poly(adp ribose) polymerase selective inhibitors

Abstract

The present application belongs to the technical field of medicine, and particularly relates to a poly (ADP ribose) polymerase (PARP) selective inhibitor compound, a pharmaceutically acceptable salt or a stereoisomer thereof, a pharmaceutical composition containing the compound, the pharmaceutically acceptable salt or the stereoisomer thereof, a method for preparing the compound, the pharmaceutically acceptable salt or the stereoisomer thereof, and the use of the compound, the pharmaceutically acceptable salt or the stereoisomer thereof.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a class of poly(ADP-ribose) polymerase selective inhibitor compounds, pharmaceutically acceptable salts thereof or their stereoisomers, pharmaceutical compositions and formulations containing said compounds, pharmaceutically acceptable salts thereof or their stereoisomers, methods for preparing said compounds, pharmaceutically acceptable salts thereof or their stereoisomers, and uses of said compounds, pharmaceutically acceptable salts thereof or their stereoisomers. Background Technology

[0002] Targeted therapy inhibiting PARP1 (poly(ADP-ribose) polymerase 1) is currently a hot research topic both domestically and internationally. PARP1 is the most typical member of the PARP family, performing over 90% of the functions within the PARP family. PARP1 is a ribozyme that regulates various cellular processes through PARylation (poly(ADP-ribosyl)ation), including DNA damage signaling, chromatin remodeling, transcription, stabilizing replication forks, sensing unconnected Okazaki fragments during replication, inflammation, and metabolism. PARP1 consists of 1014 amino acid residues and includes three domains: the N-terminal DNA-binding domain (DBD), the intermediate self-regulation domain (AD), and the C-terminal catalytic domain (CAT). The N-terminal DNA-binding domain includes three zinc finger motifs (ZnⅠ, ZnⅡ, and ZnⅢ) and a DNA strand break-sensitive element (NLS). ZnⅠ and ZnⅡ recognize damaged DNA, while ZnⅢ participates in the connection between domains and activates the protein. The intermediate self-regulatory domain includes a C-terminus of BRCA1 (Breast Cancer 1 gene) (DNA repair and cell signal transduction) and has Capase-3 cleavage function. The C-terminal catalytic domain includes a tryptophan-glycine-arginine-rich domain (WGR), an α-helix domain (HD), and an ADP-ribotransferase domain (ART). PARP1 is crucial for the timely and accurate repair of single-strand DNA damage. When DNA damage occurs, PARP1 is rapidly recruited to single-strand breaks (SSBs), binds to single-stranded DNA (ssDNA), and polymerizes with other proteins to recruit downstream DNA repair factors.

[0003] Homologous recombination repair (HRR) is one of the core repair mechanisms for DNA double-strand damage. After recruitment, BRCA1 and BRCA2 (Breast Cancer 2 gene) regulate homologous recombination repair. BRCA1 initiates HR by promoting the excision of DSBs (double-strand breaks), and then works downstream with BRCA2 and PALB2 (Partner and Localizer of BRCA2) to stimulate RAD51 aggregation at the excised single-stranded DNA, subsequently using sister chromatids as templates for precise DNA damage repair. Besides their roles in HR, BRCA1 and BRCA2 are also important in S phase, protecting stopped replication forks from nuclease degradation. Given these roles of BRCA1 and BRCA2, mutations in these genes increase the incidence of breast, ovarian, prostate, and pancreatic cancer, stemming from the loss of remaining wild-type alleles and high levels of genomic instability caused by HR defects. HR-deficient BRCA1 / 2 mutant tumors rely on compensatory DNA repair pathways. Drug inhibition of key components of these pathways (such as PARP1) can lead to DNA damage. In the absence of BRCA1 / 2, key genomic instability, mitotic catastrophe, and cell death are triggered, ultimately resulting in synergistic lethality of BRCA1 / 2 and PARP.

[0004] The molecular mechanism of action of PARP inhibitors involves two aspects. On the one hand, PARP1 inhibitors competitively bind to the CAT (catalytic domain, C-terminal catalytic domain) of PARP-1, inhibiting its catalytic activity and preventing timely repair of SSB, leading to DSB. On the other hand, PARP-1 inhibitors inhibit PARP1's own parylation, causing PARP1 to undergo allosteric changes by binding to CAT, thus enhancing the binding strength of PARP1 to damaged DNA. This "captures" PARP1 onto the damaged DNA, making it difficult for other PARP1 molecules in the cell nucleus to bind to the damaged DNA, further blocking the possible repair pathway of DSB and promoting apoptosis.

[0005] Since olaparib was approved for BRCA-mutated ovarian cancer in 2014, several PARP inhibitors have been developed and marketed with widespread success. However, adverse reactions limit their ability to be used in combination with chemotherapy drugs. Most first-generation PARP inhibitors were developed and optimized before the discovery of the concept of PARP1-DNA capture, the mechanism by which PARP inhibitors exert a synthetic lethal effect on BRCAm cells. Furthermore, because first-generation PARP inhibitors were not selectively optimized within the PARP family, this could lead to adverse side effects, including intestinal toxicity caused by tankyrase inhibition or hematologic toxicity caused by PARP2 inhibition. Therefore, developing inhibitors with capture capabilities and high selectivity for PARP1, aiming to reduce the toxicity of existing PARP inhibitors while maintaining efficacy, has become a new direction in PARP inhibitor research. Summary of the Invention

[0006] The technical problem to be solved by this invention is to provide a novel polycyclic compound with good selective inhibitory activity against PARP1. Furthermore, this type of compound can be used for the prevention and / or treatment of PARP-related diseases.

[0007] The technical solution of the present invention is as follows:

[0008] In one aspect, the present invention provides compounds represented by the following general formula (I), pharmaceutically acceptable salts thereof, or stereoisomers thereof.

[0009]

[0010] X1 and X2 are independently selected from N, C or CH, with one being N and the other being selected from C or CH;

[0011] Ring A is selected from 5-7 member nitrogen-containing monocyclic heterocyclic groups or 5-7 member nitrogen-containing monocyclic heteroaryl groups;

[0012] Ring B is selected from 3-11 membered cycloalkyl, 3-11 membered heterocyclic, phenyl, or 5-7 membered monocyclic heteroaryl;

[0013] Ar is selected from 3-11 membered cycloalkyl, 3-11 membered heterocyclic, phenyl, or 5-7 monocyclic heteroaryl groups, optionally substituted with 1-3 substituents Q; each Q is independently selected from H, halogen, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C1-6 Alkoxy, amino C 1-6 Alkyl group, -(CH2) p -3-10 membered cycloalkyl groups, -(CH2) p -3-10 membered heterocyclic alkyl groups, -(CH2) p -N(R a (R) b -(CH2) p -OR a -(CH2) p -P(O)(R a (R) b -(CH2) p -S(O)(R a -(CH2) p -S(O)2(R a -(CH2) p -C(O)(R a -(CH2) p -C(O)O(R a -(CH2) p -OC(O)(R a -(CH2) p -C(O)N(R a (R) b -(CH2) p -N(R b )-C(O)(R a );

[0014] R is selected from hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkyl thiols, hydroxyl C 1-6 Alkoxy, amino C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkylthio, C 1-6 Alkoxy-C 1-6 alkyl;

[0015] Each R 1 Each R 2 Each is independently selected from H, halogen, hydroxyl, amino, cyano, and C. 1-6 Alkyl, Halogenated C1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkyl thiols, hydroxyl C 1-6 Alkoxy, amino C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkylthio, C 1-6 Alkoxy-C 1-6 alkyl;

[0016] R a R b Selected independently from hydrogen and C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, 3-10 membered cycloalkyl or 3-10 membered heterocyclic groups;

[0017] m and n are independently selected from 0, 1, 2, 3 or 4 respectively;

[0018] p is selected from 0, 1, or 2;

[0019] q is selected from 1, 2, or 3.

[0020] In some embodiments, ring A is selected from 5-6 member nitrogen-containing monocyclic heterocyclic groups or 5-6 member nitrogen-containing monocyclic heteroaryl groups.

[0021] In some embodiments, ring A is selected from the following groups:

[0022]

[0023] In some embodiments, ring A is selected from the following groups:

[0024]

[0025] In some implementations, ring A is selected from...

[0026] In some embodiments, ring B is selected from 5-6 membered monocyclic cycloalkyl, 5-6 membered monocyclic heterocyclic, phenyl, 5-6 membered monocyclic heteroaryl, 8-11 membered fused cycloalkyl, 8-11 membered spirocyclic, 7-9 membered bridged cycloalkyl, 8-11 membered fused heterocyclic, 8-11 membered spirocyclic or 7-9 membered bridged heterocyclic.

[0027] In some embodiments, ring B is selected from 5-6 membered monocyclic cycloalkyl groups or 5-6 membered monocyclic heterocyclic groups.

[0028] In some embodiments, ring B is selected from a 6-membered monocyclic cycloalkyl group or a 6-membered monocyclic heterocyclic group, and the Ar group is located at the para position of the methylene group or the cycloalkyl group.

[0029] In some embodiments, ring B is selected from the following groups:

[0030]

[0031] In some implementations, ring B is selected from...

[0032] In some implementations, ring B is

[0033] In some embodiments, Ar is selected from 5-6 membered monocyclic cycloalkyl, 5-6 membered monocyclic heterocyclic, phenyl, or 5-6 membered monocyclic heteroaryl groups optionally substituted with 1-2 Qs; each Q is independently selected from H, halogen, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkyl group, -(CH2) p -N(R a (R) b -(CH2) p -OR a -(CH2) p -P(O)(R a (R) b -(CH2) p -S(O)(R a -(CH2) p -S(O)2(R a -(CH2) p -C(O)(R a -(CH2) p -C(O)O(R a -(CH2) p -OC(O)(R a -(CH2) p -C(O)N(Ra (R) b -(CH2) p -N(R b )-C(O)(R a );

[0034] R a R b Selected independently from hydrogen and C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, cyclopropyl or cyclobutyl.

[0035] In some embodiments, Ar is selected from phenyl groups optionally substituted with 1-2 Q groups or 5-6 membered monocyclic heteroaryl groups.

[0036] In some embodiments, Ar is selected from pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl groups optionally substituted with 1-2 Q groups.

[0037] In some embodiments, Ar is selected from pyridinyl groups optionally substituted with 1-2 Q groups.

[0038] In some embodiments, the compound represented by general formula (I), its pharmaceutically acceptable salt, or its stereoisomer, wherein,

[0039] Ring A is selected from

[0040] Ring B is

[0041] Ar is selected from pyridinyl groups optionally substituted with 1-2 Q groups; each Q group is independently selected from H, halogen, hydroxyl, amino, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkyl group, -(CH2) p -C(O)N(R a (R) b -(CH2) p -N(R b )-C(O)(Ra );

[0042] R is selected from hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkyl thiols, hydroxyl C 1-6 Alkoxy, amino C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkylthio, C 1-6 Alkoxy-C 1-6 alkyl;

[0043] Each R 1 Each R 2 Each is independently selected from H, halogen, hydroxyl, amino, cyano, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkyl thiols, hydroxyl C 1-6 Alkoxy, amino C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 alkylthio or C 1-6 Alkoxy-C 1-6 alkyl;

[0044] R a R b Selected independently from hydrogen and C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl or cyclopropyl;

[0045] m, n, and p are each independently selected from 0, 1, or 2;

[0046] q is selected from 1, 2, or 3.

[0047] In some implementations, ring A is selected from...

[0048] Ring B is

[0049] Ar is selected from pyridinyl groups optionally substituted with 1-2 Q groups; each Q group is independently selected from H, halogen, hydroxyl, amino, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, -C(O)N(R) a (R) b ) or -N(R b )-C(O)(R a );

[0050] R is selected from hydrogen, halogen, hydroxyl, amino, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, aminomethyl, or hydroxymethyl;

[0051] Each R 1 Each R 2 Each is independently selected from H, halogen, hydroxyl, amino, cyano, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkyl thiols, hydroxyl C 1-6 Alkoxy, amino C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 alkylthio or C 1-6 Alkoxy-C 1-6 alkyl;

[0052] R a R b Selected independently from hydrogen and C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6Alkyl or cyclopropyl;

[0053] m and n are independently selected from 0, 1 or 2 respectively;

[0054] q is selected from 1, 2, or 3.

[0055] In some implementations, ring A is selected from...

[0056] Ring B is

[0057] Ar is selected from pyridinyl groups optionally substituted with 1-2 Q groups; each Q group is independently selected from H, halogen, hydroxyl, amino, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, -C(O)N(R) a (R) b ) or -N(R b )-C(O)(R a );

[0058] R is selected from hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy;

[0059] Each R 1 Each R 2 Each is independently selected from H, halogen, hydroxyl, amino, cyano, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkyl thiols, hydroxyl C 1-6 Alkoxy, amino C 1-6 Alkoxy, hydroxy C 1-6Alkylthio, amino C 1-6 alkylthio or C 1-6 Alkoxy-C 1-6 alkyl;

[0060] R a R b Selected independently from hydrogen and C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl or cyclopropyl;

[0061] m and n are independently selected from 0, 1 or 2 respectively;

[0062] q is selected from 1, 2, or 3.

[0063] In some implementations, ring A is selected from...

[0064] Ring B is

[0065] Ar is selected from pyridinyl groups optionally substituted with 1-2 Q groups; each Q group is independently selected from H, fluorine, chlorine, hydroxyl, amino, C. 1-4 Alkyl, fluorinated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Alkoxy, fluorinated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino C 1-4 Alkoxy, -C(O)N(R) a (R) b );

[0066] R is selected from hydrogen, halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy;

[0067] Each R 1 Each R 2 Each is independently selected from H, fluorine, chlorine, hydroxyl, amino, cyano, and C. 1-4 Alkyl, fluorinated C 1-4Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, fluorinated C 1-4 Alkoxy, fluorinated C 1-4 Alkyl thiols, hydroxyl C 1-4 Alkoxy, amino C 1-4 Alkoxy, hydroxy C 1-4 Alkylthio, amino C 1-4 alkylthio or C 1-4 Alkoxy-C 1-4 alkyl;

[0068] R a R b Each is independently selected from hydrogen, methyl, ethyl, isopropyl, or cyclopropyl;

[0069] m and n are independently selected from 0, 1 or 2 respectively;

[0070] q is selected from 1, 2, or 3.

[0071] In some implementations, ring A is selected from...

[0072] Ring B is

[0073] Ar is selected from pyridinyl groups optionally substituted with 1-2 Q groups; each Q group is independently selected from H, fluorine, chlorine, hydroxyl, amino, C. 1-4 Alkyl, fluorinated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Alkoxy, fluorinated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino C 1-4 Alkoxy, -C(O)N(R) a (R) b );

[0074] R is selected from hydrogen, halogen, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy;

[0075] Each R 1 Each R 2 Each is independently selected from H, fluorine, chlorine, hydroxyl, amino, cyano, and C.1-4 Alkyl, fluorinated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, fluorinated C 1-4 Alkoxy, fluorinated C 1-4 Alkyl thiols, hydroxyl C 1-4 Alkoxy, amino C 1-4 Alkoxy, hydroxy C 1-4 Alkylthio, amino C 1-4 alkylthio or C 1-4 Alkoxy-C 1-4 alkyl;

[0076] R a R b Each is independently selected from hydrogen, methyl, ethyl, isopropyl, or cyclopropyl;

[0077] m and n are independently selected from 0, 1 or 2 respectively;

[0078] q is selected from 1, 2, or 3.

[0079] In some implementations, ring A is selected from...

[0080] Ring B is

[0081] Ar is selected from pyridinyl groups optionally substituted with 1-2 Q groups; each Q group is independently selected from H, fluorine, chlorine, hydroxyl, amino, C. 1-4 Alkyl, fluorinated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Alkoxy, fluorinated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino C 1-4 Alkoxy, -C(O)N(R) a (R) b );

[0082] R is selected from hydrogen, halogen, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy;

[0083] Each R 1 Each R 2Each is independently selected from H, fluorine, chlorine, hydroxyl, amino, cyano, and C. 1-4 Alkyl, fluorinated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, fluorinated C 1-4 Alkoxy, fluorinated C 1-4 Alkyl thiols, hydroxyl C 1-4 Alkoxy, amino C 1-4 Alkoxy, hydroxy C 1-4 Alkylthio, amino C 1-4 alkylthio or C 1-4 Alkoxy-C 1-4 alkyl;

[0084] R a R b Each is independently selected from hydrogen, methyl, ethyl, isopropyl, or cyclopropyl;

[0085] m and n are independently selected from 0, 1 or 2 respectively;

[0086] q is selected from 1, 2, or 3.

[0087] In some implementations, ring A is selected from...

[0088] Ring B is

[0089] Ar is selected from pyridinyl groups optionally substituted with 1-2 Q groups; each Q group is independently selected from H, fluorine, chlorine, hydroxyl, amino, C. 1-4 Alkyl, fluorinated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Alkoxy, fluorinated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino C 1-4 Alkoxy, -C(O)N(R) a (R) b );

[0090] R is selected from hydrogen or fluorine;

[0091] R 1 Selected from H, fluorine, chlorine, hydroxyl, amino, cyano, C 1-4 Alkyl, fluorinated C 1-4 Alkyl, hydroxyl C 1-4Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, fluorinated C 1-4 Alkoxy, fluorinated C 1-4 Alkyl thiols, hydroxyl C 1-4 Alkoxy, amino C 1-4 Alkoxy, hydroxy C 1-4 Alkylthio, amino C 1-4 alkylthio or C 1-4 Alkoxy-C 1-4 alkyl;

[0092] R a R b Each is independently selected from hydrogen, methyl, ethyl, isopropyl, or cyclopropyl;

[0093] m is selected from 0 or 1; n is 0;

[0094] q is selected from 1, 2, or 3.

[0095] In some implementations, ring A is selected from...

[0096] Ring B is

[0097] Ar is selected from pyridinyl groups optionally substituted with 1-2 Q groups; each Q group is independently selected from H, fluorine, chlorine, hydroxyl, amino, C. 1-4 Alkyl, fluorinated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Alkoxy, fluorinated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino C 1-4 Alkoxy, -C(O)N(R) a (R) b );

[0098] R is selected from hydrogen or fluorine;

[0099] R a R b Each is independently selected from hydrogen, methyl, ethyl, isopropyl, or cyclopropyl;

[0100] m is 0; n is 0;

[0101] q is selected from 1, 2, or 3.

[0102] In one aspect, the present invention provides compounds represented by general formula (II), pharmaceutically acceptable salts thereof, or stereoisomers thereof.

[0103]

[0104] Among them, R 1 R 2 The definitions of X1, X2, rings A, R, Ar, Q, m, n, p, and q are as described in any of the schemes above; Y1 and Y2 are independently selected from N or CH respectively.

[0105] In one aspect, the present invention provides compounds represented by the following general formula (II-1), pharmaceutically acceptable salts thereof, or stereoisomers thereof.

[0106]

[0107] Among them, R 1 R 2 The definitions of rings A, R, Ar, Q, m, n, p, and q are as described in any of the schemes above; Y1 and Y2 are independently selected from N or CH, respectively.

[0108] In one aspect, the present invention provides compounds represented by the following general formula (II-2), pharmaceutically acceptable salts thereof, or stereoisomers thereof.

[0109]

[0110] Among them, R 1 R 2 The definitions of rings A, R, Ar, Q, m, n, p, and q are as described in any of the schemes above; Y1 and Y2 are independently selected from N or CH, respectively.

[0111] In some implementations, both Y1 and Y2 are N.

[0112] In one aspect, the present invention provides compounds represented by general formula (III), pharmaceutically acceptable salts thereof, or stereoisomers thereof.

[0113]

[0114] Among them, R 1 R 2 The definitions of X1, X2, rings A, R, Q, m, n, p, and q are as described in any of the schemes above; Y1 and Y2 are independently selected from N or CH respectively; t is selected from 0, 1, or 2.

[0115] In some implementations, R is selected from hydrogen, halogen, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C1-4 Alkyl group.

[0116] In some embodiments, R is selected from hydrogen, fluorine, chlorine, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy.

[0117] In one aspect, the present invention provides compounds represented by the following general formula (III-1), pharmaceutically acceptable salts thereof, or stereoisomers thereof.

[0118]

[0119] Among them, R 1 R 2 The definitions of rings A, Q, m, n, p, and q are as described in any of the schemes above; Y1 and Y2 are independently selected from N or CH respectively; t is selected from 0, 1, or 2.

[0120] In one aspect, the present invention provides compounds represented by the following general formula (III-2), pharmaceutically acceptable salts thereof, or stereoisomers thereof.

[0121]

[0122] Among them, R 1 R 2 The definitions of rings A, Q, m, n, p, and q are as described in any of the schemes above; Y1 and Y2 are independently selected from N or CH respectively; t is selected from 0, 1, or 2.

[0123] In one aspect, the present invention provides compounds represented by the following general formula (III-3), pharmaceutically acceptable salts thereof, or stereoisomers thereof.

[0124]

[0125] Among them, R 1 R 2 Ring A, Q, m, n, p, q, R a R b The definition is as described in any of the preceding schemes;

[0126] Y1 and Y2 are each independently selected from N or CH.

[0127] In some implementations, both Y1 and Y2 are N.

[0128] In some of the above implementations, q is 1.

[0129] In some of the above embodiments, R is selected from hydrogen or fluorine.

[0130] In some of the above embodiments, R is fluorine.

[0131] In some implementations, ring A is selected from...

[0132] In some implementations, R 1 Selected from H, fluorine, chlorine, hydroxyl, amino, cyano, C 1-4 Alkyl, fluorinated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, fluorinated C 1-4 Alkoxy, fluorinated C 1-4 Alkyl thiols, hydroxyl C 1-4 Alkoxy, amino C 1-4 Alkoxy, hydroxy C 1-4 Alkylthio, amino C 1-4 alkylthio or C 1-4 Alkoxy-C 1-4 alkyl.

[0133] In some implementations, both Y1 and Y2 are N.

[0134] In some implementations, each R 2 Each is independently selected from H, fluorine, chlorine, hydroxyl, amino, cyano, and C. 1-4 Alkyl, fluorinated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, C 1-4 Alkoxy, fluorinated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino C 1-4 Alkoxy or C 1-4 Alkoxy-C 1-4 alkyl.

[0135] In some implementations, R 2 For H.

[0136] In some embodiments, each Q is independently selected from H, fluorine, chlorine, hydroxyl, amino, C 1-4 Alkyl, fluorinated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Alkoxy, fluorinated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino C 1-4 Alkoxy, -C(O)N(R)a (R) b );

[0137] R a R b Each is independently selected from hydrogen, methyl, ethyl, isopropyl, or cyclopropyl.

[0138] In some embodiments, Q is selected from H, fluorine, chlorine, hydroxyl, amino, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy.

[0139] In some implementations, R a For H, R b Selected from methyl, ethyl, isopropyl or cyclopropyl.

[0140] In some implementations, ring A is selected from... R 1 Selected from fluorine, chlorine, hydroxyl, amino, ethyl, propyl, isopropyl, and fluorinated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, C 1-4 Alkoxy, fluorinated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino C 1-4 alkoxy group or C 1-4 Alkoxy-C 1-4 alkyl.

[0141] In some implementations, ring A is selected from... R 1 Selected from H, fluorine, chlorine, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, and fluorinated C. 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, C 1-4 Alkoxy, fluorinated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino C 1-4 alkoxy group or C 1-4 Alkoxy-C 1-4 alkyl.

[0142] In one aspect, the present invention provides compounds, pharmaceutically acceptable salts thereof, or stereoisomers thereof, as shown below:

[0143]

[0144]

[0145] In another aspect, the present invention also provides a pharmaceutical composition comprising the foregoing compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition may be in any pharmaceutically acceptable dosage form. Pharmaceutically acceptable excipients are substances that are non-toxic, compatible with the active ingredient, and otherwise biologically suitable for use in organisms. The selection of a particular excipient will depend on the route of administration or the type and state of disease for treating a particular patient.

[0146] In some embodiments, the above-described pharmaceutical composition can be administered to patients or subjects requiring this treatment via oral, parenteral, rectal, or pulmonary administration. For oral administration, the pharmaceutical composition can be formulated into oral preparations, such as conventional oral solid dosage forms like tablets, capsules, pills, granules, etc.; or into oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc. For parenteral administration, the above-described pharmaceutical composition can also be formulated into injectable preparations, including injection solutions, sterile powders for injection, and concentrated solutions for injection. For rectal administration, the pharmaceutical composition can be formulated into suppositories, etc. For pulmonary administration, the pharmaceutical composition can be formulated into inhaled preparations, aerosols, powder inhalers, or sprays, etc.

[0147] In another aspect, the pharmaceutical composition of the present invention comprises the foregoing compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and may further comprise one or more second therapeutic agents.

[0148] In another aspect, the present invention also relates to the use of the foregoing compounds, pharmaceutically acceptable salts thereof, or stereoisomers thereof in the preparation of medicaments for the prevention and / or treatment of diseases associated with PARP overexpression, said diseases being selected from: neuropathic pain, epilepsy, stroke, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, schizophrenia, chronic and acute pain, ischemia, hypoxic neuronal injury, neurodegenerative diseases, atherosclerosis, hyperlipidemia, cardiac tissue injury, coronary artery disease, myocardial infarction, cardiogenic shock, diabetic neuropathy, osteoarthritis, and osteoporosis.

[0149] In another aspect, the present invention also relates to the use of the foregoing compounds, pharmaceutically acceptable salts thereof, or stereoisomers thereof in the preparation of medicaments for the prevention and / or treatment of cancer.

[0150] Furthermore, the present invention also relates to the use of pharmaceutical compositions containing the foregoing compounds, their pharmaceutically acceptable salts, or their stereoisomers in the preparation of medicaments for the prevention and / or treatment of cancers associated with PARP overexpression.

[0151] In some implementations, the cancer lacks the HR-dependent DNA DSB repair pathway.

[0152] In some embodiments, one or more cancer cells are included, said cancer cells having a reduced or eliminated ability to repair DNA DSB via HR relative to normal cells.

[0153] In some embodiments, the cancer comprises one or more cancer cells that lack BRCA1 and / or BRCA2.

[0154] In some embodiments, the cancer comprises one or more cancer cells having a BRCA1 and / or BRCA2 defective phenotype.

[0155] In some implementations, the cancer is selected from breast cancer, ovarian cancer, endometrial cancer, cervical cancer, lung cancer, prostate cancer, pancreatic cancer, leukemia, stomach cancer, gallbladder cancer, liver cancer, head and neck cancer, esophageal cancer, kidney cancer, brain cancer, leukemia, colon cancer, glioblastoma, lymphoma, or melanoma.

[0156] In another aspect, the present invention also provides a method for treating a PARP-related disease, the method comprising administering to a patient in need an effective amount of the aforementioned compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or the aforementioned pharmaceutical composition.

[0157] Furthermore, the present invention also provides a method of treating cancer, comprising administering to a patient in need an effective amount of the aforementioned compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or the aforementioned pharmaceutical composition.

[0158] In some implementations, the cancer lacks the HR-dependent DNA DSB repair pathway.

[0159] In some embodiments, one or more cancer cells are included, said cancer cells having a reduced or eliminated ability to repair DNA DSB via HR relative to normal cells.

[0160] In some embodiments, the cancer comprises one or more cancer cells that lack BRCA1 and / or BRCA2.

[0161] In some embodiments, the cancer comprises one or more cancer cells having a BRCA1 and / or BRCA2 defective phenotype.

[0162] In some implementations, the cancer is selected from breast cancer, ovarian cancer, endometrial cancer, cervical cancer, lung cancer, prostate cancer, pancreatic cancer, leukemia, stomach cancer, gallbladder cancer, liver cancer, head and neck cancer, esophageal cancer, kidney cancer, brain cancer, leukemia, colon cancer, glioblastoma, lymphoma, or melanoma.

[0163] In another aspect, the present invention also provides a kit comprising an effective amount of one or more of the compounds described above, their pharmaceutically acceptable salts, or their stereoisomers.

[0164] In another aspect, the present invention also provides a kit comprising:

[0165] (a) An effective amount of one or more of the compounds described above, their pharmaceutically acceptable salts, or their stereoisomers.

[0166] (b) an effective amount of one or more anticancer agents.

[0167] The "effective dose" as described in this invention refers to a drug dose capable of preventing, alleviating, delaying, inhibiting, or curing the subject's condition. The dosage is related to the route of drug administration, the pharmacokinetics of the drug, the severity of the disease, and the subject's individual characteristics (gender, weight, height, age), etc.

[0168] In this invention, unless otherwise stated, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for a better understanding of this invention, definitions of some terms are provided below. When the definitions and interpretations of the terms provided in this invention differ from the meanings commonly understood by those skilled in the art, the definitions and interpretations provided in this invention shall prevail.

[0169] The "halogen" mentioned in this invention refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0170] The "C" described in this invention 1-6 "Alkyl" refers to a straight-chain or branched alkyl group containing 1-6 carbon atoms, including, for example, "C". 1-4 Alkyl", C 1-3 Alkyl", C 1-2 Alkyl", C 2-6 Alkyl", C 2-5 Alkyl", C 2-4 Alkyl", C 2-3 Alkyl groups, etc., specific examples include but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, etc. The "C" in this invention... 1-4 "alkyl" refers to C 1-6 Specific examples of alkyl groups containing 1-4 carbon atoms.

[0171] The "C" described in this invention 1-6 "Alkoxy" refers to "C 1-6 alkyl-O-", the "C" 1-6 "alkyl" is as defined above. The "C" in this invention... 1-4 "Alkoxy" refers to "C 1-4 alkyl-O-", the "C" 1-4 "Alkyl" is as defined above.

[0172] The "C" described in this invention 1-6 "Alkylthio" refers to "C 1-6 Alkyl-S-", the "C" 1-6 "alkyl" is as defined above. The "C" in this invention... 1-4 "Alkylthio" refers to "C 1-4 Alkyl-S-”, the “C” 1-4 "Alkyl" is as defined above.

[0173] The "hydroxyl C" of this invention 1-6 Alkyl, amino C 1-6 Alkyl, Halogenated C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 "alkyl" refers to C 1-6 One or more hydrogens in the alkyl group are respectively converted by one or more hydroxyl, amino, halogen, cyano or C groups. 1-6 Alkyl groups are substituted. C 1-6 Alkyl, C 1-6 Alkoxy groups are as defined above.

[0174] The "hydroxyl C" of this invention 1-6 Alkoxy, amino C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano C 1-6 "Alkoxy" refers to "C 1-6 One or more hydrogen atoms in the "alkoxy" group are replaced by one or more hydroxyl, amino, halogen, or cyano groups.

[0175] The "hydroxyl C" of this invention 1-6 Alkylthio, amino C 1-6 Alkyl thiols, halogenated C 1-6 "Alkylthio" refers to "C 1-6 One or more hydrogen atoms in the "alkylthio" group are replaced by one or more hydroxyl, amino, or halogen groups.

[0176] The "fluorinated C" of this invention 1-6 Alkyl group, fluorinated C 1-6 "Alkoxy" refers to "C 1-6 Alkyl", C1-6 In an alkoxy group, one or more hydrogen atoms are replaced by one or more fluorine atoms.

[0177] The "3-11 membered heterocyclic group" as described in this invention refers to a saturated or partially saturated monocyclic or polycyclic cyclic group containing at least one heteroatom or group (e.g., 1, 2, 3, 4, or 5) and having 3-11 ring atoms, and which is non-aromatic. The heteroatom or group is selected from nitrogen, oxygen, or sulfur atoms. Optionally, the ring atoms (e.g., carbon, nitrogen, or sulfur atoms) in the cyclic structure can be substituted with oxygen. The "3-11 membered heterocyclic group" includes, but is not limited to, "3-8 membered monocyclic heterocyclic group," "8-11 membered fused heterocyclic group," "8-11 membered spirocyclic heterocyclic group," and "7-9 membered bridged heterocyclic group."

[0178] The "3-8 member monoheterocyclic group" described in this invention refers to a saturated or partially saturated monocyclic cyclic group that does not possess aromaticity and contains at least one heteroatom (e.g., 1, 2, 3, 4, or 5 heteroatoms) and has 3-8 ring atoms. The heteroatom is a nitrogen atom, an oxygen atom, and / or a sulfur atom. Optionally, the ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure can be substituted with oxygen. The "3-8 member monoheterocyclic group" described in this invention includes "3-8 member saturated monoheterocyclic groups" and "3-8 member partially saturated monoheterocyclic groups." Preferably, the "3-8 member monoheterocyclic group" described in this invention contains 1-3 heteroatoms; preferably, the "3-8 member monoheterocyclic group" described in this invention contains 1-2 heteroatoms, and the heteroatoms are selected from nitrogen atoms and / or oxygen atoms; preferably, the "3-8 member monoheterocyclic group" described in this invention contains 1 heteroatom, and the heteroatom is a nitrogen atom, an oxygen atom, and / or a sulfur atom. The "3-8 member monoheterocyclic group" is preferably a "3-7 member monoheterocyclic group", "3-6 member monoheterocyclic group", "4-7 member monoheterocyclic group", "4-6 member monoheterocyclic group", "6-8 member monoheterocyclic group", "5-7 member monoheterocyclic group", "5-7 member saturated monoheterocyclic group", "5-7 member partially saturated monoheterocyclic group", "5-6 member monoheterocyclic group", "5-6 member saturated monoheterocyclic group", "5-6 member partially saturated monoheterocyclic group", "3-6 member saturated monoheterocyclic group", "5-6 member saturated monoheterocyclic group", "3-6 member nitrogen-containing monoheterocyclic group", "3-6 member saturated nitrogen-containing monoheterocyclic group", "5-6 member nitrogen-containing monoheterocyclic group", "5-6 member saturated nitrogen-containing monoheterocyclic group", "5-6 member partially saturated nitrogen-containing monoheterocyclic group", "6 member saturated monoheterocyclic group", "6 member saturated nitrogen-containing monoheterocyclic group", etc. Specific examples of "3-8 membered monoheterocyclic groups" include, but are not limited to: aziridine, 2H-aziridine, diaziridine, 3H-diazacyclopropenyl, aziridine, oxacyclobutyl, 1,4-dioxane, 1,3-dioxane, 1,3-dioxanepentyl, 1,4-dioxanediene, tetrahydrofuranyl, dihydropyrrolyl, pyrrolylalkyl, imidazoalkyl, 4,5-dioxanediol, etc. Hydro-imidazolyl, pyrazolyl, 4,5-dihydropyrazolyl, 2,5-dihydrothiophenyl, tetrahydrothiophenyl, 4,5-dihydrothiazolyl, thiazolyl, piperidinyl, tetrahydropyridinyl, piperidinone, tetrahydropyridinone, dihydropiperidinone, piperazine, morpholinyl, 4,5-dihydrooxazolyl, 4,5-dihydroisooxazolyl, 2,3-dihydroisooxazolyl, oxazolyl, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl, etc.

[0179] The "8-11 membered fused-ring heterocyclic group" described in this invention refers to a saturated or partially saturated, non-aromatic cyclic group containing 8-11 ring atoms, formed by two or more cyclic structures sharing two adjacent atoms, and at least one ring atom being a heteroatom. One ring in the fused ring may be aromatic, but the fused ring as a whole is not aromatic. The heteroatom is a nitrogen atom, an oxygen atom, and / or a sulfur atom. The ring atoms in the cyclic structure (e.g., carbon, nitrogen, or sulfur atoms) may optionally be oxidized. Specific examples include, but are not limited to: dihydrofuranopyridine, 3,4-dihydro-2H-pyranopyridine, 3,4-dihydro-2H-oxazinopyridine, dihydrooxazinopyrimidine, benzodihydrofuranyl, etc. wait.

[0180] The "8-11 member spiroheterocyclic group" described in this invention refers to a saturated or partially saturated cyclic structure containing 8-11 ring atoms, formed by two or more cyclic structures sharing one ring atom with each other. At least one ring atom is a heteroatom or group, such as N, NH, O, S, CO, SO, SO2, etc. Preferably, the number of heteroatoms or groups is 1, 2, 3, 4, or 5, more preferably 1 or 2. Examples include "9-11 member spiroheterocyclic group," "9-11 member saturated spiroheterocyclic group," and "9-11 member partially saturated spiroheterocyclic group." Specific examples include, but are not limited to:

[0181] The "7-9 membered bridged heterocyclic group" described in this invention refers to a saturated or partially saturated cyclic structure containing 7-9 ring atoms, formed by two or more cyclic structures sharing two non-adjacent ring atoms. At least one ring atom is a heteroatom or group, such as N, NH, O, S, CO, SO, SO2, etc. Preferably, the number of heteroatoms or groups is 1, 2, 3, 4, or 5, more preferably 1 or 2. Examples include "7-8 membered bridged heterocyclic group," "7-8 membered saturated bridged heterocyclic group," "8 membered bridged heterocyclic group," and "8 membered saturated bridged heterocyclic group." Specific examples include, but are not limited to:

[0182]

[0183] The "3-11 membered cycloalkyl" as used in this invention refers to a saturated or partially saturated monocyclic or polycyclic cyclic group containing 3-11 ring atoms and lacking aromaticity. The "3-11 membered cycloalkyl" as used in this invention includes, but is not limited to, "3-8 membered monocyclic cycloalkyl," "8-11 membered fused cycloalkyl," "8-11 membered spirocyclic," and "7-9 membered bridged cycloalkyl." Among them, "3-8 membered monocyclic cycloalkyl" includes, but is not limited to, cyclopentyl, cyclohexyl, and...

[0184] The "8-11 member spirocyclic group" mentioned in this invention refers to a saturated or partially saturated cyclic structure containing 8-11 ring carbon atoms, formed by two or more cyclic structures sharing one ring atom with each other. Examples include "9-11 member spirocyclic group," "9-11 member saturated spiroheterocyclic group," and "9-11 member partially saturated spiroheterocyclic group." Specific examples include, but are not limited to:

[0185] The "7-9 member bridged ring group" described in this invention refers to a saturated or partially saturated ring structure containing 7-9 ring carbon atoms, formed by two or more ring structures sharing two non-adjacent ring atoms. Examples include "7-8 member bridged ring group," "7-8 member saturated bridged ring group," "8 member bridged heterocyclic group," "8 member saturated bridged ring group," and "8 member partially saturated bridged ring group." Specific examples include, but are not limited to:

[0186] The "8-11 fused cycloalkyl group" described in this invention refers to a saturated or partially saturated, non-aromatic cyclic group containing 8-11 cyclic carbon atoms, formed by two or more cyclic structures sharing two adjacent atoms. One of the rings in the fused ring may be an aromatic ring, but the fused ring as a whole does not possess aromaticity. Examples include, but are not limited to: wait.

[0187] The "5-7 membered monocyclic heteroaryl" described in this invention refers to an aromatic monocyclic cyclic group containing 5-7 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, oxygen atom, or sulfur atom). The ring atoms (e.g., carbon atom, nitrogen atom, or sulfur atom) in the cyclic structure may optionally be oxidized. This includes, for example, "5-6 membered monocyclic heteroaryl," "5-6 membered nitrogen-containing monocyclic heteroaryl," and "6 membered nitrogen-containing monocyclic heteroaryl," etc. The heteroatom in the "nitrogen-containing heteroaryl" contains at least one nitrogen atom; for example, it may contain only one or two nitrogen atoms, or it may contain one nitrogen atom and one or two other heteroatoms (e.g., oxygen atom and / or sulfur atom), or it may contain two nitrogen atoms and one or two other heteroatoms (e.g., oxygen atom and / or sulfur atom). Specific examples of “5-7 membered monocyclic heteroaryl groups” include, but are not limited to, furanyl, thiophene, pyrrole, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridonel, 4-pyridonel, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetraazinyl, aziridine-heptadienyl, 1,3-diazacyclicheptadienyl, etc.

[0188] The "DSB" mentioned in this invention stands for Double-strand breaks, which refers to DNA double-strand breaks.

[0189] In this invention, "HR" refers to Homologous Recombination.

[0190] In this invention, "CH" refers to the following structure:

[0191] In this invention, "N" refers to the following structure:

[0192] In this invention, "C" refers to the following structure:

[0193] The "-(CH2)" described in this invention p -P(O)(R a (R) b ")" refers to In this invention, other similar groups are defined the same as "-(CH2)". p -P(O)(R a (R) b )".

[0194] The "each R" described in this invention 1 "This refers to multiple Rs when m is 2, 3, or 4" 1 In each R 1 Independently selected from the groups described in the above technical solutions.

[0195] The "each R" described in this invention 2 "This refers to the situation where n is 2, 3, or 4, and multiple R's are equal. 2 In each R 2 Independently selected from the groups described in the above technical solutions.

[0196] The term "optionally substituted" in this invention refers to two situations: one or more hydrogen atoms on the substituted group are "substituted" or "not substituted" by one or more substituents.

[0197] When ring A contains NH, for example The H in the NH on its ring can be R 1 replace.

[0198] When ring B is selected from nitrogen-containing heterocycles or heteroaryl groups, and contains NH, the H in the NH on the ring can be converted by R. 2 replace.

[0199] The "pharmaceutically acceptable salt" as described in this invention refers to a salt formed by an acidic functional group (e.g., -COOH, -OH, -SO3H, etc.) present in a compound and a suitable inorganic or organic cation (base), including salts formed with alkali metals or alkaline earth metals, ammonium salts, and salts formed with nitrogen-containing organic bases; and a salt formed by a basic functional group (e.g., -NH2, etc.) present in a compound and a suitable inorganic or organic anion (acid), including salts formed with inorganic acids or organic acids (e.g., carboxylic acids, etc.).

[0200] The term "stereoisomer" as used in this invention refers to compounds containing one or more asymmetric centers, thus allowing them to exist as racemic mixtures and racemic mixtures, single enantiomers, diastereomer mixtures, and single diastereomers. Compounds of this invention may have asymmetric centers, each of which independently produces two optical isomers. The scope of this invention includes all possible optical isomers and mixtures thereof.

[0201] Unless otherwise specified, the compounds described in this invention, if containing an alkene double bond, include cis and trans isomers. The compounds described in this invention can exist as tautomers (a type of functional group isomer) which have different hydrogen linkages through one or more double bond shifts; for example, ketones and their enol forms are keto-enol tautomers. All tautomers and mixtures thereof are included within the scope of this invention.

[0202] All stereoisomers, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof are included within the scope of this invention.

[0203] The compounds of this invention can be prepared by enantiomer-specific synthesis or by resolution from mixtures of enantiomers to obtain individual enantiomers. Conventional resolution techniques include using various well-known chromatographic methods to separate mixtures of enantiomers of the starting material or the final product.

[0204] When the stereochemistry of a disclosed compound is determined by structural nomenclature or description, the named or described stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight relative to other stereoisomers. When a single isomer is determined by structural nomenclature or description, the described or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. Optical purity (by weight%) is the ratio of the weight of the enantiomer to the weight of the enantiomer plus the weight of its optical isomer.

[0205] Beneficial effects of the invention

[0206] 1. The compounds of the present invention, their pharmaceutically acceptable salts or stereoisomers thereof have excellent PARP1 inhibitory activity, can effectively inhibit tumor cell growth, and have good pharmacokinetic properties in vivo (e.g., mice, rats, dogs, etc.), with long-lasting effects, high bioavailability and high brain penetration rate.

[0207] 2. The compounds of the present invention, their pharmaceutically acceptable salts or stereoisomers thereof have very good selectivity and are highly selective and effective PARP1 inhibitors.

[0208] 3. The compounds of the present invention, their pharmaceutically acceptable salts or stereoisomers thereof have good therapeutic effects on cancer, and the liver microsomes (e.g., human, mouse, canine and monkey) have high stability.

[0209] 4. The compound preparation process of this invention is simple, the drug has high purity and stable quality, and it is easy to carry out large-scale industrial production. Detailed Implementation Plan

[0210] The technical solution of the present invention will be described below with reference to specific embodiments, and the above-mentioned content of the present invention will be further explained in detail. However, it should not be construed that the scope of the above-mentioned subject matter of the present invention is limited to the following embodiments. All technologies implemented based on the above-mentioned content of the present invention fall within the scope of the present invention.

[0211] abbreviation:

[0212] NBS: N-bromosuccinimide; XPhos Pd G2: Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II); DIPEA: N,N-diisopropylethylamine; DIEA: N,N-diisopropylethylamine; DMF: N,N-dimethylformamide.

[0213] Example 1: Preparation of 6-fluoro-5-(4-((6-fluoro-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-7-yl)methyl)piperazin-1-yl)-N-methylpyridine amide (compound 1)

[0214] 1. Preparation of 1-bromo-2,4-difluoro-3-nitrobenzene

[0215]

[0216] 1,3-Difluoro-2-nitrobenzene (10.0 g, 62.9 mmol) was dissolved in concentrated sulfuric acid (75 mL), and NBS (12.3 g, 69.2 mmol) was added. After the addition was complete, the mixture was reacted at 80 °C for 16 h. The solution was poured into ice water, extracted with ethyl acetate, and the organic phase was concentrated and purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 10:1) to obtain the target compound (12.0 g, yield 80.0%).

[0217] 2. Preparation of methyl 1-(4-bromo-3-fluoro-2-nitrophenyl)-1H-pyrrole-2-carboxylic acid

[0218]

[0219] 1-Bromo-2,4-difluoro-3-nitrobenzene (952 mg, 4.0 mmol), methyl 2-pyrrolecarboxylate (500 mg, 4.0 mmol), and cesium carbonate (2.6 g, 8.0 mmol) were dissolved in DMF (20 mL). After addition, the mixture was reacted at 25 °C for 2 h, and the reaction was stopped by LCMS. The solution was poured into water, extracted with ethyl acetate, and the organic phase was concentrated and purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 3:1) to obtain the target compound (900 mg, yield 65.6%).

[0220] 3. Preparation of methyl 1-(2-amino-4-bromo-3-fluorophenyl)-1H-pyrrole-2-carboxylic acid

[0221]

[0222] Methyl 1-(4-bromo-3-fluoro-2-nitrophenyl)-1H-pyrrole-2-carboxylic acid (900 mg, 2.6 mmol) was dissolved in methanol (20 mL) and water (1 mL), and ammonium chloride (1.1 g, 20.8 mmol) was added. Zinc powder (1.4 g, 20.8 mmol) was added at 0 °C. After the addition was complete, the mixture was reacted at 25 °C for 2 h. The mixture was filtered through diatomaceous earth, and the concentrated filtrate was used directly in the next step.

[0223] 4. Preparation of 7-bromo-6-fluoropyrrolo[1,2-a]quinoxaline-4(5H)-one

[0224]

[0225] Methyl 1-(2-amino-4-bromo-3-fluorophenyl)-1H-pyrrole-2-carboxylic acid (the crude product from the previous step) was dissolved in methanol (10 mL) and ethyl acetate (10 mL), and then ethyl acetate hydrochloride solution (3 mL) was added. After the addition was complete, the reaction was carried out at 25 °C for 2 h. The solution was concentrated, the pH was adjusted to >7 with saturated sodium bicarbonate aqueous solution, and the mixture was extracted with ethyl acetate. The organic phase was concentrated and purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 3:1) to obtain the target compound (400 mg, yield 54.4%).

[0226] 5. Preparation of 6-fluoro-7-(hydroxymethyl)pyrrolo[1,2-a]quinoxaline-4(5H)-one

[0227]

[0228] 7-Bromo-6-fluoropyrrolo[1,2-a]quinoxaline-4(5H)-one (400 mg, 1.4 mmol), tri-n-butyltin methanol (482 mg, 1.5 mmol), and XphosPdG2 (110 mg, 0.14 mmol) were dissolved in 1,4-dioxane (40 mL), and the reaction was carried out at 80 °C for 2 hours. The reaction was stopped by LCMS. The organic phase was dried and concentrated, and purified by column chromatography (SiO2, dichloromethane:methanol = 3:1) to give the target compound (238 mg, yield 71.9%).

[0229] Preparation of 6,7-(chloromethyl)-6-fluoropyrrolo[1,2-a]quinoxaline-4(5H)-one

[0230]

[0231] 6-Fluoro-7-(hydroxymethyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (23 mg, 0.1 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (51 mg, 0.5 mmol) and methanesulfonyl chloride (46 mg, 0.4 mmol) were added at 0 °C. After addition, the reaction was carried out at 25 °C for 4 hours. The reaction was stopped by LCMS. The concentrate was used directly for the next step.

[0232] 7. Preparation of 6-fluoro-5-(4-((6-fluoro-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-7-yl)methyl)piperazin-1-yl)-N-methylpyridine amide

[0233]

[0234] 7-(chloromethyl)-6-fluoropyrrolo[1,2-a]quinoxaline-4(5H)-one (crude product from the previous step), 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridineamide hydrochloride (28 mg, 0.1 mmol) were dissolved in DMF (10 mL), and potassium carbonate (41 mg, 0.3 mmol) was added. After the addition was complete, the reaction was carried out at 80 °C for 2 hours. The reaction was stopped by LCMS. The organic phase was concentrated and purified by silica gel plate (SiO2, dichloromethane:methanol = 15:1), and then purified by preparative liquid chromatography (acetonitrile = 0-70%) to obtain the target compound (1.7 mg, yield 3.8%).

[0235] Molecular formula: C 23 H 22F2N6O2 molecular weight: 452.5 LC-MS (m / z): 453.1 (M+H) + )

[0236] 1 H-NMR (400MHz, CDCl3) δ: 8.18 (s, 1H), 8.00 (d, J = 7.7Hz, 1H), 7.68 (s, 1H), 7.44-7.49 (m, 2H), 7.31- 7.34(m,2H),6.74(s,1H),3.74(s,2H),3.34-3.30(m,4H),3.01(d,J=5.0Hz,3H),2.70-2.74(m,4H).

[0237] Example 2: Preparation of (S)-6-fluoro-5-(4-((6-fluoro-4-oxo-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoxaloline-7-yl)methyl)piperazin-1-yl)-N-methylpyridineamide (compound 5-1)

[0238]

[0239] 1. Preparation of methyl(4-bromo-3-fluoro-2-nitrophenyl)-L-proline

[0240] 1-Bromo-2,4-difluoro-3-nitrobenzene (1.2 g, 5.0 mmol), L-proline methyl ester hydrochloride (830 mg, 5.0 mmol), and DIEA (1.9 g, 15.0 mmol) were dissolved in acetonitrile (50 mL). After addition, the mixture was reacted at 60 °C for 3 h, and the reaction was stopped by LCMS. The solution was concentrated and purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 3:1) to give the target compound (1.2 g, yield 69.0%).

[0241] 2. Preparation of methyl(2-amino-4-bromo-3-fluorophenyl)-L-proline

[0242] Methyl(4-bromo-3-fluoro-2-nitrophenyl)-L-proline (1.2 g, 3.5 mmol) was dissolved in methanol (30 mL) and water (2 mL), and ammonium chloride (1.5 g, 28.0 mmol) was added. Zinc powder (1.8 g, 28.0 mmol) was then added at 0 °C. After the addition was complete, the mixture was reacted at 25 °C for 8 h. The mixture was filtered through diatomaceous earth, and the concentrated filtrate was used directly in the next step.

[0243] 3. Preparation of (S)-7-bromo-6-fluoro-1,2,3,3a-tetrahydropyrrolo[1,2-a]quinoxaline-4(5H)-one

[0244] Methyl(2-amino-4-bromo-3-fluorophenyl)-L-proline (crude product from the previous step) was dissolved in methanol (10 mL) and ethyl acetate (10 mL), and then ethyl acetate hydrochloride solution (5 mL) was added. After the addition was complete, the reaction was carried out at 25 °C for 1 h. The solution was concentrated, the pH was adjusted to >7 with saturated sodium bicarbonate aqueous solution, and the mixture was extracted with ethyl acetate. The organic phase was concentrated and purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 3:1) to obtain the target compound (400 mg, two-step yield 40.0%).

[0245] 4. Preparation of (S)-6-fluoro-7-(hydroxymethyl)-1,2,3,3a-tetrahydropyrrolo[1,2-a]quinoxaline-4(5H)-one

[0246] (S)-7-bromo-6-fluoro-1,2,3,3a-tetrahydropyrrolo[1,2-a]quinoxaline-4(5H)-one (400 mg, 1.4 mmol), tri-n-butyltin methanol (488 mg, 1.5 mmol), and XphosPdG2 (110 mg, 0.14 mmol) were dissolved in 1,4-dioxane (40 mL), and the reaction was carried out at 80 °C for 2 hours. The reaction was stopped by LCMS. The organic phase was dried and concentrated, and purified by column chromatography (SiO2, dichloromethane:methanol = 15:1) to give the target compound (150 mg, yield 45.0%).

[0247] 5. Preparation of (S)-7-(bromomethyl)-6-fluoro-1,2,3,3a-tetrahydropyrrolo[1,2-a]quinoxaline-4(5H)-one

[0248] (S)-6-fluoro-7-(hydroxymethyl)-1,2,3,3a-tetrahydropyrrolo[1,2-a]quinoxaline-4(5H)-one (70 mg, 0.3 mmol) was dissolved in dichloromethane (5 mL). Carbon tetrabromide (149 mg, 0.45 mmol) and triphenylphosphine (118 mg, 0.45 mmol) were added at 0 °C. After the addition was complete, the reaction was carried out at 2 °C for 2 hours. The reaction was stopped by LCMS. The concentrate was used directly for the next step.

[0249] 6. Preparation of (S)-6-fluoro-5-(4-((6-fluoro-4-oxo-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoxalo-7-yl)methyl)piperazin-1-yl)-N-methylpyridine amide

[0250] (S)-7-(bromomethyl)-6-fluoro-1,2,3,3a-tetrahydropyrrolo[1,2-a]quinoxalin-4(5H)-one (crude product from the previous step), 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridineamide hydrochloride (83 mg, 0.3 mmol) were dissolved in acetonitrile (10 mL), and DIEA (116 mg, 0.9 mmol) was added. After the addition was complete, the reaction was carried out at 25 °C for 1 hour. The reaction was stopped by LCMS. The organic phase was concentrated and purified by silica gel plate (SiO2, dichloromethane:methanol = 20:1) to obtain the target compound (20 mg, yield 14.6%).

[0251] Molecular formula: C 23 H 26 F2N6O2 molecular weight: 456.5 LC-MS (m / z): 457.1 (M+H) + )

[0252] 1 H-NMR (400MHz, CDCl3)δ:8.00(d,J=8.0Hz,1H),7.59(s,1H),7.56(s,1H),7.28-7.31(m,1H),6.91-7.02(m,1H),6.38(d,J=8.4Hz,1H),3.78-3 .83(m,1H),3.61(s,2H),3.48-3.54(m,1H),3.20-3.30(m,5H),3.01(d, J=5.1Hz,3H),2.62-2.70(m,4H),2.31-2.42(m,1H),2.05-2.23(m,3H).

[0253] Example 3: Preparation of (R)-6-fluoro-5-(4-((6-fluoro-4-oxo-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoxalo-7-yl)methyl)piperazin-1-yl)-N-methylpyridine amide (compound 5-2)

[0254] Referring to the preparation method in Example 2, the starting material L-proline methyl ester hydrochloride was replaced with D-proline methyl ester hydrochloride.

[0255] Molecular formula: C 23 H 26 F2N6O2 molecular weight: 456.5 LC-MS (m / z): 457.1 (M+H) + )

[0256] 1H-NMR (400MHz, CDCl3) δ: 7.99 (d, J = 8.0 Hz, 1H), 7.59 (s, 1H), 7.5 (s, 1H), 7.28-7.31 (m, 1H), 6.92-6.88 (m, 1H), 6.39 (d, J = 8.4Hz, 1H), 3.81-3. 75(m,1H),3.60(s,2H),3.51-3.45(m,1H),3.33-3.21(m,5H),3.01(d, J=5.1Hz,3H),2.71-2.62(m,4H),2.40-2.30(m,1H),2.20-2.05(m,3H).

[0257] Example 4: Preparation of 5-(4-((2,6-difluoro-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridine amide (compound 13)

[0258]

[0259] 1. Preparation of 1-bromo-2,4-difluoro-3-nitrobenzene

[0260] 1,3-Difluoro-2-nitrobenzene (10.0 g, 62.9 mmol) was dissolved in concentrated sulfuric acid (75 mL), and NBS (12.3 g, 69.2 mmol) was added. After the addition was complete, the mixture was reacted at 80 °C for 16 h. The solution was poured into ice water, extracted with ethyl acetate, and the organic phase was concentrated and purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 10:1) to obtain the target compound (12.0 g, yield 80.0%).

[0261] 2. Preparation of methyl 1-(4-bromo-3-fluoro-2-nitrophenyl)-4-fluoro-1H-pyrrole-2-carboxylic acid ester

[0262] 1-Bromo-2,4-difluoro-3-nitrobenzene (5.0 g, 21.1 mmol), methyl 4-fluoro-1H-pyrrole-2-carboxylic acid ester (3.3 g, 23.2 mmol), and cesium carbonate (13.7 g, 42.2 mmol) were dissolved in DMF (100 mL). After addition, the mixture was reacted at 25 °C for 2 h, and the reaction was stopped by LCMS. The solution was poured into water, extracted with ethyl acetate, and the organic phase was concentrated and purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 3:1) to obtain the target compound (6.0 g, yield 79.0%).

[0263] 3. Preparation of methyl 1-(2-amino-4-bromo-3-fluorophenyl)-4-fluoro-1H-pyrrole-2-carboxylic acid ester

[0264] Methyl 1-(4-bromo-3-fluoro-2-nitrophenyl)-4-fluoro-1H-pyrrole-2-carboxylic acid ester (5.0 g, 13.9 mmol) was dissolved in methanol (200 mL) and water (10 mL), and ammonium chloride (29.7 g, 556.0 mmol) was added. Iron powder (7.8 g, 138.9 mmol) was added at 0 °C. After the addition was complete, the mixture was reacted at 80 °C for 2 h. The mixture was filtered through diatomaceous earth, and the concentrated filtrate was used directly in the next step.

[0265] 4. Preparation of 7-bromo-2,6-difluoropyrrolo[1,2-a]quinoxaline-4(5H)-one

[0266] Methyl 1-(2-amino-4-bromo-3-fluorophenyl)-4-fluoro-1H-pyrrole-2-carboxylic acid ester (the crude product from the previous step) was dissolved in methanol (100 mL) and ethyl acetate (100 mL), and then ethyl acetate hydrochloride solution (30 mL) was added. After the addition was complete, the reaction was carried out at 25 °C for 2 h. The solution was concentrated, the pH was adjusted to >7 with saturated sodium bicarbonate aqueous solution, and the mixture was extracted with ethyl acetate. The organic phase was concentrated and purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 3:1) to obtain the target compound (1.0 g, yield 24.1%).

[0267] 5. Preparation of 2,6-difluoro-7-(hydroxymethyl)pyrrolo[1,2-a]quinoxaline-4(5H)-one

[0268] 7-Bromo-2,6-difluoropyrrolo[1,2-a]quinoxaline-4(5H)-one (300 mg, 1.0 mmol), tri-n-butyltin methanol (353 mg, 1.1 mmol), and XphosPdG2 (79 mg, 0.1 mmol) were dissolved in 1,4-dioxane (20 mL), and the reaction was carried out at 80 °C for 2 hours. The reaction was stopped by LCMS. The organic phase was dried and concentrated, and purified by column chromatography (SiO2, dichloromethane:methanol = 3:1) to obtain the target compound (200 mg, yield 80.0%).

[0269] Preparation of 6,7-(chloromethyl)-2,6-difluoropyrrolo[1,2-a]quinoxaline-4(5H)-one

[0270] 2,6-Difluoro-7-(hydroxymethyl)pyrrolo[1,2-a]quinoxaline-4(5H)-one (100 mg, 0.4 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of DMF (0.1 mL) and thionyl chloride (95 mg, 0.8 mmol). After the addition was complete, the reaction was carried out at 25 °C for 1 hour. The reaction was stopped by LCMS. The product was then concentrated directly to obtain 100 mg (yield 93.3%).

[0271] 7. Preparation of 5-(4-((2,6-difluoro-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridine amide

[0272] 7-(chloromethyl)-2,6-difluoropyrrolo[1,2-a]quinoxaline-4(5H)-one (80 mg, 0.30 mmol) and 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridineamide hydrochloride (79 mg, 0.29 mmol) were dissolved in acetonitrile (5 mL), and DIEA (116 mg, 0.9 mmol) was added. After the addition was complete, the reaction was carried out at 80 °C for 2 hours. The reaction was stopped by LCMS. The organic phase was concentrated and purified by silica gel plate (SiO2, dichloromethane:methanol = 15:1) and then purified by preparative liquid chromatography (acetonitrile = 0-70%) to obtain the target compound (60 mg, yield 44.3%).

[0273] Molecular formula: C 23 H 21 F3N6O2 molecular weight: 470.2 LC-MS (m / z): 471.1 (M+H) + )

[0274] 1 H-NMR(400MHz,DMSO)δ:11.53(s,1H),8.41(m1H),8.40(s,1H),7.85-7.78(m,2H),7.58-7.55(m,1H),7. 27-7.24(m,1H),6.96(s,1H),3.66(s,2H),3.18-3.16(m,4H),2.76(d,J=4.7Hz,3H),2.51-2.50(m,4H).

[0275] The compounds shown in the following table were prepared using the same or similar methods as those used in the preparation examples above:

[0276]

[0277] Experimental protocol

[0278] The following provides exemplary experimental schemes for some compounds of the present invention to demonstrate the beneficial activity and technical effects of the compounds. However, it should be understood that the following experimental schemes are merely examples of the content of the present invention and not limitations on the scope of the present invention.

[0279] Experimental Example 1: In vitro cellular inhibitory activity of the compounds of the present invention

[0280] Test sample: The compound of the present invention, the structural formula and preparation method of which are shown in the examples.

[0281] Reagents and cell lines used in the experiment:

[0282] DMEM: Dulbecco's modified eagle medium;

[0283] ITS-G: Insulin-Transferrin-Selenium Additive;

[0284] CTG: CellTiter-Glo Cell Viability Assay Kit;

[0285] Glutathione

[0286] FBS: Fetal bovine serum;

[0287] MDA-MB-436: BRCA1-mutated human breast cancer cells.

[0288] Experimental Method (CelltiterGlo assay)

[0289] 1. Prepare cells

[0290] 1.1 Cell Culture:

[0291] MDA-MB-436 cells are adherent cells, and the culture medium is DMEM + 10% FBS + 1% ITS-G + 16 μg / ml glutathione.

[0292] 1.2 Preparation of cell suspension:

[0293] Cells in the logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was assessed using the trypan blue rejection assay to ensure it was above 90%. The concentration was adjusted, and 90 μL of cell suspension was added to each well of a 96-well plate.

[0294] Table 1. Number of cells seeded

[0295]

[0296] 2. Preparation of test compounds

[0297] 2.1 Prepare a DMSO stock solution for the test compound. The stock solution concentration of the test compound is 10 mM.

[0298] 2.2 Preparation of working stock solution for test compounds

[0299] The 10 mM stock solution of the test compound was diluted 10-fold with DMSO to 1 mM, followed by a 3-fold serial dilution with DMSO, resulting in a total of 9 concentrations. Then, 2 μL of each serially diluted compound was added to 198 μL of culture medium (DMEM + 10% FBS + 1% ITS-G + 16 μg / ml glutathione) to prepare the working stock solution (the working stock solution concentration was 10 times the final concentration, with a maximum working stock solution concentration of 10 μM).

[0300] 2.3 Compound Treatment

[0301] Add 10 μL of the compound working stock solution (10-fold dilution, final DMSO concentration 0.1%) to each well of a 96-well plate seeded with cells.

[0302] The final concentrations of the tested compounds were: 1000.00 nM, 333.33 nM, 111.11 nM, 37.04 nM, 12.35 nM, 4.11 nM, 1.37 nM, 0.46 nM, and 0.15 nM.

[0303] 2.4 Setting of reference holes

[0304] Solvent control: 0.1% DMSO (2 μL of DMSO was diluted in 198 μL of culture medium, and 10 μL was added to the well plate).

[0305] Blank control: 96-well plate readings at 0 h after drug administration.

[0306] 2.5 Place the 96-well plate in a 37°C, 5% CO2 cell culture incubator and culture for 7 days.

[0307] 3. Testing

[0308] Melt the CTG reagent and equilibrate the 96-well plate to room temperature for 30 minutes. Add 60 μL of reagent (Celltiter Gloassay kit) to each well, shake for 2 minutes to mix (protect from light), and incubate at room temperature for 20 minutes (protect from light). Read the light signal value using a multi-functional microplate reader.

[0309] 4. Data Processing

[0310] 1) Inhibition rate (%) = (DMSO solvent control well reading - test sample well reading) / (DMSO solvent control well reading - blank control well reading) × 100%;

[0311] 2) Plot the graph to obtain the curve and IC. 50 .

[0312] Experimental Results and Conclusions

[0313] Table 2. In vitro cellular activities of the compounds of the present invention

[0314]

[0315]

[0316] In addition, other compounds of the present invention also exhibit good inhibitory activity against the proliferation of MDA-MB-436 cells, such as compound 5-2 with an IC50 value of [missing information]. 50 The values ​​range from 1 to 200 nM. As shown in Table 2, the compounds of this invention can effectively inhibit the proliferation of MDA-MB-436 cells, indicating that the compounds of this invention can significantly inhibit the growth of cells with DNA repair defects and have clinical application potential in treating cancerous diseases with DNA repair defects.

[0317] Experimental Example 2: In vitro enzymatic activity of the compounds of the present invention

[0318] Test sample: The compound of the present invention, the structural formula and preparation method of which are shown in the examples.

[0319] Experimental reagents:

[0320]

[0321] Laboratory consumables:

[0322] Consumables supplier 384-Well plate Perkin Elmer

[0323] Experimental methods:

[0324] 1. Preparation of histone-coated 384-well plates

[0325] Add 5 μL of histone solution to each well of a 384-well plate and incubate overnight at 4°C.

[0326] 2. Rinse the histone-coated 384-well plate three times with PBST buffer. Incubate with 50 μL of blocking buffer at room temperature for 1 hour. Wash the plate three times with PBST buffer.

[0327] 3. Compound dilution

[0328] 1) The compound of the present invention was prepared to 20 mM using DMSO as a test stock solution.

[0329] 2) The stock solution of the compound of the present invention was serially diluted 4 times to 10 concentrations, with the highest concentration being 20 mM.

[0330] 3) Add 50 nL of the diluted compound solution to each well of a 96-well plate, then add 19.95 μL of the working solution to each well, and centrifuge at 1000 rpm for 1 min. Transfer 5 μL of the compound to a prepared 384-well plate.

[0331] 4. Enzyme reaction experiment

[0332] 1. Add 10 μL of DNA solution to the negative control well, and add 10 μL of PARP1 and DNA to the non-control well.

[0333] (Or PARP2 & DNA) mixture, then add 10 μL of NAD+ reagent to each well, and incubate at 25°C for 60 hours.

[0334] min.

[0335] 2. Wash the 384-well plate three times with PBST buffer;

[0336] 3. The final concentrations of the tested compounds were 1000 nM, 250 nM, 62.5 nM, 15.6 nM, 3.9 nM, 0.98 nM, 0.24 nM, 0.061 nM, 0.015 nM, and 0.0038 nM.

[0337] 5. Testing

[0338] 1. Add 20 μL of anti-Poly / Mono-ADP Ribose Rabbit mAb to each well, incubate at room temperature for 1.5 h, and then wash the 384-well plate three times with PBST buffer;

[0339] 2. Dilute anti-rabbit IgG and HRP-linked Antibody 2000 times with blocking buffer, add 200 μL of diluted antibody to each well, incubate at room temperature for 1 h, and wash the 384-well plate 3 times with PBST buffer.

[0340] 3. Add 25 μL of SuperSignal ELISA Femto Substrate to each well for chemiluminescence detection.

[0341] 6. Data Analysis

[0342] The inhibition rate (%inh) is calculated using the following formula:

[0343]

[0344] Where Max represents the luminescence signal intensity of the positive control well without the addition of the compound;

[0345] Min represents the luminescence signal intensity of the negative control well without enzyme addition;

[0346] Signal indicates the intensity of the luminescence signal of the test compound;

[0347] IC is calculated using the following formula. 50 :

[0348]

[0349] Where Y represents: %inhibition;

[0350] X represents the concentration of the compound;

[0351] Top: Maximum inhibition rate; Bottom: Minimum inhibition rate;

[0352] HillSlope: The absolute value of the maximum slope of the curve (i.e., the midpoint of the curve).

[0353] 7. Experimental Results:

[0354] Table 3 Enzymatic inhibitory activities of the compounds of the present invention

[0355]

[0356] 8. Experimental Conclusions

[0357] The experimental results above show that the compound of the present invention can effectively inhibit the activity of PARP1, and has good inhibitory activity and selectivity for PARP1. It is a highly selective and effective PARP1 inhibitor.

[0358] Experimental Example 3: In vivo pharmacokinetic experiment of the compound of the present invention in SD rats

[0359] Test samples: Compounds of this invention, prepared in-house; their chemical names and preparation methods are detailed in the preparation examples for each compound. Test animals: Male SD rats, 9 rats per compound.

[0360] Preparation of test solution:

[0361] Preparation of blank solvent: Weigh 20g HPC (hydroxypropyl cellulose), slowly add it to 500mL of purified water under stirring, then add 1mL of Tween 80, stir until clear and transparent, bring the volume to 1000mL, and stir evenly to obtain 2% HPC + 0.1% Tween 80.

[0362] PO (oral) administration:

[0363] Weigh 26.24 mg of compound 5-1 from the present invention, place it in a tissue homogenizer, add 25.82 mL of blank solvent, and homogenize at 1000 rpm to prepare a 1 mg / mL suspension, which is used as the PO administration solution for the test compound.

[0364] Weigh 26.84 mg of compound 13 from the present invention embodiment, place it in a tissue homogenizer, add an appropriate amount of blank solvent, homogenize thoroughly, and transfer the homogenizing solution to a glass bottle; add blank solvent in small amounts several times to clean the tissue homogenizer, and transfer the cleaning solution to the glass bottle as well; add a total of blank solvent (25.0 ml); shake to mix well, and prepare a 1 mg / mL suspension, which is used as the PO administration solution for the test compound.

[0365] Experimental methods

[0366] The PO dosage is 10 mg / kg, the concentration is 1 mg / mL, and the volume is 10 mL / kg.

[0367] Blood sampling time points: 0.167, 0.5, 1, 2, 4, 6, 8, and 24 hours after drug administration; brain sampling time points: 0.5, 4, and 24 hours after drug administration, as shown in the table below.

[0368]

[0369] Plasma collection: At each time point, approximately 100 μL of whole blood was collected via the tail vein and placed into an anticoagulant tube containing EDTA-K2. The plasma sample was obtained by centrifugation at 8000 rpm for 6 min at 4°C and then stored at -80°C for analysis.

[0370] Brain tissue collection: Before brain tissue collection, the animal was anesthetized, blood was collected as much as possible, the heart was perfused, the brain tissue was separated, the intact brain tissue was washed in 0.9% physiological saline, the moisture was blotted with filter paper, weighed, and frozen in a -80℃ freezer for analysis.

[0371] plasma sample analysis

[0372] Protein precipitation method was used: 20 μL of plasma sample was taken, and 200 μL of internal standard (acetonitrile solution containing 200 ng / mL tolbutamide) was added. After vortexing for 10 min, the sample was centrifuged at 4000 rpm for 20 min. 100 μL of supernatant was taken, and 100 μL of water was added. After vortexing for 3 min, the drug concentration in plasma was analyzed by LC-MS / MS.

[0373] Brain tissue sample analysis

[0374] Based on the weight of the brain tissue, add 5 times the weight of pure water and homogenize to obtain a brain tissue homogenate. Take 50 μL of the brain tissue homogenate, add 300 μL of internal standard (acetonitrile solution containing 200 ng / mL tolbutamide), vortex for 10 min, centrifuge at 12000 rpm for 5 min, take 100 μL of the supernatant, add 100 μL of water, vortex for 3 min, and then analyze the drug concentration in the brain tissue homogenate by LC-MS / MS.

[0375] Experimental results

[0376] Table 4. PK Evaluation Results of SD Rats

[0377]

[0378] T 1 / 2 T represents the terminal elimination half-life; max Represents peak time; C max Represents peak concentration; AUC 0-t The area under the curve (AUC) represents the drug's response time from 0 to t. 0-t The ratio (Brain / Plasma) represents the ratio of brain tissue exposure to plasma exposure.

[0379] Experimental conclusions

[0380] The test results show that the compound of this invention has good blood-brain barrier permeability in rats.

Claims

1. A compound represented by general formula (I), its pharmaceutically acceptable salt, or its stereoisomer, （I） in, X1 is N; X2 is CH; Ring A is selected from: ； Ring B is selected from: ； Ar is selected from pyridinyl groups optionally substituted with 1-2 substituents Q; each Q is independently selected from H, halogen, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkyl group, -(CH2) p -C(O)N(R a (R) b )、-(CH2) p -N(R b )-C(O)(R a ); R is selected from hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy; Each R 1 Each R 2 Each is independently selected from H, halogen, hydroxyl, amino, cyano, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy; R a R b Selected independently from hydrogen and C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl or C 1-6 Alkoxy-C 1-6 alkyl; m and n are independently selected from 0, 1 or 2 respectively; p is selected from 0, 1, or 2; q is selected from 1; And formula (I) is not one of the following compounds: 、 、 、 、 、 、 、 、 。 2. The compound of claim 1, its pharmaceutically acceptable salt, or its stereoisomer, wherein, Ring A is selected from ; Ring B is ; Ar is selected from pyridinyl groups optionally substituted with 1-2 Q groups; each Q group is independently selected from H, halogen, hydroxyl, amino, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl group, -(CH2) p -C(O)N(R a (R) b ); R is selected from hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy; Each R 1 Each R 2 Each is independently selected from H, halogen, hydroxyl, amino, cyano, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy; R a R b Selected independently from hydrogen and C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 alkyl; m, n, and p are each independently selected from 0, 1, or 2; q is 1; Furthermore, formula (I) is not one of the following compounds: 、 、 、 、 、 、 、 、 。 3. The compound of claim 2, its pharmaceutically acceptable salt, or its stereoisomer, wherein, Ar is selected from pyridinyl groups optionally substituted with 1-2 Q groups; each Q group is independently selected from H, fluorine, chlorine, hydroxyl, amino, C. 1-4 Alkyl, fluorinated C 1-4 Alkyl, C 1-4 Alkoxy, fluorinated C 1-4 Alkoxy, -C(O)N(R) a (R) b ); R is selected from hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy; Each R 1 Each R 2 Each is independently selected from H, fluorine, chlorine, hydroxyl, amino, cyano, and C. 1-4 Alkyl, fluorinated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, fluorinated C 1-4 Alkoxy; R a R b Each is independently selected from hydrogen, methyl, ethyl, or isopropyl; m and n are independently selected from 0, 1 or 2 respectively; q is 1; Furthermore, formula (I) is not one of the following compounds: 、 、 、 、 、 、 、 、 。 4. The compound of claim 1, its pharmaceutically acceptable salt, or its stereoisomer, selected from the following compounds: 。 5. A pharmaceutical composition comprising the compound of any one of claims 1-4, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and one or more pharmaceutically acceptable excipients.

6. Use of the compound of any one of claims 1-4, its pharmaceutically acceptable salt or stereoisomer thereof, or the pharmaceutical composition of claim 5 in the preparation of a medicament for the prevention and / or treatment of diseases associated with PARP overexpression, said diseases being selected from: neuropathic pain, epilepsy, stroke, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, schizophrenia, atherosclerosis, hyperlipidemia, myocardial infarction, diabetic neuropathy, osteoarthritis or osteoporosis.

7. Use of the compound of any one of claims 1-4, its pharmaceutically acceptable salt or its stereoisomer, or the pharmaceutical composition of claim 5 in the preparation of a medicament for the prevention and / or treatment of cancers associated with PARP overexpression.

8. The use as described in claim 7, wherein the cancer lacks the HR-dependent DNA DSB repair pathway.

9. The use as claimed in claim 7, wherein the cancer comprises one or more cancer cells that lack BRCA1 and / or BRCA2, or the cancer cells have a BRCA1 and / or BRCA2 defective phenotype.

10. The use as described in claim 7, wherein the cancer is selected from breast cancer, ovarian cancer, endometrial cancer, cervical cancer, lung cancer, prostate cancer, pancreatic cancer, leukemia, gastric cancer, gallbladder cancer, liver cancer, head and neck cancer, esophageal cancer, kidney cancer, brain cancer, colon cancer, lymphoma, or melanoma.

11. Use of the compound of any one of claims 1-4, its pharmaceutically acceptable salt or stereoisomer thereof, or the pharmaceutical composition of claim 5 in the preparation of a medicament for the prevention and / or treatment of diseases associated with PARP overexpression, said diseases being selected from: chronic and acute pain, ischemia, neurodegenerative diseases or coronary artery diseases.

12. Use of the compound of any one of claims 1-4, its pharmaceutically acceptable salt or stereoisomer thereof, or the pharmaceutical composition of claim 5 in the preparation of a medicament for the prevention and / or treatment of diseases associated with PARP overexpression, wherein the diseases are selected from: hypoxic neuronal injury or cardiac tissue injury.

13. Use of the compound of any one of claims 1-4, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or the pharmaceutical composition of claim 5 in the preparation of a medicament for the prevention and / or treatment of diseases associated with PARP overexpression, wherein the disease is selected from: cardiogenic shock.

14. The use as described in claim 7, wherein the cancer is selected from leukemia or glioblastoma.

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