13-4 (85 mg, 0.10 mmol), cesium fluoride (91 mg, 0.60 mmol) and DMF (1 mL) were added to a 25 mL single-mouth bottle, replaced with nitrogen three times, stirred at room temperature for 16 h, the reaction was stopped, water (80 mL) was added, a solid was precipitated, and a solid crude product was obtained by filtration. The crude product was purified by TLC preparation plate with DCM / MeOH (v / v=9 / 1) eluent to obtain 10 mg of off-white solid compound 11, with 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, CD 3 OD): δ-92.80(2F),-111.50(1F),-140.14(1F).

[0516] Example 14: Synthesis of Compound 14

[0517]

[0518] The synthesis of compound 14 was carried out according to the synthesis steps of compound 13, and M9 was used to replace M6, and finally 12 mg of light yellow solid compound 14 was obtained. LC-MS (ESI, pos.ion) m / z: 678.3 [M+H] + .

[0519] Example 15: Synthesis of Compound 15

[0520]

[0521] Step 1: Synthesis of compound 15-1

[0522] 2-1 (150 mg, 0.25 mmol), M10 (190 mg, 0.30 mmol, synthesized by referring to the synthesis method of 001-5D in pages 30-31 of patent WO2023138662), Xphos Pd G4 (22 mg, 0.025 mmol), K 3 PO 4 7H 2 O (250 mg, 0.75 mmol) and THF / H 2O (6mL / 2mL), replaced with nitrogen three times, stirred at room temperature for 16h, added saturated ammonium chloride solution (20mL), extracted with EA (10mL×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) eluent to obtain 60mg orange solid compound 15-1, with a yield of 22%. LC-MS (ESI, pos.ion) m / z: 1065.4 [M+H] + .

[0523] Step 2: Synthesis of compound 15-2

[0524] 15-1 (60 mg, 0.056 mmol) and acetonitrile (2 mL) were added to a 50 mL single-mouth bottle, cooled to 0 ° C and stirred for 5 minutes, concentrated sulfuric acid (0.054 g, 0.56 mmol) was slowly added dropwise, stirred for 120 minutes, the reaction was stopped, saturated sodium bicarbonate aqueous solution (10 mL) was added to quench, extracted with DCM (10 mL × 2), the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated to obtain a brown solid compound crude product 15-2, which was directly used in the next step. The yield was calculated as 100%, LC-MS (ESI, pos.ion) m / z: 800.3 [M+H] + .

[0525] Step 3: Synthesis of compound 15

[0526] 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-mouth bottle, replaced with nitrogen three times, stirred at room temperature for 14 h, the reaction was stopped, water (10 mL) was added, a solid was precipitated, and a solid crude product was obtained by filtration. The crude product was purified by TLC preparation plate with DCM / MeOH (v / v=12 / 1) eluent to obtain 10 mg of brown solid compound 15, with a yield of 28%, LC-MS (ESI, pos.ion) m / z: 644.4 [M+H] + ; 1 H NMR (400MHz, CD 3 OD)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),3.7 4–3.64(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). 19F NMR (376MHz, CD 3 OD)δ-113.31(1F),-140.06(1F).

[0527] Example 16: Synthesis of Compound 16

[0528]

[0529]

[0530] Step 1: Synthesis of compound 16-1

[0531] In a 100 mL single-mouth bottle, add M11 (3 g, 8.08 mmol, purchased from Shaoyuan Technology), bipyraclostrobin (3.08 g, 12.12 mmol), Pd(dppf)Cl 2 ·DCM·(0.79g, 0.97mmol), potassium acetate (2.38g, 24.24mmol) and 1,4-dioxane (100mL), after nitrogen replacement three times, heated to 85°C and stirred for 16h, the reaction was stopped, the reaction solution was filtered with diatomaceous earth, concentrated, and the crude product was purified by column chromatography with PE / DCM (v / v=10 / 1-2 / 1) eluent to obtain 2.83g of white solid compound 16-1, with a yield of 84%. LC-MS (ESI, pos.ion) m / z: 417.2[M+H] + .

[0532] Step 2: Synthesis of compound 16-2

[0533] 2-1 (110 mg, 0.18 mmol), 16-1 (110 mg, 0.27 mmol), potassium phosphate heptahydrate (180 mg, 0.54 mmol) and 1,4-dioxane / H2O were added to a 50 mL two-necked bottle. 2 O (4mL / 1mL), and cataCXium A Pd G3 (13mg, 0.018mmol), nitrogen protection, stirring at 60℃ for 14h, stopping the reaction, adding saturated ammonium chloride solution (10mL), extracting with EA (20mL×2), combining the organic phases, drying with anhydrous sodium sulfate, concentrating, and purifying with DCM / MeOH (v / v=40 / 1) eluent thin layer chromatography preparation plate to obtain 115mg yellow solid compound 16-2, with a yield of 73%. LC-MS (ESI, pos.ion) m / z: 851.3[M+H] + .

[0534] Step 3: Synthesis of compound 16

[0535] 16-2 (100 mg, 0.118 mmol) and DCM (1 mL) were added to a 50 mL single-mouth bottle, cooled to 0 ° C and stirred for 5 minutes, trifluoroacetic acid (1 mL) was slowly added dropwise, stirred at room temperature for 4 h, the reaction was stopped, saturated sodium bicarbonate aqueous solution (15 mL) was slowly added to quench, and extracted with DCM / MeOH (15 / 1 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by TLC preparation using DCM / MeOH (v / v=9 / 1) eluent to obtain 10 mg of gray solid compound 16, with a yield of 13%, LC-MS (ESI, pos.ion) m / z: 651.3 [M+H] + ; 1 H NMR (400MHz, CD 3 OD)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, CD 3 OD): δ-118.00(1F),-141.85(1F).

[0536] Example 17: Synthesis of Compound 17

[0537]

[0538]

[0539] Step 1: Synthesis of compound 17-1

[0540] In a 250 mL three-necked flask, add N-BOC-trans-4-fluoro-L-proline methyl ester (5.00 g, 20.2 mmol, Shanghai Bid Pharmaceuticals), cool to -45 °C and stir for 10 minutes, then slowly add LiHMDS (30.33 mL, 30.33 mmol, 1 M THF solution), stirred at -45 °C for 60 min, slowly added 3-chloro-2-(chloromethyl)prop-1-ene (3.03 g, 24.26 mmol, dissolved in 15 mL of anhydrous THF), slowly heated to room temperature (about 1 h) after the addition, stopped stirring, slowly added saturated ammonium chloride solution (20 mL) to quench the reaction, separated the liquids, extracted the aqueous phase with EA (50 mL × 2), combined the organic phases, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography with PE / EA (v / v = 20 / 1-5 / 1) eluent to obtain 6.06 g of yellow oily compound 17-1, with a yield of 89%. LC-MS (ESI, pos.ion) m / z: 236.0 [M-Boc+H+H] + .

[0541] Step 2: Synthesis of compound 17-2

[0542] In a 250mL single-mouth bottle, add 17-1 (6.06g, 18.05mmol) and DCM (100mL), cool to 0℃ and stir for 5 minutes, add hydrogen chloride in dioxane solution (22.56mL, 90.25mmol, 4M) dropwise, transfer to room temperature and stir for 14.5h after the addition is complete. Stop stirring, concentrate the reaction solution directly, drain to obtain 17-2, which is directly used in the next step, and the yield is calculated as 100%. LC-MS (ESI, pos.ion) m / z: 236.0 [M+H] + Step 3: Synthesis of compound 17-3

[0543] In a 250 mL single-mouth bottle, add 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) and stir at room temperature for 2 h. Stop stirring, filter the reaction solution, wash with acetonitrile (50 mL), concentrate, and purify with PE / EA (v / v=4 / 1-3 / 2) eluent column chromatography to obtain 3.00 g of yellow oily compound 17-3, with a yield of 83.5%. LC-MS (ESI, pos.ion) m / z: 200.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3)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,1 H),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).

[0544] Step 4: Synthesis of compound 17-4

[0545] In a 100mL single-mouth bottle, add 17-3 (400mg, 2.01mmol), replace with nitrogen three times, add anhydrous DCM (12mL), cool to -20℃ and stir for 10 minutes, slowly add diethyl zinc reagent (10.05mL, 10.05mmol, 1M n-hexane solution), and stir for 30 minutes. Slowly add diiodomethane (1.62mL, 20.10mmol), transfer to 0℃ and stir for 3h. Add saturated ammonium chloride (20mL) to quench. Extract the aqueous phase with EA (20mL×2), combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and purify with PE / EA (v / v=7 / 3) eluent column chromatography to obtain 223mg of yellow oily compound 17-4, with a yield of 52%. LC-MS (ESI, pos.ion) m / z: 214.4[M+H] + ; 1 H NMR (400 MHz, CDCl 3 )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),2.9 1–2.76(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).

[0546] Step 5: Synthesis of compound 17-5

[0547] In a 100 mL two-necked bottle, add LiAlH 4(0.79 g, 2.08 mmol), nitrogen was replaced 3 times, moved 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, and after the addition was complete, the temperature was raised to 0 ° C and stirred for 3.5 h. Sodium sulfate decahydrate was slowly added to quench the reaction, filtered through diatomaceous earth, concentrated and dried to obtain 162 mg of yellow oil 17-5, with a yield of 84%. LC-MS (ESI, pos.ion) m / z: 186.2 [M+H] + .

[0548] Step 6: Synthesis of compound 17-6

[0549] 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-mouth bottle, replaced with nitrogen three times, heated to 100 ° C and stirred for 8 h, the reaction was stopped, cooled to room temperature, the reaction solution was concentrated, EA (20 mL) was added for dilution, filtered, concentrated, and purified by column chromatography with DCM / MeOH (v / v=50 / 1) eluent to obtain 160 mg of red solid compound 17-6, with a yield of 13%. LC-MS (ESI, pos.ion) m / z: 615.3 [M+H] + .

[0550] Step 7: Synthesis of compound 17-7

[0551] Compound 17-6 (80 mg, 0.13 mmol), M9 (63 mg, 0.20 mmol), XphosPd G3 (22 mg, 0.026 mmol), K 3 PO 4 7H 2 O (130 mg, 0.39 mmol) and THF / H 2 O (v / v=2.5mL / 0.8mL), replaced with nitrogen three times, stirred at room temperature for 1h, added Xphos Pd G3 (22mg, 0.026mmol), continued stirring at room temperature for 8h, stopped the reaction, added DCM (15mL) to dilute, washed with saturated ammonium chloride (15mL), extracted with DCM (15mL×2), the organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and purified by thin layer chromatography with DCM / MeOH (v / v=40 / 1) eluent to obtain 51mg of red solid compound 17-7, with a yield of 51%. LC-MS (ESI, pos.ion) m / z: 774.2[M+H] + .

[0552] Step 8: Synthesis of compound 17

[0553] Compound 17-7 (51 mg, 0.066 mmol) and acetonitrile (2 mL) were added to a 25 mL single-mouth bottle, cooled to 0°C and stirred for 5 minutes, TMSOTf (0.024 mL, 0.13 mmol) was added dropwise, stirred at 0°C for 60 minutes, the reaction was stopped, saturated sodium bicarbonate aqueous solution (15 mL) was added to quench, extracted with DCM (20 mL × 2), the organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and drained, and the crude product was purified by thin layer chromatography with DCM / MeOH (v / v=10 / 1) eluent to obtain 28 mg of yellow solid compound 17, with a yield of 63%. LC-MS (ESI, pos.ion) m / z: 674.2 [M+H] + ; HRMS (ESI): 674.2425 [M+H] + ; 1 H NMR (400MHz, CD 3 OD)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 FNMR (376MHz, CD 3 OD)δ-55.73(3F),-141.87(1F),-175.37(1F).

[0554] Example 18: Synthesis of Compound 18

[0555]

[0556] Step 1: Synthesis of compound 18-1

[0557] Compound 17-6 (80 mg, 0.13 mmol), M6 (0.13 g, 0.26 mmol), Xphos Pd G3 (22 mg, 0.026 mmol), K 3 PO 4 7H 2 O (130 mg, 0.39 mmol) and THF / H 2O (v / v=2.5mL / 0.8mL), replaced with nitrogen three times, stirred at room temperature for 1h, added Xphos Pd G3 (0.2equiv.), continued stirring at room temperature for 2h, stopped the reaction, added DCM (15mL) to dilute, washed with saturated ammonium chloride (15mL), extracted with DCM (15mL×2), the organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and purified by thin layer chromatography with DCM / MeOH (v / v=50 / 1) eluent to obtain 56mg of red oily compound 18-1, with a yield of 45%. LC-MS (ESI, pos.ion) m / z: 965.4[M+H] + .

[0558] Step 2: Synthesis of compound 18-2

[0559] Compound 18-1 (56 mg, 0.058 mmol) and acetonitrile (3 mL) were added to a 25 mL single-mouth 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 sodium bicarbonate aqueous solution (20 mL) was added to quench, and 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 with DCM / MeOH (v / v=9 / 1) eluent to obtain 25 mg of red solid compound 18-2, with a yield of 52%. LC-MS (ESI, pos.ion) m / z: 821.3 [M+H] + .

[0560] Step 3: Synthesis of compound 18

[0561] 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-mouth bottle, replaced with nitrogen three times, stirred at room temperature for 13 h, the reaction was stopped, 10 mL of water was added, a solid was precipitated, and a solid crude product was obtained by filtration. The crude product was purified by thin layer chromatography with DCM / MeOH (v / v=8 / 1) as the eluent to obtain 18 mg of yellow solid compound 18, with a yield of 89%, LC-MS (ESI, pos.ion) m / z: 665.3 [M+H] + ; HRMS (ESI): 665.2824 [M+H] + ; 1 HNMR (400MHz, CD 3OD)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,1H), 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, CD 3 OD): δ-111.53(1F),-140.24(1F),-175.34(1F).

[0562] Examples 19-24 (i.e., Compound 19-24) were prepared with reference to the method for constructing the mother 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 the technician based on the conventional technical knowledge in the field. The structures and characterization data of Examples 19-42 are shown in the following table.

[0563]

[0564]

[0565]

[0566] Biologically active examples

[0567] 1. KRAS G12D / cRAF binding experiment

[0568] Experimental steps:

[0569] (1) Compounds were prepared with DMSO and diluted 3-fold in series with DMSO.

[0570] (2) Add 0.1 μl of serially diluted compounds to a 384-well plate.

[0571] (3) Add 5 μl of specific concentration of Tag2-KRASG12D>P to the 384-well plate and centrifuge at 1000 rpm for 1 minute.

[0572] (4) Add 5 μl of Tag1-cRAF of a specific concentration to the 384-well plate and centrifuge at 1000 rpm for 1 minute.

[0573] (5) Incubate at 25°C for 15 minutes.

[0574] (6) Add 10 μl of the mixture of anti-Tag1-Eu and anti-Tag2-XL665 to the 384-well plate.

[0575] (7) Centrifuge at 1000 rpm for 1 minute and incubate at 4°C for 3 hours.

[0576] (8) Read the 665 / 615 nm ratio using an ELISA reader.

[0577] (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.

[0578] Conclusion: The compounds of the present invention can effectively bind to KRAS G12D-GTP and inhibit the binding of KRAS to cRAF protein. Among them, the IC of the compounds of the present invention for KRAS G12D-GTP / cRAF 50 Preferably, the IC of the compounds of the present invention for KRAS G12D-GTP / cRAF 50 Less than 20nM.

[0579] 2. KRAS G12D / SOS1 binding experiment

[0580] Experimental steps:

[0581] (1) Compounds were prepared with DMSO and diluted 3-fold in series with DMSO.

[0582] (2) Add 0.1 μl of serially diluted compounds to a 384-well plate.

[0583] (3) Add 5 μl of specific concentration of Tag2-KRASG12D>P to the 384-well plate and centrifuge at 1000 rpm for 1 minute.

[0584] (4) Add 5 μl of Tag1-SOS1 of a specific concentration to the 384-well plate and centrifuge at 1000 rpm for 1 minute.

[0585] (5) Incubate at 25°C for 15 minutes.

[0586] (6) Add 10 μl of anti-Tag1-Tb to the 384-well plate. 3+ and a mixture of anti-Tag2-XL665.

[0587] (7) Centrifuge at 1000 rpm for 1 minute and incubate at 4°C for 3 hours.

[0588] (8) Read the 665 / 615 nm ratio using an ELISA reader.

[0589] (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.

[0590] Conclusion: The compounds of the present invention can effectively bind to KRAS G12D-GTP and inhibit the binding of KRAS to SOS1 protein. Among them, the IC of the compounds of the present invention for KRAS G12D-GTP / SOS1 is 50 Preferably, the IC of the compounds of the present invention for KRAS G12D-GTP / SOS1 is less than 50 nM. 50 Less than 20nM.

[0591] 3. In-cell Western method to detect the inhibitory effect of compounds on intracellular pERK

[0592] Reagents used

[0593]

[0594]

[0595] Experimental steps:

[0596] (1) On the first day, the following cells were revived with the corresponding culture medium and placed at 37°C with 5% CO 2 Incubate in incubator until confluent:

[0597]

[0598] (2) On the third day, the culture medium was removed and the cells were rinsed once with DPBS. 2 mL of TrypLE TM Trypsin was used for digestion and kept at room temperature until cells were detached.

[0599] (3) Add 5 mL of new culture medium to resuspend the cells to terminate digestion, gently pipette the cells, and centrifuge at 1000 rpm for 5 minutes at room temperature.

[0600] (4) Remove the supernatant, add 5 mL of new culture medium to resuspend the cells, and count them.

[0601] (5) Adjust the cell concentration to an appropriate level using the cell culture medium and plate the cells in a 384-well plate at 37°C in a 5% CO 2 Incubate overnight in an incubator.

[0602] (6) Add 200 nL of the prepared gradient dilution compound (DMSO final concentration is 0.5%) and place in a 37°C 5% CO 2 Incubate in the incubator for 3 h (HPAC cell lines only need to be incubated in the incubator for 1 h).

[0603] (7) Fix the cells.

[0604] (8) Wash twice with PBS.

[0605] (9) Add blocking solution and incubate at room temperature for 1 hour.

[0606] (10) Remove the blocking solution, add the primary antibody (phospho-ERK Rabbit mAb + GAPDH (D4C6R) MousenAb), and incubate at 4°C overnight.

[0607] (11) Wash twice with PBST (PBS + 0.05% Tween 20), 2 minutes each time.

[0608] (12) Remove PBST and add secondary antibody (IRDye 800CW Goat anti-Rabbit IgG(H+L)+IRDye680RD Goat anti-Mouse IgG(H+L)) at room temperature in the dark.

[0609] (14) Discard the secondary antibody and wash twice with PBST, 2 minutes each time.

[0610] (15) The 384-well plate was inverted, centrifuged at 1000 rpm for 1 min at room temperature, and the 384-well plate was scanned using the Odyssey CLx.

[0611] (16) Data analysis:

[0612] a) Perform assay stability checks using DMSO and reference control data:

[0613] Relative signal value = pERK (signal value of 800 channel) / GAPDH (signal value of 700 channel)

[0614] Inhibition rate % = 100-(Signal value of each sample-Relative signal value of quality control product) / (Signal value of DMSO well-Relative signal value of quality control product)×100

[0615] b) Compound IC 50Nonlinear fitting:

[0616] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)×HillSlope)).

[0617] 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.

[0618] Table A Inhibitory effect of the compounds of the present invention on pERK in KRAS G12D mutant cell line AGS

[0619]

[0620] 4. In-cell Western method to detect the inhibitory effect of compounds on intracellular pERK

[0621] Reagents used

[0622]

[0623] Experimental steps:

[0624] (2) On the first day, the following cells were revived with the corresponding culture medium and placed at 37°C with 5% CO 2 Incubate in incubator until confluent:

[0625]

[0626]

[0627] (2) On the third day, remove the culture medium, add 2 mL of trypsin for digestion, and place in an incubator until the cells fall off.

[0628] (3) Add 5 mL of new culture medium to resuspend the cells to terminate digestion, gently pipette the cells, and centrifuge at 1000 rpm for 5 minutes at room temperature.

[0629] (4) Remove the supernatant, add 5 mL of new culture medium to resuspend the cells, and count them.

[0630] (5) Adjust the cell concentration to an appropriate level with complete culture medium and plate the cells in a 96-well plate. Add 90 μL of culture medium to each well and place in a 37°C, 5% CO 2 Incubate overnight in an incubator.

[0631] (6) Add 10 μL of the prepared gradient dilution compound (DMSO final concentration is 0.5%) and place in a 37°C 5% CO 2 Incubate in incubator for 2h.

[0632] (7) Discard the supernatant and add 200 μL of 4% paraformaldehyde fixative to each cell.

[0633] (8) Wash with TBST three times.

[0634] (9) Add blocking solution and incubate at room temperature for 1 hour.

[0635] (10) Remove the blocking solution, add the primary antibody (phospho-ERK Rabbit mAb + α-Tubulin (DM1A) MousenAb), and incubate at 4°C overnight.

[0636] (11) Wash three times with 1× PBST, 5 min each time.

[0637] (12) Remove PBST and add secondary antibody (IRDye 800CW Goat anti-Rabbit IgG(H+L)+IRDye680RD Goat anti-Mouse IgG(H+L)) at room temperature in the dark.

[0638] (14) Discard the secondary antibody and wash with PBST three times, 5 minutes each time.

[0639] (15) The 96-well plate was inverted, centrifuged at 1000 rpm for 1 min at room temperature, and scanned using the Odyssey CLx.

[0640] (16) Data analysis:

[0641] c) Perform assay stability checks using DMSO and reference control data:

[0642] Relative signal value = pERK (signal value of 800 channel) / GAPDH (signal value of 700 channel)

[0643] Inhibition rate % = 100-(Signal value of each sample-Relative signal value of quality control product) / (Signal value of DMSO well-Relative signal value of quality control product)×100

[0644] d) Compound IC 50 Nonlinear fitting:

[0645] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)×HillSlope)).

[0646] 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.

[0647] Table B Inhibitory effect of the compounds of the present invention on pERK in KRAS G12D mutant cell lines

[0648]

[0649] 5. 3D-CTG method detects the effect of compounds on the proliferation inhibition of KRAS G12D mutant cells:

[0650] Reagents used

[0651]

[0652]

[0653] Experimental steps:

[0654] (1) On the first day, the following cells were revived with the corresponding culture medium and placed at 37°C with 5% CO 2 Incubate in incubator until confluent:

[0655] cell Culture medium 96-well plate cell number ASPC-1 RPMI-1640+10% fetal bovine serum+1% double antibody 3000 / hole PK-59 RPMI-1640+10% fetal bovine serum+1% double antibody 3000 / hole Panc040.03 RPMI-1640+10% fetal bovine serum+1% double antibody 3000 / hole

[0656] (2) On the next 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 digestion, transfer the cells to a centrifuge tube, and centrifuge at 1000 rpm for 5 minutes.

[0657] (3) Resuspend the cells in complete culture medium, count the cells, and adjust the cell concentration to an appropriate level using complete culture medium.

[0658] (4) Add 90 μl / well of the cell suspension to a 96-well plate and place in a 37°C, 5% CO 2 Incubate overnight in an incubator.

[0659] (5) Add 10 μl of the prepared 10× gradient dilution compound (final DMSO concentration is 0.5%) to each well and place in a 37°C 5% CO 2 Incubate in incubator.

[0660] (6) After the 7th day of incubation, add 50 μl of 3D CTG detection reagent to each well and place the well on a shaker at 350 rpm for 20 minutes.

[0661] (7) Read the signal value using an enzyme meter.

[0662] (8) Data analysis:

[0663] The IC50 values ​​of the compounds were fitted using the nonlinear regression equation of Graphpad software.

[0664] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0665] X: log value of compound concentration

[0666] Y: Inhibition rate (%inh)

[0667] Conclusion: The compounds of the present invention have good inhibitory activity on the proliferation of KRAS-G12D mutant cell lines. See Table C for the effects of some compounds of the present invention on KRAS-G12D mutant cell lines.

[0668] Table C Inhibitory effect of the compounds of the present invention on cell proliferation of KRAS G12D mutant cell lines

[0669]

[0670] 6. 3D-CTG method to detect the effect of compounds on the inhibition of GP2D and HPAC cell proliferation:

[0671] Experimental steps:

[0672] (1) GP2D and HPAC cells were revived with DMEM medium containing 10% fetal bovine serum and used for experiments after the cells recovered.

[0673] (2) On the first day, wash the cells once with PBS, add preheated trypsin, and place in a 37°C, 5% CO 2 Digest in an incubator for 3 to 5 minutes; add an appropriate amount of complete culture medium (containing 10% fetal bovine serum) to terminate the digestion, transfer it to a centrifuge tube, and centrifuge at 1000 rpm for 5 minutes.

[0674] (3) Resuspend the cells in complete culture medium, count the cells, and adjust the cell concentration to an appropriate level using complete culture medium.

[0675] (4) Using the ECHO 655 sonic 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, and 40 μl of the cell suspension counted in step (3) was added to each well. The plate was placed in a 37°C, 5% CO 2 Incubate in incubator.

[0676] (6) After the 8th day of incubation, 3D CTG detection reagent was added to each well.

[0677] (7) Use Envision to read the signal value.

[0678] (8) Data analysis:

[0679] a) Use DMSO and culture medium to test the stability of the experimental method:

[0680] H = DMSO wells

[0681] L = culture medium well

[0682] H, CV% (DMSO well) = 100 × (DMSO well SD value / DMSO well average value)

[0683] L, CV% (corresponding culture medium well) = 100 × (culture medium well SD value / corresponding culture medium well average value)

[0684] Z' = 1-3 × (DMSO well SD value + culture medium well SD value) / (DMSO well average value - corresponding culture medium well average value)

[0685] Inhibition rate, % = (mean value of DMSO wells – mean value of sample wells) / (mean value of DMSO wells – mean value of corresponding culture medium wells) x 100

[0686] b) The IC50 values ​​of the compounds were fitted using the nonlinear regression equation of XLfit 5.5.0 software.

[0687] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0688] X: log value of compound concentration

[0689] Y: Inhibition rate (%inh)

[0690] 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 values ​​of most compounds for inhibition of cell proliferation as described above 50 <100nM; most of the compounds have an IC value of less than 100nM for the inhibition of cell proliferation mentioned above. 50 <10 nM. Therefore, the compounds of the present invention have good inhibitory effects on the proliferation of GP2D and HPAC cells. The partial inhibitory activities of some compounds of the present invention are shown in Table D-1 and Table D-2.

[0691] Table D-1 Inhibitory effect of the compounds of the present invention on cell proliferation of KRAS G12D mutant cell line GP2D

[0692]

[0693] Table D-2 Inhibitory effect of the compounds of the present invention on cell proliferation of KRAS G12D mutant cell line HPAC

[0694]

[0695]

[0696] VII. Quantitative pharmacokinetic evaluation of the compounds of the present invention by intravenous injection or oral gavage in mice, rats and dogs

[0697] The inventors have evaluated the pharmacokinetic properties of the compounds of the present invention in mice, rats and dogs. The animal information is shown in Table 2.

[0698] Table 2: Information table of the test animals of the present invention

[0699] Germline grade gender weight age source BALB / c mice SPF male 18-30g 6-8 weeks Hunan Slake Jingda Experimental Animal Co., Ltd. SD rats SPF male 180-350g 6-11 weeks Hunan Slake Jingda Experimental Animal Co., Ltd. Beagle dog General male 7~12kg June-December Beijing Masi Biotechnology Co., Ltd. Cynomolgus monkey General male 2.5~6.0kg 3-6 years old Guangzhou Huazhen Biotechnology Co., Ltd.

[0700] Experimental methods

[0701] 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 administration group, the dosage was 1 mg / kg, and blood was collected venously at the following time points after administration (blood volume was about 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-K was pre-added in the blood collection tube. 2 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 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 about 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), and EDTA-K was added in advance to the blood collection tube. 2 As an anticoagulant, blood samples were centrifuged at 12,000 rpm for 2 minutes, and plasma was collected and stored at -20°C or -70°C.

[0702] The collected plasma samples were processed (frozen plasma was thawed at room temperature, vortexed for 15 seconds to mix, 10-20 μL of plasma was taken, 120-150 μL of acetonitrile solution containing internal standard was added, vortexed for 5 minutes to mix, centrifuged at 4,000 rpm for 5 minutes, 100 μL of supernatant was taken, 120-150 μL of methanol / water (v / v=1 / 1) was added to mix), and then the concentration of the compound in the plasma was analyzed by LC-MS / MS.

[0703] The analysis results show that the compounds of the present invention have good pharmacokinetic properties in mice, rats and dogs, indicating that the compounds of the present invention have better drugability and better clinical application prospects.

[0704] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "some implementation schemes", "example", "specific example" or "some examples" etc. 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 the different embodiments, implementation schemes or examples described in this specification and the features of the different embodiments, implementation schemes or examples, without contradiction.

[0705] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, substitute and vary the above embodiments within the scope of the present invention without departing from the principles and intent 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 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 Haloalkyl, C 2-6 Halogenated alkenyl, C 2-6 Haloalkynyl, C 1-6 Haloalkoxy, 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 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)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, -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 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 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, pyridyl, 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 alkylthio halide, 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 and the 3- to 6-membered heterocyclic group are substituted.

7. The compound according to any one of claims 1 to 6, wherein 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)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, 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, - 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, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl and piperazinyl. , 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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