Amide heterocyclic derivative and application thereof in medicine

Abstract

The invention relates to an amide heterocyclic derivative and application thereof in medicine, in particular to a compound shown in a general formula (I) or a stereoisomer, a deuterated compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal of the compound, an intermediate and a preparation method of the compound, and application of the compound in preparation of medicines for treating GSPT1 or MYC related diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a compound described by general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and intermediates and preparation methods thereof, as well as use of the compound in preparing drugs for treating diseases related to GSPT1 or MYC. Background Art

[0002] MYC (including C-MYC, N-MYC and L-MYC) is a group of common oncogenes in human cancers. The MYC gene is dysregulated in about 70% of human cancers. Therefore, MYC is considered a key target for the treatment of various cancers (Cancer Treatment Reviews 94 (2021) 102154). The occurrence of MYC-related cancers depends on abnormally active protein translation, thereby supporting the unlimited proliferation of cancer cells and tumor growth. GSPT1 is a translation termination factor required for protein synthesis. Therefore, targeted degradation of GSPT1 is expected to become a method for treating MYC-related cancers (Cancer Res (2022) 82 (12_Supplement): 3929). At present, no targeted drugs for GSPT1 have been approved for marketing.

[0003] Molecular glue is a type of small molecule that promotes contact between target proteins and E3 ubiquitin ligases, induces interaction between the two, and thus leads to degradation of target proteins. From a functional point of view, molecular glue mainly fills the gap between target proteins and E3 ubiquitin ligases, enhances the binding interface between the two, and promotes strong interaction between the two (Nat. Commun., 2022, 13, 815). Compared with traditional small molecule inhibitors, molecular glue has the advantages of catalytic form to drive target protein degradation and does not require binding pockets on the target protein, and has the potential to act on undruggable targets.

[0004] Therefore, it is necessary to develop new molecular glue drugs that can target and degrade GSPT1 to treat cancers related to GSPT1 or MYC. Summary of the invention

[0005] The purpose of the present invention is to provide a compound capable of degrading a target protein or its stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, as well as intermediates and preparation methods thereof, and their use in the preparation of drugs for treating diseases associated with GSPT1 or MYC regulators.

[0006] The present invention provides a compound of general formula (I) or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein

[0007]

[0008] In certain embodiments, R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, NO2, COOH, CONH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7-membered heterocyclic ring, -SC 3-6 Carbocyclic ring, -S-3 to 7 membered heterocyclic ring, -C 0-4 Alkylene-C 3-6 Carbon ring, -C 0-4 Alkylene-3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0009] In certain embodiments, R k Each independently selected from deuterium, halogen, OH, CN, NO2, NH2, COOH, CONH2, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7-membered heterocyclic ring, -SC 3-6 Carbocyclic ring, -S-3 to 7 membered heterocyclic ring, -C 0-2 Alkylene-C 3-6 Carbon ring, -C 0-2 Alkylene-3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0010] In certain embodiments, R kEach independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NO2, COOH, CONH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0011] In certain embodiments, R k Each independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NO2, COOH, CONH2, NHCH3, N(CH3)2, CHF2, CH2F, CF3, OCF3, OCHF2, OCH2F, CD3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio;

[0012] In certain embodiments, A1 is selected from CR a , CH, N;

[0013] In certain embodiments, A1 is selected from CR a , CH;

[0014] In certain embodiments, m is selected from 0, 1, 2, 3;

[0015] In certain embodiments, p is independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0016] In certain embodiments, p is independently selected from 0, 1, 2, 3;

[0017] In certain embodiments, R 1 Selected from H, deuterium, C 1-6 Alkyl, -C(=O)R 1a 、-S(=O)2R 1a 、-P(=O)R 1a R 1b , C 3-8 A carbocyclic group or a 3- to 10-membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replaced by;

[0018] In certain embodiments, R 1Selected from H, deuterium, C 1-4 Alkyl, -C(=O)R 1a 、-S(=O)2R 1a 、-P(=O)R 1a R 1b , C 3-6 A carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replaced by;

[0019] In certain embodiments, R 1 is selected from H, deuterium, methyl, ethyl, propyl, isopropyl, -C(=O)R 1a 、-S(=O)2R 1a 、-P(=O)R 1a R 1b , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl optionally substituted by 1 to 4 R k replaced by;

[0020] In certain embodiments, R 1 Selected from H;

[0021] In certain embodiments, R a Each independently selected from deuterium, halogen, OH, NH2, CN, NO2, COOH, CONH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 R k replaced by;

[0022] In certain embodiments, R a Each independently selected from deuterium, halogen, OH, NH2, CN, NO2, COOH, CONH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 3-8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 R k replaced by;

[0023] In certain embodiments, R aEach independently selected from deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl is optionally replaced by 1 to 4 R k replaced by;

[0024] In certain embodiments, Selected from p is independently selected from 0, 1, and 2;

[0025] In certain embodiments, Selected from

[0026] In certain embodiments, Ring B is selected from one of the following optionally substituted structures: When substituted, 1 to 4 R b replaced, and its left side is directly connected to L;

[0027] In certain embodiments, Ring B is selected from Ring B1, Ring B2, or Ring B3;

[0028] In certain embodiments, Ring B1 is selected from one of the following optionally substituted structures: When substituted, 1 to 4 R b replaced, and its left side is directly connected to L;

[0029] In certain embodiments, Ring B2 is selected from one of the following optionally substituted structures: When substituted, 1 to 4 R b In one embodiment, one of E2, E4, and E5 is selected from N, and the rest are selected from CR b , CH; in a certain embodiment, two of E2, E4, and E5 are selected from N, and the rest are selected from CR b , CH; in a certain embodiment, E2, E4, E5 are each independently selected from CR b , CH;

[0030] In certain embodiments, Ring B3 is selected from one of the following optionally substituted structures: When substituted, 1 to 4 R b replaced, and its left side is directly connected to L;

[0031] In certain embodiments, D1 and D2 are each independently selected from O, S, NH or NR b ;

[0032] In certain embodiments, D1 and D2 are each independently selected from O, S, and NH;

[0033] In certain embodiments, D3 and D4 are each independently selected from O, S, N, NH or NR b ; In certain embodiments, D3 and D4 are each independently selected from N and NH; In certain embodiments, D3 and D4 are each independently selected from O and N; In certain embodiments, D3 and D4 are each independently selected from S and N;

[0034] In certain embodiments, F2, F3, F4, and F5 are each independently selected from C, CR b , CH or N;

[0035] In certain embodiments, F1 is selected from NR b , NH;

[0036] In certain embodiments, F2, F3, F4, and F5 are each independently selected from C, CR b or CH, F1 is selected from NR b , NH;

[0037] In certain embodiments, F2, F3, F4, and F5 are each independently selected from C, CR b , CH or N, F1 is selected from NCH3;

[0038] In certain embodiments, F2, F3, F4, and F5 are each independently selected from C, CR b , CH or N, F1 is selected from NH;

[0039] In a certain embodiment, one of F2, F3, F4, and F5 is selected from N, and the others are selected from C, CR b , CH;

[0040] In a certain embodiment, two of F2, F3, F4, and F5 are selected from N, and the rest are selected from C, CR b , CH;

[0041] In certain embodiments, E1 is selected from C(R b 2. CHR b 、CH2、CH2CH2、CHR b CHR b ,

[0042] In certain embodiments, E1 is selected from C(═O);

[0043] In certain embodiments, Selected from optionally substituted When substituted, 1 to 4 R b replaced, and its left side is directly connected to L;

[0044] In certain embodiments, Selected from one of the following optionally substituted structures:

[0045]

[0046] When substituted, 1 to 4 R b substituted, and its left side is directly connected to L; in a certain embodiment, E2, E3, E4, and E5 are each independently selected from CR b , CH or N;

[0047] In one embodiment, one of E2, E3, and E4 is selected from N, and the others are selected from CR b , CH;

[0048] In one embodiment, two of E2, E3, and E4 are selected from N, and the rest are selected from CR b , CH;

[0049] In certain embodiments, E2, E3, and E4 are each independently selected from CR b , CH; In a certain embodiment, Selected from

[0050] In certain embodiments, Selected from

[0051] In certain embodiments, Ring B is selected from one of the following optionally substituted structures:

[0052] When substituted, 1 to 3 R b substituted, its left side is connected to L; in a certain embodiment, R b Each independently selected from halogen, OH, cyano, NH2, NO2, N(C 1-4 Alkyl)2, NH(C 1-4 Alkyl), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C1-6 Alkylthio, -C(=O)R 1a 、-S(=O)2R 1a 、-P(=O)R 1a R 1b , C 3-10 Carbocyclic group, 4 to 10 membered heterocyclic group, C 6-10 Aryl or 5 to 10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic, heterocyclic, aryl or heteroaryl is optionally substituted by 1 to 4 members selected from R k replaced by;

[0053] In certain embodiments, Ring B1 is selected from one of the following optionally substituted structures:

[0054] When substituted, 1 to 3 R b replaced, and its left side is connected to L;

[0055] In certain embodiments, Ring B2 is selected from b One of the following structures is replaced:

[0056] Its left side is connected to L;

[0057] In certain embodiments, Ring B3 is selected from b One of the following structures is replaced:

[0058] Its left side is connected to L;

[0059] In certain embodiments, R b Each independently selected from deuterium, halogen, OH, cyano, NH2, NO2, N(C 1-4 Alkyl)2, NH(C 1-4 Alkyl), C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, -C(=O)R 1a 、-S(=O)2R 1a 、-P(=O)R 1a R 1b , C 3-6 Carbocyclic group, 4 to 8 membered heterocyclic group, C 6-10The alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic, heterocyclic, aryl or heteroaryl group is optionally substituted by 1 to 4 R k replaced by;

[0060] In certain embodiments, R b each independently selected from deuterium, F, Cl, Br, I, OH, cyano, NH2, NO2, NHCH3, N(CH3)2, COOH, CONH2, -C(=O)-methyl, -C(=O)-ethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole or thiophene, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole or thiophene is optionally replaced by 1 to 4 R k replaced by;

[0061] In certain embodiments, X is selected from O, S, NH, N-CN;

[0062] In certain embodiments, X is selected from O or S;

[0063] In certain embodiments, L is selected from -C 1-4 Alkylene-, -NR L -C 1-4 Alkylene-, -OC 1-4 Alkylene-, -SC 1-4 Alkylene-, the alkylene group is optionally substituted by 1 to 6 R k replaced by;

[0064] In certain embodiments, L is selected from -CH2CH2-, -NR L -CH2-, -O-CH2-, -S-CH2-, -NR L -CH2CH2-, -O-CH2CH2-, -S-CH2CH2-, wherein the -CH2- is optionally replaced by 1 to 2 R k replaced by;

[0065] In certain embodiments, L is selected from -CH2CH2-, -NR L -CH2-, -O-CH2-, -S-CH2-, -S-CH2CH2-, -CH2CHR k -、-NR L -CHR k -、-O-CHRk -、-S-CHR k -;

[0066] In certain embodiments, L is selected from -CH2CH2-, -N(CH3)-CH2-, -N(CH2CH3)-CH2-, -O-CH2-, -O-CH(CH3)-, -OC(CH3)2-, -S-CH2-, -S-CH(CH3)-, -SC(CH3)2-, Its right side is directly connected to ring B;

[0067] In certain embodiments, Selected from

[0068] Its right side is directly connected to ring B;

[0069] In certain embodiments, Selected from -C(=S)-CH2CH2-, -C(=S)-N(CH3)-CH2-, -C(=S)-N(CH2CH3)-CH2-, -C(=S)-O-CH2-, -C(=S)-O-CH(CH3)-, -C(=S)-OC(CH3)2-, -C(=O)-O-CH(CH3)-, -C(=O)-OC(CH3)2-, -C(=O)-SC(CH3)2-, -C(=S)-S-CH2-, -C(=S)-S-CH(CH3)-, -C(=S)-SC(CH3)2-,

[0070] Its right side is directly connected to ring B2;

[0071] In certain embodiments, q is independently selected from 0, 1, 2, 3, 4;

[0072] In certain embodiments, q is independently selected from 0, 1, 2, 3;

[0073] In certain embodiments, R L Each independently selected from C 1-4 Alkyl, C 3-10 carbocyclic group, 4 to 10 membered heterocyclic group, the alkyl group, carbocyclic group, heterocyclic group is optionally substituted by 1 to 4 R k replaced by;

[0074] In certain embodiments, R L Each independently selected from C 1-4 Alkyl, C 3-8 carbocyclic group, 4 to 8 membered heterocyclic group, the alkyl group, carbocyclic group, heterocyclic group is optionally substituted by 1 to 4 R k replaced by;

[0075] In certain embodiments, R L Each is independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole or thiophene, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole or thiophene is optionally replaced by 1 to 4 R k replaced by;

[0076] In certain embodiments, R L Each is independently selected from CHF2, CH2F, CF3, CH2OH, methyl, ethyl, propyl, isopropyl, cyclopropyl or cyclobutyl;

[0077] In certain embodiments, R 2 , R 3 Each independently selected from H, deuterium, C 1-6 Alkyl, C 0-4 Alkylene-C 6-10 Aryl, C 0-4 Alkylene-5 to 10 membered heteroaryl, C 0-4 Alkylene-C 3-12 Carbocyclic group, C 0-4 Alkylene-4 to 12 membered heterocyclic group, wherein the alkyl, alkylene, aryl, heteroaryl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R c replaced by;

[0078] In certain embodiments, R 2 Selected from H, deuterium, C 1-4 Alkyl, C 0-4 Alkylene-C 6-10 Aryl, C 0-4 Alkylene-5 to 10 membered heteroaryl, C 0-4 Alkylene-C 3-10 Carbocyclic group, C 0-4 Alkylene-4 to 10 membered heterocyclic group, wherein the alkyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replaced by;

[0079] In certain embodiments, R 2Selected from H, deuterium, C 1-4 Alkyl, the alkyl group is optionally substituted by 1 to 4 R k replaced by;

[0080] In certain embodiments, R 2 is selected from H, deuterium, methyl, ethyl, propyl, isopropyl, wherein the methyl, ethyl, propyl, isopropyl is optionally substituted by 1 to 3 R k replaced by;

[0081] In certain embodiments, R 2 , R 3 Together with the nitrogen atom connected thereto, it forms a 3- to 12-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R c replaced by;

[0082] In certain embodiments, Selected from

[0083] In certain embodiments, L2 is selected from a bond or C 1-4 Alkylene, the alkylene group is optionally substituted by 1 to 4 R k replaced by;

[0084] In certain embodiments, L2 is selected from a bond, a methylene group, an ethylene group, wherein the methylene group and the ethylene group are optionally replaced by 1 to 3 R k replaced by;

[0085] In certain embodiments, L2 is selected from a bond, CH2, CH2CH2, wherein CH2, CH2CH2 is optionally replaced by 1 to 3 R k substituted, and its left end is connected to ring C2;

[0086] In certain embodiments, ring C1 is selected from a 5- to 12-membered nitrogen-containing heteroaryl group, a 4- to 12-membered nitrogen-containing heterocyclic group, and ring C1 is connected to -C=X via a nitrogen atom, and the ring C1 is optionally substituted by 1 to 4 R c replaced by;

[0087] In certain embodiments, ring C1 is selected from a 4-7 membered nitrogen-containing heteromonocyclic ring, a 5-12 membered nitrogen-containing heterocyclic ring, a 5-12 membered nitrogen-containing heterospirocyclic ring, a 7-10 membered nitrogen-containing heterobridged ring, a benzo 3- to 8-membered nitrogen-containing heterocyclic ring, a 5-10 membered nitrogen-containing heteroaryl, and ring C1 is connected to -C=X via a nitrogen atom, and the ring C1 is optionally substituted by 1 to 4 R c replaced by;

[0088] In certain embodiments, Selected from one of the following optionally substituted structures:

[0089] When substituted, 1 to 3 R c replaced by;

[0090] In certain embodiments, ring C2 is selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclic group, 4 to 12 membered heterocyclic group, wherein the ring C2 is optionally substituted by 1 to 4 R c replaced by;

[0091] In certain embodiments, ring C2 is selected from a 4-7 membered heteromonocyclic ring, a 5-12 membered heterocyclic ring, a 5-12 membered heterospirocyclic ring, a 7-10 membered heterobridged ring, a C 3-8 Monocarbocyclic group, C 6-12 Cycloalkyl, C 6-12 Spirocycloalkyl, C 5-12 Benzene-C-cycloalkyl 3-8 Carbocyclic group, benzo 4 to 8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, the ring C2 is optionally substituted by 1 to 4 R c replaced by;

[0092] In certain embodiments, ring C2 is selected from one of the following structures which are optionally substituted: cyclopropane, cyclobutane, cyclopentane, cyclohexane, azetidine, pyrrolidine, cyclohexene, azacyclohexine, piperidine, morpholine, piperazine, 1,4-diazepane, benzene, naphthalene, oxetane, tetrahydrofuran, tetrahydropyran, furan, pyrrole, pyrazole, imidazole, thiophene, thiazole, oxazole, isoxazole, triazole, pyridine, pyrimidine, pyrazine, pyridazine, 2-pyridone, benzopyrrole, benzopyrrolidine, benzothiophene, benzofuran, benzothiazole, benzopyrazole, benzimidazole, quinoline, isoquinoline, pyridopyridine, pyrazolotetrahydropyrrole, 3-pyridazinone, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline,

[0093] When substituted, 1 to 3 R c replace;

[0094] In certain embodiments, Selected from

[0095] In certain embodiments, R c Each independently selected from deuterium, halogen, OH, =O, COOH, CN, NO2, NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, OC 1-6 Alkyl, SC 1-6 Alkyl, NHC 1-6 Alkyl, N(C1-6 Alkyl)2, -C 0-4 Alkylene-C(=O)R 1a , -C 0-4 Alkylene-S(=O)2R 1a , -C 0-4 Alkylene-P(=O)R 1a R 1b 、-OC 1-4 Alkylene-OC 1-4 Alkyl, -OC 1-4 Alkylene-OC 3-10 Carbocyclic group, -C 1-4 Alkylene-OC 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkylene-OC 3-10 Carbocyclic group, -OC 0-4 Alkylene-C 3-10 Carbocyclic group, -OC 0-4 Alkylene-4 to 10 membered heterocyclic group, -SC 0-4 Alkylene-C 3-10 Carbocyclic group, -SC 0-4 Alkylene-4 to 10-membered heterocyclic group, -NH-C 0-4 Alkylene-C 3-10 Carbocyclic group, -NH-C 0-4 Alkylene-4 to 10 membered heterocyclic group, -C 0-4 Alkylene-C 3-10 Carbocyclic group, -C 0-4 Alkylene-4 to 10 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replaced by;

[0096] In certain embodiments, R c Each independently selected from deuterium, halogen, OH, =O, COOH, CN, NO2, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, -C(=O)R 1a 、-S(=O)2R 1a 、-P(=O)R 1a R 1b 、-OC 1-4 Alkylene-OC 1-4Alkyl, -OC 1-4 Alkylene-OC 3-8 Carbocyclic group, -C 1-4 Alkylene-OC 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkylene-OC 3-8 Carbocyclic group, -OC 0-4 Alkylene-C 3-8 Carbocyclic group, -OC 0-4 Alkylene-4 to 8-membered heterocyclic group, -SC 0-4 Alkylene-C 3-8 Carbocyclic group, -SC 0-4 Alkylene-4 to 8 membered heterocyclic group, -NH-C 0-4 Alkylene-C 3-8 Carbocyclic group, -NH-C 0-4 Alkylene-4 to 8 membered heterocyclic group, -C 0-4 Alkylene-C 3-8 Carbocyclic group, -C 0-4 Alkylene-4 to 8 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replaced by;

[0097] In certain embodiments, R cEach independently selected from deuterium, F, Cl, Br, I, =O, OH, NH2, NHCH3, N(CH3)2, CN, NO2, COOH, -C(=O)CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -S(=O)2NH2, -P(=O)(CH3)2, -S(=O)2CH3 or one of the following groups optionally substituted: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazolyl, phenyl, pyridinyl, azetidinyl, pyrrolidine yl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-pyrrolidinyl, -CH2-morpholinyl, -CH2-pyrazolyl, -O-cyclopropyl, -O-cyclobutyl, -O-pyrrolidinyl, -O-phenyl, -S-cyclopropyl, -S-cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, -OCH2-cyclopropyl, -OCH2-pyrrolidinyl, -OCH2CH2-cyclopropyl, -OCH2CH2-morpholinyl, When substituted, 1 to 4 R k replaced by;

[0098] In certain embodiments, R cEach independently selected from deuterium, F, Cl, Br, I, =O, OH, NH2, NHCH3, N(CH3)2, CN, NO2, COOH, -C(=O)CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -S(=O)2NH2, -P(=O)(CH3)2, -S(=O)2CH3 or one of the following groups optionally substituted: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazolyl, phenyl, pyridinyl, azetidinyl , pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuran, tetrahydropyran, piperazine, morpholinyl, pyrrolidinyl and cyclopentyl, azetidinyl spirocyclohexyl, cyclopropyl spirocyclobutyl, cyclobutyl spirocyclobutyl, cyclobutyl spirocyclopentyl, cyclobutyl spirocyclohexyl, cyclopentyl spirocyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-pyrrolidinyl, -CH2-morpholinyl, -CH2-pyrazolyl, -O-cyclopropyl, -O-cyclobutyl, -O-pyrrolidinyl, -O-phenyl, -S-cyclopropyl, -S-cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, -OCH2-cyclopropyl, -OCH2-pyrrolidinyl, -OCH2CH2-cyclopropyl, -OCH2CH2-morpholinyl, When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, COOH, CN, CHF2, CH2F, CF3, OCF3, OCHF2, OCH2F, NH2, NHCH3, N(CH3)2, CH2OH, OCH2OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl;

[0099] In certain embodiments, R 1a , R 1b Each independently selected from H, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 3-8 Carbocyclic group, 4 to 10 membered heterocyclic group, C 6-10 Aryl or 5 to 10 membered heteroaryl, wherein the alkyl, alkoxy, carbocyclic group, heterocyclic group, aryl or heteroaryl group is optionally substituted by 1 to 4 R k replaced by;

[0100] In certain embodiments, R 1a, R 1b Each independently selected from H, OH, NH2, C 1-4 Alkyl, C 1-4 Alkoxy, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 3-6 Carbocyclic group, 4 to 8 membered heterocyclic group, C 6-10 Aryl or 5 to 10 membered heteroaryl, wherein the alkyl, alkoxy, carbocyclic group, heterocyclic group, aryl or heteroaryl group is optionally substituted by 1 to 4 R k replaced by;

[0101] In certain embodiments, R 1a , R 1b Each independently selected from H, OH, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole or thiophene, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole or thiophene is optionally replaced by 1 to 3 R k replaced by;

[0102] In one embodiment, two R a Together with the atoms it is connected to, it forms C 3-10 A carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R k replaced by;

[0103] In one embodiment, two R a Together with the atoms it is connected to, it forms C 3-8 A carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R k replaced by;

[0104] In one embodiment, two R a and the atoms connected thereto together form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, oxolanyl, pyrrolidinyl, piperidinyl, 1,3-dioxolanyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, oxolanyl, pyrrolidinyl, piperidinyl, 1,3-dioxolanyl is optionally substituted by 1 to 4 R k replaced by;

[0105] In certain embodiments, the compound of the aforementioned general formula (I) is selected from the compounds described in the following general formula (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8) or their stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals.

[0106]

[0107] In some embodiments of Formula (I-1), E2, E4, and E5 are each independently selected from CR b , CH or N, and at least one of the three is selected from N;

[0108] In certain embodiments, L is selected from L1 or L3 or L4

[0109] In certain embodiments, L1 is selected from -OC 1-4 Alkylene-, -C 1-4 Alkylene-, wherein the alkylene is substituted by 1 to 6 R k replaced by;

[0110] In certain embodiments, L3 is selected from -NR L -C 1-4 Alkylene-, the alkylene group is optionally substituted by 1 to 6 R k In one embodiment, L1 is selected from -O-CH2-, -CH2-, -O-CH2CH2-, -CH2CH2-, wherein the -CH2- is optionally replaced by 1 to 2 R k replaced by;

[0111] In certain embodiments, L3 is selected from -N(CH3)-CH2-, NR L -CH2-、NR L -CH2CH2-, wherein the -CH2- is optionally substituted by 1 to 2 R k replaced by;

[0112] In certain embodiments, L4 is selected from -C 1-4 Alkylene-, -SC 1-4 Alkylene-, -OC 1-4 Alkylene-, the alkylene group is optionally substituted by 1 to 6 R k replaced by;

[0113] In certain embodiments, L4 is selected from -CH2-, -CH2-CH(CH3)-, -CH2CH2-, -CH2CH2CH2-, -S-CH2-, -O-CH2-, -S-CH2CH2-, -O-CH2CH2-, wherein -CH2- is optionally replaced by 1 to 2 R kreplaced by;

[0114] In certain embodiments, ring C3 is selected from c Replaced

[0115] In certain embodiments, ring C3 is selected from In certain embodiments, R L Each is independently selected from CHF2, CH2F, CF3, CH2OH, methyl, ethyl, propyl, isopropyl, cyclopropyl or cyclobutyl;

[0116] In certain embodiments, the compound of the aforementioned general formula (I) is selected from the following general formula (Ia-6):

[0117]

[0118] In certain embodiments, Selected from 1 to 3 R b One of the following structures is replaced:

[0119] In certain embodiments, R b Each independently selected from deuterium, F, Cl, Br, I, OH, cyano, NH2, NO2, NHCH3, N(CH3)2, COOH, CONH2, -C(=O)-methyl, -C(=O)-ethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl are optionally substituted by 1 to 4 R k replaced by;

[0120] In certain embodiments, X is selected from O or S;

[0121] In certain embodiments, L4 is selected from -CH2-, -CH2-CH(CH3)-, -CH2CH2-, -CH2CH2CH2-, -S-CH2-, -O-CH2-, -S-CH2CH2-, -O-CH2CH2-, wherein -CH2- is optionally replaced by 1 to 2 R k replaced by;

[0122] In certain embodiments, ring C2 is selected from one of the following optionally substituted structures: benzene, naphthalene, pyridine, pyrimidine, pyrazine, pyridazine, 2-pyridone, When substituted, 1 to 3 R c replace;

[0123] In certain embodiments, Rc each independently selected from deuterium, F, Cl, Br, I, =O, OH, NH2, NHCH3, N(CH3)2, CN, NO2, COOH, -C(=O)CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -S(=O)2NH2, -P(=O)(CH3)2, -S(=O)2CH3 or one of the following groups optionally substituted: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl alkyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuran, tetrahydropyran, piperazine, morpholinyl, when substituted, with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, COOH, CN, CHF2, CH2F, CF3, OCF3, OCHF2, OCH2F, NH2, NHCH3, N(CH3)2, CH2OH, OCH2OH, methyl;

[0124] Optionally, Selected from When X is selected from O and L is selected from -N(CH3)-CH2-, Not selected from

[0125] Optionally, L is selected from -N(CH3)-CH2-, Selected from hour, Not selected from

[0126] In certain embodiments, Ring B is selected from the group consisting of b Replaced X is selected from O, L is selected from -C 1-4 Alkylene-, -OC 1-4 When alkylene-, the alkylene is substituted by 1 to 6 R k replaced.

[0127] As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0128] R 1 Selected from H, deuterium, C 1-6 Alkyl, -C(=O)R 1a 、-S(=O)2R 1a 、-P(=O)R 1a R 1b , C 3-8A carbocyclic group or a 3- to 10-membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replaced by;

[0129] R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, NO2, COOH, CONH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7-membered heterocyclic ring, -SC 3-6 Carbocyclic ring, -S-3 to 7 membered heterocyclic ring, -C 0-4 Alkylene-C 3-6 Carbon ring, -C 0-4 Alkylene-3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0130] A1 is selected from CR a , CH, N;

[0131] R a Each independently selected from deuterium, halogen, OH, NH2, CN, NO2, COOH, CONH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 R k replaced by;

[0132] m is selected from 0, 1, 2, 3;

[0133] p is each independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0134] X is selected from O, S, NH, N-CN;

[0135] L is selected from -C 1-4 Alkylene-, -NR L -C 1-4 Alkylene-, -OC 1-4 Alkylene-, -SC 1-4Alkylene-, the alkylene group is optionally substituted by 1 to 6 R k replaced by;

[0136] R L Each independently selected from C 1-4 Alkyl, C 3-10 carbocyclic group, 4 to 10 membered heterocyclic group, the alkyl group, carbocyclic group, heterocyclic group is optionally substituted by 1 to 4 R k replaced by;

[0137] Ring B is selected from one of the following optionally substituted structures: When substituted, 1 to 4 R b replaced, and its left side is directly connected to L;

[0138] D1 and D2 are each independently selected from O, S, NH or NR b ;

[0139] D3 and D4 are each independently selected from O, S, N, NH or NR b ;

[0140] E2, E3, E4, and E5 are each independently selected from CR b , CH or N;

[0141] F2, F3, F4, and F5 are each independently selected from C, CR b , CH or N;

[0142] F1 selected from NR b , NH;

[0143] E1 is selected from C(R b 2. CHR b , CH2, C(=O), CH2CH2, CHR b CHR b ,

[0144] R b Each independently selected from deuterium, halogen, OH, cyano, NH2, NO2, N(C 1-6 Alkyl)2, NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -C(=O)R 1a 、-S(=O)2R 1a 、-P(=O)R 1a R 1b , C3-10 Carbocyclic group, 4 to 10 membered heterocyclic group, C 6-10 Aryl or 5 to 10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic, heterocyclic, aryl or heteroaryl is optionally substituted by 1 to 4 members selected from R k replaced by;

[0145] R 2 , R 3 Each independently selected from H, deuterium, C 1-6 Alkyl, C 0-4 Alkylene-C 6-10 Aryl, C 0-4 Alkylene-5 to 10 membered heteroaryl, C 0-4 Alkylene-C 3-12 Carbocyclic group, C 0-4 Alkylene-4 to 12 membered heterocyclic group, wherein the alkyl, alkylene, aryl, heteroaryl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R c replaced by;

[0146] R c Each independently selected from deuterium, halogen, OH, =O, COOH, CN, NO2, NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, OC 1-6 Alkyl, SC 1-6 Alkyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -C 0-4 Alkylene-C(=O)R 1a , -C 0-4 Alkylene-S(=O)2R 1a , -C 0-4 Alkylene-P(=O)R 1a R 1b 、-OC 1-4 Alkylene-OC 1-4 Alkyl, -OC 1-4 Alkylene-OC 3-10 Carbocyclic group, -C 1-4 Alkylene-OC 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkylene-OC 3-10 Carbocyclic group, -OC 0-4 Alkylene-C 3-10 Carbocyclic group, -OC 0-4 Alkylene-4 to 10 membered heterocyclic group, -SC 0-4 Alkylene-C 3-10Carbocyclic group, -SC 0-4 Alkylene-4 to 10-membered heterocyclic group, -NH-C 0-4 Alkylene-C 3-10 Carbocyclic group, -NH-C 0-4 Alkylene-4 to 10 membered heterocyclic group, -C 0-4 Alkylene-C 3-10 Carbocyclic group, -C 0-4 Alkylene-4 to 10 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replaced by;

[0147] R 1a , R 1b Each independently selected from H, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 3-8 Carbocyclic group, 4 to 10 membered heterocyclic group, C 6-10 Aryl or 5 to 10 membered heteroaryl, wherein the alkyl, alkoxy, carbocyclic group, heterocyclic group, aryl or heteroaryl group is optionally substituted by 1 to 4 R k replaced by;

[0148] Alternatively, two R a Together with the atoms it is connected to, it forms C 3-10 A carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R k replaced by;

[0149] Alternatively, R 2 , R 3 Together with the nitrogen atom connected thereto, it forms a 3- to 12-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R c replaced.

[0150] As a second embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0151] Selected from

[0152] L2 is selected from a bond or C 1-4 Alkylene, the alkylene group is optionally substituted by 1 to 4 R k replaced by;

[0153] Ring B is selected from one of the following optionally substituted structures: When substituted, 1 to 4 R b replaced, and its left side is directly connected to L;

[0154] Ring C1 is selected from a 5- to 12-membered nitrogen-containing heteroaryl group and a 4- to 12-membered nitrogen-containing heterocyclic group, and ring C1 is connected to -C=X via a nitrogen atom, and the ring C1 is optionally substituted by 1 to 4 R c replaced by;

[0155] Ring C2 is selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclic group, 4 to 12 membered heterocyclic group, wherein the ring C2 is optionally substituted by 1 to 4 R c replaced by;

[0156] A1 is selected from CR a , CH;

[0157] R c Each independently selected from deuterium, halogen, OH, =O, COOH, CN, NO2, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, -C(=O)R 1a 、-S(=O)2R 1a 、-P(=O)R 1a R 1b 、-OC 1-4 Alkylene-OC 1-4 Alkyl, -OC 1-4 Alkylene-OC 3-8 Carbocyclic group, -C 1-4 Alkylene-OC 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkylene-OC 3-8 Carbocyclic group, -OC 0-4 Alkylene-C 3-8 Carbocyclic group, -OC 0-4 Alkylene-4 to 8-membered heterocyclic group, -SC 0-4 Alkylene-C 3-8 Carbocyclic group, -SC 0-4 Alkylene-4 to 8 membered heterocyclic group, -NH-C 0-4 Alkylene-C 3-8 Carbocyclic group, -NH-C 0-4 Alkylene-4 to 8 membered heterocyclic group, -C 0-4Alkylene-C 3-8 Carbocyclic group, -C 0-4 Alkylene-4 to 8 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replaced by;

[0158] R k Each independently selected from deuterium, halogen, OH, CN, NO2, NH2, COOH, CONH2, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7-membered heterocyclic ring, -SC 3-6 Carbocyclic ring, -S-3 to 7 membered heterocyclic ring, -C 0-2 Alkylene-C 3-6 Carbon ring, -C 0-2 Alkylene-3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0159] The condition is, Selected from When X is selected from O and L is selected from -N(CH3)-CH2-, Not selected from

[0160] Or ring B is selected from When X is selected from O and L is selected from -N(CH3)-CH2-, Not selected from

[0161] or Ring B is selected from optionally 1 to 4 R b Replaced X is selected from O, L is selected from -C 1-4 Alkylene-, -OC 1-4 When alkylene-, the alkylene is substituted by 1 to 6 R k replaced by;

[0162] The definitions of the remaining substituents are consistent with those described in Scheme 1 of the present invention.

[0163] As a third embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0164] R 1 Selected from H, deuterium, C 1-4 Alkyl, -C(=O)R 1a 、-S(=O)2R 1a 、-P(=O)R 1a R 1b , C 3-6 A carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replaced by;

[0165] R a Each independently selected from deuterium, halogen, OH, NH2, CN, NO2, COOH, CONH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 3-8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 R k replaced by;

[0166] R 2 Selected from H, deuterium, C 1-4 Alkyl, C 0-4 Alkylene-C 6-10 Aryl, C 0-4 Alkylene-5 to 10 membered heteroaryl, C 0-4 Alkylene-C 3-10 Carbocyclic group, C 0-4 Alkylene-4 to 10 membered heterocyclic group, wherein the alkyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replaced by;

[0167] R L Each independently selected from C 1-4 Alkyl, C 3-8 carbocyclic group, 4 to 8 membered heterocyclic group, the alkyl group, carbocyclic group, heterocyclic group is optionally substituted by 1 to 4 R k replaced by;

[0168] R b Each independently selected from deuterium, halogen, OH, cyano, NH2, NO2, N(C 1-4 Alkyl)2, NH(C 1-4 Alkyl), C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4Alkylthio, -C(=O)R 1a 、-S(=O)2R 1a 、-P(=O)R 1a R 1b , C 3-6 Carbocyclic group, 4 to 8 membered heterocyclic group, C 6-10 The alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic, heterocyclic, aryl or heteroaryl group is optionally substituted by 1 to 4 R k replaced by;

[0169] R 1a , R 1b Each independently selected from H, OH, NH2, C 1-4 Alkyl, C 1-4 Alkoxy, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 3-6 Carbocyclic group, 4 to 8 membered heterocyclic group, C 6-10 Aryl or 5 to 10 membered heteroaryl, wherein the alkyl, alkoxy, carbocyclic group, heterocyclic group, aryl or heteroaryl group is optionally substituted by 1 to 4 R k replaced by;

[0170] Alternatively, two R a Together with the atoms it is connected to, it forms C 3-8 A carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R k replaced by;

[0171] The definitions of the remaining substituents are consistent with those described in Schemes 1 and 2 of the present invention.

[0172] As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0173] Ring C1 is selected from a 4-7 membered nitrogen-containing heteromonocyclic ring, a 5-12 membered nitrogen-containing heterocyclic ring, a 5-12 membered nitrogen-containing heterospirocyclic ring, a 7-10 membered nitrogen-containing heterobridged ring, a benzo 3- to 8-membered nitrogen-containing heterocyclic group, a 5-10 membered nitrogen-containing heteroaryl group, and the ring C1 is connected to -C=X via a nitrogen atom, and the ring C1 is optionally substituted by 1 to 4 R c replaced by;

[0174] Ring C2 is selected from 4-7 membered heteromonocyclic ring, 5-12 membered heterocyclic ring, 5-12 membered heterospirocyclic ring, 7-10 membered heterobridged ring, C 3-8 Monocarbocyclic group, C 6-12 Cycloalkyl, C 6-12 Spirocycloalkyl, C 5-12 Benzene-C-cycloalkyl 3-8Carbocyclic group, benzo 4 to 8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, the ring C2 is optionally substituted by 1 to 4 R c replaced by;

[0175] L2 is selected from a bond, a methylene group, an ethylene group, and the methylene group and the ethylene group are optionally replaced by 1 to 3 R k replaced by;

[0176] R 2 Selected from H, deuterium, C 1-4 Alkyl, the alkyl group is optionally substituted by 1 to 4 R k replaced by;

[0177] R k Each independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NO2, COOH, CONH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0178] R L Each is independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole or thiophene, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole or thiophene is optionally replaced by 1 to 4 R k replaced by;

[0179] R 1 is selected from H, deuterium, methyl, ethyl, propyl, isopropyl, -C(=O)R 1a 、-S(=O)2R 1a 、-P(=O)R 1a R 1b, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl optionally substituted by 1 to 4 R k replaced by;

[0180] R 1a , R 1b Each independently selected from H, OH, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole or thiophene, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole or thiophene is optionally replaced by 1 to 3 R k replaced by;

[0181] R a Each independently selected from deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl is optionally replaced by 1 to 4 R k replaced by;

[0182] R b each independently selected from deuterium, F, Cl, Br, I, OH, cyano, NH2, NO2, NHCH3, N(CH3)2, COOH, CONH2, -C(=O)-methyl, -C(=O)-ethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole or thiophene, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole or thiophene is optionally replaced by 1 to 4 R k replaced by;

[0183] Alternatively, two R aand the atoms connected thereto together form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, oxolanyl, pyrrolidinyl, piperidinyl, 1,3-dioxolanyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, oxolanyl, pyrrolidinyl, piperidinyl, 1,3-dioxolanyl is optionally substituted by 1 to 4 R k replaced by;

[0184] The definitions of the remaining substituents are consistent with those described in Schemes 1, 2 and 3 of the present invention.

[0185] As a fifth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0186] p is independently selected from 0, 1, 2, 3;

[0187] R 1 Selected from H;

[0188] L is selected from -CH2CH2-, -NR L -CH2-, -O-CH2-, -S-CH2-, -NR L -CH2CH2-, -O-CH2CH2-, -S-CH2CH2-, wherein the -CH2- is optionally replaced by 1 to 2 R k replaced by;

[0189] R L Each is independently selected from CHF2, CH2F, CF3, CH2OH, methyl, ethyl, propyl, isopropyl, cyclopropyl or cyclobutyl;

[0190] Ring B is selected from Ring B1, Ring B2 or Ring B3;

[0191] Ring B1 is selected from one of the following optionally substituted structures:

[0192] When substituted, 1 to 3 R b replaced, and its left side is connected to L;

[0193] Ring B3 is selected from b One of the following structures is replaced:

[0194]

[0195] Its left side is connected to L;

[0196] Ring B2 is selected from b One of the following structures is replaced: Its left side is connected to L;

[0197] Selected from one of the following optionally substituted structures:

[0198] When substituted, 1 to 3 R c replaced by;

[0199] Ring C2 is selected from one of the following structures which are optionally substituted: cyclopropane, cyclobutane, cyclopentane, cyclohexane, azetidine, pyrrolidine, cyclohexene, azacyclohexine, piperidine, morpholine, piperazine, 1,4-diazepine, benzene, naphthalene, oxetane, tetrahydrofuran, tetrahydropyran, furan, pyrrole, pyrazole, imidazole, thiophene, thiazole, oxazole, isoxazole, triazole, pyridine, pyrimidine, pyrazine, pyridazine, 2-pyridone, benzopyrrole, benzopyrrolidine, benzothiophene, benzofuran, benzothiazole, benzopyrazole, benzimidazole, quinoline, isoquinoline, pyridopyridine, pyrazolotetrahydropyrrole, 3-pyridazinone, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, When substituted, 1 to 3 R c replace;

[0200] R 2 is selected from H, deuterium, methyl, ethyl, propyl, isopropyl, wherein the methyl, ethyl, propyl, isopropyl is optionally substituted by 1 to 3 R k replaced by;

[0201] The definitions of the remaining substituents are consistent with those described in Scheme 1, 2, 3, 4 or 5 of the present invention.

[0202] As a sixth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0203] Ring B is selected from Ring B1 or Ring B3;

[0204] R cEach independently selected from deuterium, F, Cl, Br, I, =O, OH, NH2, NHCH3, N(CH3)2, CN, NO2, COOH, -C(=O)CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -S(=O)2NH2, -P(=O)(CH3)2, -S(=O)2CH3 or one of the following groups optionally substituted: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazolyl, phenyl, pyridinyl, azetidinyl, pyrrolidine yl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-pyrrolidinyl, -CH2-morpholinyl, -CH2-pyrazolyl, -O-cyclopropyl, -O-cyclobutyl, -O-pyrrolidinyl, -O-phenyl, -S-cyclopropyl, -S-cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, -OCH2-cyclopropyl, -OCH2-pyrrolidinyl, -OCH2CH2-cyclopropyl, -OCH2CH2-morpholinyl, When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, COOH, CN, CHF2, CH2F, CF3, OCF3, OCHF2, OCH2F, NH2, NHCH3, N(CH3)2, CH2OH, OCH2OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl;

[0205] L2 is selected from a bond, CH2, CH2CH2, wherein CH2, CH2CH2 are optionally replaced by 1 to 3 R k substituted, and its left end is connected to ring C2;

[0206] L is selected from -CH2CH2-, -N(CH3)-CH2-, -N(CH2CH3)-CH2-, -O-CH2-, -O-CH(CH3)-, -OC(CH3)2-, -S-CH2-, -S-CH(CH3)-, -SC(CH3)2-,

[0207] Its right side is directly connected to ring B;

[0208] X is selected from O or S;

[0209] Selected from

[0210] The definitions of the remaining substituents are consistent with those described in Scheme 1, 2, 3, 4 or 5 of the present invention.

[0211] As a seventh embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein:

[0212] Ring B is selected from Ring B2;

[0213] Selected from -C(=S)-CH2CH2-, -C(=S)-N(CH3)-CH2-, -C(=S)-N(CH2CH3)-CH2-, -C(=S)-O-CH2-, -C(=S)-O-CH(CH3)-, -C(=S)-OC(CH3)2-, -C(=O)-O-CH(CH3)-, -C(=O)-OC(CH3)2-, -C(=O)-SC(CH3)2-, -C(=S)-S-CH2-, -C(=S)-S-CH(CH3)-, -C(=S)-SC(CH3)2-,

[0214]

[0215] Its right side is connected to ring B2;

[0216] R cEach independently selected from deuterium, F, Cl, Br, I, =O, OH, NH2, NHCH3, N(CH3)2, CN, NO2, COOH, -C(=O)CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -S(=O)2NH2, -P(=O)(CH3)2, -S(=O)2CH3 or one of the following groups optionally substituted: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazolyl, phenyl, pyridinyl, azetidinyl, pyrrolidine yl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-pyrrolidinyl, -CH2-morpholinyl, -CH2-pyrazolyl, -O-cyclopropyl, -O-cyclobutyl, -O-pyrrolidinyl, -O-phenyl, -S-cyclopropyl, -S-cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, -OCH2-cyclopropyl, -OCH2-pyrrolidinyl, -OCH2CH2-cyclopropyl, -OCH2CH2-morpholinyl, When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, COOH, CN, CHF2, CH2F, CF3, OCF3, OCHF2, OCH2F, NH2, NHCH3, N(CH3)2, CH2OH, OCH2OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl;

[0217] L2 is selected from a bond, CH2, CH2CH2, wherein CH2, CH2CH2 are optionally replaced by 1 to 3 R k substituted, and its left end is connected to ring C2;

[0218] Selected from

[0219] The definitions of the remaining substituents are consistent with those described in Scheme 1, 2, 3, 4 or 5 of the present invention.

[0220] As an eighth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from the compounds described in the following general formulas (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8),

[0221]

[0222]

[0223] In the general formula (I-1), E2, E4, and E5 are each independently selected from CR b , CH or N, and at least one of the three is selected from N;

[0224] L is selected from L1, L3 or L4;

[0225] Ring B is selected from Ring B1, Ring B2 or Ring B3;

[0226] L4 is selected from -C 1-4 Alkylene-, -SC 1-4 Alkylene-, -OC 1-4 Alkylene-, the alkylene group is optionally substituted by 1 to 6 R k replaced by;

[0227] L1 is selected from -OC 1-4 Alkylene-, -C 1-4 Alkylene-, wherein the alkylene is substituted by 1 to 6 R k replaced by;

[0228] L3 is selected from -NR L -C 1-4 Alkylene-, the alkylene group is optionally substituted by 1 to 6 R k replaced by;

[0229] Ring C3 is selected from c Replaced

[0230] Ring B3 is selected from one of the following optionally substituted structures: When substituted, 1 to 4 R b replaced, and its left side is directly connected to L;

[0231] The definitions of the remaining substituents are consistent with those described in any of the aforementioned embodiments of the present invention.

[0232] As a ninth embodiment of the present invention, the compounds represented by the aforementioned general formula (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8) or their stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0233] L1 is selected from -O-CH2-, -CH2-, -O-CH2CH2-, -CH2CH2-, wherein the -CH2- is optionally replaced by 1 to 2 R k replaced by;

[0234] L3 is selected from -N(CH3)-CH2-, NR L -CH2-、NR L -CH2CH2-, wherein the -CH2- is optionally substituted by 1 to 2 R k replaced by;

[0235] L4 is selected from -CH2-, -CH2-CH(CH3)-, -CH2CH2-, -CH2CH2CH2-, -S-CH2-, -O-CH2-, -S-CH2CH2-, -O-CH2CH2-, wherein -CH2- is optionally replaced by 1 to 2 R k replaced by;

[0236] R L Each is independently selected from CHF2, CH2F, CF3, CH2OH, methyl, ethyl, propyl, isopropyl, cyclopropyl or cyclobutyl;

[0237] Ring C3 is selected from

[0238] The definitions of the remaining substituents are consistent with those described in any of the aforementioned embodiments of the present invention.

[0239] As the tenth embodiment of the present invention, the compound represented by the aforementioned general formula (Ia-6) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0240] Selected from 1 to 3 R b One of the following structures is replaced:

[0241] R bEach independently selected from deuterium, F, Cl, Br, I, OH, cyano, NH2, NO2, NHCH3, N(CH3)2, COOH, CONH2, -C(=O)-methyl, -C(=O)-ethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl are optionally substituted by 1 to 4 R k replaced by;

[0242] X is selected from O or S;

[0243] L4 is selected from -CH2-, -CH2-CH(CH3)-, -CH2CH2-, -CH2CH2CH2-, -S-CH2-, -O-CH2-, -S-CH2CH2-, -O-CH2CH2-, wherein -CH2- is optionally replaced by 1 to 2 R k replaced by;

[0244] Ring C2 is selected from one of the following structures which are optionally substituted: benzene, naphthalene, pyridine, pyrimidine, pyrazine, pyridazine, 2-pyridone, When substituted, 1 to 3 R c Preferably, ring C2 is selected from one of the following optionally substituted structures: benzene, pyridine, pyrimidine, pyrazine, pyridazine, When substituted, 1 to 3 R c replace;

[0245] R c each independently selected from deuterium, F, Cl, Br, I, =O, OH, NH2, NHCH3, N(CH3)2, CN, NO2, COOH, -C(=O)CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -S(=O)2NH2, -P(=O)(CH3)2, -S(=O)2CH3 or one of the following groups optionally substituted: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl alkyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuran, tetrahydropyran, piperazine, morpholinyl, when substituted, with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, COOH, CN, CHF2, CH2F, CF3, OCF3, OCHF2, OCH2F, NH2, NHCH3, N(CH3)2, CH2OH, OCH2OH, methyl;

[0246] R kEach is independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NO2, COOH, CONH2, NHCH3, N(CH3)2, CHF2, CH2F, CF3, OCF3, OCHF2, OCH2F, CD3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and methylthio.

[0247] The present invention relates to the following compound or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures in Table A below:

[0248] Table A

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261] The present invention relates to a pharmaceutical composition, comprising the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition contains 1-1500 mg of the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal.

[0262] The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier

[0263] The present invention relates to use of the compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in preparing a drug for treating diseases related to GSPT1 or MYC, preferably in preparing a tumor drug.

[0264] In some embodiments, the pharmaceutical composition of the present invention may be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as "preparation strength").

[0265] The "effective amount" or "therapeutically effective amount" described in this application refers to the administration of a sufficient amount of the compound disclosed in this application, which will alleviate one or more symptoms of the disease or condition being treated (e.g., treatment of diseases related to GSPT1 or MYC such as tumors) to some extent. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms or causes of the disease, or any other desired changes in the biological system. For example, an "effective amount" for therapeutic use is the amount of the compound disclosed in this application required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-60 0mg, 90-600mg, 100-600mg, 200-600mg, 1-500mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 2 5-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg,

[0266] 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25 -400mg, 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg,

[0267] 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250-400mg, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg , 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300mg, 90-300mg, 100-300mg, 125-300mg , 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40-200mg, 5 0-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1000mg, 80-800mg.

[0268] In some embodiments, the pharmaceutical composition includes but is not limited to 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg , 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg of a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

[0269] A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the therapeutically effective amount preferably being 1-1500 mg, and the disease preferably being a GSPT1 or MYC regulator-related disease (such as a tumor).

[0270] A method for treating a disease in a mammal, the method comprising administering a drug compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof to a subject at a daily dose of 1-1000 mg / day, the daily dose can be a single dose or divided doses, in some embodiments, the daily dose includes but is not limited to 10-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day, in some embodiments, the daily dose includes but is not limited to 10 mg / day, 20 mg / day, 25 mg / day,

[0271] 50mg / day, 80mg / day, 100mg / day, 125mg / day, 150mg / day, 160mg / day, 200mg / day, 300mg / day, 320mg / day, 400mg / day, 480mg / day, 600mg / day, 640mg / day, 800mg / day, 1000mg / day.

[0272] The present invention relates to a kit, which may include a composition in a single-dose or multi-dose form, and the kit contains a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as its amount in the above-mentioned pharmaceutical composition.

[0273] The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or the above-mentioned pharmaceutical composition in the preparation of drugs for treating diseases related to GSPT1 or MYC regulators.

[0274] The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, or the above-mentioned pharmaceutical composition, characterized in that the disease is selected from solid tumors such as non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), MYC-driven cancer, etc.

[0275] The amount of the compound of the invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof is in each case calculated as the free base.

[0276] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0277] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, isotopes of nitrogen include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl and bromine include 79 Br and 81 Br.

[0278] "CN" refers to cyano.

[0279] "Halogen" refers to F, Cl, Br or I.

[0280] "Halogen substituted" refers to substitution with F, Cl, Br or I, including but not limited to substitution with 1 to 10 substituents selected from F, Cl, Br or I, substitution with 1 to 6 substituents selected from F, Cl, Br or I, and substitution with 1 to 4 substituents selected from F, Cl, Br or I. "Halogen substituted" is abbreviated as "halo".

[0281] "Alkyl" refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof; alkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0282] "Alkylene" refers to substituted or unsubstituted straight-chain or branched divalent saturated hydrocarbon groups, including -(CH2) v-(v is an integer from 1 to 10), examples of alkylene include but are not limited to methylene, ethylene, propylene and butylene.

[0283] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 12 carbon atoms, and the cycloalkyl radical can be a monocyclic, cyclic, bridged, and spirocyclic ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-cyclobutyl, cyclobutyl-spirocyclobutyl, adamantane, etc. The cycloalkyl radical can be monovalent, divalent, trivalent, or tetravalent.

[0284] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon containing heteroatoms, including but not limited to 3 to 12 atoms, 3 to 8 atoms, including 1 to 3 heteroatoms selected from N, O, S or Se, and the C, N, S on the ring of the heterocycloalkyl can be oxidized to various oxidation states. Heterocycloalkyl can be a monocyclic, cyclic, bridged and spirocyclic. Heterocycloalkyl can be connected to a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxadiazine, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolane, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazininyl, morpholinyl, hexahydropyrimidinyl, piperazinyl,

[0285] The heterocycloalkyl group may be monovalent, divalent, trivalent or tetravalent.

[0286] "Alkenyl" refers to a substituted or unsubstituted straight chain or branched unsaturated hydrocarbon group having at least one, typically one, two or three carbon-carbon double bonds, with a backbone of 2 to 10, 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl groups include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-2 ... -methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-hexadiene, etc.; the alkenyl group can be monovalent, divalent, trivalent or tetravalent.

[0287] "Alkynyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon triple bonds, with a backbone comprising 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the backbone, 2 to 4 carbon atoms in the backbone, examples of alkynyl groups include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 5-pentynyl, 6-pentynyl, 7-pentynyl, 8-pentynyl, 9-pentynyl, 10-pentynyl, 11-pentynyl, 12-pentynyl, 13-pentynyl, 14-pentynyl, 15-pentynyl, 16-pentynyl, 17-pentynyl, 18-pentynyl, 19-pentynyl, 20-pentynyl, 21-pentynyl, 22-pentynyl, 23-pentynyl, 24-pentynyl, 25-pentynyl, 26-pentynyl, 27-pentynyl, 28-pentynyl, 29-pentynyl, 30-pentynyl, 31-pentynyl, 32-pentynyl, 33-pentynyl, 34-pentynyl, 35-pentynyl, 36-pentynyl, 37-pentynyl, 38-pentynyl, 39-pentynyl, 40-pentynyl, 41-pentynyl, 42-pentynyl, 43-pentynyl, 44-pentynyl, 45-pentynyl, 46-pentynyl, 47-pentynyl, 48-pentynyl 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl and the like; the alkynyl group may be monovalent, divalent, trivalent or tetravalent.

[0288] "Alkoxy" refers to substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.

[0289] "Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8-membered monocyclic ring, a 4-12-membered bicyclic ring, a 10-15-membered tricyclic ring, or a 12-18-membered quaternary system. The carbocyclyl can be attached to an aromatic ring or a non-aromatic ring, and the ring can be optionally a monocyclic ring, a cyclic ring, a bridged ring, or a spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent or tetravalent.

[0290] "Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring, a 10-15 membered tricyclic ring, or a 12-18 membered quaternary system, and contains 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O, S or Se. The C, N, S or Se selectively substituted in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclic group can be connected to a heteroatom or a carbon atom, and can be connected to an aromatic ring or a non-aromatic ring. The heterocyclic group is optionally a monocyclic, bridged, fused or spirocyclic ring. Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophenyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl,

[0291] "Heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.

[0292] "Spirocycle" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted rings share one atom (called spiro atom), and the number of ring atoms in the spiro system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and optionally may contain 0 to 5 selected from N, O or S (=O) n (n is 0, 1 or 2). Non-limiting examples include:

[0293]

[0294] "Spirocycle" or "spirocyclyl" may be monovalent, divalent, trivalent or tetravalent.

[0295] "Parallel ring" or "parallel ring group" refers to a polycyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds and may be substituted or unsubstituted, and each ring in the parallel ring system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to selected from N, S(=O) n or O, n is 0, 1 or 2). The number of ring atoms in the ring system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include:

[0296]

[0297] "Bicyclic" or "bicyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0298] "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, which may contain 0 or more double bonds, and any ring in the bridged ring system may contain 0 to 5 groups selected from heteroatoms or heteroatom-containing groups (including but not limited to N, S(=O)n or O, where n is 0, 1, 2). The number of ring atoms includes but is not limited to 5 to 20, 5 to 14, 5 to 12 or 5 to 10. Non-limiting examples include:

[0299]

[0300] Cubane, adamantane. "Bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent or tetravalent.

[0301] "Carbospirocycle", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spirocycle" wherein the ring system consists of only carbon atoms.

[0302] "Carbocyclic", "cyclic carbocyclyl", "carbocyclyl" or "carbocyclyl" refers to a "cyclic" ring system consisting of only carbon atoms.

[0303] "Carbobridged ring", "bridged ring carbocyclic group", "bridged carbocyclic group" or "carbon bridged cyclic group" refers to a "bridged ring" wherein the ring system consists of only carbon atoms.

[0304] "Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a monocyclic ring system of "heterocyclyl" or "heterocycle".

[0305] "Heterocyclic ring", "heterocyclic group", "cycloheterocyclic group" or "cycloheterocyclyl" refers to a "cyclo" containing a heteroatom.

[0306] "Heterospirocycle", "heterospirocyclyl", "spiroheterocyclyl" or "spiroheterocyclyl" refers to a "spirocycle" containing a heteroatom.

[0307] "Heterobridged ring", "heterobridged ring group", "bridged ring heterocyclyl" or "bridged heterocyclyl" refers to a "bridged ring" containing a heteroatom.

[0308] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbon ring, wherein the ring connected to the parent structure is the aryl ring, non-limiting examples of which include benzene ring, naphthalene ring, "Aryl" or "aromatic ring" can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.

[0309] "Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group, and contains 1 to 5 selected heteroatoms or groups containing heteroatoms (including but not limited to N, O, S(=O)n or Se(=O)n, n is 0, 1, 2), and the number of ring atoms in the heteroaromatic ring includes but is not limited to 5 to 15, 5 to 10 or 5 to 6. The atoms C, N, and S on the ring are optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, n is 1, 2). Non-limiting examples of heteroaryl include but are not limited to pyridyl, furanyl, thienyl, selenophenyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, pyridonyl, and the like. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples include: The heteroaryl groups appearing in this article have the same definition as this definition. The heteroaryl group can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the attachment site is located on the aromatic ring.

[0310] "Substituted" or "substituted" means substituted by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cycloalkyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -

[0311] (CH2) m -C(=O)-R a 、-O-(CH2) m -C(=O)-R a 、-(CH2) m -C(=O)-NRb R c 、-(CH2) m S(=O) n R a 、-(CH2) m -Alkenyl-R a , OR d or -(CH2) m -alkynyl-R a (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silane or -NR b R c etc., where R b With R c is independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R b With R c Can form a five- or six-membered cycloalkyl or heterocyclic group, R a With R d Each is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro or paracyclic groups.

[0312] "1 to X substituents selected from..." means substituted by 1, 2, 3...X substituents selected from..., where X is selected from any integer between 1 and 10. For example, "1 to 4 R k "Substituted" means replaced by 1, 2, 3 or 4 R k For example, "1 to 5 substituents selected from..." means substituted by 1, 2, 3, 4 or 5 substituents selected from..." For example, "the heterobridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means that the heterobridged ring is optionally substituted by 1, 2, 3 or 4 substituents selected from H or F.

[0313] The XY-membered ring (X, Y are integers, and 3≤X<Y, X<Y≤20 is selected from any integer between 4 and 20) includes X, X+1, X+2, X+3, X+4...Y-membered rings. The ring includes a heterocyclic ring, a carbocyclic ring, an aromatic ring, an aryl group, a heteroaryl group, a cycloalkyl group, a heteromonocyclic ring, a heterocyclic ring, a heterospirocyclic ring or a heterobridged ring. For example, "4-7-membered heteromonocyclic ring" refers to a 4-membered, 5-membered, 6-membered or 7-membered heteromonocyclic ring, and "5-10-membered heterocyclic ring" refers to a 5-membered, 6-membered, 7-membered, 8-membered, 9-membered or 10-membered heterocyclic ring.

[0314] C x-y Carbocycles (including aryl, cycloalkyl, monocyclic carbocycle, spirocyclic carbocycle, fused carbocycle or bridged carbocycle) include C x , C x+1 , C x+2 , C x+3 , C x+4…C y A ring of 1-membered ring (x is an integer, and 3≤x<y, y is selected from any integer between 4 and 20), for example. 3-6 "Cycloalkyl" refers to C3, C4, C5 or C6 cycloalkyl.

[0315] When a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection is non-positional and there are hydrogen atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease with the number of connected chemical bonds and become a group with the corresponding valence. For example It means that any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Also included For example Indicates that the R group on the piperidinyl group can be located on C, can be located on N, and at least includes For example, the general formula fragment is When X is selected from CH2 or NH, it means that the R group on the general fragment can be located on C or X. When X is selected from CH2, the general fragment can be When X is selected from NH, the general fragment can be

[0316]

[0317] When the listed linking groups do not specify their connection direction, their connection directions include connection from left to right and from right to left in reading order, for example, when ALB, L is selected from -MW-, it includes AMWB and AWMB.

[0318] "Optional" or "optionally" means that the event or circumstance described later may but need not occur, and the description includes situations where the event or circumstance occurs or does not occur. For example, "alkyl optionally substituted with F" means that alkyl may but need not be substituted with F, and the description includes situations where alkyl is substituted with F and situations where alkyl is not substituted with F.

[0319] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0320] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, or stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals thereof and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0321] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0322] "Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0323] "Prodrug" refers to a compound of the present invention that can be converted into a biologically active compound through in vivo metabolism. The prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.

[0324] "Co-crystal" refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components. Co-crystal is a multi-component crystal, including binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates.

[0325] "Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0326] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.

[0327] "Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomerism and amide-imino alcohol isomerism. DETAILED DESCRIPTION

[0328] The following embodiments illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0329] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were measured in 10 -6The unit of (ppm) is given. NMR measurements were performed using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometer, the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS);

[0330] MS was measured using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0331] HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm, 3.5 μM);

[0332] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) uses a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;

[0333] Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0334] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Titan Technology, Anage Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0335] THF: Tetrahydrofuran; DMF: N,N-dimethylformamide; DIPEA: N,N-diisopropylethylamine; DBU: CAS No.: 6674-

[0336] 22-2; NBS: CAS No.: 128-08-5;

[0337] Example 1: Preparation of Compound 1

[0338]

[0339] Step 1: Preparation of compound 1

[0340] 1A (110 mg, 0.35 mmol) (synthesized according to patent WO2022152822) and 1B (100 mg, 0.36 mmol) (synthesized according to patent WO202229138) were added to DMF (10 mL) in sequence, and sodium hydride (20 mg, 0.50 mmol, wt% = 60%) was added at 0°C, and the mixture was slowly heated to room temperature for 1 hour. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 2), the organic layers were combined and dried, and purified by TLC preparation plate (dichloromethane / methanol (V / V) = 10 / 1) to obtain compound 1 (60 mg, yield: 35%).

[0341] LCMS m / z=496.1[M+H] +

[0342] 1 H NMR(400MHz, DMSO-d6)δ10.99(s,1H),9.91(s,1H),7.83(dd,1H),7.76(d,1H),7.67(s,1H),7.58(d,1H),7.38(dd,1H),7.18–7.09(m, 1H),5.31(s,2H),5.12(dd,1H),4.48(d,1H),4.35(d,1H),2.99–2.85(m,1H),2.65–2.54(m,1H),2.47–2.33(m,1H),2.08–1.94(m,1H).

[0343] Example 2: Preparation of Compound 2

[0344]

[0345] Step 1: Preparation of 2C

[0346] 2A (1.00 g, 5.13 mmol), pyridine (1.22 g, 15.42 mmol) and 2B (0.89 g, 5.16 mmol) were added to acetonitrile (10 mL) in sequence and reacted at room temperature for 1 hour. Water (50 mL) was added, extracted with ethyl acetate (50 mL × 2), the organic layers were combined and dried by spin drying, and the residue was separated and purified by column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 0-10%) to obtain 2C (1.10 g, yield: 65%).

[0347] LCMS m / z=332.0[M+H] +

[0348] 1H NMR(400MHz,DMSO-d6)δ11.20(s,1H),10.98(s,1H),7.85–7.22(m,6H),5.64(s,2H),5.12(dd,1H),4 .47(d,1H),4.34(d,1H),2.99–2.83(m,1H),2.66–2.54(m,1H),2.47–2.31(m,1H),2.07–1.94(m,1H).

[0349] Step 2: Preparation of compound 2

[0350] 2C (120 mg, 0.36 mmol) and 1B (100 mg, 0.36 mmol) were added to DMF (10 mL) in sequence, sodium hydride (22 mg, 0.55 mmol, wt% = 60%) was added at 0°C, and the temperature was slowly raised to room temperature for 1 hour. Water (50 mL) was poured into the reaction solution, extracted with ethyl acetate (50 mL × 2), the organic layers were combined and dried by spin drying, and the residue was purified by preparative liquid phase (instrument: waters 2767 preparative chromatography column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: acetonitrile / water (containing 0.1% trifluoroacetic acid)) to obtain compound 2 (20 mg, yield: 11%).

[0351] LCMS m / z=512.0[M+H] +

[0352] 1 H NMR(400MHz,DMSO-d6)δ11.20(s,1H),10.98(s,1H),7.87–7.19(m,6H),5.64(s,2H),5.12(dd,1H),4 .47(d,1H),4.34(d,1H),2.99–2.83(m,1H),2.66–2.54(m,1H),2.47–2.32(m,1H),2.06–1.95(m,1H).

[0353] Example 3: Preparation of Compound 3

[0354]

[0355] Step 1: Preparation of compound 3

[0356] Compound 3A (150 mg, 0.47 mmol) (synthesized according to patent WO2018140809) was added to anhydrous dichloromethane (10 mL), and then oxalyl chloride (120 mg, 0.95 mmol) and two drops of N, N-dimethylformamide were slowly added, and the reaction was carried out at room temperature for 1 hour. After the reaction, the reaction solution was dried, and the residue was added to anhydrous tetrahydrofuran (10 mL) containing 2A (120 mg, 0.62 mmol) and pyridine (110 mg, 1.39 mmol), and the reaction was carried out at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative liquid phase (instrument: waters 2767 preparative chromatographic column: SunFire@Prep C18 (19 mm×150 mm); mobile phase composition: acetonitrile / water (containing 0.1% trifluoroacetic acid)) to obtain compound 3 (30 mg, yield: 13%).

[0357] LCMS m / z=494.1[M+H] +

[0358] 1 H NMR(400MHz,DMSO-d6)δ10.95(s,1H),10.01(s,1H),8.04(dd,1H),7.65(d,1H),7.48(s,1H),7.44–

[0359] 7.33(m,2H),7.17–7.08(m,1H),5.07(dd,1H),4.42(d,1H),4.29(d,1H),3.07–2.98(m,2H),2.89(ddd,1H),

[0360] 2.83–2.73(m,2H),2.65–2.55(m,1H),2.45–2.30(m,1H),2.05–1.93(m,1H).

[0361] Example 4: Preparation of Compound 4

[0362]

[0363] Step 1: Preparation of 4B

[0364] 4A (2.4 g, 5.29 mmol) (synthesized with reference to patent WO2021124172), triethylsilane (1.52 g, 13.07 mmol), diisopropylethylamine (1.05 g, 8.15 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (0.13 g, 0.16 mmol) were added to N,N-dimethylformamide (10 mL) in sequence and reacted at 80 ° C overnight under a carbon monoxide atmosphere. Water (30 mL) was added, extracted with ethyl acetate (50 mL × 2), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was separated and purified by column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 1 / 1) to obtain 4B (1.2 g, yield: 56%).

[0365] LCMS m / z=401.2[MH]-

[0366] Step 2: Preparation of 4C

[0367] To a solution of 4B (1.2 g, 2.98 mmol) in dichloromethane (20 mL) was added a toluene-tetrahydrofuran solution of methylmagnesium bromide (1.19 mL, 3 mol / L) at -78°C, and the mixture was stirred at -78°C for 2 hours. Saturated ammonium chloride solution (30 mL) was added, and the mixture was extracted with dichloromethane (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V)

[0368] =2 / 3) to obtain 4C (300 mg, yield: 24%).

[0369] LCMS m / z=417.1[MH] -

[0370] Step 3: 4D preparation

[0371] To 4C (300 mg, 0.72 mmol) was added a solution of hydrogen chloride in 1,4-dioxane (6.45 mL, 4 mol / L), and the mixture was reacted at 50 °C for 2 h. The mixture was concentrated in vacuo to obtain 4D, which was used directly in the next step.

[0372] LCMS m / z=319.2[M+H] +

[0373] Step 4: Preparation of 4E

[0374] To 4D obtained in the previous step were added acetonitrile (5 mL) and 30% ammonium hydroxide solution (0.1 mL), the mixture was reacted at room temperature for 1 h, and the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V) = 15 / 1) to give 4E (147 mg, yield: 71%).

[0375] LCMS m / z=289.2[M+H] +

[0376] Step 5: Preparation of compound 4

[0377] 4E (147 mg, 0.51 mmol) and 1A (177 mg, 0.56 mmol) were added to DMF (5 mL) in sequence, and sodium hydride (41 mg, 1.02 mmol, wt% = 60%) was added at 0°C, and the mixture was reacted at 0°C for 1 hour. 1N hydrochloric acid (1 mL) and water (10 mL) were added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative SFC (instrument: SFC Prep 150AP preparative column: Torus 2-PIC (19 mm × 250 mm); mobile phase composition: CO2 / methanol) to obtain compound 4 (50 mg, yield: 19%).

[0378] LCMS m / z=510.0[M+H] +

[0379] 1 H NMR(400MHz,DMSO-d6)δ10.97(s,1H),9.86(s,1H),7.80(dd,1H),7.75(d,1H),7.66(s,1H),7.61–

[0380] 7.54(m,1H),7.37(dd,1H),7.15–7.08(m,1H),5.93(q,1H),5.11(dd,1H),4.54–4.28(m,2H),2.91(ddd,1H),

[0381] 2.69–2.55(m,1H),2.47–2.30(m,1H),2.06–1.94(m,1H),1.57(d,3H).

[0382] Example 5: Preparation of Compound 5

[0383]

[0384] Step 1: Preparation of compound 5

[0385] 5A (100 mg, 0.26 mmol) (synthesized according to patent WO202273469) was added to a solution of 1,4-dioxane (10 mL) of hydrogen chloride at 0°C, stirred at room temperature for 2 h, concentrated in vacuo, and 1A (98 mg, 0.31 mmol), N,N-dimethylformamide (10 mL) and diisopropylethylamine (0.1 g, 0.77 mmol) were added, and reacted at 80°C for 2 hours. Water (20 mL) was added to the reaction solution, and then extracted with ethyl acetate (30 mL × 2), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by preparative liquid phase (instrument: waters 2767 preparative chromatography column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: acetonitrile / water (containing 0.1% trifluoroacetic acid)) to obtain compound 5 (50 mg, yield: 38%).

[0386] LCMS m / z=509.0[M+H] +

[0387] 1 H NMR(400MHz,DMSO-d)δ10.97(s,1H),8.39(s,1H),7.72(d,1H),7.66(dd,1H),7.50(s,1H),7.43(d,1H),7.39–7.31(m,1H),7.15–7.08 (m,1H),5.11(dd,1H),4.68(s,2H),4.40(dd,2H),2.98(s,3H),2.95–2.84(m,1H),2.60(d,1H),2.47–2.31(m,1H),2.07–1.95(m,1H).

[0388] Example 6: Preparation of Compound 6

[0389]

[0390] Step 1: Preparation of 6B

[0391] Referring to the synthesis method of the first step of Example 2, 6B (0.3 g) was obtained.

[0392] LCMS m / z=314.2[M+H] +

[0393] Step 2: Preparation of compound 6

[0394] 6B (177 mg, 0.57 mmol) and 1B (130 mg, 0.47 mmol) were added to DMF (10 mL), sodium hydride (28 mg, 0.70 mmol, wt% = 60%) was added at 0°C, and the temperature was slowly raised to room temperature for 1 hour. Water (50 mL) was poured into the reaction solution, extracted with ethyl acetate (50 mL × 2), the organic layers were combined and dried by spin drying, and the residue was purified by preparative liquid phase (instrument: waters2767 preparative chromatography column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: acetonitrile / water (containing 0.1% trifluoroacetic acid)) to obtain trifluoroacetate of compound 6 (30 mg, yield: 10%).

[0395] LCMS m / z=494.1[M+H] +

[0396] 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),10.98(s,1H),8.30–7.44(m,5H),7.13–6.87(m,1H),5.74–5.58(m,2H),5.19–5.06(m,1H),4. 54–4.28(m,2H),3.64–3.41(m,4H),2.99–2.84(m,1H),2.68–2.54(m,1H),2.46–2.31(m,1H),2.08–1.94(m,1H),1.69–1.47(m,6H).

[0397] Example 7: Preparation of Compound 7

[0398]

[0399] Referring to the synthesis method of Example 2, compound 7 (45 mg) was obtained.

[0400] LCMS m / z=444.1[M+H] +

[0401] 1 H NMR (400MHz, DMSO-d6) δ11.41(s,1H),10.97(s,1H),7.76(d,1H),7.68(s,1H),7.59(d,1H),7.42–7.09(m,2H),5.68(s ,2H),5.12(dd,1H),4.48(d,1H),4.35(d,1H),2.92(ddd,1H),2.68–2.55(m,1H),2.47–2.31(m,1H),2.06–1.94(m,1H).

[0402] Example 8: Preparation of trifluoroacetate salt of compound 8

[0403]

[0404] Step 1: Preparation of compound 8B

[0405] 8A (50 mg, 0.28 mmol) and triethylamine (57 mg, 0.56 mmol) were added to dichloromethane (3 mL), cooled to 0°C, and thiophosgene (39 mg, 0.34 mmol) was slowly added, and the reaction was continued at 0°C for 1 h. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 0-5%) to obtain 8B (55 mg, yield: 89%).

[0406] LCMS m / z=221.1[M+H] +

[0407] Step 2: Preparation of trifluoroacetate salt of compound 8

[0408] 8B (55 mg, 0.25 mmol), DBU (110 mg, 0.72 mmol), 1B (82 mg, 0.30 mmol) were added to DMF (3 mL) and reacted at room temperature for 2 h. The reaction solution was purified by preparative liquid chromatography (instrument: waters 2767 preparative chromatography column: SunFire@Prep C18 (19 mm×150 mm); mobile phase composition: acetonitrile / water (containing 0.1% trifluoroacetic acid)) to obtain trifluoroacetate salt of compound 8 (40 mg)

[0409] LCMS m / z=495.2[M+H] +

[0410] 1 H NMR(400MHz,DMSO-d6)δ11.36(s,1H),11.00(s,1H),8.53(s,1H),8.11(s,1H),7.83–7.43(m,3H),5.65(s,2H),5.12(dd,1H),4.48(d d,1H),4.34(dd,1H),3.63–3.42(m,4H),2.92(ddd,1H),2.68–2.54(m,1H),2.47–2.30(m,1H),2.07–1.95(m,1H),1.67–1.47(m,6H).

[0411] Example 9: Preparation of Compound 9

[0412]

[0413] Referring to the synthetic method of step 2 of Example 2, compound 9 (8 mg) was obtained.

[0414] LCMS m / z=544.1[M+33] +

[0415] 1 H NMR(400MHz,DMSO-d6)δ11.40–11.72(m,2H),7.94–7.21(m,6H),5.63(s,2H),5.12(dd,1H),4.4 7(d,1H),4.34(d,1H),2.91(ddd,1H),2.68–2.54(m,1H),2.47–2.31(m,1H),2.08–1.94(m,1H).

[0416] Example 10: Preparation of Compound 10

[0417]

[0418] Referring to the synthesis method of Example 6, trifluoroacetate salt of compound 10 (45 mg) was obtained.

[0419] LCMS m / z=459.1[M+H] +

[0420] 1 H NMR(400MHz,CF3COOD)δ9.22(s,1H),8.77(s,1H),7.97(d,1H),7.72–7.60(m,2H),5.76(s,2H),5 .52(dd,1H),4.65(s,2H),3.18–3.05(m,2H),2.83(s,3H),2.74–2.58(m,1H),2.51–2.37(m,1H).

[0421] Example 11: Preparation of Compound 11

[0422]

[0423] Step 1: Preparation of 11C

[0424] 11A (100 mg, 0.61 mmol) and 11B (156 mg, 0.67 mmol) were added to dichloromethane (10 mL) in sequence and reacted at room temperature for 12 hours. The mixture was concentrated under reduced pressure and the residue was separated and purified by column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 0-50%) to obtain 11C (80 mg, yield: 64%).

[0425] LCMS m / z=238.1[M+33] +

[0426] Step 2: Preparation of compound 11

[0427] 11C (74 mg, 0.36 mmol) and 1B (50 mg, 0.18 mmol) were added to DMF (5 mL) in sequence, and DBU (82 mg, 0.54 mmol) was added, and the reaction was carried out at room temperature for 1 hour. The reaction solution was purified by preparative liquid phase (instrument: waters 2767 preparative chromatography column: SunFire@Prep C18 (19 mm×150 mm); mobile phase composition: acetonitrile / water (containing 0.1% trifluoroacetic acid)) to obtain compound 11 (25 mg, yield: 29%).

[0428] LCMS m / z=480.4[M+H] +

[0429] 1 H NMR(400MHz,DMSO-d6)δ12.35(s,1H),10.97(s,1H),9.44(s,1H),8.92(s,1H),7.81–7.58(m,3H),5.74(s,2H),5 .12(dd,1H),4.48(d,1H),4.35(d,1H),2.91(ddd,1H),2.69–2.54(m,1H),2.47–2.32(m,1H),2.08–1.94(m,1H).

[0430] Example 12: Preparation of Compound 12

[0431]

[0432] Step 1: Preparation of compound 12B

[0433] 2A (3 g, 15.38 mmol) and 11B (4.29 g, 18.47 mmol) were added to dichloromethane (30 mL) and stirred at room temperature for 1 h. The organic phase was concentrated under reduced pressure, petroleum ether (40 mL) was added and stirred for 0.5 h, and the mixture was filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain a crude product 12B (3.5 g), which was directly used for the next step.

[0434] 1 H NMR (400MHz, CDCl3) δ7.17(t,1H),7.13–7.08(m,1H),7.08–7.03(m,1H).

[0435] Step 2: Preparation of compound 12D

[0436] 12C (300 mg, 0.93 mmol) and tetrakis(triphenylphosphine)palladium (110 mg, 0.095 mmol) were added to 1,4-dioxane (10 mL), purged with nitrogen three times, and then hydroxymethyltributyltinane (450 mg, 1.40 mmol) was added, and the mixture was reacted overnight at 100°C. After cooling to room temperature, the reaction solution was added with water (30 mL), and the aqueous phase was extracted with petroleum ether (10 mL×3), and then with dichloromethane (10 mL×3). Finally, the aqueous phase was freeze-dried to obtain a crude product of 12D (170 mg), which was directly used for the next step.

[0437] LCMS m / z=276.3[M+H] +

[0438] Step 3: Preparation of compound 12

[0439] Referring to the synthetic method of step 2 in Example 8, compound 12 (55 mg) was obtained.

[0440] LCMS m / z=513.1[M+H] +

[0441] 1 H NMR(400MHz,DMSO-d6)δ11.33(s,1H),11.00(s,1H),8.28–8.10(s,1H),7.77–7.51(m,2H),7.51–7.42(m,1H),7.42–7.32(m,1H) ,5.72(s,2H),5.18(dd,1H),4.53(d,1H),4.37(d,1H),2.92(ddd,1H),2.68–2.56(m,1H),2.48–2.36(m,1H),2.10–1.96(m,1H).

[0442] Example 13: Preparation of Compound 13

[0443]

[0444] Referring to the synthesis method of Example 12, compound 13 (7 mg) was obtained.

[0445] LCMS m / z=451.4[M+H] +

[0446] 1H NMR(400MHz,DMSO-d6)δ12.14(s,1H),11.00(s,1H),8.34(s,1H),8.25(d,1H),8.00–7.91(m,1H),7.82–7.56(m,4H),5.72 (s,2H),5.13(dd,1H),4.49(d,1H),4.35(d,1H),2.92(ddd,1H),2.65–2.55(m,1H),2.47–2.33(m,1H),2.07–1.94(m,1H).

[0447] Example 14: Preparation of Compound 14

[0448]

[0449] Step 1: Preparation of compound 14B

[0450] 14A (3 g, 13.04 mmol), NBS (2.55 g, 14.33 mmol) and azobisisobutyronitrile (210 mg, 1.28 mmol) were added to carbon tetrachloride (50 mL) and stirred at 80 °C for 24 h under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 0-10%) to obtain 14B (3 g, yield: 74%).

[0451] LCMS m / z=310.1[M+H] +

[0452] Step 2: Preparation of compound 14D

[0453] 14B (3 g, 9.71 mmol), 14C (2.08 g, 12.64 mmol) and DIPEA (5.02 g, 38.84 mmol) were added to acetonitrile (60 mL) and stirred at 85°C overnight under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: methanol / dichloromethane (V / V) = 0-5%) to obtain a crude product of 14D (1.6 g).

[0454] LCMS m / z=324.2[M+H] +

[0455] Step 3: Preparation of compound 14E

[0456] Referring to the synthetic method of step 2 of Example 12, 14E (150 mg) was obtained.

[0457] LCMS m / z=276.1[M+H] +

[0458] Step 4: Preparation of compound 14

[0459] Referring to the synthetic method of step 1 of Example 1, compound 14 (25 mg) was obtained.

[0460] LCMS m / z=497.1[M+H] +

[0461] 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),9.91(s,1H),8.87(d,1H),8.25(d,1H),7.88–7.78(m,1H),

[0462] 7.38(dd,1H),7.14(dd,1H),5.36(s,2H),5.19(dd,1H),4.55(d,1H),4.38(d, 1H),2.92(ddd,1H),2.68–2.56(m,1H),2.47–2.29(m,1H),2.10–1.98(m,1H).

[0463] Biological test cases

[0464] Test Example 1: NCI-H1155 Cell Proliferation Inhibition Experiment

[0465] NCI-H1155 cells (ATCC, Cat#30-2001) were cultured with RPMI 1640 medium (with 5% FBS and 1% double antibody), and the cells were collected and plated when the degree of fusion reached 80%-90%. The cells were transferred to a sterile centrifuge tube and centrifuged at 1000rpm for 3 minutes. After centrifugation, the cells were removed and the supernatant was discarded. The culture medium was added to the centrifuge tube to resuspend the cells and count them. According to the counting results, the cell suspension was adjusted to an appropriate concentration and added to a 96-well cell culture plate (Corning, Cat#3903). The compound was dissolved in DMSO to 10mM and stored for later use. During the experiment, the compound mother solution was diluted in sequence. The compound was added 24 hours after plating, and the culture was continued for 72 hours at 37°C and 5% CO2. After the incubation, CELL VIABILITY reagent (Promega, Cat#G7573) was added to each well and incubated at room temperature for 10 minutes. After the incubation, the well was gently shaken 5 times, and then the chemiluminescence reading was detected using a BMG microplate reader (PHERAstar FSX). According to the formula [(1–(RLU compound –RLU blank ) / (RLU control –RLU blank)) × 100%] to calculate the cell proliferation inhibition rate. The IC was obtained by four-parameter nonlinear fitting using GraphPad Prism software. 50 value.

[0466] Table 1 Inhibitory activity of test compounds on NCI-H1155 cell proliferation

[0467]

[0468]

[0469] Note: A<50nM, 50nM≤B<500nM, 500nM≤C<1μM, 1μM≤D

[0470] Conclusion: The compounds of the present invention have good NCI-H1155 cell proliferation inhibitory activity.

[0471] Test Example 2: KG-1 cell proliferation inhibition experiment

[0472] KG-1 cells (ATCC, Cat#30-2005) were cultured with IMDM medium (supplemented with 20% FBS and 1% double antibody), and cells were collected and plated when the degree of confluence reached 80%-90%. The cells were transferred to a sterile centrifuge tube and centrifuged at 1000rpm for 3 minutes. After centrifugation, the cells were removed and the supernatant was discarded. The culture medium was added to the centrifuge tube to resuspend the cells and count them. According to the counting results, the cell suspension was adjusted to an appropriate concentration and added to a 96-well cell culture plate (Corning, Cat#3903). The compound was dissolved in DMSO to 10mM and stored for later use. The compound mother solution was diluted in sequence during the experiment. The compound was added immediately after plating, and the culture was continued for 72 hours at 37°C and 5% CO2. After the incubation, CELL VIABILITY reagent (Promega, Cat#G7573) was added to each well, incubated at room temperature for 10 minutes, and gently shaken 5 times after the incubation, and then the chemiluminescence reading was detected with a BMG microplate reader (PHERAstar FSX). According to the formula [(1–(RLU compound –RLU blank ) / (RLU control –RLU blank )) × 100%] to calculate the cell proliferation inhibition rate. The IC was obtained by four-parameter nonlinear fitting using GraphPad Prism software. 50 value.

[0473] Table 2 Inhibitory activity of test compounds on KG-1 cell proliferation

[0474] Compound No. <![CDATA[IC 50 ]]> Compound 1 A Compound 2 A Compound 10 A

[0475] Note: A<50nM, 50nM≤B<500nM, 500nM≤C<1μM, 1μM≤D

[0476] Conclusion: The compounds of the present invention have good inhibitory activity on KG-1 cell proliferation.

[0477] Test Example 3: Study on GSPT1 protein degradation activity in NCI-H1155 cells

[0478] NCI-H1155 cells (ATCC, CRL-5818) were cultured with RPMI 1640 medium (with 10% FBS and 1% double antibody), and the cells were collected and plated when the cells reached the appropriate density. The cells were transferred to a sterile centrifuge tube and centrifuged at 1000rpm for 3 minutes. After centrifugation, the cells were removed, the supernatant was discarded, the cells were resuspended in the culture medium, and counted. According to the counting results, the cell suspension was adjusted to an appropriate concentration and added to a 6-well cell culture plate, and the cell information and plating date were marked. The compound was dissolved in DMSO to 10mM and stored for later use. The compound mother solution was diluted in sequence during the experiment. The compound was added immediately after plating and cultured for 24 hours at 37°C and 5% CO2. After the culture, the cells were collected and lysed on ice for 15 minutes with RIPA lysis buffer (beyotime, Cat. P0013B, cocktail: RIPA is 1:100), and then centrifuged at 12000 rpm and 4°C for 10 minutes. The supernatant protein samples were collected and quantified with a BCA kit (Beyotime, Cat. P0009). The protein was diluted to 1 mg / mL and the expression of GSPT1 (Abcam, AB234433) and the internal reference β-actin (CST, 3700S) was detected using an automatic protein blotting quantitative analyzer (Proteinsimple). The expression of GSPT1 relative to the internal reference was calculated using the fully automatic protein expression quantitative analysis software "Compass for SW" and GraphPad Prism 8.0 software was used according to the formula (Protein% = Protein 给药 / Protein 溶媒 ×100%) to calculate DC 50 Value. 给药 is the relative expression of GSPT1 in different dose groups, Protein 溶媒 is the relative expression level of GSPT1 in the vehicle control group.

[0479] Table 3. Degradation activity of GSPT1 protein in NCI-H1155 cells by test compounds

[0480] Compound No. <![CDATA[DC 50 ]]> Compound 2 A Compound 14 A

[0481] Note: A<30nM, 30nM≤B<100nM, 100nM≤C<500nM, 500nM≤D

[0482] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good degradation activity on GSPT1 protein in NCI-H1155 cells.

[0483] Test Example 4: Mouse Pharmacokinetic Test

[0484] Experimental animals: Male ICR mice, 25-30 g, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0485] Experimental design: On the day of the experiment, ICR mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours one day before administration and fed 4 hours after administration.

[0486] Table 4 Dosage information

[0487]

[0488] Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline

[0489] Oral administration solvent: 0.5% MC

[0490] (DMA: N,N-dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; MC: methylcellulose)

[0491] Before and after drug administration, 0.06 mL of blood was collected from the eye socket under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm at 4°C for 10 min to collect plasma. The blood collection time points were 5, 15, 30 min, 1, 2, 4, 7, and 24 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS / MS.

[0492] Table 5 Pharmacokinetic parameters of test compounds in mouse plasma

[0493] Test compound Dosage <![CDATA[AUC 0-t (hr×ng / mL)]]> F(％) Control compound 1 ig (3 mg / kg) 1523 34 Compound 1 ig (3 mg / kg) 25823 83

[0494] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption.

[0495] The structure of reference compound 1 is as follows, and its synthesis refers to patent WO2022 / 152821A1.

[0496]

[0497] Test Example 5: Pharmacokinetic Test in Rats

[0498] Experimental animals: Male SD rats, 200-250 g, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0499] Experimental design: On the day of the experiment, SD rats were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours one day before administration and fed 4 hours after administration.

[0500] Table 6 Dosage information

[0501]

[0502] Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline

[0503] Oral administration solvent: 0.5% MC

[0504] (DMA: N,N-dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; MC: methylcellulose)

[0505] Before and after drug administration, 0.06 mL of blood was collected from the eye socket under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm at 4°C for 10 min to collect plasma. The blood collection time points were 5, 15, 30 min, 1, 2, 4, 6, 8, and 24 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS / MS.

[0506] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic properties.

[0507] Test Example 6: CYP450 enzyme inhibition test

[0508] The purpose of this study was to evaluate the effects of the test substances on the activities of five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) of human liver microsomal cytochrome P450 (CYP) using an in vitro test system. Specific probe substrates of CYP450 isoenzymes were incubated with human liver microsomes and different concentrations of the test substances, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction, the samples were processed and the metabolites produced by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS), the changes in CYP enzyme activity were determined, and the IC 50 The inhibitory potential of the test substance on each CYP enzyme isoform was evaluated.

[0509] Conclusion: The compounds of the present invention, such as the compounds in the examples, have weak inhibition on CYP enzymes.

Claims

1. A compound or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from the compounds described in general formula (I), X is selected from O, S, NH, N-CN; L is selected from -C 1-4 Alkylene-, -NR L -C 1-4 Alkylene-, -OC 1-4 Alkylene-, -SC 1-4 Alkylene-, the alkylene group is optionally substituted by 1 to 6 R k replaced by; Selected from L2 is selected from a bond or C 1-4 Alkylene, the alkylene group is optionally substituted by 1 to 4 R k replaced by; Ring B is selected from one of the following optionally substituted structures: When substituted, 1 to 4 R b replaced, and its left side is directly connected to L; Ring C1 is selected from a 5- to 12-membered nitrogen-containing heteroaryl group and a 4- to 12-membered nitrogen-containing heterocyclic group, and ring C1 is connected to -C=X via a nitrogen atom, and the ring C1 is optionally substituted by 1 to 4 R c replaced by; Ring C2 is selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclic group, 4 to 12 membered heterocyclic group, wherein the ring C2 is optionally substituted by 1 to 4 R c replaced by; A1 is selected from CR a , CH; R c Each independently selected from deuterium, halogen, OH, =O, COOH, CN, NO2, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, -C(=O)R 1a 、-S(=O)2R 1a 、-P(=O)R 1a R 1b 、-OC 1-4 Alkylene-OC 1-4 Alkyl, -OC 1-4 Alkylene-OC 3-8 Carbocyclic group, -C 1-4 Alkylene-OC 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkylene-OC 3-8 Carbocyclic group, -OC 0-4 Alkylene-C 3-8 Carbocyclic group, -OC 0-4 Alkylene-4 to 8-membered heterocyclic group, -SC 0-4 Alkylene-C 3-8 Carbocyclic group, -SC 0-4 Alkylene-4 to 8 membered heterocyclic group, -NH-C 0-4 Alkylene-C 3-8 Carbocyclic group, -NH-C 0-4 Alkylene-4 to 8 membered heterocyclic group, -C 0-4 Alkylene-C 3-8 Carbocyclic group, -C 0-4 Alkylene-4 to 8 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replaced by; R k Each independently selected from deuterium, halogen, OH, CN, NO2, NH2, COOH, CONH2, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7-membered heterocyclic ring, -SC 3-6 Carbocyclic ring, -S-3 to 7 membered heterocyclic ring, -C 0-2 Alkylene-C 3-6 Carbon ring, -C 0-2 Alkylene-3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; R 1 Selected from H, deuterium, C 1-4 Alkyl, -C(=O)R 1a 、-S(=O)2R 1a 、-P(=O)R 1a R 1b , C 3-6 A carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replaced by; R a Each independently selected from deuterium, halogen, OH, NH2, CN, NO2, COOH, CONH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 3-8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 R k replaced by; R 2 Selected from H, deuterium, C 1-4 Alkyl, C 0-4 Alkylene-C 6-10 Aryl, C 0-4 Alkylene-5 to 10 membered heteroaryl, C 0-4 Alkylene-C 3-10 Carbocyclic group, C 0-4 Alkylene-4 to 10 membered heterocyclic group, wherein the alkyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replaced by; R L Each independently selected from C 1-4 Alkyl, C 3-8 carbocyclic group, 4 to 8 membered heterocyclic group, the alkyl group, carbocyclic group, heterocyclic group is optionally substituted by 1 to 4 R k replaced by; R b Each independently selected from deuterium, halogen, OH, cyano, NH2, NO2, N(C 1-4 Alkyl)2, NH(C 1-4 Alkyl), C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, -C(=O)R 1a 、-S(=O)2R 1a 、-P(=O)R 1a R 1b , C 3-6 Carbocyclic group, 4 to 8 membered heterocyclic group, C 6-10 The alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic, heterocyclic, aryl or heteroaryl group is optionally substituted by 1 to 4 R k replaced by; R 1a , R 1b Each independently selected from H, OH, NH2, C 1-4 Alkyl, C 1-4 Alkoxy, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 3-6 Carbocyclic group, 4 to 8 membered heterocyclic group, C 6-10 Aryl or 5 to 10 membered heteroaryl, wherein the alkyl, alkoxy, carbocyclic group, heterocyclic group, aryl or heteroaryl group is optionally substituted by 1 to 4 R k replaced by; Alternatively, two R a Together with the atoms it is connected to, it forms C 3-8 A carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R k replaced by; The condition is, Selected from When X is selected from O and L is selected from -N(CH3)-CH2-, Not selected from Or ring B is selected from When X is selected from O and L is selected from -N(CH3)-CH2-, Not selected from or Ring B is selected from optionally 1 to 4 R b Replaced X is selected from O, L is selected from -C 1-4 Alkylene-, -OC 1-4 When alkylene-, the alkylene is 1 to 6 R k replaced.

2. The compound according to claim 1 or its stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, Ring C1 is selected from a 4-7 membered nitrogen-containing heteromonocyclic ring, a 5-12 membered nitrogen-containing heterocyclic ring, a 5-12 membered nitrogen-containing heterospirocyclic ring, a 7-10 membered nitrogen-containing heterobridged ring, a benzo 3- to 8-membered nitrogen-containing heterocyclic group, a 5-10 membered nitrogen-containing heteroaryl group, and the ring C1 is connected to -C=X via a nitrogen atom, and the ring C1 is optionally substituted by 1 to 4 R c replaced by; Ring C2 is selected from 4-7 membered heteromonocyclic ring, 5-12 membered heterocyclic ring, 5-12 membered heterospirocyclic ring, 7-10 membered heterobridged ring, C 3-8 Monocarbocyclic group, C 6-12 Cycloalkyl, C 6-12 Spirocycloalkyl, C 5-12 Benzene-C-cycloalkyl 3-8 Carbocyclic group, benzo 4 to 8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, the ring C2 is optionally substituted by 1 to 4 R c replaced by; L2 is selected from a bond, a methylene group, an ethylene group, and the methylene group and the ethylene group are optionally substituted by 1 to 3 R k replaced by; R 2 Selected from H, deuterium, C 1-4 Alkyl, the alkyl group is optionally substituted by 1 to 4 R k replaced by; R k Each independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NO2, COOH, CONH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; R L Each is independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole or thiophene, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole or thiophene is optionally replaced by 1 to 4 R k replaced by; R 1 is selected from H, deuterium, methyl, ethyl, propyl, isopropyl, -C(=O)R 1a 、-S(=O)2R 1a 、-P(=O)R 1a R 1b , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl optionally substituted by 1 to 4 R k replaced by; R 1a , R 1b Each independently selected from H, OH, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole or thiophene, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole or thiophene is optionally replaced by 1 to 3 R k replaced by; R a Each independently selected from deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl is optionally replaced by 1 to 4 R k replaced by; R b each independently selected from deuterium, F, Cl, Br, I, OH, cyano, NH2, NO2, NHCH3, N(CH3)2, COOH, CONH2, -C(=O)-methyl, -C(=O)-ethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole or thiophene, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole or thiophene is optionally replaced by 1 to 4 R k replaced by; Alternatively, two R a and the atoms connected thereto together form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, oxolanyl, pyrrolidinyl, piperidinyl, 1,3-dioxolanyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, oxolanyl, pyrrolidinyl, piperidinyl, 1,3-dioxolanyl is optionally substituted by 1 to 4 R k replaced.

3. The compound according to claim 2 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, p is independently selected from 0, 1, 2, 3; R 1 Selected from H; L is selected from -CH2CH2-, -NR L -CH2-, -O-CH2-, -S-CH2-, -NR L -CH2CH2-, -O-CH2CH2-, -S-CH2CH2-, wherein the -CH2- is optionally replaced by 1 to 2 R k replaced by; R L Each is independently selected from CHF2, CH2F, CF3, CH2OH, methyl, ethyl, propyl, isopropyl, cyclopropyl or cyclobutyl; Ring B is selected from Ring B1, Ring B2 or Ring B3; Ring B1 is selected from one of the following optionally substituted structures: When substituted, 1 to 3 R b replaced, and its left side is connected to L; Ring B3 is selected from b One of the following structures is replaced: Its left side is connected to L; Ring B2 is selected from b One of the following structures is replaced: Its left side is connected to L; Selected from one of the following optionally substituted structures: When substituted, 1 to 3 R c replaced by; Ring C2 is selected from one of the following structures which are optionally substituted: cyclopropane, cyclobutane, cyclopentane, cyclohexane, azetidine, pyrrolidine, cyclohexene, azacyclohexine, piperidine, morpholine, piperazine, 1,4-diazepine, benzene, naphthalene, oxetane, tetrahydrofuran, tetrahydropyran, furan, pyrrole, pyrazole, imidazole, thiophene, thiazole, oxazole, isoxazole, triazole, pyridine, pyrimidine, pyrazine, pyridazine, 2-pyridone, benzopyrrole, benzopyrrolidine, benzothiophene, benzofuran, benzothiazole, benzopyrazole, benzimidazole, quinoline, isoquinoline, pyridopyridine, pyrazolotetrahydropyrrole, 3-pyridazinone, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, When substituted, 1 to 3 R c replace; R 2 is selected from H, deuterium, methyl, ethyl, propyl, isopropyl, wherein the methyl, ethyl, propyl, isopropyl is optionally substituted by 1 to 3 R k replaced.

4. The compound according to claim 3 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, Ring B is selected from Ring B1 or Ring B3; R c Each independently selected from deuterium, F, Cl, Br, I, =O, OH, NH2, NHCH3, N(CH3)2, CN, NO2, COOH, - C(=O)CH3、-C(=O)NH2、-C(=O)NHCH3、-C(=O)N(CH3)2、-S(=O)2NH2、-P(=O)(CH3)2、-S(=O)2CH3 or any The following groups are optionally substituted: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazolyl, phenyl, pyridyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuran, tetrahydropyran, piperazine, morpholinyl, cyclopentyl and cyclopentyl, pyrrolidinyl and cyclopentyl, azetidinyl spirocyclohexyl, cyclopropyl spirocyclobutyl, cyclobutyl spirocyclo Butyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-pyrrolidinyl, -CH2-morpholinyl, -CH2-pyrazolyl, -O-cyclopropyl, -O-cyclobutyl, -O-pyrrolidinyl, -O-phenyl, -S-cyclopropyl, -S-cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, -OCH2-cyclopropyl, -OCH2-pyrrolidinyl, -OCH2CH2-cyclopropyl, -OCH2CH2-morpholinyl, When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, COOH, CN, CHF2, CH2F, CF3, OCF3, OCHF2, OCH2F, NH2, NHCH3, N(CH3)2, CH2OH, OCH2OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl; L2 is selected from a bond, CH2, CH2CH2, wherein CH2, CH2CH2 are optionally replaced by 1 to 3 R k substituted, and its left end is connected to ring C2; L is selected from -CH2CH2-, -N(CH3)-CH2-, -N(CH2CH3)-CH2-, -O-CH2-, -O-CH(CH3)-, -O-C(CH3)2-, -S-CH2-, -S-CH(CH3)-, -S-C(CH3)2-, Its right side is directly connected to ring B; X is selected from O or S; Selected from 5. The compound according to claim 3 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: Ring B is selected from Ring B2; Selected from -C(=S)-CH2CH2-, -C(=S)-N(CH3)-CH2-, -C(=S)-N(CH2CH3)-CH2-, -C(=S)-O-CH2-, -C(=S)-O-CH(CH3)-, -C(=S)-O-C(CH3)2-, -C(=O)-O-CH(CH3)-, -C(=O)-O-C(CH3)2-, -C(=O)-S-C(CH3)2-, -C(=S)-S-CH2-, -C(=S)-S-CH(CH3)-, -C(=S)-S-C(CH3)2-, Its right side is connected to ring B2; R c Each independently selected from deuterium, F, Cl, Br, I, =O, OH, NH2, NHCH3, N(CH3)2, CN, NO2, COOH, - C(=O)CH3、-C(=O)NH2、-C(=O)NHCH3、-C(=O)N(CH3)2、-S(=O)2NH2、-P(=O)(CH3)2、-S(=O)2CH3 or any The following groups are optionally substituted: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazolyl, phenyl, pyridyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuran, tetrahydropyran, piperazine, morpholinyl, cyclopentyl and cyclopentyl, pyrrolidinyl and cyclopentyl, azetidinyl spirocyclohexyl, cyclopropyl spirocyclobutyl, cyclobutyl spirocyclo Butyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-pyrrolidinyl, -CH2-morpholinyl, -CH2-pyrazolyl, -O-cyclopropyl, -O-cyclobutyl, -O-pyrrolidinyl, -O-phenyl, -S-cyclopropyl, -S-cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, -OCH2-cyclopropyl, -OCH2-pyrrolidinyl, -OCH2CH2-cyclopropyl, -OCH2CH2-morpholinyl, When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, COOH, CN, CHF2, CH2F, CF3, OCF3, OCHF2, OCH2F, NH2, NHCH3, N(CH3)2, CH2OH, OCH2OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl; L2 is selected from a bond, CH2, CH2CH2, wherein CH2, CH2CH2 are optionally replaced by 1 to 3 R k substituted, and its left end is connected to ring C2; Selected from 6. The compound according to claim 1 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: The compound is selected from the compounds described by the following general formula (Ia-6), Selected from 1 to 3 R b One of the following structures is replaced: R b Each independently selected from deuterium, F, Cl, Br, I, OH, cyano, NH2, NO2, NHCH3, N(CH3)2, COOH, CONH2, -C(=O)-methyl, -C(=O)-ethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl are optionally substituted by 1 to 4 R k replaced by; X is selected from O or S; L4 is selected from -CH2-, -CH2-CH(CH3)-, -CH2CH2-, -CH2CH2CH2-, -S-CH2-, -O-CH2-, -S-CH2CH2-, -O-CH2CH2-, wherein -CH2- is optionally replaced by 1 to 2 R k replaced by; Ring C2 is selected from one of the following structures which are optionally substituted: benzene, naphthalene, pyridine, pyrimidine, pyrazine, pyridazine, 2-pyridone, When substituted, 1 to 3 R c replace; R c Each independently selected from deuterium, F, Cl, Br, I, =O, OH, NH2, NHCH3, N(CH3)2, CN, NO2, COOH, - C(=O)CH3、-C(=O)NH2、-C(=O)NHCH3、-C(=O)N(CH3)2、-S(=O)2NH2、-P(=O)(CH3)2、-S(=O)2CH3 or any one of the following groups which are optionally substituted: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuran, tetrahydropyran, piperazine, morpholinyl, when substituted, substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, COOH, CN, CHF2, CH2F, CF3, OCF3, OCHF2, OCH2F, NH2, NHCH3, N(CH3)2, CH2OH, OCH2OH, methyl; R k Each is independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NO2, COOH, CONH2, NHCH3, N(CH3)2, CHF2, CH2F, CF3, OCF3, OCHF2, OCH2F, CD3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and methylthio.

7. The compound according to claim 1 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures in Table A:

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition contains 1 to 1500 mg of the compound according to any one of claims 1 to 8 or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

9. Use of the compound according to any one of claims 1 to 9 or its stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal for preparing a medicament for treating a disease associated with GSPT1 or MYC.

10. The use according to claim 9, characterized in that: The disease is selected from tumors or cancers, preferably solid tumors such as non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), and MYC-driven cancers.

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