Amide-substituted indazole derivative and application thereof in medicine

Abstract

The invention relates to a compound shown in a general formula (I) or a stereoisomer, a racemate, a deuterated compound, a solvate, a prodrug, a metabolite, pharmaceutically acceptable salt or eutectic of the compound, an intermediate and a preparation method of the compound, and application of the compound in preparation of drugs for treating diseases related to PARP7 activity or expression quantity. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a compound of general formula (I) or its stereoisomers, racemates, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, and intermediates and preparation methods thereof, and their use in the preparation of drugs for treating diseases related to PARP7 activity or expression level. Background Art

[0002] PARP stands for poly-ADP-ribose polymerase, that is, polyADP-ribose polymerase, which is involved in a series of cellular processes including DNA repair, genomic stability, etc. This protein family consists of 17 members, divided into polyPARPs and monoPARPs.

[0003] The MonoPARP protein family plays a role in various stress responses related to the development of cancer, inflammatory diseases and neurodegenerative diseases. Its member PARP7 has been shown to be overactive in tumors and plays a key role in the survival of cancer cells.

[0004] Research has found that many cancer cells rely on PARP7 for intrinsic cell survival, and PARP7 enables cancer cells to "hide" outside the immune system. Inhibiting PARP7 can effectively inhibit the growth of cancer cells and restore interferon signaling, effectively releasing the "brakes" that cancer uses to avoid the immune system and inhibit innate and adaptive immune mechanisms. In several cancer models, PARP7 inhibitors have shown persistent tumor growth inhibitory effects, effective anti-proliferative activities, and interferon signaling restoration effects. PARP7 inhibitors are expected to become targets for the development of new anti-cancer drugs. Summary of the Invention

[0005] The object of the present invention is to provide a class of heterocyclic compounds or their pharmaceutically acceptable salts, and apply them to PARP7 inhibitors. The compounds in the present invention can effectively inhibit PARP7 and can be used to treat diseases such as tumors.

[0006] The present invention provides a compound of general formula (I) or its stereoisomers, racemates, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals,

[0007]

[0008] selected from a single bond or a double bond;

[0009] In some embodiments, selected from When representing a non-aromatic ring, Y2 is selected from a bond, -O-, -NH-, -OCH2-, -NHCH2-, -C(=O)CH2-, and Y3 is selected from -CH2-; When representing an aromatic ring, Y2 is selected from a bond or CH, and Y3 is selected from CH, C(CH3), or N;

[0010] In some embodiments, selected from

[0011] In some embodiments, the compound of general formula (I) is selected from general formula (Ia) or general formula (Ib),

[0012]

[0013] In some embodiments, ring A is selected from A1 is selected from phenyl or a 5- to 6-membered heteroaryl;

[0014] In some embodiments, ring A is selected from Q is selected from O, S, or NH;

[0015] In some embodiments, L is selected from -C(R L1 R L2 )- or -C(R L1 R L2 )2-;

[0016] In some embodiments, L is selected from CH2, CH(R L1 ), CH2CH2, CH2CH(R L1 );

[0017] In some embodiments, R L1 , R L2 are each independently selected from H, deuterium, halogen, cyano, OH, NH2, NHC 1-6 alkyl, N(C 1-6 alkyl)2, C 1-6 alkyl, C 1-6 alkoxy, -C 0-4 alkylene-C 3-6 cycloalkyl, -C 0-4 alkylene-4- to 6-membered heterocycloalkyl, and the alkyl, alkylene, alkoxy, cycloalkyl, and heterocycloalkyl are optionally substituted with 1 to 4 R k ;

[0018] In some embodiments, R L1 , R L2 are each independently selected from H, deuterium, halogen, cyano, OH, NH2, NHC 1-4 alkyl, N(C 1-4(alkyl)2, C 1-4 alkyl, C 1-4 alkoxy, -C 0-2 alkylene-C 3-6 cycloalkyl, -C 0-2 alkylene-4- to 6-membered heterocycloalkyl, wherein the alkyl, alkylene, alkoxy, cycloalkyl, heterocycloalkyl are optionally substituted by 1 to 4 R k substituents;

[0019] In some embodiments, R L1 is selected from CF3, CD3, methyl, ethyl, isopropyl, methoxy, -CH2-cyclopropyl, and R L2 is selected from H;

[0020] In some embodiments, Z is selected from N, C, or CH;

[0021] In some embodiments, R 1 , R 2 are each independently selected from H, deuterium, halogen, cyano, OH, NH2, NHC 1-6 alkyl, N(C 1-6 alkyl)2, C 1-6 alkyl, C 1-6 alkoxy, -C 0-4 alkylene-C 3-6 cycloalkyl, -C 0-4 alkylene-4- to 6-membered heterocycloalkyl, wherein the alkyl, alkylene, alkoxy, cycloalkyl, heterocycloalkyl are optionally substituted by 1 to 4 R k substituents;

[0022] In some embodiments, R 1 , R 2 are each independently selected from H, deuterium, halogen, cyano, OH, NH2, NHC 1-4 alkyl, N(C 1-4 alkyl)2, C 1-4 alkyl, C 1-4 alkoxy, -C 0-2 alkylene-C 3-6 cycloalkyl, -C 0-2 alkylene-4- to 6-membered heterocycloalkyl, wherein the alkyl, alkylene, alkoxy, cycloalkyl, heterocycloalkyl are optionally substituted by 1 to 4 R k substituents;

[0023] In some embodiments, R 1 , R 2Each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, -CH2-cyclopropyl, where the CH2, methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclopropyl are optionally substituted with 1 to 3 Rs k substituted;

[0024] In some embodiments, R b Each independently selected from deuterium, halogen, cyano, OH, =O, C 1-6 alkyl, C 1-6 alkoxy, -C 0-4 alkylene-C 3-6 cycloalkyl, where the alkyl, alkylene, alkoxy or cycloalkyl are optionally substituted with 1 to 4 Rs k substituted;

[0025] In some embodiments, R b Each independently selected from deuterium, halogen, cyano, OH, =O, C 1-4 alkyl, C 1-4 alkoxy, -C 0-2 alkylene-C 3-6 cycloalkyl, where the alkyl, alkylene, alkoxy or cycloalkyl are optionally substituted with 1 to 4 Rs k substituted;

[0026] In some embodiments, R b Each independently selected from deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, -CH2-cyclopropyl, where the CH2, methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclopropyl are optionally substituted with 1 to 3 Rs k substituted;

[0027] In some embodiments, when the general formula (Ib) represents a non-aromatic ring, Y2 is selected from a bond, -O-, -NH-, -OCH2-, -NHCH2-, -C(=O)CH2-, and Y3 is selected from -CH2-; when it represents an aromatic ring, Y2 is selected from a bond or CH, and Y3 is selected from CH, C(CH3) or N;

[0028] In some embodiments, ring X is selected from 5-6 membered heteroaryl, 5-6 membered heterocyclic, 8-10 membered fused heteroaryl, 8-10 membered fused heterocyclic, 11-16 membered heterocyclic or 11-16 membered heteroaromatic;

[0029] In some embodiments, ring X is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, furyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazinyl, benzothiazolyl, pyridino[2,3-d]thiazolyl, pyrimido[2,3-d]thiazolyl, pyridazino[2,3-d]thiazolyl, pyrazino[2,3-d]thiazolyl, benzoxazolyl, pyridino[2,3-d]oxazolyl, pyrimido[2,3-d]oxazolyl, pyridazino[2,3-d]oxazolyl, pyrazino[2,3-d]oxazolyl, pyridino[2,3-d]pyrrolyl, pyridino[2,3-d]pyrazolyl, pyrimido[2,3-d]thienyl, pyrimido[2,3-d]pyrazolyl, pyrimido[2,3-d]pyrrolyl, pyrimido[2,3-d]imidazolyl, pyrimido[2,3-d]triazolyl, pyrimido[2,3-d]furyl, pyrimido[2,3-d]pyrrolyl, quinolinyl, isoquinolinyl, pyrimido[2,3-d]pyridinyl, triazolyl, triazolo[4,5-d]pyridinyl, triazolo[4,5-d]thiazolyl, triazolo[4,5-d]oxazolyl, triazolo[4,5-d]imidazolyl, triazolo[4,5-d]pyrazolyl,

[0030] In some embodiments, ring X is selected from phenyl, pyridyl, pyridyl, pyridazinyl, pyrazinyl,

[0031] In some embodiments, selected from

[0032] In some embodiments, ring X1 is selected from phenyl or a 5- to 6-membered heteroaryl, preferably phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, furyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazinyl;

[0033] In some embodiments, ring X1 is selected from phenyl, pyridyl or pyrazinyl;

[0034] In some embodiments, selected from

[0035] In some embodiments, selected from

[0036] In some embodiments, R x are each independently selected from deuterium, halogen, cyano, OH, ═O, NHC 1-6 alkyl, N(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, -SO2-C 1-6 alkyl, -C(═O)C 1-6 alkyl, -C 0-4 alkylene-C3-10 a carbocyclic group or -C 0-4 an alkylene-3- to 12-membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 R k substituents;

[0037] In some embodiments, R x are each independently selected from deuterium, halogen, cyano, OH, =O, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, -SO2-C 1-4 alkyl, -C(=O)C 1-4 alkyl, -C 0-2 alkylene-C 3-6 a carbocyclic group or -C 0-2 an alkylene-3- to 6-membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 R k substituents;

[0038] In some embodiments, R x are each independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, -CH2-cyclopropyl, -O-cyclopropyl, wherein the CH2, methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl is optionally substituted with 1 to 3 R k substituents;

[0039] In some embodiments, R x are each independently selected from deuterium, F, Cl, OH, CN, CF3, CHF2, CH2F, CD3, methyl, ethyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, wherein the methyl, ethyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl is optionally substituted with 1 to 3 substituents selected from deuterium, F, Cl, Br, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl;

[0040] In some embodiments, R x are each independently selected from deuterium, F, Cl, OH, CN, CF3, CHF2, CH2F, CD3, methyl, ethyl, ethynyl, cyclopropyl,

[0041] In some embodiments, Y1 is selected from a bond, -CH2, -CH2CH2-, and said CH2 is optionally substituted with 1 to 2 substituents selected from deuterium, halogen, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;

[0042] In some embodiments, R k are each independently selected from deuterium, halogen, OH, =O, CN, NH2, C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl)2, -O-C 3-6 carbocycle, -O-4- to 7-membered heterocycle, -NH-C 3-6 carbocycle, -NH-4- to 7-membered heterocycle, -C 0-4 alkylene-C 3-6 carbocycle, -C 0-4 alkylene-4- to 7-membered heterocycle, and said alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy;

[0043] In some embodiments, R k are each independently selected from deuterium, halogen, OH, =O, CN, NH2, C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl)2, -O-C 3-6 carbocycle, -O-4- to 7-membered heterocycle, -NH-C 3-6 carbocycle, -NH-3- to 7-membered heterocycle, -C 0-2 alkylene-C 3-6 carbocycle, -C 0-2 alkylene-4- to 7-membered heterocycle, and said alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH2, C 1-4 alkyl, C 1-4 alkoxy;

[0044] In some embodiments, R kEach independently selected from deuterium, F, Cl, Br, I, OH, ═O, CN, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, 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 are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, ═O, CN, OH, NH2, methyl or methoxy;

[0045] In some embodiments, R k Each independently selected from deuterium, F, Cl, Br, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl;

[0046] In some embodiments, a is selected from 0, 1, 2, 3 or 4;

[0047] In some embodiments, b is selected from 1, 2, 3 or 4

[0048] In some embodiments, x is selected from 0, 1, 2, 3 or 4;

[0049] In some embodiments, b1 is selected from 0, 1, 2 or 3;

[0050] In some embodiments, x1 is selected from 0, 1, 2 or 3;

[0051] Optionally, the compound of general formula (I) satisfies at least one of the following conditions:

[0052] 1) R b is directly connected to R x to form a carbocyclic group or a 5- to 7-membered heterocyclic group, and the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 substituents selected from deuterium, halogen, cyano, OH, ═O, C 5-7 alkyl, C 1-4 alkoxy or C 1-4 cycloalkyl; 3-6 ;

[0053] 2) R b is directly connected to R L1 to form a carbocyclic group or a 5- to 7-membered heterocyclic group, and the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 substituents selected from deuterium, halogen, cyano, OH, ═O, C 5-7 alkyl, C 1-4 alkoxy or C 1-4 cycloalkyl; 3-6 ;

[0054] As the first embodiment of the present invention, the compound represented by the foregoing general formula (I) or its stereoisomer, racemate, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0055] is selected from a single bond or a double bond;

[0056] Ring A is selected from A1 is selected from phenyl or a 5- to 6-membered heteroaryl;

[0057] L is selected from -C(R L1 R L2 )- or -C(R L1 R L2 )2-;

[0058] R L1 、R L2 are each independently selected from H, deuterium, halogen, cyano, OH, NH2, NHalkyl, N(alkyl)2, alkyl, alkoxy, -alkylene-cycloalkyl, -alkylene-4- to 6-membered heterocycloalkyl, and the alkyl, alkylene, alkoxy, cycloalkyl, and heterocycloalkyl are optionally substituted by 1 to 4 R 1-6 alkyl, N(C 1-6 alkyl)2, C 1-6 alkyl, C 1-6 alkoxy, -C 0-4 alkylene-C 3-6 cycloalkyl, -C 0-4 alkylene-4- to 6-membered heterocycloalkyl, and the alkyl, alkylene, alkoxy, cycloalkyl, and heterocycloalkyl are optionally substituted by 1 to 4 R k substituents;

[0059] Z is selected from N, C or CH;

[0060] R 1 、R 2 are each independently selected from H, deuterium, halogen, cyano, OH, NH2, NHalkyl, N(alkyl)2, alkyl, alkoxy, -alkylene-cycloalkyl, -alkylene-4- to 6-membered heterocycloalkyl, and the alkyl, alkylene, alkoxy, cycloalkyl, and heterocycloalkyl are optionally substituted by 1 to 4 R 1-6 alkyl, N(C 1-6 alkyl)2, C 1-6 alkyl, C 1-6 alkoxy, -C 0-4 alkylene-C 3-6 cycloalkyl, -C 0-4 alkylene-4- to 6-membered heterocycloalkyl, and the alkyl, alkylene, alkoxy, cycloalkyl, and heterocycloalkyl are optionally substituted by 1 to 4 R k substituents;

[0061] R b is each independently selected from deuterium, halogen, cyano, OH, =O, C 1-6 alkyl, C 1-6 alkoxy, -C 0-4 alkylene-C 3-6A cycloalkyl group, wherein the alkyl, alkylene, alkoxy or cycloalkyl group is optionally substituted by 1 to 4 Rs k Substituted;

[0062] Ring X is selected from a 5-6 membered heteroaryl group, a 5-6 membered heterocyclic group, an 8-10 membered fused heteroaryl group, an 8-10 membered fused heterocyclic group, an 11-16 membered heterocyclic group or an 11-16 membered heteroaromatic group;

[0063] R x Each independently selected from deuterium, halogen, cyano, OH, ═O, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -SO2-C 1-6 Alkyl, -C(═O)C 1-6 Alkyl, -C 0-4 Alkylene-C 3-10 Carbocyclic group or -C 0-4 Alkylene-3 to 12 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 Rs k Substituted;

[0064] R k Each independently selected from deuterium, halogen, OH, ═O, CN, NH2, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -O-C 3-6 Carbocyclic ring, -O-4 to 7 membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-4 to 7 membered heterocyclic ring, -C 0-4 Alkylene-C 3-6 Carbocyclic ring, -C 0-4 Alkylene-4 to 7 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 substituents selected from deuterium, halogen, ═O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy;

[0065] a is selected from 0, 1, 2, 3 or 4;

[0066] b is selected from 1, 2, 3 or 4

[0067] x is selected from 0, 1, 2, 3 or 4;

[0068] Provided that the compound of general formula (I) satisfies at least one of the following conditions:

[0069] 1) R b is directly connected to R x to form a carbocyclic group or a 5- to 7-membered heterocyclic group, and the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 substituents selected from deuterium, halogen, cyano, OH, =O, C 5-7 alkyl, C 1-4 alkoxy or C 1-4 cycloalkyl; 3-6

[0070] 2) R b is directly connected to R L1 to form a carbocyclic group or a 5- to 7-membered heterocyclic group, and the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 substituents selected from deuterium, halogen, cyano, OH, =O, C 5-7 alkyl, C 1-4 alkoxy or C 1-4 cycloalkyl. 3-6

[0071] As a second embodiment of the present invention, the compound represented by the foregoing general formula (I) or its stereoisomer, racemate, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0072] R L1 and R L2 are each independently selected from H, deuterium, halogen, cyano, OH, NH2, NHC 1-4 alkyl, N(C 1-4 alkyl)2, C 1-4 alkyl, C 1-4 alkoxy, -C 0-2 alkylene-C 3-6 cycloalkyl, -C 0-2 alkylene-4- to 6-membered heterocycloalkyl, and the alkyl, alkylene, alkoxy, cycloalkyl, heterocycloalkyl are optionally substituted by 1 to 4 R k substituents;

[0073] R 1 and R 2 are each independently selected from H, deuterium, halogen, cyano, OH, NH2, NHC 1-4 alkyl, N(C 1-4 alkyl)2, C 1-4 alkyl, C 1-4 alkoxy, -C 0-2 alkylene-C 3-6 cycloalkyl, -C 0-2Alkylene-4- to 6-membered heterocycloalkyl, wherein the alkyl, alkylene, alkoxy, cycloalkyl, and heterocycloalkyl are optionally substituted by 1 to 4 Rs k substituted;

[0074] R b each independently selected from deuterium, halogen, cyano, OH, ═O, C 1-4 alkyl, C 1-4 alkoxy, -C 0-2 alkylene-C 3-6 cycloalkyl, wherein the alkyl, alkylene, alkoxy, or cycloalkyl is optionally substituted by 1 to 4 Rs k substituted;

[0075] R x each independently selected from deuterium, halogen, cyano, OH, ═O, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, -SO2-C 1-4 alkyl, -C(═O)C 1-4 alkyl, -C 0-2 alkylene-C 3-6 carbocyclic group or -C 0-2 alkylene-3- to 6-membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic group, or heterocyclic group is optionally substituted by 1 to 4 Rs k substituted;

[0076] R k each independently selected from deuterium, halogen, OH, ═O, CN, NH2, C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl)2, -O-C 3-6 carbocyclic ring, -O-4- to 7-membered heterocyclic ring, -NH-C 3-6 carbocyclic ring, -NH-3- to 7-membered heterocyclic ring, -C 0-2 alkylene-C 3-6 carbocyclic ring, -C 0-2 alkylene-4- to 7-membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring, or heterocyclic ring is optionally substituted by 1 to 4 substituents selected from deuterium, halogen, ═O, CN, OH, NH2, C 1-4 alkyl, C 1-4 alkoxy;

[0077] The definitions of the remaining substituents are the same as those described in Scheme 1 of the present invention.

[0078] As the third embodiment of the present invention, the compound represented by the foregoing general formula (I) or its stereoisomer, racemate, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0079] The compound of general formula (I) is selected from general formula (Ia) or general formula (Ib)

[0080]

[0081] A1 is selected from phenyl, pyridyl, thienyl, thiazolyl, furyl, pyrrolyl;

[0082] Y1 is selected from a bond, -CH2, -CH2CH2-, and the CH2 is optionally substituted by 1 to 2 substituents selected from deuterium, halogen, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;

[0083] When representing a non-aromatic ring, Y2 is selected from a bond, -O-, -NH-, -OCH2-, -NHCH2-, -C(=O)CH2-, and Y3 is selected from -CH2-;

[0084] When representing an aromatic ring, Y2 is selected from a bond or CH, and Y3 is selected from CH, C(CH3) or N;

[0085] L is selected from CH2, CH(R L1 ), CH2CH2, CH2CH(R L1 );

[0086] R L1 is selected from CF3, CD3, methyl, ethyl, isopropyl, methoxy, -CH2-cyclopropyl;

[0087] Ring X1 is selected from phenyl or a 5- to 6-membered heteroaryl, preferably phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, furyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazinyl;

[0088] Ring X is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, furyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazinyl, benzothiazolyl, pyridino[4,5-b]thiazolyl, pyrimido[4,5-b]thiazolyl, pyridazino[4,5-b]thiazolyl, pyrazino[2,3-b]thiazolyl, benzoxazolyl, pyridino[4,5-b]oxazolyl, pyrimido[4,5-b]oxazolyl, pyridazino[4,5-b]oxazolyl, pyrazino[2,3-b]oxazolyl, pyrido[4,5-b]pyrrolyl, pyrido[4,5-b]pyrazolyl, pyrimido[4,5-b]thienyl, pyrimido[4,5-b]pyrazolyl, pyrimido[4,5-b]pyrrolyl, pyrimido[4,5-b]imidazolyl, pyrimido[4,5-b]triazolyl, pyrimido[4,5-b]furyl, pyrimido[4,5-b]pyrrolyl, quinolinyl, isoquinolinyl, pyrimido[4,5-b]pyridinyl, triazolyl, triazolo[4,5-b]pyridinyl, triazolo[4,5-b]thiazolyl, triazolo[4,5-b]oxazolyl, triazolo[4,5-b]imidazolyl, triazolo[4,5-b]pyrazolyl,

[0089]

[0090] selected from

[0091] b1 is selected from 0, 1, 2 or 3;

[0092] x1 is selected from 0, 1, 2 or 3;

[0093] The definitions of the remaining substituents are the same as those described in Schemes 1 and 2 of the present invention.

[0094] As the fourth embodiment of the present invention, the compound represented by the foregoing general formula (I) or its stereoisomer, racemate, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0095] The compound of general formula (I) is selected from general formula (Ia) or general formula (Ib),

[0096] R 1 、R 2 each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, -CH2-cyclopropyl, and the CH2, methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclopropyl are optionally substituted by 1 to 3 R k substituents;

[0097] R b each independently selected from deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, -CH2-cyclopropyl, and the CH2, methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclopropyl are optionally substituted by 1 to 3 R k substituents;

[0098] Ring X is selected from phenyl, pyridyl, pyridyl, pyridazinyl, pyrazinyl,

[0099] Preferably, selected from

[0100] Ring X1 is selected from phenyl, pyridyl or pyrazinyl;

[0101] Preferably, selected from

[0102] R x each independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, -CH2-cyclopropyl, -O-cyclopropyl, and said CH2, methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl are optionally substituted by 1 to 3 R k substituted;

[0103] Preferably, R x each independently selected from deuterium, F, Cl, OH, CN, CF3, CHF2, CH2F, CD3, methyl, ethyl, ethynyl, cyclopropyl,

[0104] R k each independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, and said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH2, methyl or methoxy;

[0105] Preferably, R k each independently selected from deuterium, F, Cl, Br, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl;

[0106] The definitions of the remaining substituents are the same as those described in Schemes 1, 2 and 3 of the present invention.

[0107] The present invention relates to a compound or its stereoisomer, racemate, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures in Table A below:

[0108] Table A

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115] The present invention relates to a pharmaceutical composition comprising the compound or its stereoisomer, racemate, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal according to the present invention, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition contains 1 - 1500 mg of the compound or its stereoisomer, racemate, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal according to the present invention.

[0116] The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the compound or its stereoisomer, racemate, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal as described above in the present invention, and a pharmaceutically acceptable carrier.

[0117] The present invention relates to the use of the compound or its stereoisomer, racemate, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal according to the present invention in the treatment of diseases related to PARP7 activity or expression level, preferably in the preparation of drugs for tumors (such as lung cancer).

[0118] In some embodiments, the pharmaceutical composition of the present invention may be in the form of a unit dosage form (the amount of the active ingredient in the unit dosage form is also referred to as the "formulation specification").

[0119] As used herein, "effective amount" or "therapeutically effective amount" means an amount of a compound disclosed herein that, to some extent, alleviates one or more symptoms of a disease or disorder being treated (e.g., a disease related to PARP7 activity or expression level, such as a tumor). In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is an amount of a compound disclosed herein that provides a clinically significant reduction in the symptoms of the disease.Examples of a therapeutically effective amount include, but are not limited to, 1 - 1500 mg, 1 - 1200 mg, 1 - 1000 mg, 1 - 900 mg, 1 - 800 mg, 1 - 700 mg, 1 - 600 mg, 2 - 600 mg, 3 - 600 mg, 4 - 600 mg, 5 - 600 mg, 6 - 600 mg, 10 - 600 mg, 20 - 600 mg, 25 - 600 mg, 30 - 600 mg, 40 - 600 mg, 50 - 600 mg, 60 - 600 mg, 70 - 600 mg, 75 - 600 mg, 80 - 600 mg, 90 - 600 mg, 100 - 600 mg, 200 - 600 mg, 1 - 500 mg, 2 - 500 mg, 3 - 500 mg, 4 - 500 mg, 5 - 500 mg, 6 - 500 mg, 10 - 500 mg, 20 - 500 mg, 25 - 500 mg, 30 - 500 mg, 40 - 500 mg, 50 - 500 mg, 60 - 500 mg, 70 - 500 mg, 75 - 500 mg, 80 - 500 mg, 90 - 500 mg, 100 - 500 mg, 125 - 500 mg, 150 - 500 mg, 200 - 500 mg, 250 - 500 mg, 300 - 500 mg, 400 - 500 mg, 5 - 400 mg, 10 - 400 mg, 20 - 400 mg, 25 - 400 mg, 30 - 400 mg, 40 - 400 mg, 50 - 400 mg, 60 - 400 mg, 70 - 400 mg, 75 - 400 mg, 80 - 400 mg, 90 - 400 mg, 100 - 400 mg, 125 - 400 mg, 150 - 400 mg, 200 - 400 mg, 250 - 400 mg, 300 - 400 mg, 1 - 300 mg, 2 - 300 mg, 5 - 300 mg, 10 - 300 mg, 20 - 300 mg, 25 - 300 mg, 30 - 300 mg, 40 - 300 mg, 50 - 300 mg, 60 - 300 mg, 70 - 300 mg, 75 - 300 mg, 80 - 300 mg, 90 - 300 mg, 100 - 300 mg, 125 - 300 mg, 150 - 300 mg, 200 - 300 mg, 250 - 300 mg, 1 - 200 mg, 2 - 200 mg, 5 - 200 mg, 10 - 200 mg, 20 - 200 mg, 25 - 200 mg, 30 - 200 mg, 40 - 200 mg, 50 - 200 mg, 60 - 200 mg, 70 - 200 mg, 75 - 200 mg, 80 - 200 mg, 90 - 200 mg, 100 - 200 mg, 125 - 200 mg, 150 - 200 mg, 80 - 1000 mg, 80 - 800 mg.

[0120] In some embodiments, the pharmaceutical composition comprises, but is not limited to, 1 - 1000 mg, 20 - 800 mg, 40 - 800 mg, 40 - 400 mg, 25 - 200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg of the compound of the present invention or its stereoisomers, racemates, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals.

[0121] A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the compound of the present invention or its stereoisomers, racemates, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, the therapeutically effective amount preferably being 1 - 1500 mg, and the disease preferably being a disease related to PARP7 activity or expression level (such as a tumor (e.g., lung cancer)).

[0122] A method for treating a disease in a mammal, the method comprising administering to a subject a daily dose of 1 - 1000 mg / day of the compound of the present invention or its stereoisomers, racemates, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, the daily dose may be a single dose or divided doses. In some embodiments, the daily dose comprises, but is not limited to, 10 - 1500 mg / day, 10 - 1000 mg / day, 10 - 800 mg / day, 25 - 800 mg / day, 50 - 800 mg / day, 100 - 800 mg / day, 200 - 800 mg / day, 25 - 400 mg / day, 50 - 400 mg / day, 100 - 400 mg / day, 200 - 400 mg / day. In some embodiments, the daily dose comprises, but is not limited to, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 80 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 160 mg / day, 200 mg / day, 300 mg / day, 320 mg / day, 400 mg / day, 480 mg / day, 600 mg / day, 640 mg / day, 800 mg / day, 1000 mg / day.

[0123] The present invention relates to a kit, which may include a composition in single-dose or multi-dose form, and the kit contains the compound of the present invention or its stereoisomers, racemates, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and the amount of the compound of the present invention or its stereoisomers, racemates, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals is the same as that in the above-mentioned pharmaceutical composition.

[0124] The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomers, racemates, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals or the above-mentioned pharmaceutical composition in the preparation of a drug for treating diseases related to PARP7 activity or expression level.

[0125] The amount of the compound of the present invention or its stereoisomers, racemates, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals is converted in the form of the free base in each case.

[0126] Unless otherwise specified, the terms used in the specification and claims have the following meanings.

[0127] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention all include their isotope situations, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C, 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called superheavy hydrogen), and the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, the isotopes of nitrogen include 14 N and 15 N, the isotopes of fluorine include 17 F and 19 F, the isotopes of chlorine include 35 Cl and 37 Cl, the isotopes of bromine include 79 Br and 81 Br.

[0128] "CN" refers to a cyano group.

[0129] "Halogen" refers to F, Cl, Br or I.

[0130] "Halogen-substituted" means 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 "halogenated".

[0131] "Alkyl" means a substituted or unsubstituted straight-chain or branched-chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups having 1 to 20 carbon atoms, alkyl groups having 1 to 8 carbon atoms, alkyl groups having 1 to 6 carbon atoms, and alkyl groups having 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and their various branched-chain isomers; the alkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0132] "Heteroalkyl" means that one or more (including but not limited to 2, 3, 4, 5, or 6) carbon atoms in a substituted or unsubstituted alkyl group are replaced by heteroatoms (including but not limited to N, O, or S). Non-limiting examples include -X-(CH2)v-X-(CH2)v-X-(CH2)v-H (where v is an integer from 1 to 5, and each X is independently selected from a bond or a heteroatom, and the heteroatoms include but not limited to N, O, or S, and at least one X is selected from a heteroatom, and N or S in the heteroatoms can be oxidized to various oxidation states). The heteroalkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0133] "Alkylene" means a substituted or unsubstituted straight-chain and branched-chain divalent saturated hydrocarbon group, including -(CH2) v -(where v is an integer from 1 to 10), and examples of alkylene groups include but are not limited to methylene, ethylene, propylene, and butylene.

[0134] "Heteroalkylene" means that one or more (including but not limited to 2, 3, 4, 5, or 6) carbon atoms in a substituted or unsubstituted alkylene group are replaced by heteroatoms (including but not limited to N, O, or S). Non-limiting examples include -X-(CH2)v-X-(CH2)v-X-(CH2)v-, where v is an integer from 1 to 5, and each X is independently selected from a bond, N, O, or S, and at least one X is selected from N, O, or S.

[0135] "Cycloalkyl" means a substituted or unsubstituted saturated carbocyclic hydrocarbon group, usually having 3 to 12 carbon atoms, and the cycloalkyl group can be monocyclic, fused-ring, bridged-ring, or spiro-ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-fused cyclobutyl, cyclobutyl-spiro cyclobutyl, adamantane, etc. The cycloalkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0136] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated heterocyclic hydrocarbon group containing heteroatoms, including but not limited to those having 3 to 12 atoms, 3 to 8 atoms, containing 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 monocyclic, fused-ring, bridged-ring and spiro-ring. Heterocycloalkyl can be attached to a heteroatom or a carbon atom, and non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl,

[0137] Heterocycloalkyl can be monovalent, divalent, trivalent or tetravalent.

[0138] "Alkenyl" refers to a substituted or unsubstituted straight-chain and branched-chain unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon double bonds, and the main chain includes but not limited to 2 to 10, 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl include but not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-hexadiene, etc.; alkenyl can be monovalent, divalent, trivalent or tetravalent.

[0139] "Alkynyl" refers to a substituted or unsubstituted straight-chain or branched-chain unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, with a main chain comprising 2 to 10 carbon atoms, including but not limited to having 2 to 6 carbon atoms in the main chain, having 2 to 4 carbon atoms in the main chain. Examples of alkynyl include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, etc.; alkynyl can be monovalent, divalent, trivalent or tetravalent.

[0140] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropoxy and cyclobutoxy.

[0141] "Carbocyclic group" or "carbocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3- to 8-membered monocyclic, 4- to 12-membered bicyclic, 10- to 15-membered tricyclic, 12- to 18-membered tetracyclic system. The carbocyclic group can be attached to an aromatic or non-aromatic ring, and the ring is optionally monocyclic, fused-ring, bridged-ring or spiro-ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclic group" or "carbocycle" can be monovalent, divalent, trivalent or tetravalent.

[0142] "Heterocyclic group" or "heterocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, a 10- to 15-membered tricyclic ring, or a 12- to 18-membered tetracyclic system, and contains one or more (including but not limited to 2, 3, 4, or 5) heteroatoms selected from N, O, S, or Se. The optionally substituted C, N, S, or Se in the ring of the heterocyclic group can be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom, and can be attached to an aromatic or non-aromatic ring. The heterocyclic group is optionally a monocyclic, bridged, fused, or spiro ring. Non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiolyl, dihydrofuryl, dihydropyranyl, dithiolanyl, tetrahydrofuryl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuryl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl, benzofuryl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecanyl, azadamantyl, oxaspiro[3.3]heptanyl, "Heterocyclic group" or "heterocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0143] "Spiro ring" or "spiro group" refers to a polycyclic group in which a substituted or unsubstituted monocyclic ring shares one atom (called the spiro atom). The number of ring atoms in the spiro ring system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, and one or more of the rings can contain 0 or more (including but not limited to 1, 2, 3, or 4) double bonds, and optionally can contain 0 to 5 heteroatoms selected from N, O, or S(=O) n (n is 0, 1, or 2). "Spiro ring" or "spiro group" can be monovalent, divalent, trivalent, or tetravalent.

[0144] "Fused ring" or "fused ring group" refers to a polycyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, where one or more rings may contain zero or more (including but not limited to 1, 2, 3, or 4) double bonds, and may be substituted or unsubstituted. Each ring in the fused ring system may contain from 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to selected from N, S(=O) n or O, where n is 0, 1, or 2). The number of ring atoms in the fused ring system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include: "Fused ring" or "fused ring group" can be monovalent, divalent, trivalent, or tetravalent.

[0145] "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two non-directly connected atoms, which may contain zero or more double bonds. Any ring in the bridged ring system may contain from 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to N, S(=O)n or O, where n is 0, 1, 2). The number of ring atoms includes but is not limited to 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include cubane, adamantane. "Bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent, or tetravalent.

[0146] "Carbospirocycle", "spirocarbocyclic group", "spirocarbon group" or "carbospiro group" refers to a "spirocycle" whose ring system is composed only of carbon atoms.

[0147] "Carbofused ring", "fused carbocyclic group", "carbo-fused ring group" or "carbofused group" refers to a "fused ring" whose ring system is composed only of carbon atoms.

[0148] "Carbobridged ring", "bridged carbocyclic group", "bridged carbon group" or "carbobridged group" refers to a "bridged ring" whose ring system is composed only of carbon atoms.

[0149] "Heteromonocycle", "monocyclic heterocyclic group" or "heteromonocyclic group" refers to a "heterocyclic group" or "heterocycle" of a monocyclic system.

[0150] "Heterofused ring", "heterofused ring group", "fused heterocyclic group" or "hetero-fused ring group" refers to a "fused ring" containing heteroatoms.

[0151] "Heterospirocycle", "heterospirocyclic group", "spiroheterocyclic group" or "spirohetero group" refers to a "spirocycle" containing heteroatoms.

[0152] "Heterobridged ring", "heterobridged ring group", "bridged heterocyclic group" or "bridged hetero group" refers to a "bridged ring" containing heteroatoms.

[0153] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a monocyclic or fused ring, and the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbocyclic ring, and the ring connected to the parent structure is the aryl ring. Non-limiting examples include benzene ring, naphthalene ring, "Aryl" or "aromatic ring" can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the connection site is on the aryl ring.

[0154] "Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or groups containing heteroatoms (including, but not limited to, N, O, S(=O)n or Se(=O)n, where n is 0, 1, 2), and the number of ring atoms in the heteroaromatic ring includes, but is not limited to, 5 to 15, 5 to 10, or 5 to 6. The atoms C, N, S on the ring are optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, where n is 1, 2). Non-limiting examples of heteroaryl include, but are not limited to, pyridyl, furyl, thienyl, selenophenyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, pyridone, etc. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, and the ring connected to the parent structure is the aryl ring. Non-limiting examples include The heteroaryl appearing in this text has the same definition as this definition. Heteroaryl can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the connection site is on the aromatic ring.

[0155] "Substituted" or "substitution" means being substituted by one or more (including, but not limited to, 2, 3, 4 or 5) substituents, and the substituents include, but are not limited to, H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, mercaptan, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic group, bridged ring group, spiro ring group, fused ring group, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH2) m -C(=O)-R a 、-O-(CH2) m -C(=O)-R a 、-(CH2) m -C(=O)-NR b R c 、-(CH2) m S(=O) n R a 、-(CH2) m -alkenyl-Ra 、 OR d or -(CH2) m -alkynyl-R a (where m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c and other groups, where R b and R c are independently selected from the group consisting of H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl. Optionally, R b and R c can form a five- or six-membered cycloalkyl or heterocyclic group, R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic group, carbonyl, ester group, bridged ring group, spiro ring group or fused ring group.

[0156] "substituted with 1 to X substituents selected from..." means substituted with 1, 2, 3... X substituents selected from..., and X is any integer between 1 and 10. For example, "substituted with 1 to 4 R k " means substituted with 1, 2, 3 or 4 R k substituents. For example, "substituted with 1 to 5 substituents selected from..." means substituted with 1, 2, 3, 4 or 5 substituents selected from.... For example, "the heterobridged ring is optionally substituted with 1 to 4 substituents selected from H or F" means the heterobridged ring is optionally substituted with 1, 2, 3 or 4 substituents selected from H or F.

[0157] The X-Y membered ring (X, Y are integers, and 3 ≤ X < Y, X < Y ≤ 20, X and Y are any integers between 4 and 20) includes X, X + 1, X + 2, X + 3, X + 4... Y membered rings. The ring includes heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, hetero-fused rings, heterospiro rings or heterobridged rings. For example, "4-7 membered heteromonocyclic ring" means a 4-membered, 5-membered, 6-membered or 7-membered heteromonocyclic ring, and "5-10 membered hetero-fused ring" means a 5-membered, 6-membered, 7-membered, 8-membered, 9-membered or 10-membered hetero-fused ring.

[0158] C x-y The carbocyclic ring (including aryl, cycloalkyl, monocyclic carbocyclic ring, spirocarbocyclic ring, fused carbocyclic ring or bridged carbocyclic ring) includes C x 、 C x+1 、 C x+2 、 C x+3 、 C x+4 … C y membered rings (x is an integer, and 3 ≤ x < y, y is any integer between 4 and 20). For example. Such as C 3-6 cycloalkyl" means C3, C4, C5 or C6 cycloalkyl;

[0159] When a certain 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 connection mode of the chemical bond is non-specific and there are hydrogen atoms at the connectable sites, then when connecting the chemical bonds, the number of H atoms at this site will correspondingly decrease with the number of connected chemical bonds to become a group with the corresponding valence. For example indicates that any connectable site on the piperidyl group can be connected to other groups through 1 chemical bond, including at least these 4 connection modes. Even if an H atom is drawn on the -N-, it also includes For example indicates that the R group on the piperidyl group can be located on C or on N, including at least

[0160] When the listed connecting groups do not specify their connection directions, their connection directions include the directions of reading orders from left to right and from right to left for connection. For example, for A-L-B, when L is selected from -M-W-, it includes A-M-W-B and A-W-M-B.

[0161] "Optional" or "optionally" means that the subsequent described event or circumstance can but does not have to occur, and this description includes the occasions where the event or circumstance occurs or does not occur. For example: "alkyl optionally substituted by F" means that the alkyl can but does not have to be substituted by F, and the description includes the situation where the alkyl is substituted by F and the situation where the alkyl is not substituted by F.

[0162] "Pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" means a salt obtained by reacting the free acid or free base of the compound of the present invention while maintaining the biological effectiveness and characteristics of the free acid or free base, and the free acid reacts with a non-toxic inorganic base or organic base, and the free base reacts with a non-toxic inorganic acid or organic acid.

[0163] "Pharmaceutical composition" means a mixture formed by one or more compounds of the present invention, or their stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals and other chemical components, wherein "other chemical components" refer to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0164] "Dosage form specification" means the weight of the active ingredient contained in each vial, tablet or other each unit dosage form.

[0165] "Carrier" means a material that does not cause obvious irritation to the organism and does not eliminate the biological activity and characteristics of the administered compound.

[0166] "Prodrug" refers to a compound of the present invention that can be metabolically converted in vivo into a bioactive compound. The prodrugs of the present invention are prepared by modifying the amino group or carboxyl group in the compound of the present invention, and this modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian individual, the prodrug is cleaved to form a free amino group or carboxyl group.

[0167] "Co-crystal" refers to a crystal formed by the binding of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, where both the pure states of the API and the CCF are solids at room temperature and there is a fixed stoichiometric ratio between the components. A co-crystal is a multi-component crystal, including binary co-crystals formed between two neutral solids, as well as multi-component co-crystals formed between a neutral solid and a salt or solvate.

[0168] "Animal" refers to including mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0169] "Stereoisomer" refers to an isomer produced by the different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereoisomers, and conformational isomers.

[0170] "Tautomer" refers to a functional group isomer produced by the rapid movement of a certain atom in a molecule between two positions, such as keto-enol tautomerism and amide-imidol tautomerism, etc.

[0171] "IC 50 " is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a certain component in the process, such as an enzyme, receptor, cell, etc.) by half. Detailed implementation mode

[0172] Scheme 1: Synthesis method when the compound of general formula (II) is selected from the compound of general formula (M-11)

[0173]

[0174] PG, PG1, or PG2 are each independently selected from amino protecting groups, preferably Boc (tert-butoxycarbonyl), Cbz (benzyloxycarbonyl), PMB (p-methoxybenzyl);

[0175] X is selected from leaving groups, preferably halogen, OMs, OTs, or OTf,

[0176] The definitions of the remaining groups are the same as those of the aforementioned general formula compound (I);

[0177] The compound of general formula (M-1) reacts with an amino protecting reagent to obtain the compound of general formula (M-2);

[0178] The compound of general formula (M-2) reacts with X2 through a nucleophilic substitution reaction to obtain the compound of general formula (M-3);

[0179] The compound of general formula (M-3) reacts with under a basic reagent (such as NaH) through a nucleophilic substitution reaction to obtain the compound of general formula (M-4);

[0180] The compound of general formula (M-4) undergoes a deamination protecting group reaction to obtain the compound of general formula (M-5);

[0181] The compound of general formula (M-5) reacts under basic conditions (such as triethylamine, DIPEA) to obtain the compound of general formula (M-6);

[0182] The compound of general formula (M-6) undergoes a deamination protecting group reaction to obtain the compound of general formula (M-7);

[0183] The compound of general formula (M-7) reacts with the compound of general formula (A-1) under basic conditions (such as potassium carbonate, cesium carbonate) through a nucleophilic substitution reaction to obtain the compound of general formula (M-8);

[0184] Alternatively, the compound of general formula (M-7) reacts with the compound of general formula (A-1) in the presence of a metal catalyst through a coupling reaction to obtain the compound of general formula (M-8);

[0185] The compound of general formula (M-8) undergoes a decarboxylation reaction under high temperature conditions to obtain the compound of general formula (M-9);

[0186] The compound of general formula (M-9) undergoes a halogenation reaction to obtain the compound of general formula (M-10);

[0187] The compound of general formula (M-10) reacts with the compound of general formula (A-2) under basic conditions (such as triethylamine, DIPEA, potassium carbonate, cesium carbonate) through a nucleophilic substitution reaction to obtain the compound of general formula (M-11);

[0188] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to this.

[0189] The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The NMR measurement is performed using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic resonance spectrometers, and the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS);

[0190] For the determination of MS (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0191] For the determination of HPLC, an Agilent 1260 DAD high - pressure liquid chromatograph (Zorbax SB - C18 100×4.6mm, 3.5μM) was used;

[0192] For thin - layer chromatography, silica gel plates from Yantai Huanghai HSGF254 or Qingdao GF254 were used. The specifications of the silica gel plates used for thin - layer chromatography (TLC) were 0.15mm - 0.20mm, and the specifications of the silica gel plates used for separating and purifying products by thin - layer chromatography were 0.4mm - 0.5mm;

[0193] For column chromatography, silica gel with 200 - 300 mesh from Yantai Huanghai was generally used as the carrier.

[0194] The known starting materials of the present invention can be synthesized by adopting or according to methods known in the art, or can be purchased from companies such as Titan Technology, Anychem Chemical, Shanghai Dermo, Chengdu Kelong Chemical Industry, Shaoyuan Chemical Technology, J&K Scientific, etc.

[0195] The wavy line in the structural formula represents a stereoconfiguration of R, S or a mixture thereof;

[0196] Example 1: Preparation of Compound 1

[0197]

[0198] The first step: Preparation of 1b

[0199] Under a nitrogen atmosphere, a solution of potassium carbonate (18.49 g, 133.78 mmol) and 1a (12.00 g, 32.23 mmol) in dimethyl sulfoxide (40 mL) was reacted at 150 °C for 4 h. After cooling to room temperature, 40 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether (containing 16% ethyl acetate): dichloromethane (containing 9% methanol) (v / v) = 5:1) to obtain 1b (4.5 g, 46%).

[0200] LCMS m / z = 301.1[M + 1] +

[0201] The second step: Preparation of 1c

[0202] At -78 °C, lithium diisopropylamide (2.44 mL, 4.88 mmol, 2 mmol / mL) was slowly added to a dry tetrahydrofuran (40 mL) solution of 1b (1.00 g, 3.33 mmol). The reaction was carried out at -78 °C for 1 h. A solution of iodine (1.01 g, 3.98 mmol) in tetrahydrofuran (10 mL) was added dropwise. The reaction was carried out at -78 °C for 1 h and at room temperature for 1 h. The reaction was quenched with 1N dilute hydrochloric acid. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether:tetrahydrofuran (v / v) = 5:1) to obtain 1c (70 mg, 5%).

[0203] LCMS m / z = 427.0 [M+1] +

[0204] Step 3: Preparation of Compound 1

[0205] 1c (80 mg, 0.19 mmol) was added to a solution of 1d (31 mg, 0.19 mmol) and cesium carbonate (124 mg, 0.38 mmol) in N,N-dimethylformamide (2 mL). The reaction was carried out at room temperature for 2 h. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative plate to obtain Compound 1.

[0206] LCMS m / z = 460.1 [M+1] +

[0207] Resolution of Compound 1

[0208]

[0209] Compound 1 (200 mg) was purified by Pre-HPLC (instrument and preparative column: waters 2767 preparative liquid phase, preparative column model is Xbridge Prep C18 (19 mm × 250 mm) 5um, inner diameter * length = 19 mm * 150 mm). Preparation method: The crude product was dissolved in DMF and filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile / water (containing 0.05% ammonium bicarbonate). Gradient elution method: Acetonitrile was eluted from 20% to 55% in a gradient (flow rate: 15 mL / min; elution time: 24 min). After lyophilization, Compound 1-A (36 mg, retention time T = 19.54 min, Compound 1-A is one of the structures of Compound 1-1 and Compound 1-2) and Compound 1-B (65 mg, retention time T = 20.36 min, Compound 1-B is one of the structures of Compound 1-1 and Compound 1-2) were obtained.

[0210] Compound 1-A

[0211] LCMS m / z = 460.2 [M+1] +

[0212] 1 H NMR (400 MHz, CD3OD) δ 8.63 (s, 2H), 8.52 (s, 1H), 8.11 (dd, 1H), 7.98 (dd, 1H), 7.28 - 7.18 (m, 1H), 5.46 (t, 1H), 4.98 - 4.86 (m, 2H), 4.73 - 4.62 (m, 1H), 3.83 - 3.69 (m, 1H), 3.26 - 3.06 (m, 2H), 3.02 - 2.88 (m, 1H), 2.72 - 2.55 (m, 1H), 2.51 - 2.35 (m, 1H), 2.31 - 2.15 (m, 1H), 2.13 - 1.98 (m, 1H).

[0213] Compound 1-B

[0214] LCMS m / z = 460.2 [M+1] +

[0215] 1 H NMR (400 MHz, CD3OD) δ 8.62 (s, 2H), 8.46 (s, 1H), 8.10 (dd, 1H), 7.97 (dd, 1H), 7.27 - 7.16 (m, 1H), 5.55 - 5.43 (m, 1H), 5.00 - 4.84 (m, 2H), 4.62 - 4.48 (m, 1H), 3.84 - 3.66 (m, 1H), 3.21 - 3.06 (m, 1H), 3.01 - 2.86 (m, 2H), 2.85 - 2.70 (m, 1H), 2.54 - 2.41 (m, 1H), 2.40 - 2.26 (m, 1H), 2.00 - 1.84 (m, 1H).

[0216] Biological test examples

[0217] 1. NCI-H1373 cell proliferation inhibition

[0218] The NCI-H1373 cells were purchased from ATCC. The culture conditions were as follows: RPMI-1640 + 10% FBS + 1% double antibody. The cells were cultured in an incubator at 37°C with 5% CO2. On the first day, NCI-H1373 cells in the exponential growth phase were collected and seeded into a clear-bottom white 96-well culture plate at a seeding density of 500 cells / well. They were cultured overnight in an incubator at 37°C with 5% CO2. At the same time of seeding, the T0 wells were also seeded. On the second day, before adding the drugs, the medium was aspirated, and 90 μL of fresh medium and 10 μL of compounds at different concentrations were added to each well, so that the final concentration of DMSO in each well was 0.1%. After culturing for 72 hours in an incubator at 37°C with 5% CO2, the medium was replaced and new compounds were freshly prepared, and then cultured for another 72 hours. At the same time of adding the drugs on the second day, the CellTiter-Glo kit was used to detect the T0 plate, and it was recorded as RLU0. After the culture was completed, 50 μL of the detection solution (Cell Viability Assay, Promega, G7573) was added to each well, mixed for 2 minutes, incubated at room temperature for 10 minutes, and the chemiluminescence readings were detected by a microplate reader. The results were processed according to formula (1) to calculate the cell survival rate at each concentration of the compound, and the origin9.2 software was used to calculate the concentration GI of the compound when the proliferation rate was 50%. 50 value. RLU compound is the reading of the drug treatment group, and RLU control is the average value of the solvent control group.

[0219] Growth% = (RLU compound - RLU0) / (RLU control - RLU0) × 100% Formula (1)

[0220] Conclusion: The compounds of the present invention, such as the compounds of the examples, have good cell proliferation inhibitory activity against NCI-H1373 cells.

[0221] 2. PARP7 enzyme activity test experiment

[0222] The PARP7 chemiluminescence detection kit was purchased from BPS Bioscience. The histone solution in the kit was diluted 5-fold with 1X PBS. 25 μL of the histone dilution was taken into a microplate and incubated overnight at 4°C. After the incubation was completed, the plate was washed 3 times with PBST (0.05% Tween-20). 100 μL of the blocking solution was taken into the microplate and incubated at 25°C for 90 minutes; after the incubation was completed, the plate was washed 3 times with PBST. 2.5 μL of the compounds at different concentrations diluted with the test buffer and 12.5 μL of the substrate mixed solution (1.25 μL of 10X PARP test buffer; 1.25 μL of 10X PARP test mixture; 10 μL of double-distilled water) were taken into the microplate. The PARP7 enzyme was diluted to 6 ng / μL, and 10 μL was taken into the microplate. The reaction system was incubated at 25°C for 60 minutes;

[0223] After the incubation was completed, the microplate was washed three times with PBST. Streptavidin-HRP was diluted 50-fold with the blocking solution, and then 25 μL was taken and added to the microplate, followed by incubation at 25 °C for 30 minutes. After the incubation was completed, the microplate was washed three times with PBST. ELISA ECL substrates A and B were mixed at 1:1 (v / v), 50 μL was taken and added to the microplate, and the chemiluminescence value was read.

[0224] The inhibition rate was calculated according to Equation 2, where RLU sample was the reading value of the compound well, RLU max was the reading value of the solvent control well, and RLU min was the reading value of the control well without PARP7 enzyme. Curve fitting was performed using GraphPad Prism software by four-parameter (log(inhibitor) vs. response--Variable slope) and the IC 50 value was calculated.

[0225] Inhibition%=(1-(RLU sample -RLU min )) / (RLU max -RLU min ))×100% (Equation 2)

[0226] Conclusion: The compounds of the present invention, such as the compounds of the examples, have good inhibitory effects on PARP7 enzyme. Specifically, the inhibitory activity IC 50 of compound 1-A on PARP7 enzyme is less than 2 nM.

[0227] 3. Mouse Pharmacokinetics Test

[0228] 3.1 Test animals: Male Balb / c mice, about 22 g, 6-8 weeks old, 6 mice / compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0229] 3.2 Test design: On the day of the test, Balb / c mice were randomly grouped according to body weight. One day before dosing, the mice were fasted for 12-14 h without water deprivation, and food was given 4 h after dosing.

[0230] Table 1. Dosing Information

[0231]

[0232] Intravenous administration vehicle: 5% DMA + 5% Solutol + 90% Saline; Gavage administration vehicle: 0.5% MC

[0233] Before drug administration and after drug administration, 0.03 ml of blood was taken from the orbit under isoflurane anesthesia and placed in an EDTAK2 centrifuge tube. It was centrifuged at 5000 rpm at 4 °C for 10 min to collect plasma. Blood sampling time points for the intravenous group and the gavage group: 0, 2, 5, 15, 30 min, 1, 2, 4, 7 h; before analysis and detection, all samples were stored at -80 °C.

[0234] Table 2. Pharmacokinetic parameters of the test compound in mouse plasma Conclusion: The compounds of the present invention, such as compound 1-A, have good pharmacokinetic properties, high exposure in mice, and good bioavailability.

Claims

1. A compound or a stereoisomer, racemate, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from the compounds described in general formula (I), is selected from a single bond or a double bond; Ring A is selected from A1 is selected from phenyl or 5- to 6-membered heteroaryl; L is selected from -C(R L1 R L2 )-or-C(R L1 R L2 )2-; R L1 , R L2 Each independently selected from H, deuterium, halogen, cyano, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, -C 0-4 Alkylene-C 3-6 Cycloalkyl, -C 0-4 Alkylene-4 to 6 membered heterocycloalkyl, wherein the alkyl, alkylene, alkoxy, cycloalkyl, heterocycloalkyl is optionally substituted by 1 to 4 R k replace; Z is selected from N, C or CH; R 1 , R 2 Each independently selected from H, deuterium, halogen, cyano, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, -C 0-4 Alkylene-C 3-6 Cycloalkyl, -C 0-4 Alkylene-4 to 6 membered heterocycloalkyl, wherein the alkyl, alkylene, alkoxy, cycloalkyl, heterocycloalkyl is optionally substituted by 1 to 4 R k replace; R b Each independently selected from deuterium, halogen, cyano, OH, =O, C 1-6 Alkyl, C 1-6 Alkoxy, -C 0-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkoxy or cycloalkyl is optionally substituted by 1 to 4 R k replace; Ring X is selected from 5-6 membered heteroaryl, 5-6 membered heterocyclyl, 8-10 membered cycloheteroaryl, 8-10 membered cycloheterocyclyl, 11-16 membered heterocyclyl or 11-16 membered heterocyclic aryl; R x Each independently selected from deuterium, halogen, cyano, OH, =O, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -SO2-C 1-6 Alkyl, -C(=O)C 1-6 Alkyl, -C 0-4 Alkylene-C 3-10 Carbocyclic or -C 0-4 Alkylene-3 to 12-membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace; R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 Carbocyclic ring, -O-4 to 7 membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-4 to 7 membered heterocyclic ring, -C 0-4 Alkylene-C 3-6 Carbon ring, -C 0-4 Alkylene-4 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; a is selected from 0, 1, 2, 3 or 4; b is selected from 1, 2, 3 or 4 x is selected from 0, 1, 2, 3 or 4; The condition is that the compound of general formula (I) satisfies at least one of the following conditions: 1) R b With R x Direct connection to form C 5-7 A carbocyclic group or a 5- to 7-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 groups selected from deuterium, halogen, cyano, OH, =O, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted by a cycloalkyl substituent; 2) R b With R L1 Direct connection to form C 5-7 A carbocyclic group or a 5- to 7-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 groups selected from deuterium, halogen, cyano, OH, =O, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 The cycloalkyl group is substituted with a substituent.

2. The compound according to claim 1 or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: R L1 , R L2 Each independently selected from H, deuterium, halogen, cyano, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl, -C 0-2 Alkylene-4 to 6 membered heterocycloalkyl, wherein the alkyl, alkylene, alkoxy, cycloalkyl, heterocycloalkyl is optionally substituted by 1 to 4 R k replace; R 1 , R 2 Each independently selected from H, deuterium, halogen, cyano, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl, -C 0-2 Alkylene-4 to 6 membered heterocycloalkyl, wherein the alkyl, alkylene, alkoxy, cycloalkyl, heterocycloalkyl is optionally substituted by 1 to 4 R k replace; R b Each independently selected from deuterium, halogen, cyano, OH, =O, C 1-4 Alkyl, C 1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkoxy or cycloalkyl is optionally substituted by 1 to 4 R k replace; R x Each independently selected from deuterium, halogen, cyano, OH, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, -SO2-C 1-4 Alkyl, -C(=O)C 1-4 Alkyl, -C 0-2 Alkylene-C 3-6 Carbocyclic or -C 0-2 Alkylene-3 to 6 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace; R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocyclic ring, -O-4 to 7 membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7-membered heterocyclic ring, -C 0-2 Alkylene-C 3-6 Carbon ring, -C 0-2 Alkylene-4 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 1-4 Alkyl, C 1-4 The alkoxy group is substituted with an alkoxy substituent.

3. The compound according to claim 2 or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: The compound of general formula (I) is selected from general formula (Ia) or general formula (Ib) A1 is selected from phenyl, pyridyl, thienyl, thiazolyl, furanyl, pyrrolyl; Y1 is selected from a bond, -CH2, -CH2CH2-, wherein CH2 is optionally substituted by 1 to 2 groups selected from deuterium, halogen, cyano, OH, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted by a cycloalkyl substituent; When it represents a non-aromatic ring, Y2 is selected from a bond, -O-, -NH-, -OCH2-, -NHCH2-, -C(=O)CH2-, and Y3 is selected from -CH2-; When it represents an aromatic ring, Y2 is selected from a bond or CH, and Y3 is selected from CH, C(CH3) or N; L is selected from CH2, CH(R L1 )、CH2CH2、CH2CH(R L1 ); R L1 Selected from CF3, CD3, methyl, ethyl, isopropyl, methoxy, -CH2-cyclopropyl; Ring X1 is selected from phenyl or 5- to 6-membered heteroaryl, preferably phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazinyl; Ring X is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazinyl, benzothiazolyl, pyridothiazolyl, pyrimidothiazolyl, pyridazinothiazolyl, pyrazinothiazolyl, benzoxazolyl, pyridooxazolyl, pyrimidooxazolyl, pyridooxazolyl, pyridooxazolyl, pyridooxazolyl, pyridooxazolyl, pyridoopyrrolyl, pyridopyrazolyl, pyrimidothiphenyl, pyrimidopyrazolyl, pyrimidopyrrolyl, pyrimidooimidazolyl, pyrimidotriazolyl, pyrimidofuranyl, pyrimidopyrrolyl, quinolyl, isoquinolyl, pyrimidopyridinyl, triazolopyridinyl, triazolothiazolyl, triazolooxazolyl, triazoloimidazolyl, triazolopyrazolyl, Selected from b1 is selected from 0, 1, 2 or 3; x1 is selected from 0, 1, 2 or 3.

4. The compound according to claim 3 or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: R 1 , R 2 Each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, -CH2-cyclopropyl, wherein the CH2, methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclopropyl are optionally substituted by 1 to 3 R k replace; R b Each independently selected from deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, -CH2-cyclopropyl, wherein the CH2, methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclopropyl are optionally substituted by 1 to 3 R k replace; Ring X is selected from phenyl, pyridyl, pyridyl, pyridazinyl, pyrazinyl, Preferably, Selected from Ring X1 is selected from phenyl, pyridyl or pyrazinyl; Preferably, Selected from R x Each independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, -CH2-cyclopropyl, -O-cyclopropyl, wherein the CH2, methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl are optionally substituted by 1 to 3 R k replace; Prioritize, R x Each independently selected from deuterium, F, Cl, OH, CN, CF3, CHF2, CH2F, CD3, methyl, ethyl, ethynyl, cyclopropyl, R k each independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, 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 with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH2, methyl or methoxy; Preferably, R k Each is independently selected from deuterium, F, Cl, Br, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and cyclopropyl.

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

6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition comprises 1 to 1500 mg of the compound according to any one of claims 1 to 5 or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

7. Use of the compound according to any one of claims 1 to 5 or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal for preparing a medicament for treating a disease associated with PARP7 activity or expression.

8. The use according to claim 7, characterized in that: The disease is selected from tumors (eg lung cancer).

9. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 8 or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the therapeutically effective amount preferably being 1-1500 mg, and the disease preferably being a disease related to PARP7 activity or expression.

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