KRAS inhibitor compound, and pharmaceutical composition and use thereof

Abstract

The present invention relates to the technical field of drugs, and relates to a KRAS inhibitor compound, and a pharmaceutical composition and use thereof. Specifically, the present invention relates to 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). The present invention relates to the compound and the pharmaceutical composition thereof, as well as a use of the compound and the pharmaceutical composition thereof in the preparation of a drug for preventing or treating KRAS-mediated related diseases, especially in the preparation of a drug for preventing or treating cancers.

Description

KRAS inhibitor compounds, pharmaceutical compositions thereof and their uses Technical Field

[0001] This invention belongs to the field of pharmaceutical technology. Specifically, this invention relates to a KRAS inhibitor compound, a pharmaceutical composition thereof, and the use of such compounds and pharmaceutical compositions thereof in the preparation of medicaments for the prevention or treatment of KRAS-mediated diseases. Background Technology

[0002] The RAS gene is one of the most commonly mutated genes in cancer (20%-25%). The known members of the RAS gene family include KRAS, NRAS, and HRAS, with KRAS mutations being the most common, accounting for approximately 85%. KRAS has the highest mutation rate in pancreatic ductal adenocarcinoma (PDAC), reaching 97%, followed by colorectal cancer, multiple myeloma, and lung cancer, at 52%, 42%, and 32%, respectively. The most frequently mutated sites in the KRAS gene are codons 12, 13, and 61, with mutations including KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12A, KRAS G12V, KRAS G13D, and KRAS Q61H. RAS gene mutations are often associated with poor prognosis in cancer. KRAS can be transiently activated by upstream growth factors or tyrosine kinases (such as EGFR). Activated KRAS can activate downstream pathways, such as the PI3K-AKT-mTOR signaling pathway that controls cell production and the RAS-RAF-MEK-ERK signaling pathway that controls cell proliferation. This provides a biological basis for the combined use of many targets.

[0003] In recent years, researchers have made some progress in drug development using allosteric sites of KRAS G12C mutants. For example, in 2013, a research group reported the discovery of small molecule inhibitors of KRAS G12C (Nature, 2013, 503, 548-551). They identified a novel binding pocket located below the molecular switch II region in the KRAS G12C mutant. These inhibitors bind to this allosteric pocket and covalently bind to nearby Cys12, thereby selectively inhibiting the activation of KRAS G12C. Since the KRAS G12C target protein is pathologically associated with a variety of diseases, there is still a need for novel KRAS G12C inhibitors for clinical treatment. Highly selective and highly active KRAS G12C inhibitors can effectively treat diseases such as cancer caused by KRAS G12C mutations and have the potential to reduce off-target effects, thus meeting a more urgent clinical need. Summary of the Invention

[0004] This invention provides a compound that can be used as a KRAS inhibitor. It also relates to pharmaceutical compositions comprising this class of compounds, and the use of this class of compounds and pharmaceutical compositions thereof in the preparation of medicaments for the prevention or treatment of KRAS-mediated diseases. The medicament treats diseases and / or conditions, particularly cancer, by inhibiting KRAS activity.

[0005] On the one hand, the present invention provides compounds of formula (I), or stereoisomers, tautomers, nitrides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of compounds of formula (I).

[0006] in,

[0007] Q 1 For N or CH;

[0008] R 1 is -H, -D, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, -C(=O)OR 9a -C(=O)NR 9 R 10 -C(=O)R 9a -S(=O)2NR 9 R 10 -NR 9 R 10 C 1-6 Alkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, 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 1-6 mercaptoalkyl, C 6-10 Aryl, 5-12 heteroaryl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups;

[0009] Each R 5a R 5b R 5c R 5d R 5e R 5f R 5g and R 5hIndependently, it can be H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -COOH, oxo, -NHC(=O)H, -C(=O)R 9c -C(=O)OR 9c -C(=O)NR 9b R 10b -NR 9b C(=O)R 10b -NR 9b S(=O)2R 10b -S(=O)2N(R) 10b )2、-NR 9b C(=O)N(R 10b )2、-NR 9b S(=O)2N(R 10b )2、-OS(=O)2N(R 10b )2、-S(=O)2R 9c -C 1-6 Alkylene-S(=O)2N(R) 10b 2. C 1-6 Alkyl, C 1-6 Alkylthio, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 2-6 Haloalkenyl, C 2-6 Halogenated alkynyl group, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkylthio group, C 6-10 Aryl, 5-10 heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups;

[0010] Ring B is C 6-12 Aryl or 5-12 heteroaryl groups;

[0011] Each R 2 Independently, it can be H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -NH2, or -CH2C(=O)NR. 9b R 10b -C(=O)R 9c -C(=O)OR 9c -C(=O)NR 9b R 10b -NR 9b C(=O)R10b -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Hydroxyalkynyl group, C 1-6 Alkoxy, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 2-6 Haloalkenyl, C 2-6 Halogenated alkynyl group, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkylthio group, C 6-12 Aryl, 5-12 heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Hydroxyalkynyl group, C 1-6 Alkoxy, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 2-6 Haloalkenyl, C 2-6 Halogenated alkynyl group, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkylthio group, C 6-12 Aryl, 5-12 heteroaryl, C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 11 Replaced;

[0012] Each R 11 Independently, it can be D, -OH, -F, -Cl, -Br, -I, CN, -C(=O)OR 9 -NR 9 R 10 -C(=O)NR 9 R 10 -NR 9 C(=O)R 10 C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups;

[0013] R 3 -H, -D, -OH, -SH, -F, -Cl, -Br, -I, -CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, or C 1-4 Halogenated alkyl groups;

[0014] L stands for bond, C 1-4 Alkylene or C 1-4 Heteroalkylene, the C 1-4 Alkylene and C 1-4 Each heteroalkyl group is independently and optionally surrounded by 1, 2, 3 or 4 R's. 12a Replaced;

[0015] Each R 12a Independently -H, -D, -OH, -F, -Cl, -Br, -I, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or C 1-6 Cyanoalkyl; or two R atoms attached to the same carbon atom 12a Together with the carbon atom attached to it, they form C 3-6 Carbon rings or 3-6 membered heterocycles;

[0016] R 4 for

[0017] Where R 12f and R 12g Each of the following can be independently -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 9d R 10d -C(=O)NR 9d R 10d -CH2NR 9d R 10d -CH2OC(=O)NR 9d R 10d C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Cyanoalkyl, (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 groups;

[0018] Or, R 12f and R 12g Together

[0019] R 13a R 13b R 13c and R 13d Each can be independently -H, -D, -F, -CN, -Cl, -Br, -I, or -C. 1-6 alkyl;

[0020] R 12b -H, -D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl or C 1-6 Hydroxyalkyl;

[0021] R 12c C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 6-10 Aryl, 5-12 heteroaryl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; wherein the R 12c Optionally, it can be selected by 1, 2, 3 or 4 elements chosen from -D, -F, CN, -Cl, -Br, -I, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 3-6 The substituents are cycloalkyl, 3-10-membered heterocyclic and 5-12-membered heteroaryl groups, wherein the C in the substituent is... 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 3-6 Cycloalkyl, 3-10-membered heterocyclic and 5-12-membered heteroaryl groups are optionally surrounded by 1, 2, 3 or 4 groups selected from -D, -F, -CN, -Cl, -Br, -I, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkyl groups;

[0022] Or, R 12b R 12c Together with the nitrogen atoms attached to them, they form 3-10 membered nitrogen heterocyclic groups, wherein the 3-10 membered nitrogen heterocyclic groups are optionally surrounded by 1, 2, 3 or 4 atoms selected from -D, -F, -CN, -Cl, -Br, -I, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkyl groups;

[0023] R a and R a0 Each of the following is independently -H, -D, -CN, -F, -Cl, -Br, -I, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl or C 1-6 Hydroxyalkyl;

[0024] R 12d -H, -D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl or C 1-6 Hydroxyalkyl;

[0025] R 12e -H, -D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl or -C(=O)NR 9 R 10 ;

[0026] R 6 R 7 and R 8 Each of the following is independently -H, -D, -OH, -F, -Cl, -Br, -I, -CN, C 1-6 Alkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl or C 1-6 Halogenated alkyl groups;

[0027] R 9 R 10 R 9a R 9b R 9c R 10b R 9d and R 10d Each can be independently -H, -D, or -C. 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally surrounded by 1, 2, 3, or 4 atoms selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkoxy, C 6-12 Aryl, C 3-6 Substituents of cycloalkyl and 3-6 membered heterocyclic groups;

[0028] m can be 1, 2, 3, or 4;

[0029] n is 1, 2, 3, 4, 5, 6, or 7.

[0030] In some implementation schemes, R 1 is -H, -D, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, -C(=O)OR 9a -C(=O)NR 9 R 10 -C(=O)R 9a -S(=O)2NR 9 R 10 -NR 9 R 10 C 1-4 Alkyl, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, 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 1-4 Mercaptoalkyl, phenyl, 5-6 heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups;

[0031] R 9 R 10 R 9a R 9b R 9c R 10b R 9d and R 10d Each can be independently -H, -D, or -C. 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally surrounded by 1, 2, 3, or 4 atoms selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NH2, -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 1-4 Alkoxy, phenyl, C 3-6 Substituents of cycloalkyl and 3-6 membered heterocyclic groups.

[0032] In some implementation schemes, R 1 is -H, -D, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, -C(=O)OR 9a -C(=O)NR 9 R10 -C(=O)R 9a -S(=O)2NR 9 R 10 -NR 9 R 10 , -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)2CH(CH3)2, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH(CH3)CN, -C(CH3)2CN, -CH2O H, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -(CH2)2CHF2, -(CH2)2CF(CF3)2, -CF3, -CHF2, -CH2F, -(CH2)2F, -(CH2)2Cl, -CH2CF3, -CH2OCH3, -(CH2)2OCH3, -(CH2)2OCH2CH 3, -CH2OCH2CH3, -CH2OC(CH3)3, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -(CH2)2-cyclopentyl, -(CH2)3-cyclopentyl, -(CH2)2-cyclohexyl, -CH2-azacyclobutyl, -CH2-oxacyclobutyl, -CH2-pyrrolidinyl, -CH2-morpholinyl, -(CH2)2-pyrrolidinyl, -(CH2)3-piperidinyl, -(CH2)2-piperidinyl, -CH2-phenyl, -CH2-imidazolyl, -CH2-pyrazolyl, -CH2SH, -(CH2)2SH, phenyl, naphthyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, oxacyclobutyl, tetrahydropyranyl, aziridine, or pyrrolidinyl;

[0033] R 9 R 10 R 9a R 9b R 9c R 10b R 9d and R 10dEach of the following is independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl groups are each 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, -NH(CH3), -N(CH3)2, -NH(CH2CH3), methoxy, ethoxy, n-propoxy, isopropoxy, isobutoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, ethylene oxide, oxecyclobutyl, aziroxy, and pyrrolidinyl.

[0034] In some implementation schemes, each R 5a R 5b R 5c R 5d R 5e R 5f R 5g and R 5h Independently, -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -COOH, oxo, -NHC(=O)H, -C(=O)R 9c -C(=O)OR 9c -C(=O)NR 9b R 10b -NR 9b C(=O)R 10b -NR 9b S(=O)2R 10b -S(=O)2N(R) 10b )2、-NR 9b C(=O)N(R 10b )2、-NR 9b S(=O)2N(R 10b )2、-OS(=O)2N(R 10b )2、-S(=O)2R 9c -C 1-4 Alkylene S(=O)2N(R) 10b 2. C 1-4 Alkyl, C 1-4 Alkylthio, C 1-4 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Cyanoalkyl, C 1- 4-hydroxyalkyl, C 1-4 Halogenated alkyl groups, -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 2-4Haloalkenyl, C 2-4 Halogenated alkynyl group, C 1-4 Halogenated alkoxy groups, C 1-4 Haloalkylthio, 6-10 aryl, 5-10 heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; wherein, R 9b R 9c and R 10b Each has the definition as described in this invention.

[0035] In some implementation schemes, each R 5a R 5b R 5c R 5d R 5e R 5f R 5g and R 5h Independently, -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -COOH, oxo, -NH(C=O)H, -C(=O)R 9c -C(=O)OR 9c -C(=O)NR 9b R 10b -NR 9b C(=O)R 10b -NR 9b S(=O)2R 10b -S(=O)2N(R) 10b )2、-NR 9b C(=O)N(R 10b )2、-NR 9b S(=O)2N(R 10b )2、-OS(=O)2N(R 10b )2、-S(=O)2R 9c -CH2S(=O)2N(R) 10b )2、-(CH2)2S(=O)2N(R 10b)2, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -S(CH2)2CH3, -SCH2CH (CH3)2, -SCH(CH3)2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH2CH(CH3)2, -OCH(CH3)2, -CH=CH2, -CH=CHCH3, -CH 2CH=CH2、-C≡CH、-C≡CCH3、-CH2C≡CH、-CH2CN、-(CH2)2CN、-(CH2)3CN、-CH2OH、-(CH2)2OH、-(CH2)3OH、-CH(OH )CH3, -CF3, -CHF2, -CH2F, -(CH2)2F, -(CH2)2Cl, -CH2CF3, -NHCH3, -NH(CH2CH3), -NH((CH2)2CH3), -NH((CH2) 3CH3), -NH(CH(CH3)2), -N(CH3)2, -N(CH2CH3)2, -N((CH2)2CH3)2, -CHFCH=CH2, -CH=CHF, -CH=CHCl, -CH=CHC H2F, -C≡CCH2F, -OCF3, -OCH2F, -OCHF2, -OCH2CF3, -OCH2CHF2, -SCF3, -SCH2F, -SCHF2, -SCH2CF3, -SCH2CHF2, benzene Furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, benzopyridyl, benzimidazolyl, benzopyrrolyl, benzopyrazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridinepropyl, aziridinebutyl, oxaziridinebutyl, pyrrolylalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolylalkyl, pyrazolylalkyl, pyrazolinyl, oxazolylalkyl, imidazolyl, piperidinyl, piperazinyl, or morpholinyl; wherein, R 9b R 9c and R 10b Each has the definition as described in this invention.

[0036] In some implementation schemes, for

[0037] In some implementations, ring B is one of the following substructures:

[0038] Each R 2Independently, -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -NH2, -CH2C(=O)NR 9b R 10b -C(=O)R 9c -C(=O)OR 9c -C(=O)NR 9b R 10b -NR 9b C(=O)R 10b -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkylthio, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-4 Hydroxyalkynyl group, C 1-4 Alkoxy, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 2-4 Haloalkenyl, C 2-4 Halogenated alkynyl group, C 1-4 Halogenated alkoxy groups, C 1-4 Haloalkylthio group, C 6-10 Aryl, 5-12 heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein -NH2, -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkylthio, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-4 Hydroxyalkynyl group, C 1-4 Alkoxy, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 2-4 Haloalkenyl, C 2-4 Halogenated alkynyl group, C 1-4 Halogenated alkoxy groups, C 1-4 Haloalkylthio group, C 6-10 Aryl, 5-12 heteroaryl, C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 11 Replaced; of which, R 9b R 9c R 10b and R 11 Each has the definition as described in this invention.

[0039] In some implementation schemes, each R 2 Independently, -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -NH2, -CH2C(=O)NR 9b R 10b -C(=O)R 9c -C(=O)OR 9c -C(=O)NR 9b R 10b -NR 9b C(=O)R 10b, -NH(CH3), -NH(CH2CH3), -N(CH3)2, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH 2. -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)3O H, -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, oxazolyl, tetrahydrofuranyl, piperidinyl or piperazineyl,The terms -NH2, -NH(CH3), -NH(CH2CH3), -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)2OH, -(CH2)2CH3 ... )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, oxazolyl, tetrahydrofuranyl, piperidinyl, and piperazineyl are each independently and optionally divided by 1, 2, 3, or 4 Rs. 11 Replaced; of which, R 9b R 9c R 10b and R 11 Each has the definition as described in this invention.

[0040] In some implementation schemes, R 11 is -D, -OH, -F, -Cl, -Br, -I, CN, -C(=O)OR 9 -NR 9 R 10 -C(=O)NR 9 R 10 -NR 9 C(=O)R 10 C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups; or

[0041] R 11 is -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)OR 9 -NR 9 R 10 -C(=O)NR 9 R10 -NR 9 C(=O)R 10 -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, -O(CH2)2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl;

[0042] Among them, R 9 and R 10 Each has the definition as described in this invention.

[0043] In some implementation schemes, for

[0044] In some implementations, L is a bond, -CH2-, -(CH2)2-, -(CH2)3-, or -CH2OCH2-, wherein -CH2-, -(CH2)2-, -(CH2)3-, and -CH2OCH2- are each independently and optionally controlled by 1, 2, 3, or 4 Rs. 12a Replaced;

[0045] Each R 12a Independently, it can be H, -D, -OH, -F, -Cl, -Br, -I, -CN, or C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy or C 1-4 Cyanoalkyl; or two R atoms attached to the same carbon atom 12a Together with the carbon atom attached thereto, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, pyrrolidinyl, or tetrahydrofuranyl groups;

[0046] Or L is

[0047] In some implementation schemes, R 12f and R 12g Each of the following can be independently -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 9d R 10d -C(=O)NR 9d R 10d -CH2NR 9d R 10d -CH2OC(=O)NR9d R 10d C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Cyanoalkyl, (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 groups;

[0048] R 13a R 13b R 13c and R 13d Each can be independently -H, -D, -F, -CN, -Cl, -Br, -I, or -C. 1-4 alkyl;

[0049] R 12b For H, D, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl or C 1-4 Hydroxyalkyl;

[0050] R 12c C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, phenyl, naphthyl, 5-6 membered heteroaryl, 7-12 membered heteroaryl, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups; wherein the R 12c Optionally selected by 1, 2, 3 or 4 elements chosen from -D, -F, -CN, -Cl, -Br, -I, C 1-4 Alkyl, C 1-4 Alkoxy, phenyl, C 3-6 The substituents are cycloalkyl, 3-6 membered heterocyclic and 5-6 membered heteroaryl, wherein the C in the substituent is... 1-4 Alkyl, C 1-4 Alkoxy, phenyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclic and 5-6-membered heteroaryl groups are optionally surrounded by 1, 2, 3 or 4 groups selected from -D, -F, -CN, -Cl, -Br, -I, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkyl groups;

[0051] Or, R 12b R12c Together with the nitrogen atoms attached to them, they form 3-7 membered nitrogen heterocyclic groups, wherein the 3-7 membered nitrogen heterocyclic groups are optionally surrounded by 1, 2, 3 or 4 atoms selected from -D, -F, -CN, -Cl, -Br, -I, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkyl groups;

[0052] R a and R a0 Each of the following is independently -H, -D, -CN, -F, -Cl, -Br, -I, -OH, -NH2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl or C 1-4 Hydroxyalkyl;

[0053] R 12d -H, -D, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl or C 1-4 Hydroxyalkyl;

[0054] R 12e -H, -D, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl or -C(=O)NR 9 R 10 .

[0055] In some implementation schemes, R 12f and R 12g Each of the following can be independently -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 9d R 10d -C(=O)NR 9d R 10d -CH2NR 9d R 10d -CH2OC(=O)NR 9d R 10d, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -OCH3, -OCH2CH3, -O(CH2)2CH3 , -OCH(CH3)2, -(CH2)2F, -CH2CHF2, -CH2CF3, -CHF2, -CH2F, -(CH2)2Cl, -OCF3, -OCHF2, -OCH2CHF 2. -OCH2CF3, -OCHClCHCl2, -OCH2CH2F, -CH2CN, -(CH2)2CN, -(CH2)3CN, -(CH2)4CN, morpholinylmethyl, pyrrolylmethyl, piperazinylmethyl, aziridinemethyl, piperidinylmethyl, tetrahydropyranylmethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopentyl, cyclohexyl, morpholinyl, piperidinyl, pyrrolyl, piperazinyl or aziridine;

[0056] R 13a R 13b R 13c and R 13d Each can be independently -H, -D, -F, -CN, -Cl, -Br, -I, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3 or -CH(CH3)2;

[0057] R 12b The suffixes are -H, -D, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -(CH2)2F, -CH2CHF2, -CH2CF3, -CHF2, -CH2F, -(CH2)2Cl, -CH2CN, -(CH2)2CN, -(CH2)3CN, -(CH2)4CN, -CH2OH, -(CH2)2OH, or -(CH2)3OH;

[0058] R 12cis -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -(CH2)2F, -CH2CHF2, -CH2CF3 , -CHF2, -CH2F, -(CH2)2Cl, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -CH2OCH3, -CH2OCH2CH 3, -CH2CH2OCH3, -C(CH3)2CH2OCH3, -CH2CH2OCH2CH3, -CH2OCH3, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, thiazolyl, imidazolyl, pyrroleyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, 2H-pyrroleyl, pyrroleyl, imidazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl or morpholinyl; wherein R 12c Optionally substituted with 1, 2, 3, or 4 substituents selected from -D, -F, -CN, -Cl, -Br, -I, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2H-pyrrolyl, pyrrolylalkyl, imidazoalkyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl, or pyrrolyl, wherein the substituents are -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -OCH3, or -OCH2 CH3, -O(CH2)2CH3, -OCH(CH3)2, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2H-pyrrolyl, pyrrolylalkyl, imidazoalkyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl, and pyrrolyl are each independently and optionally substituted by 1, 2, 3, or 4 substituents selected from D, F, CN, -Cl, -Br, -I, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -(CH2)2F, -CH2CHF2, -CH2CF3, -CHF2, -CH2F, and -(CH2)2Cl;

[0059] Or, R 12b R 12cTogether with the nitrogen atoms attached to them, they form aziridine, pyrrolidinyl, imidazoalkyl, pyrazolyl, piperidinyl, morpholinyl, piperazinyl, 1,3-oxazolidinyl, or aziridine-heptyl, wherein the aziridine, pyrrolidinyl, imidazoalkyl, pyrazolyl, piperidinyl, morpholinyl, piperazinyl, 1,3-oxazolidinyl, and aziridine-heptyl are optionally surrounded by 1, 2, 3, or 4 atoms selected from -D, -F, -CN, -Cl, -Br, The substituents of -I, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -(CH2)2F, -CH2CHF2, -CH2CF3, -CHF2, -CH2F and -(CH2)2Cl are substituted;

[0060] R a and R a0 Each can be independently -H, -D, -CN, -F, -Cl, -Br, -I, -OH, -NH2, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CN, -(CH2)2CN, -(CH2)3CN, -(CH2)4CN, -CH2OH, -(CH2)2OH, or -(CH2)3OH;

[0061] R 12d The suffixes are -H, -D, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CN, -(CH2)2CN, -(CH2)3CN, -(CH2)4CN, -CH2OH, -(CH2)2OH, or -(CH2)3OH;

[0062] R 12e -H, -D, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CN, -(CH2)2CN, -(CH2)3CN, -(CH2)4CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, or -C(=O)NR 9 R 10 .

[0063] In some implementation schemes, R 4 for

[0064] In some implementation schemes, R 6 R 7 and R 8 Each of the following is independently -H, -D, -OH, -F, -Cl, -Br, -I, CN, C 1-4 Alkyl, C 1- 4-Cyanoalkyl, C 1-4 Hydroxyalkyl or C 1-4 Halogenated alkyl groups.

[0065] On the other hand, the present invention provides a pharmaceutical composition comprising the compounds described herein.

[0066] In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient.

[0067] In some embodiments, the excipients described in this invention include, but are not limited to, carriers, excipients, diluents, solvents, or combinations thereof. In some embodiments, the pharmaceutical composition may be a liquid, solid, semi-solid, gel, or spray formulation.

[0068] On the other hand, the present invention provides the use of the pharmaceutical composition described herein in the preparation of a medicament for the prevention, treatment or relief of a patient’s disease mediated by KRAS G12C.

[0069] In some embodiments, the disease mediated by KRAS G12C described in this invention is cancer.

[0070] In some embodiments, the cancers described in this invention are lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, glioma, cervical cancer, urothelial carcinoma, gastric cancer, endometrial cancer, liver cancer, bile duct cancer, breast cancer, colon cancer, leukemia, and melanoma.

[0071] On the other hand, the present invention also provides a method for preventing or treating KRAS G12C-mediated diseases, the method comprising administering to a patient a therapeutically effective amount of the compound or pharmaceutical composition thereof described in the present invention.

[0072] In some embodiments, the disease mediated by KRAS G12C described in this invention is cancer.

[0073] In some embodiments, the cancers described in this invention are lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, glioma, cervical cancer, urothelial carcinoma, gastric cancer, endometrial cancer, liver cancer, bile duct cancer, breast cancer, colon cancer, leukemia, and melanoma.

[0074] On the other hand, the present invention also provides the use of the compounds or pharmaceutical compositions thereof described herein for the treatment of KRAS G12C-mediated diseases.

[0075] In some embodiments, the disease mediated by KRAS G12C described in this invention is cancer.

[0076] In some embodiments, the cancers described in this invention are lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, glioma, cervical cancer, urothelial carcinoma, gastric cancer, endometrial cancer, liver cancer, bile duct cancer, breast cancer, colon cancer, leukemia, and melanoma.

[0077] On the other hand, the present invention relates to methods for the preparation, separation and purification of compounds represented by formula (I).

[0078] Unless otherwise indicated, all stereoisomers, tautomers, nitrides, hydrates, solvates, metabolites, salts, and pharmaceutically acceptable prodrugs of the compounds of this invention are within the scope of this invention.

[0079] Specifically, the salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically or toxicologically suitable in relation to the other components of the formulation and the mammal intended for treatment.

[0080] The salts of the compounds of the present invention also include salts used for the preparation or purification of intermediates of the compound of formula (I) or for the isolation of enantiomers of the compound of formula (I), but are not necessarily pharmaceutically acceptable salts.

[0081] The foregoing description only outlines certain aspects of the invention, but is not limited to these aspects. These and other aspects will be described in more detail below.

[0082] Detailed Description of the Invention

[0083] Definitions and general terms

[0084] Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications, and equivalents, all of which are included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice the invention. The invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0085] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0086] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0087] As used in this invention, the term "test subject" refers to an animal. Typically, the animal is a mammal. Test subjects also include, for example, primates (e.g., humans, males or females), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In some embodiments, the test subject is a primate. In other embodiments, the test subject is a human.

[0088] As used in this invention, the term "patient" refers to a person (including adults and children) or other animal. In some embodiments, "patient" refers to a person.

[0089] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0090] "Stereoisomers" refer to compounds that have the same chemical structure but differ in the spatial arrangement of their atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometrical isomers (cis / trans isomers), trans-blocking isomers, and so on. Unless otherwise stated, all stereoisomers or mixtures of stereoisomers of the structures described in this invention are within the scope of this invention. Furthermore, unless otherwise stated, the structural formulas of the compounds described in this invention include enriched isotopes of one or more different atoms.

[0091] The stereochemical definitions and rules used in this invention generally follow those of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994.

[0092] Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0093] The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons. A specific example of a keto-enol tautomer is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of a phenol-keto tautomer is the interconversion between pyridine-4-ol and pyridine-4(1H)-keto. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0094] As described in this invention, the compounds of this invention can be independently and optionally substituted by one or more substituents, such as the general formula compounds above, or as the specific examples, subclasses, and classes of compounds included in this invention, as described in the embodiments. It should be understood that the terms "independently and optionally substituted" or "optionally substituted" are used interchangeably with the term "substituted or unsubstituted." Generally, the term "substituted" means that one or more hydrogen atoms in the given structure are substituted by a specific substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substituted position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted at the same or different positions.

[0095] Additionally, it should be noted that, unless otherwise explicitly stated, the descriptive terms “each…independently is”, “…each independently is”, and “…independently is” used in this invention are interchangeable and should be interpreted broadly. They can mean that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0096] In various parts of this specification, the substituents of the compounds disclosed herein are disclosed according to the type or scope of the groups. In particular, the invention includes every independent secondary combination of the various members of these group types and scopes. For example, the term "C..." 1-6 "Alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0097] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the 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 "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0098] 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 optionally be substituted by one or more substituents described in this invention. In one embodiment, the alkyl group contains 1 to 6 carbon atoms, denoted as C1. 1-6 Alkyl group; in yet another embodiment, the alkyl group contains 1-4 carbon atoms, denoted as C1 1-4 Alkyl group; in another embodiment, the alkyl group contains 1-3 carbon atoms, denoted as C1 1-3Alkyl groups. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-B) u、-C(CH3)3), n-pentyl(-CH2CH2CH2CH2CH3), 2-pentyl(-CH(CH3)CH2CH2CH3), 3-pentyl(-CH(CH2CH3)2), 2-methyl-2-butyl(-C(CH3)2CH2CH3), 3-methyl-2-butyl(-CH(CH3)CH(CH3)2), 3-methyl-1-butyl(-CH2CH2CH(CH3)2), 2-methyl-1 -Butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3) ), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, etc.

[0099] The term "heteroalkyl" means that one or more carbon atoms in an alkyl group are replaced by heteroatoms, wherein the heteroatoms are O, S, N, S, or P. The alkyl group has the definition as described in this invention.

[0100] The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon. In some embodiments, the alkylene group contains 1-6 carbon atoms, denoted as C1. 1-6 Alkylene; in other embodiments, the alkylene group contains 1-4 carbon atoms, denoted as C1. 1-4 Alkylene; in other embodiments, the alkylene group contains 1-3 carbon atoms, denoted as C1. 1-3 Alkylene group; in other embodiments, the alkylene group contains 1-2 carbon atoms, denoted as C2. 1-2Alkylene groups. Examples of alkylene groups include, but are not limited to: -CH2-, -CH2CH2-, -CH(CH3)CH2-, etc.

[0101] The term "heteroalkylene" indicates that one or more carbon atoms in an alkylene group are replaced by a heteroatom, wherein the heteroatom is O, S, N, S, or P. The alkylene group has the definition as described in this invention. In some embodiments, the heteroalkylene contains 1-6 carbon atoms, denoted as C1. 1-6 Heteroalkyl group; in other embodiments, the heteroalkyl group contains 1-4 carbon atoms, denoted as C1. 1-4 Heteroalkyl group; in other embodiments, the heteroalkyl group contains 1-3 carbon atoms, denoted as C1. 1-3 Heteroalkyl group; in other embodiments, the heteroalkyl group contains 1-2 carbon atoms, denoted as C1. 1-2 Heteroalkyl groups. Examples of heteroalkyl groups include, but are not limited to: -CH2O-, -CH2NCH2-, -CH(CH3)CH2- or -CH2SCH2-, etc.

[0102] The term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-12 carbon atoms, with at least one unsaturated site, i.e., one carbon-carbon sp. 2 The double bond, wherein the alkenyl group may optionally be substituted by one or more substituents described in this invention, including the orientation of "cis" and "trans", or the orientation of "E" and "Z". In one embodiment, the alkenyl group comprises 2-6 carbon atoms, denoted as C 2- 6. Alkenyl group; in yet another embodiment, the alkenyl group comprises 2-4 carbon atoms, denoted as C0. 2-4 Alkenyl groups. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), 1-propenyl (i.e., propenyl, -CH=CH-CH3), etc.

[0103] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one unsaturated site, i.e., one carbon-carbon sp triple bond, wherein the alkynyl group may optionally be substituted by one or more substituents described in this invention. In one embodiment, the alkynyl group comprises 2-6 carbon atoms, denoted as C1. 2-6 Alkynyl group; in yet another embodiment, the alkynyl group comprises 2-4 carbon atoms, denoted as C0. 2-4 Alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), 1-propynyl (-C≡C-CH3), etc.

[0104] The term "cyanoalkyl" refers to an alkyl group substituted with one or more cyano groups, wherein the cyano and alkyl groups have the definitions described herein. In some embodiments, "cyanoalkyl" refers to an alkyl group substituted with one cyano group. In some embodiments, "cyanoalkyl" is C10. 1-6 Cyanoalkyl, i.e., C4 groups substituted with one or more cyano groups. 1-6 Alkyl group. In some preferred embodiments, C 1-6 Cyanoalkyl is a C group substituted with one cyano group. 1-6 Alkyl. In other embodiments, "cyanoalkyl" is C1 1-4 Cyanoalkyl, i.e., C4 groups substituted with one or more cyano groups. 1-4 Alkyl groups. Examples of cyanoalkyl groups include, but are not limited to, -CH2CN, -CH2CH2CH2CH2CN, -CH2CH2CN, -CH2CH(CN)CH2CH2CN, -CH2CH(CN)CH2CH(CH3)CN, etc.

[0105] 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 in this invention. 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 C14-C ... 1-6 Hydroxyalkyl, i.e., C 1-6 Alkyl groups are substituted with one or more hydroxyl groups, preferably C 1-6 Hydroxyalkyl indicates C 1-6 An alkyl group is an alkyl group substituted with a hydroxyl group. In some embodiments, hydroxyalkyl represents C10. 1-4 Hydroxyalkyl. In some embodiments, hydroxyalkyl means C 1-3 Hydroxyalkyl groups. Examples of hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2CH2CH2OH, -CH2CH2OH, -CH2CH(OH)CH2CH2OH, -CH2CH(OH)CH2CH(CH3)OH, etc.

[0106] The term "hydroxyynyl" refers to an ynyl group substituted with one or more hydroxyl groups, wherein the ynyl and hydroxyl groups have the definitions as described in this invention. In some embodiments, hydroxyynyl represents an ynyl group substituted with 1, 2, 3, or 4 hydroxyl groups. In some embodiments, hydroxyynyl represents an ynyl group substituted with one or two hydroxyl groups. In some embodiments, hydroxyalkyl represents C... 2-6 Hydroxyalkyl, i.e., C 2-6 The alkynyl group is replaced by one or more hydroxyl groups, preferably C 2-6 Hydroxyalkynyl group represents C 2-6An alkynyl group is a group in which an alkynyl group is replaced by a hydroxyl group. In some embodiments, the hydroxyalkynyl group represents C0. 2-4 Hydroxyalkynyl group. Examples of hydroxyalkynyl groups include, but are not limited to, -CH2C≡COH, -C≡CCH2OH, -C≡C(CH2)2OH, etc.

[0107] The term "haloalkyl" indicates that an alkyl group is replaced by one or more halogen atoms, wherein the alkyl group and the halogen atom have the definitions described herein. In some embodiments, the haloalkyl group is C10. 1-6 Haloalkyl, indicating C 1-6 The alkyl group is replaced by one or more halogen atoms; in other embodiments, the haloalkyl group is C10. 1-4 Haloalkyl, indicating C 1-4 The alkyl group is replaced by one or more halogen atoms; in other embodiments, the haloalkyl group is C10. 1-3 Haloalkyl, indicating C 1-3 The alkyl group is replaced by one or more halogen atoms. Examples of such groups 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 so on.

[0108] The term "haloalkenyl" indicates that an alkenyl group is replaced by one or more halogen atoms, wherein the alkenyl group has the definition as described in this invention. In some embodiments, the haloalkenyl group is C0. 2-6 Haloalkenyl groups represent C 2-6 The alkenyl group is replaced by one or more halogen atoms; in other embodiments, the haloalkenyl group is C. 2-4 Haloalkenyl groups represent C 2-4 The alkenyl group is replaced by one or more halogen atoms. Examples of such groups include, but are not limited to, 1-chlorovinyl (-CCl=CH2), 2-fluorovinyl (-CH=CHF), 1-fluoroallyl (-CHFCH=CH2), 3-fluoropropenyl (i.e., -CH=CH-CH2F), and 3,3-difluoropropenyl (i.e., -CH=CH-CHF2).

[0109] The term "haloalkynyl" indicates that an alkynyl group is replaced by one or more halogen atoms, wherein the alkynyl group has the definition as described in this invention. In some embodiments, the haloalkynyl group is C0. 2-6 Halogenated alkynyl group, indicating C 2-6 The alkynyl group is replaced by one or more halogen atoms; in other embodiments, the haloalkynyl group is C. 2-4 Halogenated alkynyl group, indicating C2-4 The alkynyl group is replaced by one or more halogen atoms. Examples of such groups include, but are not limited to, 2-chloroethynyl (-C≡CCl), 1-chloropropynyl (-CHClC≡CH), 3-chloropropynyl (-C≡C-CH2Cl), and so on.

[0110] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group, wherein the alkoxy group and the alkyl group have the definitions described herein. In some embodiments, alkoxyalkyl means C 1-6 Alkoxy C 1-6 Alkyl; in other embodiments, alkoxyalkyl means C 1-4 Alkoxy C 1-4 Alkyl; in other embodiments, alkoxyalkyl means C 1-4 Alkoxy C 1-3 Alkyl; in some embodiments, alkoxyalkyl means C 1-3 Alkoxy C 1-3 Alkyl. Examples of alkoxy groups include, but are not limited to, methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, methoxyethyl, methoxy-n-propyl, methoxyisopropyl, ethoxyethyl, ethoxy-n-propyl, ethoxyisopropyl, n-propoxyethyl, isopropoxyethyl, n-propoxy-n-propyl, n-propoxyisopropyl, isopropoxy-n-propyl, isopropoxyisopropyl, etc.

[0111] The term "carboxyalkyl" refers to an alkyl group substituted with one or more carboxyl groups, wherein the carboxyl and alkyl groups are specifically defined as described herein. In some embodiments, the carboxyalkyl group is C10. 1-6 Carboxyalkyl, indicating a C group substituted with one or more carboxyl groups. 1-6 Alkyl; in other embodiments, the carboxyl alkyl group is C10. 1-4 Carboxyalkyl, indicating a C group substituted with one or more carboxyl groups. 1-4 Alkyl; in other embodiments, the carboxyl alkyl group is C10. 1-3 Carboxyalkyl, indicating a C group substituted with one or more carboxyl groups. 1-3 Alkyl groups. Examples of carboxyalkyl groups include, but are not limited to, carboxymethyl (-CH2COOH), 2-carboxyethyl (-(CH2)2COOH), 3-carboxypropyl (-(CH2)3COOH), etc.

[0112] The term "alkylamino" or "alkylamino" refers to an amino group substituted with one or two alkyl groups, including "N-alkylamino" and "N,N-dialkylamino," wherein the alkyl and amino groups have the meanings as described in this invention. In some embodiments, alkylamino represents C 1-6 Alkylamino refers to an alkylamino group containing 1-6 carbon atoms; in other embodiments, alkylamino represents C1-4 Alkylamino refers to an alkylamino group containing 1-4 carbon atoms; alkylamino represents C... 1-3 Alkylamino refers to an alkylamino group containing 1 to 3 carbon atoms. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and examples include, but are not limited to, N-methylamino (methylamino, -NHCH3), N-ethylamino (ethylamino, -NHCH2CH3), N,N-dimethylamino (dimethylamino, -N(CH3)2), N,N-diethylamino (diethylamino, -N(CH2CH3)2), etc.

[0113] The term "thiol alkyl" refers to an alkyl group substituted with one or more mercapto groups, wherein the alkyl group has the meaning as described in this invention. In some embodiments, thiol alkyl represents C 1-6 Mercaptoalkyl, which is a C group substituted with one or more mercapto groups. 1-6 Alkyl; preferably, C 1-6 The mercaptoalkyl group is a C group substituted with a mercapto group. 1-6 Alkyl group. In other embodiments, mercaptoalkyl group represents C10. 1-4 Mercaptoalkyl. In other embodiments, mercaptoalkyl represents C... 1-3 Mercaptoalkyl. Examples of mercaptoalkyl include, but are not limited to, mercaptomethyl (-CH2SH), 2-mercaptoethyl (-(CH2)2SH), 3-mercaptopropyl (-(CH2)3SH), 2,3-dimercaptopropyl (-CH2CH(SH)CH2(SH)), etc.

[0114] The term "alkoxy group" indicates that an alkyl group is attached to the remainder of the molecule by an oxygen atom, wherein the alkyl group has the meaning as described in this invention. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms, representing C0. 1-6 Alkoxy group; in another embodiment, the alkoxy group contains 1-4 carbon atoms, representing C 1-4 Alkoxy group; in yet another embodiment, the alkoxy group contains 1-3 carbon atoms, representing C 1-3Alkoxy group. The alkoxy group may optionally be substituted by one or more substituents described in this invention. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2- Propoxy (t-BuO, t-butoxy, -OC(CH3)3), 1-pentoxy (n-pentoxy, -OCH2CH2CH2CH2CH3), 2-pentoxy (-OCH(CH3)CH2CH2CH3), 3-pentoxy (-OCH(CH2CH3)2), 2-methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-methyl-l-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-l-butoxy (-OCH2CH(CH3)CH2CH3), etc.

[0115] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group and the halogen have the definitions as defined in this invention. In some embodiments, a haloalkoxy group refers to a haloalkoxy group containing 1-6 carbon atoms, i.e., C6. 1-6 Haloalkoxy group; in other embodiments, haloalkoxy group refers to a haloalkoxy group containing 1-4 carbon atoms, i.e., C646-C ... 1-4 Haloalkoxy group; in other embodiments, haloalkoxy group refers to a haloalkoxy group containing 1-3 carbon atoms, i.e., C646-C ... 1-3 Halogenated alkoxy groups. Examples of halogenated alkoxy groups include, but are not limited to, trifluoromethoxy (-OCF3), monofluoromethoxy (-OCH2F), 2-fluoroethoxy (-OCH2CH2F), etc.

[0116] The term "carbocyclic" or "carbocyclic group" refers to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic carbocyclic system comprising 3 to 12 ring atoms, wherein the -CH2- group in the carbocyclic ring may optionally be replaced by -C(=O)- (or -(CO)-). In one embodiment, the carbocyclic group comprises 3 to 6 ring carbon atoms, denoted as C. 3-6 Carbocyclic group; in other embodiments, the carbocyclic group is a saturated ring comprising 3-6 ring carbon atoms, denoted as C 3-6 cycloalkyl; in other embodiments, the C3-6 The cycloalkyl group is a saturated monocyclic ring. In one embodiment, the carbocyclic group comprises 7-12 cyclic carbon atoms, denoted as C1. 7-12 Carbocyclic group; in other embodiments, the carbocyclic group is a saturated ring comprising 7-12 ring carbon atoms, denoted as C 7-12 Cycloalkyl groups. Examples of carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, octahydro-1H-indenyl, octahydrocyclopentadienyl, etc. Examples of carbocyclic groups in which the -CH2- group can be replaced by -C(=O)- include, but are not limited to, cyclopentanone, cyclobutanone, etc.

[0117] The term "cycloalkyl" refers to a monovalent saturated monocyclic or bicyclic carbocyclic system with 3-12 carbon atoms, wherein the -CH2- group in the carbocyclic ring may optionally be replaced by -C(=O)- (or -(CO)-). In some embodiments, the cycloalkyl group comprises 3-12 cyclic carbon atoms, i.e., C 3-12 Cycloalkyl groups. In other embodiments, the cycloalkyl group comprises 3-10 cyclic carbon atoms, i.e., C16+10 cyclic carbon atoms. 3-10 Cycloalkyl groups. In other embodiments, the cycloalkyl group comprises 7-12 cyclic carbon atoms, i.e., C64... 7-12 Cycloalkyl. In other embodiments, the C 7-12 The cycloalkyl group is a bicyclic system. In other embodiments, the cycloalkyl group comprises 7-10 ring carbon atoms, i.e., C1. 7-10 Cycloalkyl. In other embodiments, the C 7-10 The cycloalkyl group is a bicyclic system. In other embodiments, the cycloalkyl group comprises 3-6 cyclic carbon atoms, i.e., C16+6 carbon atoms. 3-6 Cycloalkyl. In other embodiments, the C 3-6 The cycloalkyl group is a monocyclic system. In other embodiments, the cycloalkyl group comprises 3-5 ring carbon atoms, i.e., C1. 3-5 Cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydro-1H-indenyl, octahydrocyclopentadienyl, etc. Examples of carbocyclic groups in which the -CH2- group can be replaced by -C(=O)- include, but are not limited to, cyclopentanone, cyclobutanone, etc.

[0118] The term "heterocycle" or "heterocyclic group" refers to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic system comprising 3 to 12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms; wherein the heterocycle or heterocyclic group is non-aromatic and does not contain any aromatic ring. The bicyclic or tricyclic system includes bridged ring systems or spirocyclic systems. A bridged ring system is a ring system formed by two rings sharing two ring atoms, and a spirocyclic system is a ring system formed by two rings sharing one ring atom. When a heterocycle is attached to other parts of a molecule through a linking site, the heterocycle is represented as a monovalent heterocyclic group. Unless otherwise stated, the heterocyclic group can be carbonyl or nitrogenyl, and the -CH2- group may optionally be replaced by -C(=O)-. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. In some embodiments, the heterocycle or heterocyclic group consists of 3-12 atoms, represented as a 3-12 membered heterocycle or a 3-12 membered heterocyclic group. In some embodiments, the heterocycle or heterocyclic group consists of 3-10 atoms, represented as a 3-10 membered heterocycle or a 3-10 membered heterocyclic group. In other embodiments, the heterocycle or heterocyclic group consists of 3-9 atoms, represented as a 3-9 membered heterocycle or a 3-9 membered heterocyclic group. In other embodiments, the heterocycle or heterocyclic group consists of 5-9 atoms, represented as a 5-9 membered heterocycle or a 5-9 membered heterocyclic group. In other embodiments, the heterocycle or heterocyclic group consists of 3-7 atoms, represented as a 3-7 membered heterocycle or a 3-7 membered heterocyclic group. In still other embodiments, the 3-7 membered heterocycle or 3-7 membered heterocyclic group is a 3-7 membered monocyclic heterocycle or a 3-7 membered monocyclic heterocyclic group. In some embodiments, the heterocycle or heterocyclic group consists of 3-6 atoms and is represented as a 3-6 membered heterocycle or a 3-6 membered heterocyclic group. In some embodiments, the 3-6 membered heterocycle or 3-6 membered heterocyclic group is a 3-6 membered monocyclic heterocycle or a 3-6 membered monocyclic heterocyclic group. In some embodiments, the heterocycle or heterocyclic group consists of 7-12 atoms and is represented as a 7-12 membered heterocycle or a 7-12 membered heterocyclic group. In some embodiments, the 7-12 membered heterocycle or 7-12 membered heterocyclic group is a 7-12 membered bicyclic heterocycle or a 7-12 membered bicyclic heterocyclic group. In some embodiments, the heterocycle or heterocyclic group consists of 7-10 atoms and is represented as a 7-10 membered heterocycle or a 7-10 membered heterocyclic group. In some embodiments, the 7-10 membered heterocycle or 7-10 membered heterocyclic group is a 7-10 membered bicyclic heterocycle or a 7-10 membered bicyclic heterocyclic group. In other embodiments, the heterocycle or heterocyclic group consists of 5-6 atoms and is represented as a 5-6 membered heterocycle or 5-6 membered heterocyclic group.Examples of the heterocycles include, but are not limited to, ethylene oxide, aziridine, aziridine, oxacyclobutane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, thiazoline, pyrazolidine, pyrazolidine, pyrazoline, oxazolidine, imidazoline, piperidine, piperazine, morpholine, 3,8-diazabicyclo[3.2.1]octane, 3,6-diazabicyclo[3.1.1]heptane, and 2,5-diazabicyclo[2.2.2]octane. The heterocyclic groups include, but are not limited to, ethylene oxide, aziridine, aziridine, oxacyclobutane, thioheterocyclic, pyrrolidine, tetrahydrofuranyl, tetrahydrothiopheneyl, thiazoline, pyrazolidine, pyrazolidine, pyrazolidine, oxazolidine, imidazoline, piperidinyl, piperazinyl, or morpholinyl.

[0119] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic system containing 6-14, 6-12, or 6-10 ring atoms, wherein at least one ring system is aromatic, and each ring system comprises a ring of 3-7 atoms. In some embodiments, the aryl group contains 6-12 ring atoms, denoted as C 6-12 Aryl or 6-12-membered aryl. In some embodiments, the aryl group contains 6-10 ring atoms, denoted as C. 6-10 Aryl or 6-10 aryl groups. Examples of aryl groups may include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, and anthracene.

[0120] The term "heteroaryl" or "heteroaromatic ring" refers to a monovalent monocyclic, bicyclic, or tricyclic system containing 5-14, 5-12, 5-10, or 5-6 ring atoms, wherein at least one ring is aromatic and at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, and sulfur. The heteroaryl group is typically, but not necessarily, linked to the parent molecule via its aromatic ring. When a -CH2- group is present in the heteroaryl group, the -CH2- group may optionally be replaced by -C(=O)-. Unless otherwise stated, the heteroaryl group may be linked to the remainder of the molecule (e.g., the main structure in the general formula) through any reasonable site (which may be C or N). The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, the heteroaryl group is a heteroaryl group containing 5-12 ring atoms, denoted as a 5-12-membered heteroaryl group; in other embodiments, the heteroaryl group is a heteroaryl group containing 5-10 ring atoms, denoted as a 5-10-membered heteroaryl group; in still other embodiments, the heteroaryl group is a heteroaryl group containing 5-6 ring atoms, denoted as a 5-6-membered heteroaryl group. Examples of heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrole, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, thiophene, thiazolyl, triazolyl, tetrazolyl, benzopyridinyl, benzimidazolyl, benzopyrroleyl, benzopyrazolyl, benzopyrroleyl, etc.

[0121] The term "alkathioyl" indicates that an alkyl group is attached to other parts of the molecule via a sulfur atom, wherein the alkyl group has the definition as described in this invention. In some embodiments, the alkathioyl group is C10. 1-6 Alkylthio group, indicating an alkylthio group containing 1-6 carbon atoms; in other embodiments, the alkylthio group is C10. 1-4 Alkylthio group, indicating an alkylthio group containing 1-4 carbon atoms; in other embodiments, the alkylthio group is C10. 1-3 Alkylthio group refers to an alkylthio group containing 1 to 3 carbon atoms. Examples of alkylthio groups include, but are not limited to, methylthio (-SCH3), ethylthio (-SCH2CH3), etc.

[0122] The term "haloalkylthio" refers to an alkylthio group substituted with one or more halogen atoms, wherein the alkylthio group has the definition as described in this invention. In some embodiments, the haloalkylthio group is C10. 1-6 Haloalkylthio group indicates a C-aryl group substituted with one or more halogens. 1-6 Alkylthio group; in other embodiments, the haloalkylthio group is C10. 1-4 Haloalkylthio group indicates a C-aryl group substituted with one or more halogens. 1-4 Alkylthio group; in other embodiments, the haloalkylthio group is C10. 1-3Haloalkylthio group indicates a C-aryl group substituted with one or more halogens. 1-3 Alkylthio groups. The definition of haloalkylthio groups includes, but is not limited to, trifluoromethylthio (-SCF3), 2,2,2-trifluoroethylthio (-SCH2CF3), monofluoromethylthio (-SCH2F), etc.

[0123] The term "arylalkyl" refers to an alkyl group substituted with an aryl group, wherein the aryl group and the alkyl group have the definitions described herein. In some embodiments, the arylalkyl group is (C 6-10 (aryl)-C 1-6 Alkyl or (6-10 aryl)-C 1-6 Alkyl; in other embodiments, the arylalkyl group is (C 6-10 (aryl)-C 1-4 Alkyl or (6-10 aryl)-C 1-4 Alkyl; in other embodiments, the arylalkyl group is (C 6-10 (aryl)-C 1-3 Alkyl or (6-10 aryl)-C 1-3 Alkyl; in other embodiments, the aryl alkyl group is a phenyl C 1-6 Alkyl; in other embodiments, the aryl alkyl group is a phenyl C 1-4 Alkyl; in other embodiments, the aryl alkyl group is a phenyl C 1-3 Alkyl groups. Examples of arylalkyl groups include, but are not limited to, phenylmethyl, phenylethyl, naphthylmethyl, etc.

[0124] The term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the heteroaryl group and the alkyl group have the definitions described herein. In some embodiments, the heteroarylalkyl group is (5-12-membered heteroaryl)-C 1-6 Alkyl; in other embodiments, the heteroarylalkyl group is (5-12-membered heteroaryl)-C 1-4 Alkyl; in other embodiments, the heteroarylalkyl group is (5-12-membered heteroaryl)-C 1-3 Alkyl; in other embodiments, the heteroarylalkyl group is (5-6 membered heteroaryl)-C 1-6 Alkyl; in other embodiments, the heteroarylalkyl group is (5-6 membered heteroaryl)-C 1-4 Alkyl; in other embodiments, the heteroarylalkyl group is (5-6 membered heteroaryl)-C 1-3 Alkyl groups. Examples of heteroarylalkyl groups include, but are not limited to, pyrimidinylmethyl, pyridinylmethyl, pyridinylethyl, pyrazolylmethyl, etc.

[0125] The term "heterocyclic alkyl" refers to an alkyl group substituted with a heterocyclic group, wherein the heterocyclic group and alkyl group are specifically defined as described herein. In some embodiments, the heterocyclic alkyl group is a (3-12 membered heterocyclic group)-C 1-6 Alkyl; in other embodiments, the heterocyclic alkyl group is (3-6 membered heterocyclic)-C 1-6 Alkyl; in other embodiments, the heterocyclic alkyl group is (3-6 membered heterocyclic)-C 1-4 Alkyl; in other embodiments, the heterocyclic alkyl group is (3-6 membered heterocyclic)-C 1-4 Alkyl; in other embodiments, the heterocyclic alkyl group is (3-6 membered heterocyclic)-C 1-3 Alkyl groups. Examples of heterocyclic alkyl groups include, but are not limited to, piperidinylmethyl, piperidinylethyl, pyrrolidinylmethyl, etc.

[0126] The term "cycloalkylalkyl" refers to an alkyl group substituted with one cycloalkyl group. In some embodiments, the cycloalkylalkyl group is (C 3-12 cycloalkyl)-C 1-6 Alkyl; in other embodiments, the cycloalkyl group is (C 3-6 cycloalkyl)-C 1-6 Alkyl; in other embodiments, the cycloalkyl group is (C 3-6 cycloalkyl)-C 1-4 Alkyl; in other embodiments, the cycloalkyl group is (C 3-6 cycloalkyl)-C 1-3 Alkyl. Examples of cycloalkyl groups include, but are not limited to: cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, etc.

[0127] The term "halogen" refers to F (fluorine), Cl (chlorine), Br (bromine), or I (iodine).

[0128] The term "oxo" means =O.

[0129] The term "cyano" means -CN or -C≡N.

[0130] The term "thiol" represents -SH.

[0131] The term "hydroxyl group" represents -OH.

[0132] The term "carboxyl group" represents -C(=O)OH.

[0133] The term "amino" represents -NH2.

[0134] The term "composed of jk atoms" or "jk element" indicates that the cyclic group is composed of jk ring atoms, including 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 between them. For example, "composed of 3-8 atoms" or "3-8 element", "composed of 3-6 atoms" or "3-6 element", "composed of 5-10 atoms" or "5-10 element", or "composed of 5-6 atoms" or "5-6 element" indicates 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, including carbon atoms and / or heteroatoms such as O, N, S, P, etc.

[0135] As described in this invention, substituent (R) q A ring system formed by a single bond connecting to a central ring represents q substituents R that can be substituted at any substituted or reasonable position on the ring. For example, formula a represents a naphthalene ring that can be substituted by n Rs. 2 Replacement, when n is greater than 1, each R 2 They can be independently selected from the same or different substituents.

[0136] As used in this invention, the term "prodrug" refers to the conversion of a compound into a compound represented by formula (I) or (I-1) in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds of this invention can be esters; among existing inventions, esters that can serve as prodrugs include phenyl esters and aliphatic (C) esters. 1-24 Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, one compound in this invention contains a hydroxyl group, meaning it can be acylated to yield a prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a parent compound with a hydroxyl group.

[0137] "Metabolic products" refer to the products obtained from the metabolism of a specific compound or its salt in the body. The metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized by experimental methods as described in this invention. Such products can be obtained by subjecting the compound to oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc. Accordingly, this invention includes the metabolites of compounds, including metabolites produced by sufficiently exposing the compounds of this invention to mammals for a period of time.

[0138] The term "pharmaceutically acceptable salt" as used in this invention refers to both organic and inorganic salts of the compounds of this invention. Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reactions with amino groups, such as hydrochlorides, hydrobromic acids, phosphates, sulfates, and perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, and malonates, or these salts obtained by other methods described in the literature, such as ion exchange. This invention also contemplates the formation of quaternary ammonium salts from any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained through quaternization. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations that resist the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-C8 sulfonates, and aromatic sulfonates.

[0139] In this invention, "solvent" refers to an association formed by one or more solvent molecules and a compound of this invention. Solvents forming solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term "hydrate" refers to an association formed when the solvent molecules are water.

[0140] When the solvent is water, the term "hydrate" may be used. In one embodiment, a molecule of the compound of the present invention may bind to one water molecule, such as a monohydrate; in another embodiment, a molecule of the compound of the present invention may bind to more than one water molecule, such as a dihydrate; and in yet another embodiment, a molecule of the compound of the present invention may bind to fewer than one water molecule, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the bioavailability of the non-hydrated form of the compound.

[0141] As used in this invention, the term "treatment" refers to any disease or condition, and in some embodiments, it means improving the disease or condition (i.e., slowing down or stopping or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, "treatment" means alleviating or improving at least one bodily parameter, including bodily parameters that may not be perceived by the patient. In still other embodiments, "treatment" means regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing bodily parameters) or both. In still other embodiments, "treatment" means preventing or delaying the onset, occurrence, or worsening of the disease or condition.

[0142] The term “prevention” or “avoidance” refers to the reduction of the risk of acquiring a disease or disorder (i.e., stopping the development of at least one clinical symptom of the disease in a subject who may be facing or predisposed to facing the disease, but has not yet experienced or exhibited symptoms of the disease).

[0143] The term "therapeutic effective dose" refers to the amount of a compound that is sufficient to treat a disease when administered to a subject. The "therapeutic effective dose" can vary depending on the compound, the disease and its severity, and the condition, age, weight, and sex of the subject being treated.

[0144] Unless otherwise stated, all suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs of the compounds of this invention are included within the scope of this invention.

[0145] In the structures disclosed in this invention, when the stereochemistry of any particular chiral atom is not specified, all stereoisomers of that structure are considered within the scope of this invention and are included in this invention as disclosed compounds. When the stereochemistry is indicated by a solid wedge or dashed line representing a particular configuration, the stereoisomers of that structure are thus clearly defined.

[0146] The nitrogen oxides of the compounds of this invention are also included within the scope of this invention. The nitrogen oxides of the compounds of this invention can be prepared by oxidizing the corresponding nitrogen-containing basic substances in the presence of an acid, such as acetic acid, using a common oxidizing agent (e.g., hydrogen peroxide) at elevated temperature, or by reacting with a peracid in a suitable solvent, such as with peracetic acid in dichloromethane, ethyl acetate, or methyl acetate, or with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.

[0147] The compound shown in formula (I) can exist in the form of a salt.

[0148] Any structural formulas provided in this invention are intended to represent both the unenriched and isotopically enriched forms of these compounds. Isotopically enriched compounds have the structures described by the general formulas provided in this invention, except that one or more atoms are replaced by atoms having a chosen atomic weight or mass number. Exemplary isotopes that may be introduced into the compounds of this 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.

[0149] Description of the compounds of the present invention

[0150] This invention provides a compound, or a pharmaceutical composition thereof, which can be used as a KRAS inhibitor, particularly as a KRAS12C inhibitor. The invention further relates to the use of said compound or pharmaceutical composition thereof in the preparation of a medicament that treats diseases and / or conditions by inhibiting KRAS activity through said compound.

[0151] The excellent properties of the compounds of this invention, such as half-life, clearance rate, selectivity, bioavailability, chemical stability, metabolic stability, membrane permeability, and solubility, can promote the reduction of side effects, the expansion of the therapeutic index, or the improvement of tolerability.

[0152] On the one hand, the present invention provides compounds of formula (I), or stereoisomers, tautomers, nitrides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of compounds of formula (I).

[0153] Among them, R 1 R 2 R 3 R 4 R 5a R 5b R 5c R 5d R 5e R 5f R 5g R 5h R 6 R 7 R 8 L, Q 1Ring B and n each have the definitions described in this invention.

[0154] In the compounds represented by formula (I) of this invention, "*" and "**" are used only to indicate The connection position with other groups, where "*" indicates The "*" connector and Connected, "**" indicates The "**" connection end and Connected.

[0155] In some implementation schemes, Q 1 Let N be the number of elements in the array.

[0156] In some implementation schemes, Q 1 For CH.

[0157] In some implementations, n is 1, 2, 3, 4, 5, 6, or 7.

[0158] In some implementation schemes, R 1 is -H, -D, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, -C(=O)OR 9a -C(=O)NR 9 R 10 -C(=O)R 9a -S(=O)2NR 9 R 10 -NR 9 R 10 C 1-6 Alkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, 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 1-6 mercaptoalkyl, C 6-10 Aryl, 5-12 heteroaryl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group; wherein, R 9 R 10 and R 9a Each has the definition as described in this invention.

[0159] In some implementation schemes, R 1 is -H, -D, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, -C(=O)OR9a -C(=O)NR 9 R 10 -C(=O)R 9a -S(=O)2NR 9 R 10 -NR 9 R 10 C 1-4 Alkyl, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, 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 1-4 Mercaptoalkyl, phenyl, 5-6 heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; wherein, R 9 R 10 and R 9a Each has the definition as described in this invention.

[0160] In some implementation schemes, R 1 is -H, -D, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, -C(=O)OR 9a -C(=O)NR 9 R 10 -C(=O)R 9a -S(=O)2NR 9 R 10 -NR 9 R 10, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)2CH(CH3)2, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH(CH3)CN, -C(CH3)2CN, -CH2OH , -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -(CH2)2CHF2, -(CH2)2CF(CF3)2, -CF3, -CHF2, -CH2F, -(CH2)2F, -(CH2)2Cl, -CH2CF3, -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-azacyclobutyl, -CH2-oxacyclobutyl, -CH2-pyrrolidinyl, -CH2morpholinyl, -(C H2)2-pyrrolidinyl, -(CH2)3-piperidinyl, -(CH2)2-piperidinyl, -CH2-phenyl, -CH2-imidazolyl, -CH2-pyrazoleyl, -CH2SH, -(CH2)2SH, phenyl, naphthyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, oxacyclobutyl, tetrahydropyranyl, aziridine, or pyrrolidinyl; wherein, R 9 R 10 and R 9a Each has the definition as described in this invention.

[0161] In some implementation schemes, each R 5a R 5b R 5c R 5d R 5e R 5f R 5g and R 5h Independently, -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -COOH, oxo, -NHC(=O)H, -C(=O)R 9c -C(=O)OR 9c -C(=O)NR 9b R 10b -NR 9b C(=O)R 10b -NR 9b S(=O)2R 10b -S(=O)2N(R) 10b)2、-NR 9b C(=O)N(R 10b )2、-NR 9b S(=O)2N(R 10b )2、-OS(=O)2N(R 10b )2、-S(=O)2R 9c -C 1-6 Alkylene-S(=O)2N(R) 10b 2. C 1-6 Alkyl, C 1-6 Alkylthio, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Cyanoalkyl, C 1- 6-hydroxyalkyl, C 1-6 Halogenated alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 2-6 Haloalkenyl, C 2-6 Halogenated alkynyl group, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkylthio group, C 6-10 Aryl, 5-10 heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; wherein, R 9b R 9c and R 10b Each has the definition as described in this invention.

[0162] In some implementation schemes, each R 5a R 5b R 5c R 5d R 5e R 5f R 5g and R 5h Independently, -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -COOH, oxo, -NHC(=O)H, -C(=O)R 9c -C(=O)OR 9c -C(=O)NR 9b R 10b -NR 9b C(=O)R 10b -NR 9b S(=O)2R 10b -S(=O)2N(R) 10b )2、-NR 9b C(=O)N(R 10b )2、-NR 9bS(=O)2N(R 10b )2、-OS(=O)2N(R 10b )2、-S(=O)2R 9c -C 1-4 Alkylene S(=O)2N(R) 10b 2. C 1-4 Alkyl, C 1-4 Alkylthio, C 1-4 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Cyanoalkyl, C 1- 4-hydroxyalkyl, C 1-4 Halogenated alkyl groups, -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 2-4 Haloalkenyl, C 2-4 Halogenated alkynyl group, C 1-4 Halogenated alkoxy groups, C 1-4 Haloalkylthio, 6-10 aryl, 5-10 heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; wherein, R 9b R 9c and R 10b Each has the definition as described in this invention.

[0163] In some implementation schemes, each R 5a R 5b R 5c R 5d R 5e R 5f R 5g and R 5h Independently, -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -COOH, oxo, -NH(C=O)H, -C(=O)R 9c -C(=O)OR 9c -C(=O)NR 9b R 10b -NR 9b C(=O)R 10b -NR 9b S(=O)2R 10b -S(=O)2N(R) 10b )2、-NR 9b C(=O)N(R 10b )2、-NR 9b S(=O)2N(R 10b )2、-OS(=O)2N(R 10b )2、-S(=O)2R9c -CH2S(=O)2N(R) 10b )2、-(CH2)2S(=O)2N(R 10b )2, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -S(CH2)2CH3, -SCH2CH (CH3)2, -SCH(CH3)2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH2CH(CH3)2, -OCH(CH3)2, -CH=CH2, -CH=CHCH3, -CH 2CH=CH2、-C≡CH、-C≡CCH3、-CH2C≡CH、-CH2CN、-(CH2)2CN、-(CH2)3CN、-CH2OH、-(CH2)2OH、-(CH2)3OH、-CH(OH )CH3, -CF3, -CHF2, -CH2F, -(CH2)2F, -(CH2)2Cl, -CH2CF3, -NHCH3, -NH(CH2CH3), -NH((CH2)2CH3), -NH((CH2) 3CH3), -NH(CH(CH3)2), -N(CH3)2, -N(CH2CH3)2, -N((CH2)2CH3)2, -CHFCH=CH2, -CH=CHF, -CH=CHCl, -CH=CHC H2F, -C≡CCH2F, -OCF3, -OCH2F, -OCHF2, -OCH2CF3, -OCH2CHF2, -SCF3, -SCH2F, -SCHF2, -SCH2CF3, -SCH2CHF2, benzene Furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, benzopyridyl, benzimidazolyl, benzopyrrolyl, benzopyrazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridinepropyl, aziridinebutyl, oxaziridinebutyl, pyrrolylalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolylalkyl, pyrazolylalkyl, pyrazolinyl, oxazolylalkyl, imidazolyl, piperidinyl, piperazinyl, or morpholinyl; wherein, R 9b R 9c and R 10b Each has the definition as described in this invention.

[0164] In some implementations, ring B is C. 6-12 Aryl or 5-12 heteroaryl groups.

[0165] In some implementations, ring B is one of the following substructures:

[0166] In some implementation schemes, each R 2 Independently, -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -NH2, -CH2C(=O)NR 9b R 10b -C(=O)R 9c -C(=O)OR 9c -C(=O)NR 9b R 10b -NR 9b C(=O)R 10b -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1- 6-alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Hydroxyalkynyl group, C 1-6 Alkoxy, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 2-6 Haloalkenyl, C 2-6 Halogenated alkynyl group, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkylthio group, C 6-12 Aryl, 5-12 heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkylthio, C 2-6 alkenyl, C 2- 6-acetylinyl, C 2-6 Hydroxyalkynyl group, C 1-6 Alkoxy, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 2-6 Haloalkenyl, C 2-6 Halogenated alkynyl group, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkylthio group, C 6-12 Aryl, 5-12 heteroaryl, C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 11 Replaced; of which, R 9b R 9c R 10b and R11 Each has the definition as described in this invention.

[0167] In some implementation schemes, each R 2 Independently, -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -NH2, -CH2C(=O)NR 9b R 10b -C(=O)R 9c -C(=O)OR 9c -C(=O)NR 9b R 10b -NR 9b C(=O)R 10b -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 1- 4-alkylthio, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-4 Hydroxyalkynyl group, C 1-4 Alkoxy, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 2-4 Haloalkenyl, C 2-4 Halogenated alkynyl group, C 1-4 Halogenated alkoxy groups, C 1-4 Haloalkylthio group, C 6-10 Aryl, 5-12 heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein -NH2, -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkylthio, C 2-4 alkenyl, C 2- 4-Alynyl group, C 2-4 Hydroxyalkynyl group, C 1-4 Alkoxy, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 2-4 Haloalkenyl, C 2-4 Halogenated alkynyl group, C 1-4 Halogenated alkoxy groups, C 1-4 Haloalkylthio group, C 6-10 Aryl, 5-12 heteroaryl, C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 11 Replaced; of which, R9b R 9c R 10b and R 11 Each has the definition as described in this invention.

[0168] In some implementation schemes, each R 2 Independently, -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -NH2, -CH2C(=O)NR 9b R 10b -C(=O)R 9c -C(=O)OR 9c -C(=O)NR 9b R 10b -NR 9b C(=O)R 10b, -NH(CH3), -NH(CH2CH3), -N(CH3)2, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH 2. -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)3O H, -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, oxazolyl, tetrahydrofuranyl, piperidinyl or piperazineyl,The terms -NH2, -NH(CH3), -NH(CH2CH3), -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)2OH, -(CH2)2CH3 ... )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, oxazolyl, tetrahydrofuranyl, piperidinyl, and piperazineyl are each independently and optionally divided by 1, 2, 3, or 4 Rs. 11 Replaced; of which, R 9b R 9c R 10b and R 11 Each has the definition as described in this invention.

[0169] In some implementation schemes, each R 11 Independently -D, -OH, -F, -Cl, -Br, -I, CN, -C(=O)OR 9 -NR 9 R 10 -C(=O)NR 9 R 10 -NR 9 C(=O)R 10 C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; wherein, R 9 and R 10 Each has the definition as described in this invention.

[0170] In some implementation schemes, each R 11 Independently -D, -OH, -F, -Cl, -Br, -I, CN, -C(=O)OR9 -NR 9 R 10 -C(=O)NR 9 R 10 -NR 9 C(=O)R 10 C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; wherein, R 9 and R 10 Each has the definition as described in this invention.

[0171] In some implementation schemes, each R 11 Independently -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)OR 9 -NR 9 R 10 -C(=O)NR 9 R 10 -NR 9 C(=O)R 10 -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, -O(CH2)2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl; wherein, R 9 and R 10 Each has the definition as described in this invention.

[0172] In some implementation schemes, R 3 -H, -D, -OH, -SH, -F, -Cl, -Br, -I, -CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, or C 1-4 Halogenated alkyl groups.

[0173] In some implementations, L stands for key and C stands for key. 1-4 Alkylene or C 1-4 Heteroalkylene, the C 1-4 Alkylene and C 1-4 Each heteroalkyl group is independently and optionally surrounded by 1, 2, 3 or 4 R's. 12a Replaced; of which, R 12a It has the definition as described in this invention.

[0174] In some implementations, L is a bond, -CH2-, -(CH2)2-, -(CH2)3-, or -CH2OCH2-, wherein -CH2-, -(CH2)2-, -(CH2)3-, and -CH2OCH2- are each independently and optionally controlled by 1, 2, 3, or 4 Rs. 12a Replaced; of which, R 12a It has the definition as described in this invention.

[0175] In some implementations, L represents a bond, -CH2-, -(CH2)2-, -(CH2)3-, Or -CH2OCH2-.

[0176] In some implementations, L is

[0177] In some implementation schemes, each R 12a Independently -H, -D, -OH, -F, -Cl, -Br, -I, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or C 1-6 Cyanoalkyl.

[0178] In some implementation schemes, each R 12a Independently -H, -D, -OH, -F, -Cl, -Br, -I, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy or C 1-4 Cyanoalkyl.

[0179] In some implementations, two R atoms bonded to the same carbon atom 12a Together with the carbon atom attached to it, they form C 3-6 Carbon rings or 3-6 membered heterocycles.

[0180] In some implementations, two R atoms bonded to the same carbon atom 12a Together with the carbon atom attached thereto, it forms cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, pyrrolidinyl, or tetrahydrofuranyl.

[0181] In some implementation schemes, R 4 for Among them, R 13c R 13d R 12f R 12g R 12b R12c R 12d R 12e R a and R a0 Each has the definition as described in this invention.

[0182] In some implementations, m is 1, 2, 3, or 4.

[0183] In some implementation schemes, R 12f and R 12g Each of the following can be independently -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 9d R 10d -C(=O)NR 9d R 10d -CH2NR 9d R 10d -CH2OC(=O)NR 9d R 10d C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Cyanoalkyl, (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 groups; wherein, R 9d and R 10d Each has the definition as described in this invention.

[0184] In some implementation schemes, R 12f and R 12g Each of the following can be independently -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 9d R 10d -C(=O)NR 9d R 10d -CH2NR 9d R 10d -CH2OC(=O)NR 9d R 10d C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Cyanoalkyl, (3-6 membered heterocyclic)-C 1-4 Alkyl, (C 3-6 cycloalkyl)-C 1-4 Alkyl, C3-6 Cycloalkyl or 3-6 membered heterocyclic groups; wherein, R 9d and R 10d Each has the definition as described in this invention.

[0185] In some implementation schemes, R 12f and R 12g Each of the following can be independently -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 9d R 10d -C(=O)NR 9d R 10d -CH2NR 9d R 10d -CH2OC(=O)NR 9d R 10d , -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -(CH2)2F, -CH2CHF2, -CH2CF3, -CHF2, -CH2F, -(CH2)2Cl, -OCF3, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCHClCHCl2, -OCH2CH2F, -CH2CN, -(CH2)2CN, -(CH2)3CN, -(CH2)4CN, morpholinylmethyl, pyrrolylmethyl, piperazinylmethyl, aziridinemethyl, piperidinylmethyl, tetrahydropyranylmethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopentyl, cyclohexyl, morpholinyl, piperidinyl, pyrrolyl, piperazinyl or aziridine; wherein, R 9d and R 10d Each has the definition as described in this invention.

[0186] In some implementation schemes, R 12f and R 12g Together Among them, R 13a and R 13b Each has the definition as described in this invention.

[0187] In some implementation schemes, R 13a R 13b R 13c and R 13d Each can be independently -H, -D, -F, -CN, -Cl, -Br, -I, or -C. 1-6 alkyl.

[0188] In some implementation schemes, R 13a R13b R 13c and R 13d Each can be independently -H, -D, -F, -CN, -Cl, -Br, -I, or -C. 1-4 alkyl.

[0189] In some implementation schemes, R 13a R 13b R 13c and R 13d Each can be independently -H, -D, -F, -CN, -Cl, -Br, -I, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3 or -CH(CH3)2.

[0190] In some implementation schemes, R 12b -H, -D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl or C 1-6 Hydroxyalkyl.

[0191] In some implementation schemes, R 12b -H, -D, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl or C 1-4 Hydroxyalkyl.

[0192] In some implementation schemes, R 12b It can be -H, -D, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -(CH2)2F, -CH2CHF2, -CH2CF3, -CHF2, -CH2F, -(CH2)2Cl, -CH2CN, -(CH2)2CN, -(CH2)3CN, -(CH2)4CN, -CH2OH, -(CH2)2OH or -(CH2)3OH.

[0193] In some implementation schemes, R 12b -H, -D, C 2-6 alkyl.

[0194] In some implementation schemes, R 12b -H, -D, C 2-4 alkyl.

[0195] In some implementation schemes, R 12b It can be -H, -D, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3 or -CH(CH3)2.

[0196] In some implementation schemes, R 12c C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 6-10 Aryl, 5-12 heteroaryl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; wherein the R 12c Optionally selected by 1, 2, 3 or 4 elements chosen from -D, -F, -CN, -Cl, -Br, -I, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 3-6 The substituents are cycloalkyl, 3-10-membered heterocyclic and 5-12-membered heteroaryl groups, wherein the C in the substituent is... 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 3-6 The cycloalkyl, 3-10-membered heterocyclic, and 5-12-membered heteroaryl groups are optionally surrounded by 1, 2, 3, or 4 groups selected from -D, -F, -CN, -Cl, -Br, -I, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 The alkyl halogroup is substituted by a substituent.

[0197] In some implementation schemes, R 12c C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, phenyl, naphthyl, 5-6 membered heteroaryl, 7-12 membered heteroaryl, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups; wherein the R 12c Optionally selected by 1, 2, 3 or 4 elements chosen from -D, -F, -CN, -Cl, -Br, -I, C 1-4 Alkyl, C 1-4 Alkoxy, phenyl, C 3-6 The substituents are cycloalkyl, 3-6 membered heterocyclic and 5-6 membered heteroaryl, wherein the C in the substituent is... 1-4 Alkyl, C 1-4 Alkoxy, phenyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclic and 5-6-membered heteroaryl groups are optionally surrounded by 1, 2, 3 or 4 groups selected from -D, -F, -CN, -Cl, -Br, -I, C 1-4 Alkyl, C 1-4Alkoxy, C 1-4 The alkyl halogroup is substituted by a substituent.

[0198] In some implementation schemes, R 12c is -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -(CH2)2F, -CH2CHF2, -CH2CF3 , -CHF2, -CH2F, -(CH2)2Cl, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -CH2OCH3, -CH2OCH2CH 3, -CH2CH2OCH3, -C(CH3)2CH2OCH3, -CH2CH2OCH2CH3, -CH2OCH3, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, thiazolyl, imidazolyl, pyrroleyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, 2H-pyrroleyl, pyrroleyl, imidazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl or morpholinyl; wherein R 12c Optionally substituted with 1, 2, 3, or 4 substituents selected from -D, -F, -CN, -Cl, -Br, -I, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2H-pyrrolyl, pyrrolylalkyl, imidazoalkyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl, or pyrrolyl, wherein the substituents are -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -OCH3, or -OCH2 CH3, -O(CH2)2CH3, -OCH(CH3)2, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2H-pyrrolyl, pyrrolylalkyl, imidazoalkyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl, and pyrrolyl are optionally substituted by 1, 2, 3, or 4 substituents selected from -D, -F, -CN, -Cl, -Br, -I, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -(CH2)2F, -CH2CHF2, -CH2CF3, -CHF2, -CH2F, and -(CH2)2Cl.

[0199] In some implementation schemes, R 12b -H, -D, C 2-6 Alkyl; R 12c C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 6-10 Aryl, 5-12 heteroaryl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, wherein the R 12c Optionally selected by 1, 2, 3 or 4 elements chosen from -D, -F, -CN, -Cl, -Br, -I, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 3-6 The substituents are cycloalkyl, 3-10-membered heterocyclic and 5-12-membered heteroaryl groups, wherein the C in the substituent is... 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 3-6 The cycloalkyl, 3-10-membered heterocyclic, and 5-12-membered heteroaryl groups are optionally surrounded by 1, 2, 3, or 4 groups selected from -D, -F, -CN, -Cl, -Br, -I, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 The alkyl halogroup is substituted by a substituent.

[0200] In some implementation schemes, R 12b -H, -D, C 2-4 Alkyl; R 12c C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, phenyl, naphthyl, 5-6 membered heteroaryl, 7-12 membered heteroaryl, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the R 12c Optionally selected by 1, 2, 3 or 4 elements chosen from -D, -F, -CN, -Cl, -Br, -I, C 1-4 Alkyl, C 1-4 Alkoxy, phenyl, C 3-6 The substituents are cycloalkyl, 3-6 membered heterocyclic and 5-6 membered heteroaryl, wherein the C in the substituent is... 1-4 Alkyl, C 1-4 Alkoxy, phenyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclic and 5-6-membered heteroaryl groups are optionally surrounded by 1, 2, 3 or 4 groups selected from -D, -F, -CN, -Cl, -Br, -I, C 1-4 Alkyl, C1-4 Alkoxy, C 1-4 The alkyl halogroup is substituted by a substituent.

[0201] In some implementation schemes, R 12b -H, -D, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3 or -CH(CH3)2; R 12c The following are not part of the given text: -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -(CH2)2F, -CH2CHF2, -CH2CF3, -CHF2, -CH2F, -(CH2)2Cl, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -C(CH3)2CH2OCH3, -CH2CH2OCH2CH3, -CH2OCH3, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, thiazolyl, imidazolyl, pyrroloyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, 2H-pyrroloyl, pyrroloalkyl, imidazoalkyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl, wherein the R... 12cOptionally substituted with 1, 2, 3, or 4 substituents selected from -D, -F, -CN, -Cl, -Br, -I, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2H-pyrrolyl, pyrrolylalkyl, imidazoalkyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl, or pyrrolyl, wherein the substituents are -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -OCH3, or -OCH2 CH3, -O(CH2)2CH3, -OCH(CH3)2, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2H-pyrrolyl, pyrrolylalkyl, imidazoalkyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl, and pyrrolyl are optionally substituted by 1, 2, 3, or 4 substituents selected from -D, -F, -CN, -Cl, -Br, -I, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -(CH2)2F, -CH2CHF2, -CH2CF3, -CHF2, -CH2F, and -(CH2)2Cl.

[0202] In some implementation schemes, R 12b R 12c Together with the nitrogen atoms attached to them, they form 3-10 membered nitrogen heterocyclic groups, wherein the 3-10 membered nitrogen heterocyclic groups are optionally surrounded by 1, 2, 3 or 4 atoms selected from -D, -F, -CN, -Cl, -Br, -I, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 The alkyl halogroup is substituted by a substituent.

[0203] In some implementation schemes, R 12b R 12c Together with the nitrogen atoms attached to them, they form 3-7 membered nitrogen heterocyclic groups, wherein the 3-7 membered nitrogen heterocyclic groups are optionally surrounded by 1, 2, 3 or 4 atoms selected from -D, -F, -CN, -Cl, -Br, -I, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 The alkyl halogroup is substituted by a substituent.

[0204] In some implementation schemes, R 12b R12c Together with the nitrogen atoms attached to them, they form aziridine, pyrrolidinyl, imidazoalkyl, pyrazolyl, piperidinyl, morpholinyl, piperazinyl, 1,3-oxazolidinyl, or aziridine-heptyl, wherein the aziridine, pyrrolidinyl, imidazoalkyl, pyrazolyl, piperidinyl, morpholinyl, piperazinyl, 1,3-oxazolidinyl, and aziridine-heptyl are optionally surrounded by 1, 2, 3, or 4 atoms selected from -D, -F, -CN, -Cl, -Br, The substituents are -I, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -(CH2)2F, -CH2CHF2, -CH2CF3, -CHF2, -CH2F and -(CH2)2Cl.

[0205] In some implementation schemes, R a and R a0 Each of the following is independently -H, -D, -CN, -F, -Cl, -Br, -I, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl or C 1-6 Hydroxyalkyl.

[0206] In some implementation schemes, R a and R a0 Each of the following is independently -H, -D, -CN, -F, -Cl, -Br, -I, -OH, -NH2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl or C 1-4 Hydroxyalkyl.

[0207] In some implementation schemes, R a and R a0 Each can be independently -H, -D, -CN, -F, -Cl, -Br, -I, -OH, -NH2, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CN, -(CH2)2CN, -(CH2)3CN, -(CH2)4CN, -CH2OH, -(CH2)2OH, or -(CH2)3OH.

[0208] In some implementation schemes, R 12d -H, -D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl or C1-6 Hydroxyalkyl.

[0209] In some implementation schemes, R 12d -H, -D, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl or C 1-4 Hydroxyalkyl.

[0210] In some implementation schemes, R 12d It can be -H, -D, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CN, -(CH2)2CN, -(CH2)3CN, -(CH2)4CN, -CH2OH, -(CH2)2OH or -(CH2)3OH.

[0211] In some implementation schemes, R 12e -H, -D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl or -C(=O)NR 9 R 10 Among them, R 9 and R 10 Each has the definition as described in this invention.

[0212] In some implementation schemes, R 12e -H, -D, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl or -C(=O)NR 9 R 10 Among them, R 9 and R 10 Each has the definition as described in this invention.

[0213] In some implementation schemes, R 12e -H, -D, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CN, -(CH2)2CN, -(CH2)3CN, -(CH2)4CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, or -C(=O)NR 9 R 10 Among them, R 9 and R 10 Each has the definition as described in this invention.

[0214] In some implementation schemes, R6 R 7 and R 8 Each of the following is independently -H, -D, -OH, -F, -Cl, -Br, -I, -CN, C 1-6 Alkyl, C 1- 6-cyanoalkyl, C 1-6 Hydroxyalkyl or C 1-6 Halogenated alkyl groups.

[0215] In some implementations, R 6 R 7 and R 8 Each of the following is independently -H, -D, -OH, -F, -Cl, -Br, -I, -CN, C 1-4 Alkyl, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl or C 1-4 Halogenated alkyl groups.

[0216] In some implementation schemes, R 9 R 10 R 9a R 9b R 9c R 10b R 9d and R 10d Each can be independently -H, -D, or -C. 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally surrounded by 1, 2, 3, or 4 atoms selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkoxy, C 6-12 Aryl, C 3-6 Substituents of cycloalkyl and 3-6 membered heterocyclic groups.

[0217] In some implementation schemes, R 9 R 10 R 9a R 9b R 9c R 10b R 9d and R 10d Each can be independently -H, -D, or -C. 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally surrounded by 1, 2, 3, or 4 atoms selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NH2, -NH(C1-4 alkyl), -N(C) 1-4 Alkyl)2, C 1-4 Alkoxy, phenyl, C 3-6 Substituents of cycloalkyl and 3-6 membered heterocyclic groups.

[0218] In some implementation schemes, R 9 R 10 R 9a R 9b R 9c R 10b R 9d and R 10d Each of the following is independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl groups are each 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, -NH(CH3), -N(CH3)2, -NH(CH2CH3), methoxy, ethoxy, n-propoxy, isopropoxy, isobutoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, ethylene oxide, oxecyclobutyl, aziroxy, and pyrrolidinyl.

[0219] In some implementation schemes, for

[0220] In some implementation schemes, for

[0221] In some implementation schemes, R 4 for

[0222] In some embodiments, the compounds of this invention are compounds with the following structures, or stereoisomers, tautomers, nitrides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs, or the following structures.

[0223] On the other hand, the present invention provides a pharmaceutical composition comprising the compounds described herein.

[0224] In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient.

[0225] In some embodiments, the excipients described in this invention include, but are not limited to, carriers, excipients, diluents, solvents, or combinations thereof. In some embodiments, the pharmaceutical composition may be a liquid, solid, semi-solid, gel, or spray formulation.

[0226] On the other hand, the present invention provides the use of the pharmaceutical composition described herein in the preparation of a medicament for the prevention, treatment or relief of a patient’s disease mediated by KRAS G12C.

[0227] In some embodiments, the disease mediated by KRAS G12C described in this invention is cancer.

[0228] In some embodiments, the cancers described in this invention are lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, glioma, cervical cancer, urothelial carcinoma, gastric cancer, endometrial cancer, liver cancer, bile duct cancer, breast cancer, colon cancer, leukemia, and melanoma.

[0229] On the other hand, the present invention also provides a method for preventing or treating KRAS G12C-mediated diseases, the method comprising administering to a patient a therapeutically effective amount of the compound or pharmaceutical composition thereof described in the present invention.

[0230] In some embodiments, the disease mediated by KRAS G12C described in this invention is cancer.

[0231] In some embodiments, the cancers described in this invention are lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, glioma, cervical cancer, urothelial carcinoma, gastric cancer, endometrial cancer, liver cancer, bile duct cancer, breast cancer, colon cancer, leukemia, and melanoma.

[0232] On the other hand, the present invention also provides the use of the compounds or pharmaceutical compositions thereof described herein for the treatment of KRAS G12C-mediated diseases.

[0233] In some embodiments, the disease mediated by KRAS G12C described in this invention is cancer.

[0234] In some embodiments, the cancers described in this invention are lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, glioma, cervical cancer, urothelial carcinoma, gastric cancer, endometrial cancer, liver cancer, bile duct cancer, breast cancer, colon cancer, leukemia, and melanoma.

[0235] On the other hand, the present invention relates to methods for the preparation, separation and purification of compounds of formula (I).

[0236] Unless otherwise indicated, all stereoisomers, tautomers, nitrides, hydrates, solvates, metabolites, salts, and pharmaceutically acceptable prodrugs of the compounds of this invention are within the scope of this invention.

[0237] Specifically, the salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically or toxicologically suitable in relation to the other components of the formulation and the mammal intended for treatment.

[0238] The salts of the compounds of the present invention also include salts used for the preparation or purification of intermediates of the compound of formula (I) or for the isolation of enantiomers of the compound of formula (I), but are not necessarily pharmaceutically acceptable salts.

[0239] Formulation, administration and use of pharmaceutical compositions of the compounds of the present invention

[0240] The pharmaceutical compositions of the present invention are characterized by comprising compounds of formula (I), compounds listed in the present invention, or compounds of the examples, and pharmaceutically acceptable carriers. The amounts of compounds in the pharmaceutical compositions of the present invention are effective in treating or alleviating diseases mediated by KRAS G12C in patients.

[0241] The compounds of the present invention exist in free form or as suitable, pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adducts or derivatives that can be administered directly or indirectly as needed by a patient, compounds described in other aspects of the present invention, their metabolites, or their residues.

[0242] As described in this invention, pharmaceutically acceptable compositions of the present invention further comprise pharmaceutically acceptable excipients, such as those used in this invention, including any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for a particular target dosage form. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of which are summarized herein demonstrate that various excipients can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. The use of any conventional adjuvants that are incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions that occur in a harmful manner with any other component of a pharmaceutically acceptable composition, is also within the scope of this invention.

[0243] Substances that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering agents such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl cellulose. Sodium thiosulfate, ethyl cellulose 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; glycols 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 salts; Ringer's solution; ethanol, phosphate buffer solution, and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and spices, preservatives and antioxidants.

[0244] In preparing the pharmaceutical compositions provided by this invention, the active ingredient is typically mixed with an excipient, diluted by the excipient, or packaged in a carrier, such as a capsule, sachet, paper, or other container. If the excipient is used as a diluent, it can be a solid, semi-solid, or liquid material, serving as a carrier, container, or medium for the active ingredient. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethyl cellulose, low-melting-point wax, cocoa butter, etc. Therefore, the composition can be in the form of tablets, pills, powders, lozenges, capsules, flat capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), such as ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterilely packaged powders. In one embodiment, the composition is formulated for oral administration. In one embodiment, the composition is formulated as a tablet or capsule.

[0245] The compounds or pharmaceutical compositions of this invention can be administered in oral dosage forms, such as tablets, capsules (each comprising a sustained-release or timed-release formulation), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsifiers. They can also be administered intravenously (in pills or infusions), intraperitoneally, subcutaneously, or intramuscularly, all dosage forms used being well known to those skilled in the art of pharmacy. They can be administered alone, but generally a pharmaceutical carrier will be selected for co-administration based on the chosen route of administration and standard pharmaceutical practice.

[0246] The compounds or pharmaceutical compositions of the present invention can be administered intranasally via a suitable intranasal carrier or transdermally via a transdermal patch. When administered via a transdermal delivery system, the dose is continuous rather than intermittent throughout the course of treatment.

[0247] The compounds or pharmaceutical compositions of the present invention can also be administered in the form of liposome delivery systems, such as small monolayer vesicles, large monolayer vesicles, and multilayer vesicles. Liposomes can be formed from different phospholipids, such as cholesterol, stearamine, or phosphatidylcholine.

[0248] The compounds or pharmaceutical compositions of the present invention are also coupled with soluble polymers that act as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylate-phenol, polyhydroxyethyl asparagine, or polyvinyl oxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention can be coupled with a class of biodegradable polymers for controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polycaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates, and crosslinked or amphiphilic blocking copolymers of hydrogels.

[0249] The dosing regimen of the compounds or pharmaceutical compositions of this invention will vary depending on a variety of known factors, such as the pharmacokinetic characteristics and patterns of administration of the specific agent; the recipient's race, age, sex, health status, medical condition, and weight; the nature and severity of symptoms; the types of concurrent treatments; the frequency of treatment; the route of administration; the patient's renal and hepatic 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 halt the development of cancer.

[0250] The compounds and compositions described in this invention can be administered alone or in combination with other compounds or other therapeutic agents. The compounds or compositions of this invention can be administered simultaneously or sequentially with other therapeutic agents via the same or different routes of administration. The compounds of this invention can be included in a single formulation along with other therapeutic agents or in a separate formulation.

[0251] When the compounds of the present invention are administered together with other therapeutic agents, the amount of each component in a typical daily dose and typical dosage form may generally be reduced relative to the usual dose when administered alone, taking into account the additional or synergistic effects of the therapeutic agents when administered in combination.

[0252] The compounds, pharmaceutical salts, hydrates, or pharmaceutical compositions thereof involved in this invention are effective in preventing, treating, or alleviating diseases mediated by KRAS G12C, particularly lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, glioma, cervical cancer, urothelial carcinoma, gastric cancer, endometrial cancer, liver cancer, bile duct cancer, breast cancer, colon cancer, leukemia, and melanoma.

[0253] General Synthesis Process

[0254] To describe this invention, the following embodiments will be used to further illustrate the technical solution of this invention. These embodiments are only used to illustrate specific implementation methods of this invention so that those skilled in the art can understand it, but are not intended to limit the scope of protection of this invention. In the specific implementation methods of this invention, technical means or methods not specifically described are conventional technical means or methods in the art.

[0255] Unless otherwise specified, the substituents are defined as described in this invention. The following reaction schemes and examples are provided to further illustrate the content of this invention.

[0256] Those skilled in the art will recognize that the chemical reactions described in this invention can be suitably used to prepare other compounds of this invention, and that other methods for preparing the compounds of this invention are considered to be within the scope of this invention. For example, the synthesis of those non-illustrative compounds according to this invention can be successfully accomplished by those skilled in the art through modification methods, such as by appropriately protecting interfering groups, by utilizing other known reagents besides those described in this invention, or by making some conventional modifications to the reaction conditions. Furthermore, the reactions disclosed in this invention or the known reaction conditions are also generally accepted to be applicable to the preparation of other compounds of this invention.

[0257] In the examples described below, unless otherwise specified, all temperatures are in degrees Celsius (°C). Room temperature in the examples represents 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 specified, general reagents were purchased from Tianjin Fuyu Fine Chemical Co., Ltd., Beijing Innocare Technology Co., Ltd., Chengdu Kelon Chemical Co., Ltd., Anaiji Chemical Beijing Sihailongxing Petrochemical Co., Ltd., etc.

[0258] Anhydrous tetrahydrofuran, dioxane, toluene, and diethyl ether are obtained by reflux drying with metallic sodium. Anhydrous dichloromethane and chloroform are obtained by reflux drying with calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide are used after prior drying with anhydrous sodium sulfate.

[0259] The following reactions are generally carried out under positive pressure of nitrogen or argon or with a drying tube attached to an anhydrous solvent (unless otherwise specified). All reaction flasks are sealed with suitable rubber stoppers, and the substrate is injected using a syringe. All glassware is dried.

[0260] The chromatographic column used was a silica gel column. The silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.

[0261] 1 H NMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer. 1 ¹H NMR spectra are performed using CDCl₃, DMSO-d₆, CD₃OD, or acetone-d₆ as solvents (in ppm), with TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiplets are observed, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), br s (broadened singlet), dd (doublet of doublets), dt (doublet of triplets). The coupling constant J is expressed in Hertz (Hz).

[0262] Low-resolution mass spectrometry (MS) at 210 nm / 254 nm, using UV detection, was performed as follows:

[0263] The compounds of this invention are detected by HPLC using UV detection, and the specific test method is as follows:

[0264] Mobile phase: Phase A: Weigh approximately 12.24 g of anhydrous sodium perchlorate, dissolve it in 1 L of ultrapure water, adjust the pH to 3.0 with perchloric acid, filter through a 0.22 μm or 0.45 μm aqueous filter membrane, take 900 mL of filtrate and mix with 100 mL of acetonitrile, degas by sonication, and obtain the mobile phase; Phase B: Acetonitrile; Column: Waters Xbridge C18, 4.6 × 150 mm, 3.5 μm; Add a trap column (recommended: Shimadzu, Ghost Trap DS 7.6 mm × 30 mm (holder set)).

[0265] Flow rate: 1.0 mL / min; Detection wavelength: 220 nm; Column temperature: 30 °C;

[0266] Run time: 30 minutes, subsequent run: 5 minutes

[0267] Gradient elution table:

[0268] The following abbreviations or English terms are used throughout this invention: B2Pin2,B2Pin2 Pinaol diboronate N2 Nitrogen DIPEA Diisopropylethylamine TMSOTf Trimethylsilyl trifluoromethanesulfonate Pd(dppf)Cl2·CH2Cl2 [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex XPhos Pd G4 Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) NBS N-bromosuccinimide THF / H2O A mixture of tetrahydrofuran and water PMBCl 4-methoxybenzyl chloride DCM Dichloromethane PMB 4-methoxybenzyl DMF N,N-dimethylformamide Boc Tert-butyloxycarbonyl EtOH Ethanol NIS N-Iodiodosuccinimide (PE), Petroleum ether (TFA), Trifluoroacetic acid (EA), Ethyl acetate (TLC), Thin-layer chromatography (TLC), g / L, mg / mL, mol / mol, DPEphos, PdCl2, PdCl2(DPEphos), Bis(diphenylphosphine) mmol / mmol mormol ether, Palladium(II) dichloride, rt, Room temperature, Dixoane or 1,4-Dioxane, 1,4-dioxane, 2-MeTHF, 2-methyltetrahydrofuran, t-BuOK, Potassium tert-butoxide (DABCO), Triethylenediamine (LiHMDS), Bistrimethylsilylaminolithium (Pd / C), Palladium / carbon (N2), Nitrogen (ACN, CH3CN), Acetonitrile (HATU), 2-(7-azobenzotriazole)-N,N,N',N'-Tetramethylurea hexafluorophosphate (TFA), trifluoroacetic acid (CMPI), 2-chloro-1-methylpyridine iodide (DMSO), dimethyl sulfoxide (MSA), methanesulfonic acid (DMTMM), 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine (μmol), micromolar morpholine hydrochloride.

[0269] The following examples further illustrate the compounds, pharmaceutical compositions, and their applications provided by the present invention.

[0270] Synthesis Scheme 1

[0271] Compound (I) can be synthesized according to the method of synthetic scheme 1, wherein Q 1 Ring B, R 1 R 2 R 3 R 4 R 6 R 7 R 8 L, R 5a R 5b R 5c R 5d R 5e R 5f R 5g R 5h And n each have the definition as described in this invention; Hal 1 Hal 2 and Hal 4 Each compound is independently a halogen, preferably Cl or Br. Compound (I-1) reacts with compound (I-2) under suitable conditions (e.g., in the presence of DIPEA, in dichloromethane solvent, at low temperature) to give compound (I-3); compound (I-3) reacts with compound (I-4) under alkaline conditions (e.g., potassium carbonate) to give compound (I-5); compound (I-5) reacts with compound (I-6) under a coupling reaction to give compound (I-7); compound (I-7) undergoes a deprotection reaction to give compound (I-8); compound (I-8) reacts with compound (I-9) under suitable conditions (e.g., in the presence of DIPEA) to give compound (I). Example

[0272] Synthesis of intermediate compound M2

[0273] M2:(3-Cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzo[b]thiophene-2-yl)tert-butyl carbamate

[0274] N-(4-bromo-3-cyano-7-fluoro-1-benzothiophene-2-yl)tert-butyl carbamate (2 g, 5.39 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxacyclopentaborane (4.11 g, 16.17 mmol), potassium acetate (2.12 g, 21.56 mmol), and toluene (40 mL) were added to a reaction flask. After purging with nitrogen three times, Pd(dppf)Cl2·CH2Cl2 (0.44 g, 0.54 mmol) was added, followed by purging with nitrogen three more times. After bubbling for 10 min, the temperature was raised to 80 °C and reacted for 2 h, during which the color gradually turned black. The reaction was stopped by TLC monitoring until the reactants were completely reacted. The reaction solution was directly evaporated to dryness and purified by silica gel column chromatography (eluent PE / DCM (v / v) = 100 / 0-10 / 3) to give 1.72 g of a yellowish-white solid, yield 76.32%. MS (ESI, neg.ion) m / z: 417.1 [MH] - .

[0275] Example 1: Synthesis of Compound 1

[0276] Step 1: Synthesis of Compounds 1-2

[0277] Compound 1-1 (1.3836 g, 4.23 mmol) and toluene (7 mL) were added to a 50 mL double-necked flask. POCl3 (1.95 g, 12.69 mmol) was slowly added, followed by dropwise addition of DIPEA (1.64 g, 12.69 mmol). The mixture was stirred at 110 °C for 3 h. The reaction solution was concentrated to obtain a brown oily product.

[0278] Step 2: Synthesis of compounds 1-3

[0279] Compounds 1-2 (1.45 g, 3.98 mmol) and DCM (13 mL) were added to a 50 mL single-necked flask. (2R,5S)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (1.02 g, 4.78 mmol) was added at -40 °C, followed by dropwise addition of DIPEA (1.53 g, 11.86 mmol). The reaction was allowed to proceed for 30 min. TLC analysis confirmed complete reaction of the starting material. The reaction was quenched with saturated ammonium chloride solution (1.5 mL), separated, and the organic phase was concentrated. The residue was purified by silica gel column chromatography (PE / EA (v / v = 9 / 1)) to give compounds 1-3 as a white, foamy solid (1.4 g, 65% yield). MS (ESI, pos.ion) m / z: 541.6 [M+H] + .

[0280] Step 3: Synthesis of compounds 1-5

[0281] Add NaH (185 mg, 4.63 mmol, 60% purity) to a 10 mL single-necked flask, followed by the addition of dry THF (15 mL). Cool to 0 °C and add dropwise a THF solution (5 mL) containing compounds 1-4 (350.02 mg, 1.85 mmol). Then heat to room temperature and react for 30 min. Cool to 0 °C and add dropwise a THF solution (5 mL) containing compounds 1-3 (1000 mg, 1.85 mmol). Heat to room temperature and continue the reaction for 5 h. When the starting material has basically reacted completely, stop the reaction. Add saturated ammonium chloride (3 mL) to the reaction solution. Extract the resulting mixture with ethyl acetate (20 mL × 2). Concentrate the organic phase. Purify the residue by silica gel column chromatography (DCM / MeOH (v / v = 50 / 1)) to obtain compounds 1-5 as a white foamy solid (370 mg, yield 28.86%). MS(ESI,pos.ion)m / z:694.3[M+H] + .

[0282] Step 4: Synthesis of compounds 1-6

[0283] Compounds 1-5 (200 mg, 0.30 mmol), intermediate M2 (188.23 mg, 0.45 mmol), and DPEphosPdCl2 (109.24 mg, 0.15 mmol) were added to a 25 mL two-necked flask. The mixture was purged with nitrogen three times. 1,4-Dioxane (10 mL) was added, and the mixture was purged with nitrogen three times. The temperature was raised to 100 °C, and the reaction was allowed to proceed for 4.5 h. TLC analysis confirmed complete reaction of the starting material (DCM / MeOH (v / v = 30 / 1)). The reaction solution was cooled to room temperature, and DCM (20 mL) was added to dissolve the reactants. The mixture was filtered, washed with DCM (5 mL), and the filtrate was concentrated. The residue was separated by silica gel column chromatography (DCM / MeOH (v / v = 30 / 1)) to obtain compounds 1-6 as a pale yellow, foamy solid (150 mg, yield 55.01%). HRMS: 906.3272 [M+H] + .

[0284] Step 5: Synthesis of compounds 1-7

[0285] Compounds 1-6 (35 mg, 0.039 mmol) were dissolved in DCM (3.5 mL), and TFA (2.11 g, 18.53 mmol) was added. The mixture was stirred at room temperature for approximately 30 min. TLC analysis showed that the reaction proceeds were complete (DCM / MeOH (v / v) = 30 / 1). The reaction solution was concentrated, and toluene (3 mL × 3) was added to the concentrate. The solution was then concentrated under reduced pressure to give compounds 1-7 (27.26 mg, 99.98% yield). MS (ESI, negative ion) m / z: 704.1 [MH] - .

[0286] Step 6: Synthesis of Compound 1

[0287] Compounds 1-7 (27 mg, 0.038 mmol) and DCM (3 mL) were added to a 25 mL two-necked flask, followed by DIPEA (36.83 mg, 0.28 mmol). The mixture was stirred at -78 °C for 5 min. A DCM solution of acryloyl chloride (3.10 mg, 0.034 mmol) (0.2 mL) was added dropwise over 10 min, and the reaction was maintained at this temperature for 5 min. TLC was used to confirm the reaction was complete. Methanol (0.5 mL) with three drops of water was added dropwise to the reaction mixture, and the reaction was quenched by stirring for 3 min. The mixture was then transferred to room temperature, concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v = 15 / 1)) to obtain the target compound 1 as a pale yellow solid (15 mg, yield 51.6%). MS (ESI, pos.ion) m / z: 760.4 [M+H] + ; 1H NMR (400MHz, CDCl3) δ8.00(d,J=12.3Hz,1H),7.20(d,J=8.1Hz,1H),6.98(t,J=8.8Hz,1H),6.58(ddd,J=29.4,17.8,9.6Hz ,1H),6.34(dd,J=31.2,15.3Hz,1H),5.77(t,J=10.2Hz,1H),5.66(d,J=13.5Hz,1H),5.06–4.85(m,1H),4.48–4.04(m,4H) ,3.81(t,J=17.7Hz,2H),3.74–3.58(m,3H),3.26(s,1H),2.81(d,J=15.9Hz,1H),2.66(dd,J=17.1,8.1Hz,1H),2.43(d,J= 15.4Hz,1H),2.19(dd,J=12.5,6.7Hz,2H),1.99–1.90(m,2H),1.88–1.77(m,1H),1.30–1.23(m,6H); HRMS:760.2344[M+H] + .

[0288] Example 2: Synthesis of Compound 2

[0289] Step 1: Synthesis of Compound 2-2

[0290] Compound 2-1 (10 g, 37.98 mmol) and THF (100 mL) were added to a two-necked flask. Under N2 protection, bis(trimethylsilylaminolithium) (75.96 mL, 75.96 mmol) was slowly added dropwise. The mixture was stirred at low temperature for 1 h, followed by slow addition of 4-bromo-1-butene (12.82 g, 94.95 mmol). After the addition was complete, the temperature was raised to 20 °C, and the reaction was stirred for 14 h. TLC analysis showed that the starting material had basically reacted completely. The reaction was quenched by adding 100 mL of saturated ammonium chloride aqueous solution. The mixture was extracted with EA (70 mL × 3), dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (PE ~ PE / EA (v / v = 6 / 1)). Compound 2-2 was obtained as a pale yellow liquid (10.17 g, yield 84.37%). MS (ESI, pos.ion) m / z: 318.90 [M+H] + .

[0291] Step 2: Synthesis of compounds 2-3

[0292] Compound 2-2 (10.1 g, 31.82 mmol) and DCM (100 mL) were added to a two-necked flask, followed by m-chloroperoxybenzoic acid (12.08 g, 70.00 mmol). The mixture was substituted three times with N2 and stirred at room temperature for 13 h under N2 protection. The reaction mixture became turbid, and a white solid precipitated. TLC confirmed that the reactants had reacted completely, and the reaction was stopped. The reaction was quenched with 150 mL of saturated sodium sulfite aqueous solution. The mixture was filtered through diatomaceous earth, and the filtrate was washed with 100 mL of saturated sodium bicarbonate aqueous solution. The filtrate was concentrated and purified by silica gel column chromatography (PE~PE / EA (v / v=6 / 1)) to give compound 2-3 as a colorless liquid (7.08 g, yield 66.73%). MS (ESI, pos.ion) m / z: 333.90 [M+H] + .

[0293] Step 3: Synthesis of compounds 2-4

[0294] Compound 2-3 (7 g, 21.00 mmol) and methanol (70 mL) were added to a flask, followed by Pd / C (0.45 g, 4.2 mmol). The mixture was substituted three times with H2, and the reaction was carried out under H2 protection with stirring at room temperature for 16 h. The reaction was confirmed by TLC. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated and purified by silica gel column chromatography (DCM / MeOH (v / v = 100 / 0-5 / 1)) to give compound 2-4 as a pale yellow oil (3.24 g, yield 77.45%). MS (ESI, pos.ion) m / z: 200.20 [M+H] + .

[0295] Step 4: Synthesis of compounds 2-5

[0296] In one flask, periodic acid (4.29 g, 18.82 mmol), ACN (25 mL), and chromium trioxide (0.38 g, 3.77 mmol) were added and stirred at room temperature for 0.5 h to obtain an oxidized solution for later use. In another flask, compound 2-4 (1.5 g, 7.53 mmol) and ACN (25 mL) were added and stirred. The mixture was cooled to 0 °C, and the above oxidized solution was slowly added dropwise. The mixture was stirred at 0 °C for 10 min, then heated to rt and stirred for 1 h. The reaction was monitored by TLC to confirm completion. The reaction solution was filtered, and the filter cake was washed with acetonitrile (50 mL) to obtain an acetonitrile solution of compound 2-5. The filtrate was directly added to the next step, and the yield was calculated as 100%. MS (ESI, pos.ion) m / z: 214.15 [M+H] + .

[0297] Step 5: Synthesis of compounds 2-6

[0298] An acetonitrile solution of compounds 2-5 obtained in step 4 was added to a flask, and the temperature was lowered to 0°C. HATU (4.61 g, 12.12 mmol) and DIPEA (2.61 g, 20.2 mmol) were added, followed by a solution of 4-methoxybenzylmethylamine (1.53 g, 10.1 mmol) in ACN (25 mL). The mixture was stirred for 10 min, then allowed to rise to room temperature and stirred for 15.5 h. The reaction was quenched with water (20 mL), extracted with DCM (100 mL × 2), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (DCM ~ DCM / EA (v / v = 5 / 1)) to give compounds 2-6 as a yellow liquid (2.6 g, yield 92.88%). MS (ESI, pos.ion) m / z: 347.20 [M+H] + .

[0299] Step 6: Synthesis of compounds 2-7

[0300] Compound 2-6 (1 g, 2.89 mmol) and THF (75 mL) were added to a flask, and the temperature was lowered to -40 °C. Lithium aluminum hydride (2.31 mL, 5.78 mmol) was slowly added, and the mixture was stirred at -40 °C for 30 min. Saturated sodium sulfate aqueous solution (5 mL) was added, and the mixture was filtered through diatomaceous earth. The filtrate was washed with DCM (100 mL), concentrated, and purified by silica gel column chromatography (DCM ~ DCM / CH3OH (v / v = 10 / 1)) to obtain compound 2-7 as a yellowish-brown oil (0.24 g, yield 26.11%). MS (ESI, pos.ion) m / z: 319.10 [M+H] + .

[0301] Step 7: Synthesis of compounds 2-8

[0302] Compound 2-7 (0.3 g, 0.94 mmol) and TFA (30 mL) were added to a flask, heated to 60 °C, and stirred for 5 h. The reaction was then stopped, and the reaction mixture was cooled to room temperature. Saturated potassium phosphate solution was slowly added, and the mixture was extracted with DCM (100 mL × 2). The organic phase was collected, concentrated, and purified by silica gel column chromatography (DCM / CH3OH (v / v = 100 / 0-5 / 1)) to give compound 2-8 as a yellowish-brown oil (0.185 g, yield 99.04%). MS (ESI, pos.ion) m / z: 199.15 [M+H] + .

[0303] Step 8: Synthesis of compounds 2-9

[0304] Take a 100 mL two-necked flask, dissolve compounds 1-2 (2 g, 5.51 mmol) in DCM (20 mL), stir at -40 °C for 3 min, add (S)-4-N-tert-butoxycarbonyl-2-methylpiperazine (1.47 g, 7.36 mmol), add DIPEA (2.36 g, 18.27 mmol) dropwise, react for 0.5 h, quench with 2 mL saturated ammonium chloride solution, extract the organic layer with DCM (20 mL), evaporate the solvent, and purify by silica gel column chromatography (PE / EA (v / v) = 10 / 1), to obtain compounds 2-9 as white foamy solids (2.12 g, yield 65.62%). MS (ESI, pos.ion) m / z: 527.0 [M+H] +

[0305] Step 8: Synthesis of compounds 2-10

[0306] Compound 2-9 (0.2 g, 0.38 mmol), compound 2-8 (0.090 g, 0.46 mmol), and potassium carbonate (0.16 g, 1.14 mmol) were added to a flask. The mixture was purged with nitrogen three times, and 1,4-dioxane (7 mL) was added. The mixture was heated to 105 °C and stirred for 16 h. The reaction was then stopped. Water (2 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with EA (20 mL × 2). The organic phase was collected, concentrated, and purified by silica gel column chromatography (DCM ~ DCM / CH3OH (v / v = 20 / 1)) to give compound 2-10 as a pale yellow oil (70 mg, yield 26.79%). MS (ESI, pos.ion) m / z: 689.90 [M+H] + .

[0307] Step 9: Synthesis of Compound 2-11

[0308] Under nitrogen protection, compound 2-10 (0.070 g, 0.10 mmol), M2 (0.050 g, 0.12 mmol), and cesium carbonate (0.098 g, 0.30 mmol) were added sequentially to the flask. The mixture was purged with N2 three times. Then, 1,4-dioxane (5 mL) was added, followed by DPEphosPdCl2 (0.036 g, 0.050 mmol). The mixture was purged with N2 three times. The reaction was carried out at 100 °C for 4 h under N2 protection. The reaction was then stopped, concentrated, and purified by silica gel column chromatography (DCM~DCM / CH3OH (v / v=15 / 1)) to give compound 2-11 as a pale yellow solid (50 mg, yield 54.67%). MS (ESI, pos.ion) m / z: 901.95 [M+H] + .

[0309] Step 10: Synthesis of Compound 2-12

[0310] Compound 2-11 (0.050 g, 0.055 mmol) and DCM (5 mL) were added to a flask-within-a-flask. The mixture was cooled to 0 °C and stirred. Trifluoroacetic acid (1.50 mL, 20.19 mmol) was added dropwise. The mixture was heated to rt and stirred for 30 min, then the reaction was stopped. The reaction solution was directly concentrated by rotary evaporation. 2 mL of toluene was added to the concentrate, and the mixture was concentrated by rotary evaporation to obtain compound 2-12 as a yellowish-brown oil. This was directly added to the next step. The yield was calculated as 100%.

[0311] Step 11 Synthesis of Compound 2

[0312] Compound 2-12 (0.035 g, 0.050 mmol) from step 10 and anhydrous DCM (5 mL) were added to a flask. The temperature was lowered to -78 °C, and DIPEA (0.052 g, 0.40 mmol) was added. Acryloyl chloride (0.0027 g, 0.030 mmol) in 1 mL of anhydrous DCM solution was slowly added dropwise. The mixture was stirred at low temperature for 10 min. The reaction was monitored by TLC until completion. Water (0.2 mL) and CH3OH (1 mL) were added to quench the reaction. The mixture was heated to rt and stirred for 10 min. The solution was concentrated and purified by silica gel column chromatography (DCM / MeOH (v / v) = 100 / 1-8 / 1) to obtain target compound 2 as a yellow solid (30 mg, yield 79.58%). MS (ESI, pos.ion) m / z: 755.3 [M+H] + . 1 H NMR(400MHz, CDCl3)δ7.98(s,1H),7.20–7.13(m,1H),6.95(td,J=8.6,3.5Hz,1H),6.36(d,J=16.7Hz,1H), 6.27–6.09(m,2H),5.76(d,J=10.5Hz,1H),4.76(s,1H),4.71(d,J=11.7Hz,1H),4.60(d,J=13.9Hz,2H),4.3 3(d,J=31.4Hz,1H),3.66(s,2H),3.65(s,2H),3.09(s,2H),3.08(s,2H),2.81(t,J=4.7Hz,3H),2.51(d,J=1 2.1Hz,1H),2.48–2.30(m,2H),2.29–2.18(m,2H),2.11(dd,J=18.8,10.4Hz,2H),1.39(s,2H),1.24(s,3H).

[0313] Example 3: Synthesis of Compound 3

[0314] Step 1: Synthesis of Compound 3-1

[0315] Compound 2-5 (1.07 g, 5.02 mmol) was added to a two-necked flask, followed by a 10 mL solution of tert-butylamine (0.55 g, 7.53 mmol) in acetonitrile. The mixture was cooled to 0 °C, and CMPI (1.92 g, 753 mmol) was added. The mixture was stirred for 10 min, and then triethylamine (1.52 g, 24.35 mmol) was slowly added dropwise. The mixture was stirred for 10 min, and then the mixture was allowed to rise to room temperature and stirred for 4 h. The mixture was purified by silica gel column chromatography (PE ~ PE / EA (v / v = 2 / 3)) to give compound 3-1 as a brown viscous liquid (0.65 g, yield 48.3%). MS (ESI, pos.ion) m / z: 269.2 [M+H] + .

[0316] Step 2: Synthesis of compound 3-2

[0317] Compound 3-1 (0.21 g, 0.78 mmol) and THF (9 mL) were added to a two-necked flask, and the temperature was lowered to -40 °C. Lithium aluminum hydride (0.059 g, 1.56 mmol) was slowly added, and the mixture was stirred at -40 °C for 30 min. A saturated sodium sulfate aqueous solution (0.5 mL) was added, and the mixture was filtered through diatomaceous earth. The filtrate was washed with DCM (20 mL), and the filtrate was concentrated to give compound 3-2 as a yellow-brown viscous liquid (188 mg, 99.9% yield). MS (ESI, pos.ion) m / z: 241.1 [M+H] + .

[0318] Step 3: Synthesis of compound 3-3

[0319] At room temperature, compound 1-3 (0.50 g, 0.92 mmol) and DMSO (5 mL) were added to a two-necked flask, purged with nitrogen three times, followed by the addition of potassium fluoride (0.29 g, 5.06 mmol), triethylenediamine (0.0093 g, 0.083 mmol), and methanesulfonic acid (0.0088 g, 0.092 mmol), purged with nitrogen three times, and the mixture was heated to 65 °C and stirred for 1 h. The reaction was then stopped. Post-treatment: The reaction solution was cooled to 0 °C, and the reaction was quenched by slowly adding ice water (10 mL). Extraction was performed with EA (10 mL × 3), the organic phase was collected, washed with water (5 mL × 3), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE / EA (v / v = 100 / 0-6 / 1)) to give compound 3-3 as a yellow solid (0.40 g, yield 82.6%). MS (ESI, pos.ion) m / z: 525.1 [M+H] + .

[0320] Step 4: Synthesis of compounds 3-4

[0321] Compound 3-3 (320 mg, 0.61 mmol), compound 3-2 (131.95 mg, 0.55 mmol), and 2-methyltetrahydrofuran (14 mL) were added to a 10 mL double-necked flask. The mixture was cooled to -30 °C, and a 1 M solution of potassium tert-butoxide (.082 g, 0.73 mmol) in THF was slowly added dropwise over approximately 10 min. The reaction mixture was allowed to react for 10 min. A saturated sodium sulfate aqueous solution (3 mL) was added to the reaction mixture, followed by extraction with EA (6 mL × 3). The organic phases were combined, concentrated, and purified by silica gel column chromatography (PE / EA (v / v = 1 / 2)) to obtain compound 3-4 as a white, foamy solid (230 mg, yield 50.64%). MS (ESI, pos.ion) m / z: 745.2 [M + H] + .

[0322] Step 5: Synthesis of compounds 3-5

[0323] Under nitrogen protection, compounds 3-4 (100 mg, 0.13 mmol), M2 (108.76 mg, 0.26 mmol), and cesium carbonate (127.07 mg, 0.39 mmol) were added sequentially to the flask. The mixture was purged with N2 three times. Then, 1,4-dioxane (2 mL) was added, followed by DPEphosPdCl2 (46.53 mg, 0.065 mmol). The mixture was purged with N2 three times. The reaction was carried out at 100 °C for 2 h under N2 protection, and then the reaction was stopped. Post-treatment: The mixture was cooled, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (DCM ~ DCM / CH3OH (v / v = 30 / 1)) to give compounds 3-5 as a reddish-brown solid (80 mg, yield 63.33%). MS (ESI, pos.ion) m / z: 957.3 [M+H] + .

[0324] Step 6: Synthesis of compounds 3-6

[0325] Compound 3-5 (80 mg, 0.084 mmol) and DCM (12 mL) were added to a flask, cooled to 0 °C and stirred. TFA (2.29 mL, 30.84 mmol) was added dropwise, and the mixture was heated to rt and stirred for 30 min, at which point the reaction was stopped. The reaction solution was concentrated by rotary evaporation, and after adding 2 mL of toluene, it was concentrated again by rotary evaporation to give compound 3-6 as a yellow oil (0.063 g, 100% yield). MS (ESI, pos.ion) m / z: 757.2 [M+H] + .

[0326] Step 7: Synthesis of Compound 3

[0327] Compound 3-6 (80 mg, 0.11 mmol) and DCM (3 mL) were added to a flask, and the temperature was lowered to -78 °C. DIPEA (99.51 mg, 0.77 mmol) was added, followed by the slow addition of 0.5 mL of anhydrous DCM solution containing acryloyl chloride (8.96 mg, 0.099 mmol). The mixture was stirred at low temperature for 5 min. The reaction was quenched with water (0.2 mL) and CH3OH (1 mL). The temperature was raised to rt and stirred for 10 min. Post-treatment: The reaction solution was directly evaporated to dryness and purified by silica gel column chromatography (DCM / MeOH (v / v) = 100 / 1-10 / 1) to obtain target compound 3 as a pale yellow solid (48 mg, yield 56.00%). 1 H NMR (400MHz, CDCl3) δ8.05 (s, 1H), 7.21 (s, 2H), 7.00 (t, J = 8.3Hz, 1H), 6.61 (d, J = 32.5Hz, 1H),6.38(t,J=14.3Hz,1H),5.80(t,J=14.8Hz,3H),5.00(dd,J=47.2,17.7Hz,3H),4.70( s,2H),4.39(d,J=58.0Hz,3H),4.16(d,J=24.2Hz,1H),3.83(s,2H),3.78–3.61(m,4H),3. 11(dd,J=14.8,7.4Hz,3H),2.48(s,2H),2.24(s,4H),2.13(s,2H),1.39(d,J=6.3Hz,9H). MS(ESI,pos.ion)m / z:811.25[M+H] + .

[0328] Example 4: Synthesis of Compound 4

[0329] Step 1: Synthesis of Compound 4-1

[0330] At 20°C, 2-9 (2.35 g, 4.45 mmol) and DMSO (24 mL) were added to a flask, and the mixture was purged with nitrogen three times. Potassium fluoride (1.42 g, 24.48 mmol), triethylenediamine (0.045 g, 0.40 mmol), and methanesulfonic acid (0.043 g, 0.45 mmol) were then added, and the mixture was purged with nitrogen three times. The mixture was then heated to 65°C and stirred for 1 h. Post-treatment: The reaction solution was cooled to 0°C, quenched slowly with ice water (10 mL), extracted with EA (50 mL × 3), and the organic phase was collected. The mixture was washed with water (20 mL × 3), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE / EA (v / v) = 10 / 1) to obtain compound 4-1 as a pale yellow foamy solid (2.05 g, 90% yield). MS (ESI, pos.ion) m / z: 511.1 [M+H]+ .

[0331] Step 2: Synthesis of compound 4-2

[0332] Compound 4-1 (200 mg, 0.39 mmol), compound 3-2 (121.85 mg, 0.51 mmol), and 2-methyltetrahydrofuran (12 mL) were added to a 10 mL double-necked flask. The mixture was cooled to -30 °C, and potassium tert-butoxide (0.057 g, 0.51 mmol, 1 M) tetrahydrofuran solution was slowly added dropwise over approximately 10 min. The reaction was allowed to proceed for 10 min. TLC analysis confirmed complete reaction of the starting material (PE / EA (v / v) = 5 / 1). Saturated sodium dihydrogen phosphate (0.3 mL) was added, followed by extraction with EA (5 mL × 2). The organic phases were combined, concentrated, and purified by silica gel column chromatography (PE / EA (v / v = 1 / 2) to obtain compound 4-2 as a pale yellow foamy solid (160 mg, yield 55.91%). MS (ESI, pos.ion) m / z: 732.2 [M+H] + .

[0333] Step 3: Synthesis of compound 4-3

[0334] Under nitrogen protection, compound 4-2 (60 mg, 0.082 mmol), M2 (68.60 mg, 0.16 mmol), and cesium carbonate (80.15 mg, 0.25 mmol) were added sequentially to the reaction flask. The mixture was purged with N2 three times. Then, 1,4-dioxane (1.5 mL) was added, followed by DPEphosPdCl2 (29.35 mg, 0.041 mmol). The mixture was purged with N2 three times. The reaction was carried out at 100 °C for 2 h under N2 protection, and then the reaction was stopped. Post-treatment: The mixture was cooled, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (DCM~DCM / CH3OH (v / v=30 / 1)) to obtain compound 4-3 as a reddish-brown solid (45 mg, yield 58.19%). MS (ESI, pos.ion) m / z: 944.2 [M+H] + .

[0335] Step 4: Synthesis of compound 4-4

[0336] Compound 4-3 (0.13 g, 0.14 mmol) and DCM (12 mL) were added to a flask, cooled to 0 °C and stirred. TFA (3.82 mL, 51.40 mmol) was added dropwise, and the mixture was heated to rt and stirred for 30 min until the reaction was complete. The reaction solution was then stopped by rotary evaporation. The solution was concentrated, and 2 mL of toluene was added. The mixture was then concentrated by rotary evaporation to obtain compound 4-4 as a yellow oil (94.5 mg). MS (ESI, pos.ion) m / z: 743.2 [M+H] + .

[0337] Step 5: Synthesis of Compound 4

[0338] Compound 4-4 (59 mg, 0.079 mmol) and DCM (6 mL) were added to a flask, and the temperature was lowered to -78°C. DIPEA (71.47 mg, 0.55 mmol) was added, followed by the slow addition of anhydrous DCM solution (0.5 mL) of acryloyl chloride (6.44 mg, 0.071 mmol). The mixture was stirred at low temperature for 5 min. After 10 min of reaction, the reaction was monitored by TLC to indicate completion. The reaction was quenched with water (0.2 mL) and CH3OH (1 mL). The mixture was then heated to rt and stirred for 10 min. Post-treatment: The mixture was directly concentrated and purified by silica gel column chromatography (DCM / MeOH (v / v = 100 / 1-10 / 1)) to obtain target compound 4 as a pale yellow solid (45 mg, yield 71.10%). 1 H NMR (400MHz, CDCl3) δ7.98(s,1H),7.17(s,1H),6.96(s,1H),6.60(s,1H),6.36(d,J=15.8Hz,1H),5.97(s,1H),5.75(s, 1H), 4.65 (d, J = 82.1Hz, 3H), 4.32 (s, 2H), 3.64 (s, 4H), 3.06 (s, 2H), 2.36 (s, 2H), 2.01 (s, 6H), 1.77 (s, 9H), 1.46 (s, 6H). MS(ESI,pos.ion)m / z:797.2[M+H] + .

[0339] Example 5: Synthesis of Compound 5

[0340] Steps 1-2: Synthesis of compound 5-2

[0341] The synthesis of compound 5-2 was performed following the synthesis of 3-2 in Example 3, except that the starting material tert-butylamine in step 1 of Example 3 was replaced with isopropylamine, ultimately yielding 165 mg of a pale yellow oily liquid, 5-2. MS (ESI, pos.ion) m / z: 227.2 [M+H] + .

[0342] Steps 3-7: Synthesis of Compound 5

[0343] The synthesis of compound 5 is based on steps 1-5 of Example 4, except that raw material 3-2 in step 2 of Example 4 is replaced with 5-2, and the final target compound 5 is 52 mg of pale yellow solid. 1H NMR (400MHz, CDCl3) δ7.99 (s, 1H), 7.22–7.13 (m, 1H), 6.97 (t, J = 8.9Hz, 1H), 6.70–6.50 (m,1H),6.38(d,J=16.6Hz,1H),6.04(s,2H),5.79(d,J=11.8Hz,1H),4.77(s,1H),4.51– 4.23(m,4H),4.07(dd,J=12.8,6.4Hz,3H),3.62(dd,J=13.3,6.7Hz,3H),3.24(s,3H),2 .88 (s, 1H), 2.26 (d, J = 12.3Hz, 2H), 2.00 (dd, J = 34.2, 7.2Hz, 8H), 1.16 (d, J = 3.4Hz, 6H). MS(ESI,pos.ion)m / z:783.2[M+H] + .

[0344] Example 6: Synthesis of Compound 6

[0345] Step 1: Synthesis of Compound 6-1

[0346] Compound 2-5 (700 mg, 3.51 mmol), DMF (10 mL), and dimethylamine hydrochloride (429.31 mg, 5.26 mmol) were added to a single-necked flask. The temperature was lowered to 0 °C, and COMU (2254.84 mg, 5.26 mmol) was added. The mixture was stirred for 10 min, and DIPEA (1814.53 mg, 14.04 mmol) was slowly added dropwise. The mixture was stirred for 10 min, and the temperature was raised to 25 °C and stirred for 4 h. The reaction proceeded completely. The reaction was quenched with water (2 mL), extracted with DCM (10 mL × 2), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE / EA (v / v = 1 / 1)) to give compound 6-1 as a brown solid (400 mg, yield 47.38%). MS (ESI, pos.ion) m / z: 241.1 [M+H] + .

[0347] Step 2: Synthesis of Compound 6-2

[0348] Compound 6-1 (200 mg, 0.83 mmol) and methanol (0.5 mL) were added to a flask. Under nitrogen protection, the mixture was cooled to 0 °C, and sodium methoxide (1.49 mg, 0.0083 mmol) was added. Sodium borohydride (89.19 mg, 2.49 mmol) was then slowly added. The mixture was stirred at low temperature for 10 min, then brought to room temperature and stirred continuously. The reaction was stopped after 2.5 h. Post-treatment: The reaction was quenched by adding saturated ammonium chloride (50 mL), and the mixture was stirred until no bubbles were generated. The pH was adjusted to approximately 7, and the mixture was extracted with ethyl acetate (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 6-2 as a pale yellow oily liquid (0.16 g, yield 90.56%). MS (ESI, pos.ion) m / z: 213.2 [M+H] + .

[0349] Steps 3-6: Synthesis of Compound 6

[0350] The synthesis of compound 6 is based on steps 2-5 of Example 4, except that raw material 3-2 in step 2 of Example 4 is replaced with 6-2, and the final product is 52 mg of a pale yellow solid. 1 H NMR(400MHz, CDCl3)δ8.00(s,1H),7.20(s,1H),7.08–6.94(m,1H),6.61(s,1H),6.39(d, J=16.7Hz,1H),5.88(s,1H),5.79(d,J=9.7Hz,1H),5.36(s,1H),4.57(dd,J=129.5,36.6H z,5H),3.95(d,J=78.4Hz,1H),3.69(dd,J=13.8,7.2Hz,5H),3.24(s,3H),3.12(dd,J=14 .5,7.3Hz,3H),2.98(s,3H),2.02(s,5H),0.90(s,4H)MS(ESI,pos.ion)m / z:769.20[M+H] + .

[0351] Example 7: Synthesis of Compound 7

[0352] Steps 1-2: Synthesis of compound 7-2

[0353] The synthesis of compound 7-2 was performed following the synthesis of 3-2 in Example 3, except that the starting material tert-butylamine in step 1 of Example 3 was replaced with cyclobutylamine. The final product, compound 7-2, was a pale yellow oily liquid (950 mg). MS (ESI, pos.ion) m / z: 239.2 [M+H] + .

[0354] Steps 3-7: Synthesis of Compound 7

[0355] The synthesis of compound 7 followed steps 1-5 of Example 4, except that starting material 3-2 in step 2 of Example 4 was replaced with 7-2. The final product was 52 mg of the target compound 7 as a pale yellow solid. MS (ESI, pos.ion) m / z: 795.20 [M+H] + . 1 H NMR(400MHz, CDCl3)δ7.99(s,1H),7.23–7.16(m,1H),7.02–6.97(m,1H),6.59(s,2H),6.38(d,J=16.6H z,1H),5.78(d,J=11.9Hz,1H),5.71(d,J=15.3Hz,1H),4.85–4.60(m,2H),4.35(dt,J=23.6,10.8Hz,4H) ,4.05(d,J=14.0Hz,1H),3.81(s,1H),3.27(s,1H),3.04(s,1H),2.71(d,J=7.6Hz,1H),2.30(d,J=4.1Hz ,2H),2.22–2.14(m,2H),1.95(d,J=5.8Hz,5H),1.90(d,J=10.1Hz,5H),1.73–1.66(m,3H),1.46(s,3H).

[0356] Example 8: Synthesis of Compound 8

[0357] The synthesis of compound 8 was performed following steps 4-7 of Example 3, except that starting material 3-2 in step 4 of Example 3 was replaced with 7-2. The final product, target compound 8, was a pale yellow solid (57 mg). MS (ESI, pos.ion) m / z: 809.20 [M+H] + . 1H NMR(400MHz, CDCl3)δ8.00(d,J=12.7Hz,1H),7.22–7.15(m,1H),6.97(t,J=8.7Hz,1H),6.65–6.49(m,1H),6.36(t,J=14.4 Hz,1H),5.87(s,2H),5.77(t,J=9.4Hz,1H),5.01(s,1H),4.85(d,J=20.1Hz,1H),4.43(s,1H),4.40–4.31(m,2H),4.24–4. 10(m,1H),4.00(s,1H),3.85–3.78(m,1H),3.77–3.66(m,1H),3.54–3.40(m,1H),3.23(s,1H),2.82(s,1H),2.28(d,J=3.9 Hz, 5H), 2.03 (d, J = 6.2Hz, 5H), 1.95 (d, J = 9.0Hz, 5H), 1.77 (d, J = 8.8Hz, 1H), 1.70 (d, J = 6.1Hz, 2H), 1.43 (d, J = 6.7Hz, 3H).

[0358] Example 9: Synthesis of Compound 9

[0359] The synthesis of compound 9 was performed following steps 4-7 of Example 3, except that starting material 3-2 in step 4 of Example 3 was replaced with 6-2. The final product, target compound 9, was a pale yellow solid (75 mg). MS (ESI, pos.ion) m / z: 783.20 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.06 (d, J = 29.0Hz, 1H), 7.20–7.13 (m, 1H), 6.97 (s, 1H), 6. 54(s,1H),6.36(s,1H),6.18(s,1H),5.91(d,J=45.1Hz,1H),5.76(s,1H),4.9 3(s,3H),4.63(d,J=49.3Hz,1H),4.24(s,3H),3.89–3.57(m,4H),3.40(s,3H) ,3.00(d,J=13.4Hz,3H),2.56(s,2H),2.33(s,3H),2.22(s,3H),1.43(s,6H).

[0360] Example 10: Synthesis of Compound 10

[0361] The synthesis of compound 10 was performed following steps 3-6 of Example 1, except that starting materials 1-3 in step 3 of Example 1 were replaced with 2-9. The final product, target compound 10, was a pale yellow solid (30 mg). 1 H NMR (400MHz, CDCl3) δ7.98(s,1H),7.19(s,1H),6.99(t,J=8.6Hz,1H),6.61(s,1H ),6.37(d,J=16.6Hz,1H),5.78(d,J=9.3Hz,1H),4.29(s,3H),3.84(s,2H),3. 66(dd,J=13.3,6.8Hz,4H),3.46–3.01(m,5H),2.82(d,J=14.1Hz,1H),2.67(d ,J=8.2Hz,1H),2.43(d,J=15.8Hz,1H),2.19(s,1H),1.95(s,3H),1.95(s,3H). MS(ESI,pos.ion)m / z:746.9[M+H] + .

[0362] Example 11: Synthesis of Compound 11

[0363] Step 1: Synthesis of Compound 11-1

[0364] Compound 2-5 (1 g, 4.69 mmol) and acetonitrile (10 mL) were added to a flask, and the mixture was cooled to 0 °C. DIPEA (2.42 g, 18.76 mmol) and HATU (3.57 g, 9.38 mmol) were added, followed by morpholine (0.82 g, 9.38 mmol). The mixture was stirred for 10 min, then allowed to rise to room temperature and stirred for 4 h. The reaction was then stopped. Water (10 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with EA (20 mL × 3). The combined organic phases were washed with water (2 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (PE / EA (v / v) = 1 / 1) to give compound 11-1 as a pale yellow liquid (0.95 g, yield 71.75%). MS (ESI, pos.ion) m / z: 283.20 [M+H] + .

[0365] Step 2: Synthesis of compound 11-2

[0366] Compound 11-1 (0.45 g, 1.59 mmol) and methanol (5 mL) were added to a flask. Under nitrogen protection, the mixture was cooled to 0 °C, and sodium methoxide (2.86 mg, 15.9 μmol) was added. Sodium borohydride (0.17 g, 4770.00 μmol) was then slowly added. The mixture was stirred at low temperature for 10 min, then heated to room temperature and stirred for another 4 h. The reaction was then stopped. Saturated ammonium chloride (30 mL) was added to quench the reaction, and the mixture was stirred until no more bubbles were produced. The pH was adjusted to approximately 7, and the mixture was extracted with ethyl acetate (50 mL). The extract was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM ~ DCM / CH3OH (v / v = 20 / 1)) to obtain compound 11-2 as a yellow oil (162 mg, yield 39.96%). MS (ESI, pos.ion) m / z: 255.20 [M+H] + .

[0367] Steps 3-6: Synthesis of Compound 11

[0368] The synthesis of compound 11 was performed following steps 2-5 of Example 4, with the addition of 11-2 to react with starting material 3-2 in step 2 of Example 4. The final product, target compound 11, was a pale yellow solid (70 mg). MS (ESI, pos.ion) m / z: 811.20 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.99(s,1H),7.18(s,1H),6.99(t,J=8.5Hz,1H),6.59(s,1H),6.37(d,J=16.7Hz,1H),5.77(d,J=10.5Hz ,1H),5.68(s,1H),4.75(d,J=20.9Hz,2H),4.48–4.19(m,3H),4.02(d,J=30.4Hz,1H),3.80(s,2H),3.72(d,J=14.3Hz,2H),3. 63(s,2H),3.61(d,J=8.3Hz,4H),3.45(s,1H),3.27(s,1H),3.09(dd,J=14.8,7.4Hz,1H),2.84(s,1H),2.60(d,J=7.9Hz,1H), 2.36–2.28(m,1H),2.25–2.19(m,1H),2.00(s,2H),1.65–1.59(m,1H),1.56–1.51(m,1H),1.46(d,J=5.7Hz,3H),1.42(s,2H).

[0369] Example 12: Synthesis of Compound 12

[0370] The synthesis of compound 12 was performed in accordance with steps 4-7 of Example 3, except that raw material 3-2 in step 4 of Example 3 was replaced with 11-2, and 91 mg of the target compound 12 pale yellow solid was finally obtained. 1 H NMR (400MHz, CDCl3) δ8.07–7.97(m,1H),7.19(s,1H),7.00(t,J=8.7Hz,1H),6.59(dt,J=27.4,16.6Hz,1H),6.37(t,J=14.5Hz,1 H),5.76(d,J=10.6Hz,1H),5.57(s,2H),5.01(s,1H),4.85(d,J=33.1Hz,1H),4.37(dd,J=36.1,15.9Hz,2H),4.24–4.03(m,2H),3 .88(s,1H),3.81(d,J=14.0Hz,2H),3.75–3.68(m,2H),3.64(s,2H),3.61(d,J=11.1Hz,3H),3.45(s,1H),3.09(dd,J=14.8,7.4Hz ,1H),2.78(s,1H),2.59(s,1H),2.38–2.30(m,1H),2.27–2.13(m,2H),2.00(s,1H),1.62(s,1H),1.57–1.51(m,2H),1.42(s,6H). MS(ESI,pos.ion)m / z:825.20[M+H] + .

[0371] Example 13: Synthesis of Compound 13

[0372] Steps 1-2: Synthesis of compound 13-2

[0373] The synthesis of compound 13-2 was performed according to steps 1-2 of Example 11, except that the starting material morpholine in step 1 of Example 11 was replaced with 3-methylazacyclobutane hydrochloride. The final product, compound 13-2, was a pale yellow oil, 0.78 g in size. MS (ESI, pos.ion) m / z: 239.20 [M+H] + .

[0374] Steps 3-6: Synthesis of Compound 13

[0375] The synthesis of compound 13 was performed according to steps 4-7 of Example 3, except that starting material 3-2 in step 4 of Example 3 was replaced with 13-2. The final product, compound 13, was a pale yellow solid, 75 mg. MS (ESI, pos.ion) m / z: 809.20 [M+H]+ . 1 H NMR (400MHz, CDCl3) δ8.01(s,1H),7.14(s,1H),6.93(t,J=20.9Hz,3H),6.55(dd,J=29.7,11.3Hz,1H), 6.38(d,J=15.4Hz,1H),5.76(s,1H),5.22(s,1H),5.00(s,1H),4.73(s,1H),4.54(d,J=11.9Hz,1H),4. 43–4.22(m,2H),4.15(s,1H),3.97–3.82(m,3H),3.67(s,3H),3.39(s,1H),3.09(s,2H),2.69(d,J=49. 5Hz,3H),2.43(s,3H),2.08(s,2H),1.49(d,J=6.3Hz,3H),1.41(d,J=6.3Hz,3H),1.13(d,J=5.1Hz,3H).

[0376] Example 14: Synthesis of Compound 14

[0377] The synthesis of compound 14 was performed according to steps 2-5 of Example 4, except that starting material 3-2 in step 2 of Example 4 was replaced with 13-2. The final product, target compound 14, was a pale yellow solid, 42 mg. MS (ESI, pos.ion) m / z: 795.20 [M+H] + . 1 H NMR (400MHz, CDCl3)δ8.00(s,1H),7.21–7.14(m,1H),6.97(t,J=8.7Hz,1H),6.59(s,1H),6.38(d,J=16.6H z,1H),6.09(s,1H),5.78(d,J=10.7Hz,1H),4.90–4.53(m,3H),4.31(s,2H),4.00(s,2H),3.84(s,1H), 3.74–3.57(m,4H),3.48(s,2H),3.26(s,1H),3.15–3.06(m,1H),2.63(s,1H),2.33(d,J=7.6Hz,2H),2. 24–2.18(m,1H),1.84(s,2H),1.63(s,1H),1.51–1.45(m,4H),1.41(d,J=6.9Hz,2H),1.20–1.14(m,3H).

[0378] Example 15: Synthesis of Compound 15

[0379] Step 1: Synthesis of Compound 15-1

[0380] Compound 2-5 (0.59 g, 2.96 mmol) and ACN (10 mL) were added to a single-necked flask, followed by a solution of 3-oxacyclobutylamine (0.32 g, 4.44 mmol). The mixture was cooled to 0 °C, and DMTMM (1.64 g, 5.92 mmol) was added. The mixture was stirred for 10 min, then allowed to rise to room temperature and stirred for 1.5 h. The reaction was quenched with water (6 mL), extracted with EA (30 mL × 2), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE ~ PE / EA (v / v = 1 / 3)) to give compound 15-1 as a brown viscous liquid (0.48 g, yield 64.5%). MS (ESI, pos.ion) m / z: 269.20 [M + H] + .

[0381] Step 2: Synthesis of Compound 15-2

[0382] Compound 15-1 (0.10 g, 0.29 mmol) and THF (5 mL) were added to a two-necked flask, and the temperature was lowered to -30 °C. Lithium aluminum hydride (0.011 g, 0.29 mmol) was slowly added, and the mixture was stirred at low temperature for 30 min. A saturated sodium sulfate aqueous solution (0.2 mL) was added, and the mixture was filtered through diatomaceous earth. The filter cake was washed with DCM (10 mL), and the filtrates were combined and concentrated. Purification was performed by silica gel column chromatography (DCM ~ DCM / CH3OH (v / v = 20 / 1)) to obtain compound 15-2 as a yellow-brown viscous liquid (0.04 g, 45% yield). MS (ESI, pos.ion) m / z: 241.10 [M+H] + .

[0383] Steps 3-6: Synthesis of Compound 15

[0384] The synthesis of compound 15 followed steps 4-7 of Example 3, except that starting material 3-2 in step 4 of Example 3 was replaced with 15-2. The final product, compound 15, was a pale yellow solid, 42 mg. MS (ESI, pos.ion) m / z: 811.20 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.05(s,1H),7.22(s,1H),7.02(t,J=8.7Hz,1H),6.71–6.50(m,1H),6.41(dd,J=28.5,16.6 Hz,1H),5.79(d,J=9.9Hz,1H),5.66(d,J=16.0Hz,1H),5.02(s,1H),4.93–4.80(m,2H),4.62–4.45(m,2H),4.42– 4.25(m,3H),4.25–4.08(m,1H),3.87(d,J=13.5Hz,1H),3.72(s,1H),3.40(d,J=18.6Hz,1H),3.15(s,1H),2.74( s,1H),2.33(d,J=7.6Hz,1H),2.28–2.15(m,2H),2.01(dd,J=27.8,15.8Hz,9H),1.76(s,2H),1.49–1.41(m,4H).

[0385] Example 16: Synthesis of Compound 16

[0386] Steps 1-2: Synthesis of compound 16-2

[0387] The synthesis of compound 16-2 was performed according to the synthesis of compound 11-2 in Example 11, except that the starting material morpholine in step 1 of Example 11 was replaced with bicyclic [1.1.1]pentan-2-amine. The final product, compound 16-2, was a pale yellow oil (250 mg). MS (ESI, pos.ion) m / z: 251.20 [M+H] + Steps 3-6: Synthesis of Compound 16

[0388] The synthesis of compound 16 was performed in accordance with steps 2-5 of Example 4, except that the starting material 3-2 in step 2 of Example 4 was replaced with 16-2, and the target compound 16 was obtained as a pale yellow solid (42 mg). 1H NMR (400MHz, CDCl3) δ7.98(s,1H),7.17(d,J=4.5Hz,1H),6.97(dd,J=16.1,7.6Hz,1H),6.61(s,1H),6.37(d,J=16.1Hz ,1H),6.08(s,1H),5.80(dd,J=23.2,8.2Hz,2H),4.76(s,1H),4.69(s,1H),4.54(s,1H),4.42(s,1H),4.29(s,1H),4.13 –3.77(m,2H),3.64(s,3H),3.53–3.41(m,1H),3.19(d,J=50.1Hz,1H),2.98(s,1H),2.44(d,J=7.3Hz,1H),2.34(s,2H), 2.26–2.19(m,2H),2.09(d,J=9.4Hz,4H),1.88(s,2H),1.65–1.55(m,2H),1.48(d,J=7.2Hz,3H),1.42(d,J=6.4Hz,2H). MS(ESI,pos.ion)m / z:807.20[M+H] + .

[0389] Example 17: Synthesis of Compound 17

[0390] Steps 1-2: Synthesis of Compound 17-2

[0391] The synthesis of compound 17-2 was performed following steps 1-2 of Example 15, except that the starting material 3-oxacyclobutylamine in step 1 of Example 15 was replaced with 2-fluoroaniline. The final product, compound 17-2, was a pale yellow oil, 0.18 g in size. MS (ESI, pos.ion) m / z: 279.2 [M+H] + .

[0392] Step 3: Synthesis of Compound 17-3

[0393] Under nitrogen protection, compound 3-3 (2000 mg, 3.81 mmol), M2 (2071.79 mg, 4.95 mmol), and cesium carbonate (557.15 mg, 1.71 mmol) were added sequentially to the flask. The mixture was purged with N2 three times. Then, 1,4-dioxane (50 mL) was added, followed by DPEphosPdCl2 (545.00 mg, 0.76 mmol). The mixture was purged with N2 three times. The reaction was carried out at 65 °C for 4 h under N2 protection. The mixture was cooled, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (PE~PE / EA (v / v=5 / 1)). Compound 17-3 was obtained as a white solid (0.9 g, yield 32%). MS (ESI, pos.ion) m / z: 736.7 [M+H] + .

[0394] Step 4: Synthesis of Compound 17-4

[0395] Under N2 protection, sodium hydride (0.017 g, 0.42 mmol) and dry tetrahydrofuran (5 mL) were added to a two-necked flask. The temperature was lowered to 0 °C, and compound 17-2 (0.043 g, 0.15 mmol) dissolved in dry tetrahydrofuran (0.5 mL) was added dropwise over 20 min. After the addition was complete, the mixture was stirred for 5 min, then brought to room temperature and stirred for 1 h. The temperature was lowered to 0 °C, and compound 17-3 (100 mg, 0.14 mmol) dissolved in dry tetrahydrofuran (0.5 mL) was slowly added dropwise over 40 min. The mixture was stirred at 0 °C for 30 min. The reaction mixture was then added to an ice-cold saturated ammonium chloride aqueous solution (1 mL), and extracted with EA (3 mL × 3). The combined organic layers were dried over Na2SO4, the filtrate was concentrated, and purified by silica gel column chromatography (PE ~ PE / EA (v / v = 1 / 2)). The purified compound 17-4 was obtained as an off-white solid (0.06 g, yield 44%). MS(ESI,pos.ion)m / z:995.3.

[0396] Step 5: Synthesis of Compound 17-5

[0397] Compound 17-4 (50 mg, 0.050 mmol) and DCM (1.2 mL) were added to a single-necked flask, cooled to 0 °C and stirred. TFA (0.28 mL, 3.74 mmol) was added dropwise, and the mixture was heated to room temperature and stirred. The reaction proceeded for 30 min until the reactants were fully reacted. The reaction solution was concentrated by rotary evaporation, and after adding 2 mL of toluene, it was concentrated again by rotary evaporation to give compound 17 as a yellow oil (39.94 mg, 100% yield). MS (ESI, pos.ion) m / z: 795.2 [M+H] + .

[0398] Step 6: Synthesis of Compound 17

[0399] Add 17-5 (39.94 mg, 0.050 mmol) and anhydrous DCM (2 mL) to a two-necked flask, lower the temperature to -78 °C, add DIPEA (0.052 g, 0.40 mmol), and slowly add anhydrous DCM (0.5 mL) solution of acryloyl chloride (3.64 mg, 0.040 mmol). React at -78 °C for 10 min, then quench the reaction with 0.5 mL of water and 2 mL of CH3OH. Heat to RT and stir for 10 min. Post-treatment: The reaction solution was directly evaporated to dryness, and purified by silica gel column chromatography (DCM ~ DCM / MeOH (v / v = 15 / 1)) to obtain compound 17 as an off-white solid (20 mg, yield 46%). MS (ESI, pos.ion) m / z: 849.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.03(s,1H),7.39(d,J=20.0Hz,1H),7.09(d,J=8.5Hz,3H),7.00(d,J=6.8Hz,1H),6.59(dd, J=28.4,13.1Hz,1H),6.47–6.32(m,1H),5.84(dt,J=23.6,9.8Hz,2H),5.57(s,1H),5.46–5.33(m,2H),5.13–4.87( m,4H),4.62(d,J=16.5Hz,2H),4.09(t,J=6.6Hz,1H),3.91(s,1H),3.77(s,1H),3.67(s,1H),3.11(d,J=7.6Hz,1H) ,2.96–2.81(m,1H),2.70–2.56(m,1H),2.25(dd,J=15.5,8.0Hz,2H),2.09–2.02(m,4H),1.39(s,3H),1.33(s,3H).

[0400] Example 18: Synthesis of Compound 18

[0401] Step 1: Synthesis of Compound 18-1

[0402] The synthesis of compound 18-1 was performed according to step 1 of Example 15, except that the starting material 3-oxetanediamine in step 1 of Example 15 was replaced with 3-aminotetrahydrofuran. The final product, compound 18-1, was a pale yellow oil, 0.51 g in size. MS (ESI, pos.ion) m / z: 283.3 [M+H] + .

[0403] Step 2: Synthesis of compound 18-2

[0404] Compound 18-1 (0.40 g, 1.42 mmol) and methanol (10 mL) were added to a two-necked flask. Under nitrogen protection, the mixture was cooled to 0 °C, and sodium methoxide (25.57 mg, 0.142 mmol) was added. Sodium borohydride (0.15 g, 4.260 mmol) was then slowly added. The mixture was stirred at 0 °C for 10 min, then warmed to room temperature and stirred for another 4.5 h. Post-treatment: The reaction was quenched with saturated ammonium chloride (3 mL), stirred until no bubbles were produced, adjusted to pH ≈ 7, extracted with ethyl acetate (15 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and evaporated to dryness to obtain compound 18-2 as a white solid (0.28 g, 77% yield). MS (ESI, pos.ion) m / z: 255.2 [M+H] + .

[0405] Steps 3-5: Synthesis of Compound 18

[0406] The synthesis of compound 18 is based on steps 4-6 of Example 17, except that starting material 17-2 in step 4 of Example 17 is replaced with 18-2, and the target compound 18 is obtained as a pale yellow solid (35 mg). 1 H NMR (400MHz, MeOD) δ8.19(s,1H),7.26(s,1H),7.05(t,J=8.7Hz,1H),6.94–6.74(m,1H),6.31(dd,J=16.8,6.5Hz,1H),6.24(d,J=17.2Hz, 1H),6.13(dd,J=17.1,9.9Hz,1H),5.84(d,J=7.0Hz,1H),5.72(d,J=10.1Hz,1H),5.02(s,1H),4.72–4.57(m,2H),4.59–4.45(m,2H),4.41( s,2H),3.86(dd,J=16.6,7.6Hz,2H),3.65(d,J=9.1Hz,1H),3.57–3.43(m,2H),2.24(dd,J=50.3,28.6Hz,8H),2.03(dd,J=21.4,13.7Hz,2 H),1.94–1.83(m,1H),1.82–1.69(m,1H),1.52(d,J=6.5Hz,2H),1.47(s,3H),1.37(s,3H),1.37(s,3H).MS(ESI,pos.ion)m / z:825.3[M+H] + .

[0407] Example 19: Synthesis of Compound 19

[0408] Step 1: Synthesis of Compound 19-1

[0409] The synthesis of compound 19-1 was performed according to step 1 of Example 15, except that the starting material 3-oxacyclobutamine in step 1 of Example 15 was replaced with 1-amino-4-methylpiperazine. The final product was 0.25 g of compound 19-1 as a brown oil. MS (ESI, pos.ion) m / z: 296.3 [M+H] + .

[0410] Step 2: Synthesis of Compound 19-2

[0411] The synthesis of compound 19-2 was performed according to step 2 of Example 18, except that starting material 18-1 was replaced with 19-1 in step 2 of Example 18. The final product was 0.052 g of a yellow oily substance, compound 19-2. MS (ESI, pos.ion) m / z: 268.3 [M+H] + .

[0412] Steps 3-5: Synthesis of Compound 19

[0413] The synthesis of compound 19 was performed in steps 4-6 of Example 17, except that starting material 17-2 in step 4 of Example 17 was replaced with 19-2, and the target compound 19 was obtained as a pale yellow solid (26 mg). 1 H NMR (400MHz, CDCl3)δ8.03(d,J=7.2Hz,1H),7.07–6.94(m,1H),6.71–6.52(m,1H),6.41(t,J=18.0Hz,2H),6.15(dd,J =17.3,10.4Hz,1H),5.88(d,J=10.3Hz,1H),5.86–5.65(m,2H),4.97(dd,J=32.0,20.0Hz,2H),4.50–4.28(m,2H), 4.23(s,1H),3.89(d,J=13.1Hz,2H),3.71(dt,J=13.3,6.6Hz,4H),3.51(s,1H),3.13(q,J=7.4Hz,4H),2.71(s,2H ),2.55(s,2H),2.48(s,2H),2.29–2.21(m,2H),1.77(s,1H),1.64(s,1H),1.52(s,3H),1.45(s,3H),1.33(s,3H). MS(ESI,pos.ion)m / z:839.2[M+H] +

[0414] Example 20: Synthesis of Compound 20

[0415] Step 1: Synthesis of Compound 20-1

[0416] The synthesis of compound 20-1 was performed following step 1 of Example 3, which describes the synthesis of compound 3-1, except that the starting material tert-butylamine in step 1 of Example 3 was replaced with cyclopentylamine. The final product, compound 20-1, was obtained as a brown oily substance, 0.298 g. MS (ESI, pos.ion) m / z: 281.2 [M+H] + .

[0417] Step 2: Synthesis of compound 20-2

[0418] The synthesis of compound 20-2 was performed following step 2 of Example 18, except that starting material 18-1 was replaced with 20-1. The final product, compound 20-2, was a yellow oily substance, 0.145 g. MS (ESI, pos.ion) m / z: 253.2 [M+H] + .

[0419] Steps 3-5: Synthesis of Compound 20

[0420] The synthesis of compound 20 is based on steps 4-6 of Example 17, except that starting material 17-2 in step 4 of Example 17 is replaced with 20-2, and the target compound 20 is obtained as a pale yellow solid (72 mg). 1 H NMR (400MHz, CDCl3) δ7.97 (d, J = 12.6Hz, 1H), 7.13 (s, 1H), 6.91 (s, 1H), 6.7 1–6.28(m,4H),5.74(d,J=9.9Hz,1H),4.92(d,J=42.2Hz,2H),4.57(s,2H), 4.18(s,4H),3.97–3.44(m,4H),2.98(s,1H),2.40(s,2H),2.18(s,3H),2.0 4(s,2H),1.92(s,3H),1.73(s,2H),1.55(s,4H),1.42(s,3H),1.25(s,3H). MS(ESI,pos.ion)m / z:823.20[M+H] + .

[0421] Example 21: Synthesis of Compound 21

[0422] Steps 1-2: Synthesis of compound 21-2

[0423] The synthesis of compound 21-2 was performed according to steps 1-2 of Example 11, except that the starting material morpholine in step 1 of Example 11 was replaced with perpiperidine. The final product, compound 21-2, was 0.2 g of a pale green oil. MS (ESI, pos.ion) m / z: 267.20 [M+H] + Steps 3-5: Synthesis of Compound 21

[0424] The synthesis of compound 21 is based on steps 4-6 of Example 17, except that starting material 17-2 in step 4 of Example 17 is replaced with 21-2, and the target compound 21 is obtained as a pale yellow solid (41 mg). 1 H NMR(400MHz, CDCl3) δ7.99(d,J=6.4Hz,1H),7.20(s,1H),7.01(d,J=8.5Hz,1H),6.65–6.4 8(m,1H),6.37(t,J=14.2Hz,1H),5.77(d,J=10.7Hz,1H),5.58(s,2H),4.95(d,J=33.2Hz, 2H),4.35–4.18(m,3H),4.04(dd,J=56.5,16.4Hz,2H),3.78(d,J=39.2Hz,4H),3.57–3.23 (m,3H),2.68(d,J=27.8Hz,2H),2.30–2.01(m,3H),1.80(s,9H),1.42(s,6H),1.25(s,3H). MS(ESI,pos.ion)m / z:837.90[M+H] + .

[0425] Example 22: Synthesis of Compound 22

[0426] Steps 1-2: Synthesis of compound 22-2

[0427] The synthesis of compound 22-2 was performed following steps 1-2 of Example 11, except that the starting material morpholine in step 1 of Example 11 was replaced with tetrahydropyrrole. The final product, compound 22-2, was a white solid, 0.2 g in size. MS (ESI, pos.ion) m / z: 239.20 [M+H] + .

[0428] Steps 3-5: Synthesis of Compound 22

[0429] The synthesis of compound 22 was performed in accordance with steps 4-6 of Example 17, except that starting material 17-2 in step 4 of Example 17 was replaced with 22-2, and the target compound 22 was obtained as a pale yellow solid (41 mg).1 H NMR(599MHz, CDCl3)δ8.00(d,J=19.6Hz,1H),7.18(s,1H),6.97(s,1H),6.68–6.52(m,1 H),6.46–6.30(m,1H),5.77(d,J=10.4Hz,1H),4.93(s,1H),4.37–4.15(m,2H),4.16–4. 05(m,1H),4.02–3.81(m,2H),3.72–3.63(m,1H),3.64–3.39(m,3H),3.12(dd,J=14.5,7 .2Hz,1H),1.78(s,9H),1.62–1.42(m,6H),1.27(s,7H),0.89(dd,J=17.6,10.8Hz,2H). MS(ESI,pos.ion)m / z:809.25[M+H] + .

[0430] Example 23: Synthesis of Compound 23

[0431] Steps 1-2: Synthesis of compound 23-2

[0432] The synthesis of compound 23-2 was performed following steps 1-2 of Example 11, with the addition of 4-aminotetrahydropyran to morpholine in step 1 of Example 11. The final product, compound 23-2, was a white solid, 0.1 g. MS (ESI, pos.ion) m / z: 269.20 [M+H] + .

[0433] Steps 3-5: Synthesis of Compound 23

[0434] The synthesis of compound 23 is based on steps 4-6 of Example 17, except that starting material 17-2 in step 4 of Example 17 is replaced with 23-2, and the target compound 23 is obtained as a pale yellow solid (20 mg). 1H NMR(400MHz, CDCl3)δ8.01(d,J=10.8Hz,1H),7.20(s,1H),6.99(t,J=8.1Hz,1H), 6.69–6.51(m,1H),6.47–6.31(m,1H),6.06(s,1H),5.78(d,J=9.9Hz,1H),4.90(s ,1H),4.52(s,1H),4.39–4.10(m,3H),3.95(s,3H),3.78(dd,J=56.6,24.6Hz,2H) ,3.47(d,J=11.2Hz,3H),2.96(s,1H),2.29–1.71(m,16H),0.88(d,J=14.6Hz,6H). MS(ESI,pos.ion)m / z:839.20[M+H] + .

[0435] Example 24: Synthesis of Compound 24

[0436] Step 1: Synthesis of Compound 24-1

[0437] The synthesis of compound 24-1 was performed following step 2 of Example 1, which describes the synthesis of compounds 1-3, except that the starting material (2R,5S)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester in step 2 of Example 1 was replaced with tert-butyl(S)-2-(cyanomethyl)piperazine-1-carboxylate. The final product was compound 24-1, a white solid weighing 1.56 g. MS (ESI, pos.ion) m / z: 552.00 [M+H] + .

[0438] Steps 2-6: Synthesis of Compound 24

[0439] The synthesis of compound 24 is based on the synthesis of compound 3 in steps 3-7 of Example 3, except that raw materials 1-3 in step 3 of Example 3 are replaced with 24-1, and compound 24 is finally obtained as a white solid of 21 mg. 1H NMR(599MHz, CDCl3)δ8.07(s,1H),7.12–6.95(m,1H),6.61(s,1H),6.43(d, J=15.8Hz,1H),5.86(s,1H),4.41(s,2H),4.18–3.74(m,3H),3.66(s,1H),3 .51(s,1H),2.81(dd,J=135.8,69.3Hz,3H),2.30(d,J=70.7Hz,2H),1.75(d d,J=142.6,116.4Hz,8H),1.42(d,J=34.1Hz,3H),1.28(s,9H),0.90(s,3H). MS(ESI,pos.ion)m / z:822.15[M+H] + .

[0440] Example 25: Synthesis of Compound 25

[0441] The synthesis of compound 25 is performed according to steps 4-7 of Example 3, except that raw material 3-2 in step 4 of Example 3 is replaced with 25-1, and the final product is 10 mg of white solid, compound 25. 1 H NMR (400MHz, CDCl3) δ8.03(d,J=7.5Hz,1H),7.24–7.16(m,1H),6.98(t,J=8.8Hz,1H),6.77–6.50(m,1H),6.38(t,J=15.0Hz,1H) ,6.03(d,J=10.4Hz,2H),5.78(d,J=10.1Hz,1H),5.23(s,2H),4.98(d,J=40.5Hz,1H),4.76(d,J=10.8Hz,1H),4.66(s,1H),4.52– 4.32(m,2H),4.14(d,J=7.3Hz,1H),3.96(s,1H),3.92–3.65(m,3H),3.56(d,J=14.5Hz,1H),3.14(d,J=15.8Hz,1H),2.96(d,J=1 0.0Hz, 1H), 2.63 (d, J = 15.4Hz, 1H), 2.43 (dd, J = 12.4, 6.3Hz, 1H), 2.30–2.10 (m, 3H), 2.03 (s, 2H), 1.45 (dd, J = 15.2, 10.1Hz, 4H). MS(ESI,pos.ion)m / z:724.8[M+H] + .

[0442] Examples 26-64

[0443] Using suitable raw materials, the target compounds 26-64 of Examples 26-64 were prepared according to the synthetic route of Example 3. The specific structures and characterization data are shown in the table below.

[0444] Structural and characterization data of compounds 26-64

[0445] Bioactive Examples

[0446] I. Effect of 3D-CTG method on the inhibitory effect of compounds on NCI-H358 cell proliferation

[0447] Experimental steps:

[0448] (1) Resuscitate NCI-H358 cells with RPMI 1640 medium containing 10% fetal bovine serum and passage them once. After the cells have recovered, they can be used for experiments.

[0449] (2) On the first day, rinse the cells once with PBS, add preheated trypsin, and place them in a 5% CO2 incubator at 37°C for 3-5 minutes to digest. Add an appropriate amount of complete culture medium (containing 10% fetal bovine serum) to stop the digestion, and transfer it to a centrifuge tube and centrifuge at 1000 rpm for 5 minutes.

[0450] (3) Resuspend the cells in complete culture medium, count them, and adjust the cell concentration to a suitable level using complete culture medium.

[0451] (4) Using the ECHO 655 sonic liquid processing system, take 0.2 μl of the prepared 200× gradient dilution compound (DMSO final concentration of 0.5%) and add it to the 384-well ultra-low adhesion circular plate. Then add 40 μl of the cell suspension counted in step (3) to each well and incubate in a 5% CO2 incubator at 37°C.

[0452] (6) After 6 days of incubation, add 3D CTG detection reagent to each well.

[0453] (7) Use Envision to read the signal value.

[0454] (8) Data Analysis:

[0455] a) The stability of the experimental method was tested using DMSO and culture medium:

[0456] H = DMSO hole

[0457] L = Culture medium pores

[0458] H,CV% (DMSO orifice) = 100 × (DMSO orifice SD value / DMSO orifice average value)

[0459] L,CV% (corresponding to culture medium well) = 100 × (SD value of culture medium well / average value of corresponding culture medium well)

[0460] Z' = 1 - 3 × (SD value of DMSO wells + SD value of culture medium wells) / (average value of DMSO wells - average value of corresponding culture medium wells)

[0461] Inhibition rate, % = (average DMSO well value – average sample well value) / (average DMSO well value – average corresponding culture medium well value) x 100

[0462] b) The nonlinear regression equation of the compound was used to perform IC50 analysis on the compound. 50 Fitting.

[0463] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0464] X: Log value of compound concentration

[0465] Y: Inhibition rate (%inh)

[0466] Experimental results show that the compounds of this invention have a good inhibitory effect on the proliferation of NCI-H358 cells. Data for some compounds of this invention are shown in Table 1 below.

[0467] Table 1. Inhibitory activity of the compounds of the present invention against the proliferation of NCI-H358 cells.

[0468] II. Experimental steps for detecting the enzyme inhibitory activity of compounds against the KRAS G12C active state (GTP-bound) using the RAS_GMPPNP-RAF binding method:

[0469] Experimental methods

[0470] (1) Prepare 1x buffer (modified HEPES buffer).

[0471] (2) The compound was serially diluted with DMSO, and the diluted compounds of different concentrations were transferred to the detection plate with ECHO. The final concentration of DMSO was 1%.

[0472] (3) Transfer 5 μL of the prepared RAS_GMPPNP enzyme mixture solution to the detection plate. Use 5 μL of 1x buffer for the blank control.

[0473] (4) Transfer 5 μL of the prepared RAF mixture solution to the detection plate.

[0474] (5) Incubate at room temperature for 1 hour.

[0475] (6) Use an Envision microplate reader to read the Ex615 / EM665 signal value.

[0476] (7) Data Analysis

[0477] a) Calculate the inhibition value in Excel: Inh% = (Max - Signal) / (Max - Min) * 100.

[0478] b) The IC50 of the compound was fitted using the nonlinear regression equation of XLfit software.

[0479] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0480] X: Log value of compound concentration

[0481] Y: Inhibition rate (%inh)

[0482] Experimental results show that the compound of the present invention has a good inhibitory effect on enzymes in the KRAS G12C active state (GTP-bound).

[0483] III. Liver microsomal stability

[0484] The stability of the compound of the present invention in mouse liver microsomes was evaluated. The compound of the present invention was co-incubated with mouse liver microsomes at 37°C and pH 7.4. The sample concentration was measured at different incubation times, and the rate constant was obtained by plotting "Log[drug concentration]" against "incubation time". The drug half-life and in vivo clearance rate Cl were then calculated. in vivo The stability of the drug in liver microsomes was evaluated using drug half-life and in vivo clearance values. The specific experimental system is as follows:

[0485] Instruments: SCIEXTriple Quad 5500+ triple quadrupole LC-MS / MS system, Analyst 1.6.3 software (Applied Biosystems, Inc., USA); LC-40B XR liquid chromatography system (Shimadzu Corporation, Japan); appropriate mobile phase and column were used, along with suitable LC-MS / MS parameters, to determine the concentration of the analyte compounds.

[0486] Software: Microsoft Excel, Graphpad Prism.

[0487] Experimental results show that the compounds of this invention are stable in mouse liver microsomes and have a relatively long half-life. Data for some compounds of this invention are shown in Table 2 below.

[0488] Table 2 Half-life of the compounds of the present invention in mouse liver microsomes

[0489] IV. Covalent binding analysis of GmppNp-KRAS G12C protein and compounds based on LC-HRMS

[0490] 1. Experimental objective:

[0491] The aim of this study was to determine the covalent binding of the compound to the Kras[G12C](GmppNp Loaded) protein. After incubation with the Kras[G12C](GmppNp Loaded) protein, mass spectrometry analysis was performed to determine the complete molecular weight of the protein and the protein-compound complex, and the binding rate was calculated.

[0492] 2. Experimental steps:

[0493] (1) Dilution of the compound:

[0494] Prepare a 30 mM stock solution of the compound with DMSO. Take 1 μL of the stock solution and add it to 99 μL of purified water containing 10% DMSO. Vortex mix to prepare a 300 μM working solution. Then take 10 μL of the 300 μM working solution and add it to 90 μL of purified water containing 10% DMSO. Vortex mix to prepare a 30 μM working solution for later use.

[0495] (2) Determination of protein-bound samples (Biotin-Kras[G12C](GmppNp Loaded): compound = 1 μM: 3 μM):

[0496] ①. Add 1.4 μL of protein solution (0.26 mg / mL) of Biotin-Kras [G12C] (GmppNp Loaded) to 12.1 μL buffer (50 mM Hepes, 10 mM MgCl2, 1 mM EGTA, pH 7.4) for dilution.

[0497] ②. Add 1.5 μL of the compound (30 μM) to the protein dilution solution and incubate at room temperature for 10 min.

[0498] ③. Add 15 μL of the reaction solution to a 1.5 mL EP tube containing 15 μL of 2% formic acid, place it in a liquid chromatography vial, and prepare for injection.

[0499] 3. Instrumentation Methods

[0500] Thermo Q Exactive Plus; SN: SN03407L

[0501] Thermo Vanquish Flex

[0502] Mobile phase: ultrapure water (A) containing 0.1% formic acid and acetonitrile (B) containing 0.1% formic acid.

[0503] Column: Shim-pack Scepter Claris C4-300 (2.1 x 50 mm) column

[0504] Column temperature: 60℃

[0505] Elution gradient:

[0506] Spray voltage (kV): 3.8

[0507] Ion source: Electrospray ionization (ESI)

[0508] Ion source heater temperature: 320℃

[0509] Full scan range: 300-2000 m / z, resolution 17500

[0510] MS1 full scan mode

[0511] Experimental results show that the compounds of this invention can rapidly form a covalent bond with the GmppNp-KRAS G12C protein. Data for some of the compounds of this invention are shown in Table 3 below.

[0512] Table 3. Covalent binding rates of the compounds of this invention to GmppNp-KRAS G12C protein

[0513] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "some implementations," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments, implementations, or examples described in this specification, as well as the features of different embodiments, implementations, or examples.

[0514] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention without departing from the principles and spirit of the present invention, the scope of which is defined by the claims and their equivalents.

Claims

1. A compound, which is a compound of formula (I), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (I), in, Q 1 For N or CH; R 1 is -H, -D, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, -C(=O)OR 9a -C(=O)NR 9 R 10 -C(=O)R 9a -S(=O)2NR 9 R 10 -NR 9 R 10 C 1-6 Alkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, 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 1-6 mercaptoalkyl, C 6-10 Aryl, 5-12 heteroaryl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups; Each R 5a R 5b R 5c R 5d R 5e R 5f R 5g and R 5h Independently, -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -COOH, oxo, -NHC(=O)H, -C(=O)R 9c -C(=O)OR 9c -C(=O)NR 9b R 10b -NR 9b C(=O)R 10b -NR 9b S(=O)2R 10b -S(=O)2N(R) 10b )2、-NR 9b C(=O)N(R 10b )2、-NR 9b S(=O)2N(R 10b )2、-OS(=O)2N(R 10b )2、-S(=O)2R 9c -C 1-6 Alkylene-S(=O)2N(R) 10b 2. C 1-6 Alkyl, C 1-6 Alkylthio, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 2-6 Haloalkenyl, C 2-6 Halogenated alkynyl group, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkylthio group, C 6-10 Aryl, 5-10 heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; Ring B is C 6-12 Aryl or 5-12 heteroaryl groups; Each R 2 Independently, -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -NH2, -CH2C(=O)NR 9b R 10b -C(=O)R 9c -C(=O)OR 9c -C(=O)NR 9b R 10b -NR 9b C(=O)R 10b -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Hydroxyalkynyl group, C 1-6 Alkoxy, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 2-6 Haloalkenyl, C 2-6 Halogenated alkynyl group, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkylthio group, C 6-12 Aryl, 5-12 heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Hydroxyalkynyl group, C 1-6 Alkoxy, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 2-6 Haloalkenyl, C 2-6 Halogenated alkynyl group, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkylthio group, C 6-12 Aryl, 5-12 heteroaryl, C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 11 Replaced; Each R 11 Independently -D, -OH, -F, -Cl, -Br, -I, CN, -C(=O)OR 9 -NR 9 R 10 -C(=O)NR 9 R 10 -NR 9 C(=O)R 10 C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; R 3 -H, -D, -OH, -SH, -F, -Cl, -Br, -I, -CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, or C 1-4 Halogenated alkyl groups; L stands for bond, C 1-4 Alkylene or C 1-4 Heteroalkylene, the C 1-4 Alkylene and C 1-4 Each heteroalkyl group is independently and optionally surrounded by 1, 2, 3 or 4 R's. 12a Replaced; Each R 12a Independently -H, -D, -OH, -F, -Cl, -Br, -I, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or C 1-6 Cyanoalkyl; or two R atoms attached to the same carbon atom 12a Together with the carbon atom attached to it, they form C 3-6 Carbon rings or 3-6 membered heterocycles; R 4 for Where R 12f and R 12g Each of the following can be independently -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 9d R 10d -C(=O)NR 9d R 10d -CH2NR 9d R 10d -CH2OC(=O)NR 9d R 10d C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Cyanoalkyl, (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 groups; Or, R 12f and R 12g Together R 13a R 13b R 13c and R 13d Each can be independently -H, -D, -F, -CN, -Cl, -Br, -I, or -C. 1-6 alkyl; R 12b -H, -D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl or C 1-6 Hydroxyalkyl; R 12c C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 6-10 Aryl, 5-12 heteroaryl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; wherein the R 12c Optionally selected by 1, 2, 3 or 4 elements chosen from -D, -F, -CN, -Cl, -Br, -I, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 3-6 The substituents are cycloalkyl, 3-10-membered heterocyclic and 5-12-membered heteroaryl groups, wherein the C in the substituent is... 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 3-6 The cycloalkyl, 3-10-membered heterocyclic and 5-12-membered heteroaryl groups are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from -D, -F, -CN, -Cl, -Br, -I, C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkyl groups; Or, R 12b R 12c Together with the nitrogen atoms attached to them, they form 3-10 membered nitrogen heterocyclic groups, wherein the 3-10 membered nitrogen heterocyclic groups are optionally surrounded by 1, 2, 3 or 4 atoms selected from -D, -F, -CN, -Cl, -Br, -I, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkyl groups; R a and R a0 Each of the following is independently -H, -D, -CN, -F, -Cl, -Br, -I, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl or C 1-6 Hydroxyalkyl; R 12d -H, -D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl or C 1-6 Hydroxyalkyl; R 12e -H, -D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl or -C(=O)NR 9 R 10 ; R 6 R 7 and R 8 Each of the following is independently -H, -D, -OH, -F, -Cl, -Br, -I, -CN, C 1-6 Alkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl or C 1-6 Halogenated alkyl groups; R 9 R 10 R 9a R 9b R 9c R 10b R 9d and R 10d Each can be independently -H, -D, or -C. 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally surrounded by 1, 2, 3, or 4 atoms selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkoxy, C 6-12 Aryl, C 3-6 Substituents of cycloalkyl and 3-6 membered heterocyclic groups; m can be 1, 2, 3, or 4; n is 1, 2, 3, 4, 5, 6, or 7.

2. The compound according to claim 1, wherein, R 1 is -H, -D, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, -C(=O)OR 9a -C(=O)NR 9 R 10 -C(=O)R 9a -S(=O)2NR 9 R 10 -NR 9 R 10 C 1-4 Alkyl, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, 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 1- 4-mercaptoalkyl, phenyl, 5-6-membered heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; R 9 R 10 R 9a R 9b R 9c R 10b R 9d and R 10d Each can be independently -H, -D, or -C. 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally surrounded by 1, 2, 3, or 4 atoms selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NH2, -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 1-4 Alkoxy, phenyl, C 3-6 Substituents of cycloalkyl and 3-6 membered heterocyclic groups.

3. The compound according to any one of claims 1-2, wherein, R 1 is -H, -D, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, -C(=O)OR 9a -C(=O)NR 9 R 10 -C(=O)R 9a -S(=O)2NR 9 R 10 -NR 9 R 10 , -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)2CH(CH3)2, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH(CH3)CN, -C(CH3)2CN, -CH2O H, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -(CH2)2CHF2, -(CH2)2CF(CF3)2, -CF3, -CHF2, -CH2F, -(CH2)2F, -(CH2)2Cl, -CH2CF3, -CH2OCH3, -(CH2)2OCH3, -(CH2)2OCH2CH 3, -CH2OCH2CH3, -CH2OC(CH3)3, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -(CH2)2-cyclopentyl, -(CH2)3-cyclopentyl, -(CH2)2-cyclohexyl, -CH2-azacyclobutyl, -CH2-oxacyclobutyl, -CH2-pyrrolidinyl, -CH2-morpholinyl, -(CH2)2-pyrrolidinyl, -(CH2)3-piperidinyl, -(CH2)2-piperidinyl, -CH2-phenyl, -CH2-imidazolyl, -CH2-pyrazolyl, -CH2SH, -(CH2)2SH, phenyl, naphthyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, oxacyclobutyl, tetrahydropyranyl, aziridine, or pyrrolidinyl; R 9 R 10 R 9a R 9b R 9c R 10b R 9d and R 10d Each of the following is independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl groups are each 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, -NH(CH3), -N(CH3)2, -NH(CH2CH3), methoxy, ethoxy, n-propoxy, isopropoxy, isobutoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, ethylene oxide, oxecyclobutyl, aziroxy, and pyrrolidinyl.

4. The compound according to any one of claims 1-3, wherein, Each R 5a R 5b R 5c R 5d R 5e R 5f R 5g and R 5h Independently, -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -COOH, oxo, -NHC(=O)H, -C(=O)R 9c -C(=O)OR 9c -C(=O)NR 9b R 10b -NR 9b C(=O)R 10b -NR 9b S(=O)2R 10b -S(=O)2N(R) 10b )2、-NR 9b C(=O)N(R 10b )2、-NR 9b S(=O)2N(R 10b )2、-OS(=O)2N(R 10b )2、-S(=O)2R 9c -C 1-4 Alkylene S(=O)2N(R) 10b 2. C 1-4 Alkyl, C 1-4 Alkylthio, C 1-4 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups, -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 2-4 Haloalkenyl, C 2-4 Halogenated alkynyl group, C 1-4 Halogenated alkoxy groups, C 1-4 Haloalkylthio, 6-10 aryl, 5-10 heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

5. The compound according to any one of claims 1-4, wherein, Each R 5a R 5b R 5c R 5d R 5e R 5f R 5g and R 5h Independently, -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -COOH, oxo, -NH(C=O)H, -C(=O)R 9c -C(=O)OR 9c -C(=O)NR 9b R 10b -NR 9b C(=O)R 10b -NR 9b S(=O)2R 10b -S(=O)2N(R) 10b )2、-NR 9b C(=O)N(R 10b )2、-NR 9b S(=O)2N(R 10b )2、-OS(=O)2N(R 10b )2、-S(=O)2R 9c -CH2S(=O)2N(R) 10b )2、-(CH2)2S(=O)2N(R 10b )2, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -S(CH2)2CH3, -SCH2C H(CH3)2, -SCH(CH3)2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH2CH(CH3)2, -OCH(CH3)2, -CH=CH2, -CH=CHCH3, -C H2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(O H)CH3, -CF3, -CHF2, -CH2F, -(CH2)2F, -(CH2)2Cl, -CH2CF3, -NHCH3, -NH(CH2CH3), -NH((CH2)2CH3), -NH((CH 2)3CH3), -NH(CH(CH3)2), -N(CH3)2, -N(CH2CH3)2, -N((CH2)2CH3)2, -CHFCH=CH2, -CH=CHF, -CH=CHCl, -CH=C HCH2F, -C≡CCH2F, -OCF3, -OCH2F, -OCHF2, -OCH2CF3, -OCH2CHF2, -SCF3, -SCH2F, -SCHF2, -SCH2CF3, -SCH2CHF 2. Phenyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, thiophene, thiazolyl, triazolyl, tetrazolyl, benzopyridinyl, benzimidazolyl, benzopyrrolyl, benzopyrazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridine, aziridine, oxaziridine, pyrrolylyl, tetrahydrofuranyl, tetrahydrothiophene, thiazolyl, pyrazolylyl, pyrazolinyl, oxazolylyl, imidazolyl, piperidinyl, piperazinyl, or morpholinyl.

6. The compound according to any one of claims 1-5, wherein, for 7. The compound according to any one of claims 1-6, wherein, Ring B is one of the following substructures: Each R 2 Independently, -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -NH2, -CH2C(=O)NR 9b R 10b -C(=O)R 9c -C(=O)OR 9c -C(=O)NR 9b R 10b -NR 9b C(=O)R 10b -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkylthio, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-4 Hydroxyalkynyl group, C 1-4 Alkoxy, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 2-4 Haloalkenyl, C 2-4 Halogenated alkynyl group, C 1-4 Halogenated alkoxy groups, C 1-4 Haloalkylthio group, C 6-10 Aryl, 5-12 heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein -NH2, -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkylthio, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-4 Hydroxyalkynyl group, C 1-4 Alkoxy, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 2-4 Haloalkenyl, C 2-4 Halogenated alkynyl group, C 1-4 Halogenated alkoxy groups, C 1-4 Haloalkylthio group, C 6-10 Aryl, 5-12 heteroaryl, C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 11 What it replaced.

8. The compound according to any one of claims 1-7, wherein, Each R 2 Independently, -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -NH2, -CH2C(=O)NR 9b R 10b -C(=O)R 9c -C(=O)OR 9c -C(=O)NR 9b R 10b -NR 9b C(=O)R 10b , -NH(CH3), -NH(CH2CH3), -N(CH3)2, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH 2. -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)3O H, -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, oxazolyl, tetrahydrofuranyl, piperidinyl or piperazineyl,The terms -NH2, -NH(CH3), -NH(CH2CH3), -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)2OH, -(CH2)2CH3 ... )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, oxazolyl, tetrahydrofuranyl, piperidinyl, and piperazineyl are each independently and optionally divided by 1, 2, 3, or 4 Rs. 11 What it replaced.

9. The compound according to any one of claims 1-8, wherein, Each R 11 Independently -D, -OH, -F, -Cl, -Br, -I, CN, -C(=O)OR 9 -NR 9 R 10 -C(=O)NR 9 R 10 -NR 9 C(=O)R 10 C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups; or Each R 11 Independently -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)OR 9 -NR 9 R 10 -C(=O)NR 9 R 10 -NR 9 C(=O)R 10 -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, -O(CH2)2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxaziridine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl.

10. The compound according to any one of claims 1-9, wherein, for 11. The compound according to any one of claims 1-10, wherein, L is a bond, -CH2-, -(CH2)2-, -(CH2)3-, or -CH2OCH2-, wherein -CH2-, -(CH2)2-, -(CH2)3-, and -CH2OCH2- are each independently and optionally converted by 1, 2, 3, or 4 Rs. 12a Replaced; Each R 12a Independently -H, -D, -OH, -F, -Cl, -Br, -I, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy or C 1-4 Cyanoalkyl; or two R atoms attached to the same carbon atom 12a Together with the carbon atom attached thereto, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, pyrrolidinyl, or tetrahydrofuranyl groups; Or L is 12. The compound according to any one of claims 1-11, wherein, R 12f and R 12g Each of the following can be independently -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 9d R 10d -C(=O)NR 9d R 10d -CH2NR 9d R 10d -CH2OC(=O)NR 9d R 10d C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Cyanoalkyl, (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 groups; R 13a R 13b R 13c and R 13d Each can be independently -H, -D, -F, -CN, -Cl, -Br, -I, or -C. 1-4 alkyl; R 12b -H, -D, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl or C 1-4 Hydroxyalkyl; R 12c C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, phenyl, naphthyl, 5-6 membered heteroaryl, 7-12 membered heteroaryl, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups; wherein the R 12c Optionally selected by 1, 2, 3 or 4 elements chosen from -D, -F, -CN, -Cl, -Br, -I, C 1-4 Alkyl, C 1-4 Alkoxy, phenyl, C 3-6 The substituents are cycloalkyl, 3-6 membered heterocyclic and 5-6 membered heteroaryl, wherein the C in the substituent is... 1-4 Alkyl, C 1-4 Alkoxy, phenyl, C 3-6 The cycloalkyl, 3-6-membered heterocyclic and 5-6-membered heteroaryl groups are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from -D, -F, -CN, -Cl, -Br, -I, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkyl groups; Or, R 12b R 12c Together with the nitrogen atoms attached to them, they form 3-7 membered nitrogen heterocyclic groups, wherein the 3-7 membered nitrogen heterocyclic groups are optionally surrounded by 1, 2, 3 or 4 atoms selected from -D, -F, -CN, -Cl, -Br, -I, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkyl groups; R a and R a0 Each of the following is independently -H, -D, -CN, -F, -Cl, -Br, -I, -OH, -NH2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl or C 1-4 Hydroxyalkyl; R 12d -H, -D, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl or C 1-4 Hydroxyalkyl; R 12e -H, -D, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl or -C(=O)NR 9 R 10 .

13. The compound according to any one of claims 1-12, wherein, R 12f and R 12g Each of the following can be independently -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 9d R 10d -C(=O)NR 9d R 10d -CH2NR 9d R 10d -CH2OC(=O)NR 9d R 10d , -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -OCH3, -OCH2CH3, -O(CH2)2CH3 , -OCH(CH3)2, -(CH2)2F, -CH2CHF2, -CH2CF3, -CHF2, -CH2F, -(CH2)2Cl, -OCF3, -OCHF2, -OCH2CHF 2. -OCH2CF3, -OCHClCHCl2, -OCH2CH2F, -CH2CN, -(CH2)2CN, -(CH2)3CN, -(CH2)4CN, morpholinylmethyl, pyrrolylmethyl, piperazinylmethyl, aziridinemethyl, piperidinylmethyl, tetrahydropyranylmethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopentyl, cyclohexyl, morpholinyl, piperidinyl, pyrrolyl, piperazinyl or aziridine; R 13a R 13b R 13c and R 13d Each can be independently -H, -D, -F, -CN, -Cl, -Br, -I, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3 or -CH(CH3)2; R 12b The suffixes are -H, -D, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -(CH2)2F, -CH2CHF2, -CH2CF3, -CHF2, -CH2F, -(CH2)2Cl, -CH2CN, -(CH2)2CN, -(CH2)3CN, -(CH2)4CN, -CH2OH, -(CH2)2OH, or -(CH2)3OH; R 12c is -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -(CH2)2F, -CH2CHF2, -CH2CF3 , -CHF2, -CH2F, -(CH2)2Cl, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -CH2OCH3, -CH2OCH2CH 3, -CH2CH2OCH3, -C(CH3)2CH2OCH3, -CH2CH2OCH2CH3, -CH2OCH3, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, thiazolyl, imidazolyl, pyrroleyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, 2H-pyrroleyl, pyrroleyl, imidazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl or morpholinyl; wherein R 12c Optionally substituted with 1, 2, 3, or 4 substituents selected from -D, -F, -CN, -Cl, -Br, -I, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2H-pyrrolyl, pyrrolylalkyl, imidazoalkyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl, or pyrrolyl, wherein the substituents are -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -OCH3, -OCH2CH 3. -O(CH2)2CH3, -OCH(CH3)2, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2H-pyrrolyl, pyrrolylalkyl, imidazolyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl, and pyrrolyl are each independently and optionally substituted by 1, 2, 3, or 4 substituents selected from -D, -F, -CN, -Cl, -Br, -I, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -(CH2)2F, -CH2CHF2, -CH2CF3, -CHF2, -CH2F, and -(CH2)2Cl; Or, R 12b R 12c Together with the nitrogen atoms attached to them, they form aziridine, pyrrolidinyl, imidazoalkyl, pyrazolyl, piperidinyl, morpholinyl, piperazinyl, 1,3-oxazolidinyl, or aziridine-heptyl, wherein the aziridine, pyrrolidinyl, imidazoalkyl, pyrazolyl, piperidinyl, morpholinyl, piperazinyl, 1,3-oxazolidinyl, and aziridine-heptyl are optionally surrounded by 1, 2, 3, or 4 atoms selected from -D, -F, -CN, -Cl, -Br, The substituents of -I, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -(CH2)2F, -CH2CHF2, -CH2CF3, -CHF2, -CH2F and -(CH2)2Cl are substituted; R a and R a0 Each can be independently -H, -D, -CN, -F, -Cl, -Br, -I, -OH, -NH2, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CN, -(CH2)2CN, -(CH2)3CN, -(CH2)4CN, -CH2OH, -(CH2)2OH, or -(CH2)3OH; R 12d The suffixes are -H, -D, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CN, -(CH2)2CN, -(CH2)3CN, -(CH2)4CN, -CH2OH, -(CH2)2OH, or -(CH2)3OH; R 12e -H, -D, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CN, -(CH2)2CN, -(CH2)3CN, -(CH2)4CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, or -C(=O)NR 9 R 10 .

14. The compound according to any one of claims 1-13, wherein, R 4 for 15. The compound according to any one of claims 1-14, wherein, R 6 R 7 and R 8 Each of the following is independently -H, -D, -OH, -F, -Cl, -Br, -I, -CN, C 1-4 Alkyl, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl or C 1-4 Halogenated alkyl groups.

16. The compound according to any one of claims 1-15, wherein it is a compound with the following structure, or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug, 17. A pharmaceutical composition comprising the compound of any one of claims 1-16; optionally, the pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

18. Use of the compound of claims 1-16 or the pharmaceutical composition of claim 17 in the purpose of preventing, treating or alleviating a patient’s disease mediated by KRAS G12C.

19. The use according to claim 18, wherein, KRAS G12C-mediated diseases are cancers; optionally, the cancers are lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, glioma, cervical cancer, urothelial carcinoma, gastric cancer, endometrial cancer, liver cancer, bile duct cancer, breast cancer, colon cancer, leukemia, and melanoma.

Images