PARP1 inhibitors

Abstract

The present invention provides a PARP1 inhibitor represented by formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate, or solvate thereof. The present invention also provides a method for producing the compound, a pharmaceutical composition containing the compound, and the effect of the compound in the prevention and treatment of cancer, ischemic disease, or neurodegenerative disease. [C1] TIFF2026501329000048.tif53156

Description

[Technical Field]

[0001] This application claims priority to Chinese Patent Application No. 202211668333.2 filed on December 23, 2022, and Chinese Patent Application No. 202311484011.7 filed on November 8, 2023, which are incorporated herein by reference in their entireties.

[0002] <Technical field> The present invention relates to novel PARP1 inhibitors, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, crystalline polymorphs, hydrates, or solvates thereof. The present invention further relates to methods for preparing said compounds, pharmaceutical compositions containing said compounds, and the effects of said compounds in the prevention and treatment of PARP1-mediated diseases, such as cancer. [Background technology]

[0003] Adenosine diphosphate ribosylation (ADP-ribosylation) is an enzymatic reaction process that cleaves the substrate nicotinamide adenine dinucleotide (NAD+) into nicotinamide and an ADP-ribose group covalently attached to receptor proteins. ADP-ribosylation is a common and reversible post-translational protein modification that plays an important role in a range of biological processes, including DNA damage repair, cell proliferation and differentiation, metabolism, and stress.

[0004] Poly ADP-ribose polymerase (PARP) is a family of proteins that can catalyze ADP-ribosylation. PARP1 is the most widely studied and important member of this family of proteins. It is highly expressed in cells and has a rapid response rate. It can rapidly catalyze and modify DNA repair factors, interact with them, and participate in various DNA repair processes. In normal cells, DNA single-strand breaks can be repaired by base excision. PARP1 uses NAD+ as a substrate, binds to the damaged site via its zinc finger domain, changes its conformation, and catalyzes the transfer of ADP-ribose groups, ultimately completing the single-strand repair. In cancer cells with double-strand breaks (DSBs), DNA breaks are primarily repaired by homologous recombination (HR), and BRCA1 and BRCA2 are key proteins mediating HR. In cancer cells with BRCA1 / 2 mutations, simultaneous inhibition of PARP1 function leads to the impairment of major DNA repair pathways, ultimately resulting in cell death, a synthetic lethal effect that has now been well-validated clinically. Therefore, PARP1 has become a promising target for cancer therapy.

[0005] In recent years, four small molecule PARP inhibitors (PARPi) have been approved by the US FDA for cancer treatment: olaparib, niraparib, rucaparib, and telazoparib. These drugs have already demonstrated excellent clinical efficacy in treating patients with BRCA1 / 2-mutated ovarian and / or breast cancer, and also show excellent prospects for patients with other BRCA-mutated cancers, including prostate and pancreatic cancers.

[0006] Recent studies have demonstrated that the mechanism of action of PARPi can be attributed to two distinct but interrelated mechanisms. First, by inhibiting PARP1 catalytic inhibition, these PARPi block the synthesis of PAR chains, thereby inhibiting the generation of poly(ADP-ribosylation) modification (PARylation) and blocking PARP1-mediated DNA damage repair signaling. Second, PARP inhibitors can also induce PARP1 trapping, leading to DNA double-strand breaks and ultimately cancer cell death. When PARP1 protein undergoes PARylation modification, it detaches from DNA damage sites due to steric hindrance and charge repulsion of PAR chains. However, treatment with PARP inhibitors blocks PARP1 self-repair, resulting in PARP1 being trapped at DNA damage sites. The prolonged PARP-DNA complex occupies the DNA damage site, preventing subsequent DNA replication, leading to stalled replication forks and subsequent double-strand DNA breaks, and thereby causing cell death. However, PARP1 trapping occurs in association with inhibition of PARP1 catalytic activity, and thus, although functionally distinct, inhibition of PARP1 catalytic activity by PARP inhibitors and PARP1 trapping are intrinsically related.

[0007] Based on the synthetic lethality mechanism, cell lines with BRCA1 / 2 mutations or homologous recombination deficiency (HRD) are highly sensitive to PARP inhibitors, providing a very wide therapeutic safety window for drug treatment. However, some normal cells in the body, such as bone marrow-derived cells, are constantly in a state of rapid proliferation, making DNA damage inevitable. Furthermore, many selected patients have germline mutations, and the use of approved non-selective PARP1 / 2 inhibitors can cause various hematologic toxicities, including anemia, neutropenia, and thrombocytopenia. The occurrence of grade 3 or 4 hematologic toxicities often leads to dose reduction, interruption, or discontinuation of the drug, significantly impacting the therapeutic efficacy of PARP inhibitors in patients.

[0008] On the other hand, chemotherapy drugs and PARP inhibitors have the basis for potential synergistic effects when combined, but because chemotherapy drugs suppress rapidly proliferating cells and have strong hematologic toxicity, the combination of the two drugs causes additive hematologic toxicity, which significantly limits the use of PARP inhibitors.

[0009] Research has shown that the anemic response caused by PARP inhibitors may be primarily due to inhibition of PARP2 (Farres J, et al. Cell Death Differ. 2015 Jul;22(7):1144-57). All currently available PARPi drugs also have inhibitory activity against PARP1 / 2. Therefore, the development of highly selective PARP1 inhibitors with reduced inhibition of PARP2 may potentially avoid the anemic toxicity caused by conventional PARP1 / 2 inhibitors. WO 2021013735A1 disclosed a series of selective PARP1 inhibitors, such as AZD5305. [ka]

[0010] Therefore, the development of more highly selective PARP1 inhibitors has important clinical application value, and there is a need for such inhibitors in the art. Summary of the Invention [Problem to be solved by the invention]

[0011] The present invention uses PARP1 as a target to develop novel small molecule inhibitors, which can be used to treat various cancers.

[0012] The compounds of the present invention target PARP1 and have excellent PARP1 inhibitory activity and selectivity, thereby avoiding anemia toxicity. At the same time, the compounds of the present invention have different distribution volumes (reducing neutrophil and platelet toxicity) and different trapping activities (helping to adjust drug doses), which can reduce blood toxicity while maintaining the clinical efficacy of PARP1 / 2 inhibitors, and enable the further combination of highly selective PARP1 inhibitors with chemotherapy drugs.

[0013] In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, [ka] where: L1 is selected from CRR′, O, S, NH, —C(O)—, —S(O)—, or —S(O)2—; R and R' are independently H, D, halogen, or C 1-6 Alkyl group or C 1-6 haloalkyl groups, A is CR A or N, E is CR E or N, G is CR G or N, R A , R E and R G are independently H, D, halogen, CN, -L-OR a , -L-SR a , -L-NR b R c , C1-6 Alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -LC 3-10 a cycloalkyl group or an -L-3 to 10-membered heterocyclyl group; R1 is H, D, halogen, CN, -L-OR a , -L-SR a , -L-NR b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -LC 3-10 Cycloalkyl group, -L-3 to 10-membered heterocyclyl group, -LC 6-10 an -L-aryl group or an -L-5 to 10 membered heteroaryl group, which optionally has one, two or three R 1s is replaced by R 1s are independently H, D, halogen, CN, OR a , S.R. a , N.R. b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-10 Cycloalkyl groups, 3- to 10-membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 10-membered heteroaryl group; [ka] represents a single bond or a double bond, M1 is selected from N, C, or CR5; M2 is N or CR6; R5 and R6 are independently H, D, halogen, or C 1-6 Alkyl group or C 1-6 haloalkyl groups, R4 independently represents H, D, halogen, CN, =O, OR a , S.R.a , N.R. b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 cycloalkyl or 3- to 7-membered heterocyclyl group, which optionally has one, two, or three R 4s is replaced by Or R4 and R2 in the ortho position of M1 and the atoms connected thereto together form C 5-7 R4 and Z3 in the ortho position of M1 and the atoms connected thereto together form a cycloalkyl group or a 5- to 7-membered heterocyclyl group, or C 5-7 Forming a cycloalkyl group or a 5- to 7-membered heterocyclyl group, which optionally contains one, two, or three R 4s is replaced by R 4s are independently H, D, halogen, CN, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 selected from a cycloalkyl group or a 3- to 7-membered heterocyclyl group; n is 0, 1, 2, 3 or 4; Z1 is selected from CR7 or N; Z2 is selected from CR8 or N; Z3 is selected from CR9 or N; R2, R7, R8 and R9 are independently H, D, halogen, CN, OR a , S.R. a , N.R. b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 cycloalkyl or 3- to 7-membered heterocyclyl group, which optionally has one, two, or three R 2s is replaced by R 2s are independently H, D, halogen, CN, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 selected from a cycloalkyl group or a 3- to 7-membered heterocyclyl group; R3 is H, -L-OR a , -L-SR a , -L-NR b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -LC 3-10 Cycloalkyl group, -L-3 to 10-membered heterocyclyl group, -LC 6-10 an -L-aryl group or an -L-5 to 10 membered heteroaryl group, which optionally has one, two or three R 3s is replaced by R 3s are independently H, D, halogen, CN, OR a , S.R. a , N.R. b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-10 Cycloalkyl groups, 3- to 10-membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 10-membered heteroaryl group; L is a chemical bond, C 1-6 Alkylene group, C 2-6 Alkenylene group or C 2-6 Alkynylene groups, which may optionally be H, D, halogen, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group or C 2-6 alkynyl groups; R a , R b and R c are independently H, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-10 cycloalkyl group or 3- to 10-membered heterocyclyl group, or R b , R cand the atoms to which they are connected, taken together, form a 5- to 10-membered heterocyclyl group; wherein each of the above group definitions is optionally deuterated until fully deuterated.

[0014] In another aspect, the present invention provides a pharmaceutical composition, said pharmaceutical composition comprising a compound of the present invention and optionally a pharmaceutically acceptable excipient, such as a carrier, adjuvant, or vehicle.

[0015] In another aspect, the present invention provides the use of a compound of the present invention or a pharmaceutical composition of the present invention in the manufacture of a medicament for treating and / or preventing a PARP-mediated disease, preferably wherein said PARP is PARP1.

[0016] In another aspect, the present invention provides a method for treating and / or preventing a PARP-mediated disease in a subject, said method comprising administering to said subject a compound of the present invention or a pharmaceutical composition of the present invention, wherein preferably said PARP is PARP1.

[0017] In another aspect, the present invention provides a compound of the present invention or a pharmaceutical composition of the present invention for treating and / or preventing a PARP-mediated disease, preferably wherein said PARP is PARP1.

[0018] In particular embodiments, the present invention is for treating and / or preventing cancer, ischemic diseases and neurodegenerative diseases.

[0019] In another specific embodiment, said cancer is deficient in an HR-dependent DNA DSB repair pathway.

[0020] In another specific embodiment, said cancer has a BRCA1 or BRCA2 deficient phenotype.

[0021] In another specific embodiment, the present invention is for treating and / or preventing the following cancers: breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer, and lung cancer.

[0022] definition chemistry definition Specific functional groups and chemical term definitions are described in more detail below.

[0023] When numerical ranges are recited, it is intended to include each value and subrange within said range. For example, "C 1-6 "Alkyl group" refers to C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 and C 5-6 Contains an alkyl group.

[0024] "C 1-6 An "alkyl group" refers to the radical of a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 Alkyl group, C 1-3 Alkyl groups and C 1-2 Alkyl groups are preferred. 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). 1-6The term "alkyl group" further includes heteroalkyl groups, in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced with a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkyl groups are optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Common alkyl group abbreviations include Me(-CH), Et(-CHCH), iPr(-CH(CH)), nPr(-CHCHCH), n-Bu(-CHCHCHCHCH), or i-Bu(-CHCH(CH)).

[0025] "C 2-6 An "alkenyl group" refers to the radical of a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 Alkenyl groups are preferred. 2-6 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. 2-6 The term "alkenyl group" further includes heteroalkenyl groups, in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkenyl groups are optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0026] "C 2-6 An "alkynyl group" refers to the radical of a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 Alkynyl groups are preferred. 2-6Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), hexynyl (C6), and the like. 2-6 The term "alkynyl group" further includes heteroalkynyl groups, in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkynyl groups are optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0027] "C 1-6 The alkylene group is C 1-6 It refers to a divalent radical formed by removing another hydrogen from an alkyl group, and may be substituted or unsubstituted. In some embodiments, C 1-4 Alkylene group, C 2-4 Alkylene group and C 1-3 An alkylene group is preferred. Examples of the unsubstituted alkylene group include, but are not limited to, a methylene group (-CH-), an ethylene group (-CHCH-), a propylene group (-CHCHCH-), a butylene group (-CHCHCHCHCH-), a pentene group (-CHCHCHCHCHCH-), a hexylene group (-CHCHCHCHCHCHCH-), and the like. Exemplary substituted alkylene groups, for example, alkylene groups substituted with one or more alkyl groups (methyl groups), include substituted methylene groups (-CH(CH)-, -C(CH)-), substituted ethylene groups (-CH(CH)CH-, -CHCH(CH)-, -C(CH)CH-, -CHC(CH)-). 2- ), substituted propylene groups (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-).

[0028] "C2-6 The "alkenylene group" is C 2-6 It refers to a divalent radical formed by removing another hydrogen from an alkenyl group, and may be substituted or unsubstituted. In some embodiments, C 2-4 Alkenylene groups are particularly preferred. Exemplary unsubstituted alkenylene groups include, but are not limited to, vinylene groups (-CH=CH-) and propenylene groups (e.g., -CH=CHCH-, -CH-CH=CH-). Exemplary substituted alkenylene groups, for example, alkenylene groups substituted with one or more alkyl groups (methyl groups), include, but are not limited to, substituted ethylene groups (-C(CH)=CH-, -CH=C(CH)-), substituted propenylene groups (-C(CH)=CHCH-, -CH=C(CH)CH-, -CH=CHCH(CH)-, -CH=CHC(CH)-, -CH(CH)-CH=CH-, -C(CH)-CH=CH-, -CH-C(CH)=CH-, -CH-CH=C(CH)-).

[0029] "C 2-6 The "alkynylene group" is C 2-6 It refers to a divalent radical formed by removing another hydrogen from an alkynyl group, and may be substituted or unsubstituted. In some embodiments, C 2-4 Alkynylene groups are particularly preferred. Exemplary alkynylene groups include, but are not limited to, ethynylene groups (-C≡C-), substituted or unsubstituted propynylene groups (-C≡CCH2-), and the like.

[0030] "C 0-6 The "alkylene group" is a group formed by a chemical bond and the above "C 1-6 "C" refers to an alkylene group. 0-4 The "alkylene group" is a group formed by a chemical bond and the above "C 1-4 It refers to an "alkylene group."

[0031] "Halogenated" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0032] Therefore, "C 1-6 "Haloalkyl group" refers to the above "C 1-6 In some embodiments, C refers to an "alkyl group" which is substituted with one or more halogen groups. 1-4 Haloalkyl groups are particularly preferred, more preferably C 1-3 haloalkyl groups, more preferably C 1-2 haloalkyl groups. Exemplary haloalkyl groups include, but are not limited to, -CF, -CHF, -CHFCHF, -CHCHF, -CFCF, -CCl, -CHCl, -CHCl, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like. Haloalkyl groups can be substituted at any available attachment point with, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0033] "C 1-6 "Deuterated alkyl group" refers to the above "C 1-6 In some embodiments, C refers to an "alkyl group" which is substituted with one or more deuterium groups. 1-4 Deuterated alkyl groups are particularly preferred, more preferably C 1-2 deuterated alkyl groups, more preferably C 1-2 Deuterated alkyl groups. Exemplary deuterated alkyl groups include, but are not limited to, -CD3, -CHD2, -CH2D, -CHDCH2D, -CH2CD3, -CD2CD3, etc. The deuterated alkyl group may be substituted at any available attachment point with, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0034] "C 3-10 "Cycloalkyl group" refers to the radical of a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms, which optionally contains 1, 2, or 3 double or triple bonds. In some embodiments, C 5-10 Cycloalkyl groups, C 3-7 Cycloalkyl groups and C 3-6 Cycloalkyl groups are particularly preferred, more preferably C 5-7Cycloalkyl groups and C 5-6 Cycloalkyl groups are also included. Cycloalkyl groups further include ring systems in which the cycloalkyl ring is fused to one or more aryl or heteroaryl groups and the point of attachment is at the cycloalkyl ring; in such cases, the number of carbons continues to represent the number of carbons in the cycloalkyl group system. Cycloalkyl groups further include the cycloalkyl rings in which substituents at any non-adjacent carbon atoms are linked to each other to form a bridged ring, and together form a polycyclic alkane sharing two or more carbon atoms. Cycloalkyl groups further include the cycloalkyl rings in which substituents at the same carbon atom are linked to each other to form a ring, and together form a polycyclic alkane sharing one carbon atom. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), etc. The cycloalkyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0035] "C 3-10 The "cycloalkylene group" is C 3-10 It refers to a divalent radical formed by removing another hydrogen from a cycloalkyl group, and may be substituted or unsubstituted. 5-10 Cycloalkylene group, C 5-7 Cycloalkylene group, C 3-7 Cycloalkylene group, C 3-6 Cycloalkylene group and C 3-4 A cycloalkylene group is particularly preferred, and a cyclopropylene group is particularly preferred.

[0036] A "3- to 10-membered heterocyclyl group" refers to a saturated or unsaturated group of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 5 cycloheteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, and optionally containing 1, 2, or 3 double or triple bonds. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, if valence permits. In some embodiments, it is preferably a 5- to 10-membered heterocyclyl group, which is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 5 cycloheteroatoms; in some embodiments, it is preferably a 3- to 7-membered heterocyclyl group, which is a 3- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 4 cycloheteroatoms; preferably a 5- to 7-membered heterocyclyl group, which is a 5- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 3 cycloheteroatoms; preferably a 3- to 6-membered heterocyclyl group, which is a 3- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 cycloheteroatoms; preferably a 4- to 6-membered heterocyclyl group, which is a 4- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 cycloheteroatoms; more preferably a 5- to 6-membered heterocyclyl group, which is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 cycloheteroatoms. Heterocyclyl groups also include ring systems in which the heterocyclyl ring is fused to one or more cycloalkyl groups and the point of attachment is on the heterocyclyl ring, or in which the heterocyclyl ring is fused to one or more aryl or heteroaryl groups and the point of attachment is on the heterocyclyl ring; in such cases, the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system. Heterocyclyl groups also include heterocyclyl rings in which substituents on any non-adjacent carbon or nitrogen atoms are linked to each other to form a bridged ring, and together form a polycyclic heteroalkane sharing two or more carbon or nitrogen atoms. Heterocyclyl groups also include heterocyclyl rings in which substituents on the same carbon atom are linked to each other to form a ring, and together form a polycyclic heteroalkane sharing one carbon atom.Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuryl, dihydrofuryl, 2,5-dihydrofuryl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, pyrazolidinyl, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxane. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 5-membered heterocyclyl groups (herein referred to as 5,6-bicyclic heterocyclic groups) fused to a C6 aryl ring include, but are not limited to, dihydroindolyl groups, isodihydroindolyl groups, dihydrobenzofuryl groups, dihydrobenzothienyl groups, benzoxazolinone groups, etc. Exemplary 6-membered heterocyclyl groups (herein referred to as 6,6-bicyclic heterocyclic groups) fused to a C6 aryl group include, but are not limited to, tetrahydroquinolyl groups, tetrahydroisoquinolyl groups, etc.Heterocyclyl groups further include ring systems in which the heterocyclyl group shares one or two atoms with a cycloalkyl, heterocyclyl, aryl, or heteroaryl group to form a bridged or spiro ring, and the shared atoms may be carbon or nitrogen atoms, if valence permits. Heterocyclyl groups further include ring systems in which the heterocyclyl group and the heterocyclyl radical may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0037] "C 6-10 An "aryl group" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having 6 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, an aryl group has 6 ring carbon atoms (a "C6 aryl group," e.g., a phenyl group). In some embodiments, an aryl group has 10 ring carbon atoms (a "C 10 "Aryl" groups, e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl groups. Aryl further includes ring systems in which the aryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is at the aryl; in such cases, the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Aryl groups are optionally substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0038] A "5- to 10-membered heteroaryl group" refers to a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π-electrons shared in a cyclic arrangement) having ring carbon atoms and 1 to 4 cycloheteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryls containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, if valence permits. Bicyclic systems of heteroaryl groups may contain one or more heteroatoms in one or both rings. Heteroaryl groups further include ring systems in which the heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is at the heteroaryl ring; in such cases, the number of carbon atoms continues to refer to the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5- to 6-membered heteroaryl groups are particularly preferred, which are 5- to 6-membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1 to 4 cycloheteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and thienyl groups. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl groups. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl groups. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl groups. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridyl or pyridonyl groups. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl groups. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl groups, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl groups.Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuryl, benzisofuryl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indanyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolyl, quinoxalyl, phthalazinyl, and quinazolyl. The heteroaryl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0039] Divalent radicals formed by removing another hydrogen from groups such as alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups defined above are collectively referred to as "subunits." Groups that form rings with cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are collectively referred to as "cyclic groups."

[0040] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups, etc., as defined herein are optionally substituted groups.

[0041] Exemplary atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(ORcc )2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa)2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), alkyl groups, haloalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, wherein each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, Or two geminal hydrogens on a carbon atom are =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb or =NOR cc is substituted with a group R aa each independently selected from an alkyl group, a haloalkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, or two R aagroups join to form a heterocyclyl group or a heteroaryl ring, where each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R bb each independently represents hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups, or two R bb groups are linked to form a heterocyclyl group or a heteroaryl ring, where each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R cc each independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, or two R ccare joined to form a heterocyclyl group or a heteroaryl ring, where each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R dd each independently represents a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2,,-N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)Ree , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R gg or two geminal R dd the substituents can be linked to form =O or =S; R ee are independently selected from alkyl groups, haloalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups, heterocyclyl groups, and heteroaryl groups, wherein each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R gg is substituted with a group, R ff each independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, or two R ff groups are linked to form a heterocyclyl group or a heteroaryl ring, where each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R gg is substituted with a group, R gg each independently represents a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC1-6 Alkyl group, -ON(C 1-6 alkyl)2, -N(C 1-6 alkyl)2, -N(C 1-6 Alkyl)3 + X - , -NH(C 1-6 alkyl)2 + X - , -NH2(C 1-6 alkyl) + X - , -NH3 + X - , -N(OC 1-6 Alkyl)(C 1-6 alkyl), -N(OH)(C 1-6 alkyl), -NH(OH), -SH, -SC 1-6 Alkyl group, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl group, -SO2OC 1-6 Alkyl group, -OSO2C 1-6 Alkyl group, -SOC 1-6 Alkyl group, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3, -C(=S)N(C 1-6 alkyl)2, C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl group, -SC(=S)SC 1-6 Alkyl group, -P(=O)2(C 1-6 alkyl), -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl group, C 1-6 Haloalkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C7 cycloalkyl groups, C6-C 10 Aryl groups, C3-C7 heterocyclyl groups, C5-C 10 A heteroaryl group, or two geminal R gg The substituents can be linked to form =O or =S, where X - is the counter ion.

[0042] Exemplary nitrogen atom substituents are hydrogen, —OH, —OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa, -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, including but not limited to alkyl groups, haloalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, or two R groups connected to a nitrogen atom cc groups are linked to form a heterocyclyl group or a heteroaryl ring, where each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R dd group, where R aa , R bb , R cc and R dd is as described below.

[0043] Other definitions The term "cancer" includes the following: heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung: bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, hamartoma, mesothelioma; gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma); stomach (carcinoma, lymphoma, leiomyosarcoma); pancreas (tubular adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, hemangioma); small intestine (adenocarcinoma, lymphoma, carcinoid tumor); Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma); large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma); , leiomyoma), genitourinary system: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma), choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma), liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, biliary tract: gallbladder carcinoma, ampulla carcinoma, bile duct carcinoma, bone: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell chordoma, osteochondral exostosisexostoses), benign chondroma, chondroblastoma, fibrochondroma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor, nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningioma, meningeal sarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma), gynecology: uterus (endometrial cancer), cervix (cervical cancer, precancerous cervical dysplasia, etc.), ovary (ovarian cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa cell tumor, supportive stromal cell tumor, dysgerminoma, malignant teratoma ), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma)), fallopian tube (cancer), hematology: blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma (MCL), follicular lymphoma, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma), skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, and adrenal gland: neuroblastoma.

[0044] In one embodiment, the term "cancer" includes, but is not limited to, breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer, and lung cancer.

[0045] The term "treatment" as used herein relates to the reversal, alleviation, suppression or prevention of the progression of the disorder or condition to which the term applies, or the reversal, alleviation, suppression of one or more symptoms of such disorder or condition. The noun "treatment" as used herein relates to the verb treat, the latter being as defined above.

[0046] As used herein, the term "pharmaceutically acceptable salts" refers to those carboxylate salts, amino acid addition salts of the compounds of the present invention which, within the scope of sound medical judgment, are suitable for contact with the tissues of a patient, do not produce excessive toxicity, irritation, allergic response, or the like, and are commensurate with a reasonable benefit / risk ratio and are effective for the intended application, including (where possible) zwitterionic forms of the compounds of the present invention.

[0047] Pharmaceutically acceptable base addition salts are those formed with metals or amines, such as alkali and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, calcium, etc. Examples of suitable amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.

[0048] Base addition salts of acidic compounds may be prepared by contacting the free acid form with sufficient necessary base to produce the salt in a conventional manner. The free acid can be regenerated by contacting the salt form with an acid in a conventional manner, followed by isolation of the free acid. The free acid forms may differ somewhat from their respective salt forms in some physical properties, e.g., solubility in polar solvents, but for purposes of this invention, the salts are equivalent to the respective free acids.

[0049] The salts may be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides prepared from inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, etc. Representative salts include hydrobromides, hydrochlorides, sulfates, bisulfates, nitrates, acetates, oxalates, pentanoates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, phosphates, toluenesulfonates, citrates, maleates, fumarates, succinates, tartrates, naphthoates, methanesulfonates, glucoheptanoates, lactose, laurylsulfonates, isethionates, and the like. Salts may be prepared from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Representative salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthoate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Pharmaceutically acceptable salts may include cations based on alkali metals and alkaline earth metals, e.g., sodium, lithium, potassium, calcium, magnesium, etc., and non-toxic ammonium, quaternary ammonium and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. Salts of amino acids, e.g., arginate, gluconate, galacturonate, etc., are also encompassed (see, e.g., Berge SM et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19, incorporated herein by reference).

[0050] A "subject" to be administered includes, but is not limited to, humans (i.e., male or female of any age, e.g., pediatric subjects (e.g., infants, children, adolescents) or adults (e.g., young adults, middle-aged adults, elderly)) and / or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, goats, sheep, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. As used herein, the terms "human," "patient," and "subject" may be used interchangeably.

[0051] "Disease," "disorder," and "symptom" may be used interchangeably herein.

[0052] Unless otherwise stated, the term "treatment" as used herein includes actions that occur when a subject has a particular disease, disorder or condition, such as reducing the severity of the disease, disorder or condition or slowing or slowing the progression of the disease, disorder or condition ("therapeutic treatment"), and further includes actions that occur before a subject begins to have a particular disease, disorder or condition ("prophylactic treatment").

[0053] Generally, the "effective amount" of a compound refers to an amount sufficient to induce a target biological response. As will be understood by those skilled in the art, the effective amount of the compound of the present invention may vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease to be treated, the method of administration, and the age, health condition, and symptoms of the subject. The effective amount includes a therapeutically effective amount and a prophylactically effective amount.

[0054] Unless otherwise specified, a "therapeutically effective amount" of a compound, as used herein, is an amount sufficient to provide a therapeutic effect in the process of treating a disease, disorder, or condition, or an amount that delays or minimizes one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent, either used alone or in combination with other therapies, that provides a therapeutic effect in the process of treating a disease, disorder, or condition. The term "therapeutically effective amount" may also include an amount that improves overall treatment, reduces or avoids the symptoms or pathogenesis of a disease or condition, or enhances the therapeutic effect of other therapeutic agents.

[0055] Unless otherwise specified, a "prophylactically effective amount" of a compound, as used herein, is an amount sufficient to prevent a disease, disorder, or condition, or to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent the recurrence of a disease, disorder, or condition. A prophylactically effective amount of a compound refers to the amount of a therapeutic agent, either used alone or in combination with other agents, that provides a prophylactic benefit in the process of preventing a disease, disorder, or condition. The term "prophylactically effective amount" can also include an amount that improves overall prophylaxis or enhances the prophylactic effect of other prophylactic agents.

[0056] "Combination" and related terms refer to the simultaneous or sequential administration of a compound of the invention and another therapeutic agent. For example, the compound of the invention may be administered simultaneously or sequentially with the other therapeutic agent in separate unit dosage forms, or may be administered simultaneously with the other therapeutic agent in a single unit dosage form. [Brief explanation of the drawings]

[0057] [Figure 1] 1 shows the effect curves of the compounds of the present invention on PARP1 / 2-DNA trapping at 2 hours. [Figure 2] 1 shows the time-effect curves of the compounds of the present invention on PARP1 / 2-DNA trapping at different time points. [Figure 3] 1 shows the effect of the compound of the present invention on the change in tumor volume in subcutaneously transplanted tumors in MDA-MB-436 mice. [Figure 4]FIG. 1 shows induction of apoptosis in DLD-1 BRCA2− / − by compounds of the invention in three separate experiments. [Figure 5] This shows the expression status of cleaved caspase-3 and caspase-3 protein in tumor tissue. [Figure 6] The effect of the compound of Example 4 and reference AZD5305 at the same dose on Cleaved Caspase-3 protein in tumor tissue (*, p<0.05, performed by one-way ANOVA, no statistically significant difference between the other groups). DETAILED DESCRIPTION OF THE INVENTION

[0058] As used herein, "compounds of the present invention" refers to compounds of the following formula (I), formula (II), etc., pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, crystalline polymorphs, hydrates, or solvates thereof.

[0059] Compounds are named herein using standard nomenclature. Compounds having asymmetric centers should be understood to include all optical isomers and mixtures thereof (unless otherwise specified). It should be noted that all isomeric compounds and carbon-carbon double bonds included in the present invention may exist in Z and E forms unless otherwise specified. In the case of compounds that exist in different tautomeric forms, one is not limited to a particular tautomer, but is intended to encompass all tautomeric forms.

[0060] In one embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate, or solvate thereof: [ka] where: L1 is selected from CRR′, O, S, NH, —C(O)—, —S(O)—, or —S(O)2—; R and R' are independently H, D, halogen, or C1-6 Alkyl group or C 1-6 haloalkyl groups, A is CR A or N, E is CR E or N, G is CR G or N, R A , R E and R G are independently H, D, halogen, CN, -L-OR a , -L-SR a , -L-NR b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -LC 3-10 a cycloalkyl group or an -L-3 to 10-membered heterocyclyl group; R1 is H, D, halogen, CN, -L-OR a , -L-SR a , -L-NR b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -LC 3-10 Cycloalkyl group, -L-3 to 10-membered heterocyclyl group, -LC 6-10 an -L-aryl group or an -L-5 to 10 membered heteroaryl group, which optionally has one, two or three R 1s is replaced by R 1s are independently H, D, halogen, CN, OR a , S.R. a , N.R. b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-10 Cycloalkyl groups, 3- to 10-membered heterocyclyl groups, C6-10 an aryl group or a 5- to 10-membered heteroaryl group; [ka] represents a single bond or a double bond, M1 is selected from N, C, or CR5; M2 is N or CR6; R5 and R6 are independently H, D, halogen, or C 1-6 Alkyl group or C 1-6 haloalkyl groups, R4 independently represents H, D, halogen, CN, =O, OR a , S.R. a , N.R. b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 cycloalkyl or 3- to 7-membered heterocyclyl group, which optionally has one, two, or three R 4s is replaced by Or R4 and R2 in the ortho position of M1 and the atoms connected thereto together form C 5-7 R4 and Z3 in the ortho position of M1 and the atoms connected thereto together form a cycloalkyl group or a 5- to 7-membered heterocyclyl group, or C 5-7 Forming a cycloalkyl group or a 5- to 7-membered heterocyclyl group, which optionally contains one, two, or three R 4s is replaced by R 4s are independently H, D, halogen, CN, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 selected from a cycloalkyl group or a 3- to 7-membered heterocyclyl group; n is 0, 1, 2, 3 or 4; Z1 is selected from CR7 or N; Z2 is selected from CR8 or N; Z3 is selected from CR9 or N; R2, R7, R8 and R9 are independently H, D, halogen, CN, ORa , S.R. a , N.R. b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 cycloalkyl or 3- to 7-membered heterocyclyl group, which optionally contains 1, 2, or 3 R 2s is replaced by R 2s are independently H, D, halogen, CN, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 selected from a cycloalkyl group or a 3- to 7-membered heterocyclyl group; R3 is H, -L-OR a , -L-SR a , -L-NR b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -LC 3-10 Cycloalkyl group, -L-3 to 10-membered heterocyclyl group, -LC 6-10 aryl group or -L-5 to 10 membered heteroaryl group, which optionally has 1, 2 or 3 R 3s is replaced by R 3s are independently H, D, halogen, CN, OR a , S.R. a , N.R. b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-10 Cycloalkyl groups, 3- to 10-membered heterocyclyl groups, C 6-10 selected from an aryl group or a 5- to 10-membered heteroaryl group; L is a chemical bond, C 1-6 Alkylene group, C 2-6 Alkenylene group or C 2-6 Alkynylene groups, which may optionally be H, D, halogen, C1-6 Alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group or C 2-6 alkynyl groups; R a , R b and R c are independently H, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-10 cycloalkyl group or 3- to 10-membered heterocyclyl group, or R b , R c and the atoms to which they are connected, taken together, form a 5- to 10-membered heterocyclyl group; Here, each of the above group definitions is optionally deuterated until fully deuterated.

[0061] L1 In one embodiment, L1 is CRR', e.g., CH2; in another embodiment, L1 is O; in another embodiment, L1 is S; in another embodiment, L1 is NH; in another embodiment, L1 is -C(O)-; in another embodiment, L1 is -S(O)-; in another embodiment, L1 is -S(O)2-.

[0062] In one more specific embodiment, L1 is selected from CRR', O, S, NH, or -C(O)-; in another more specific embodiment, L1 is CRR' or -C(O)-; in another more specific embodiment, L1 is CRR'; in another more specific embodiment, L1 is CH2.

[0063] R and R' In one embodiment, R is H, in another embodiment, R is D, in another embodiment, R is halogen, in another embodiment, R is C 1-6 Alkyl groups, such as C 1-3 In another embodiment, R is C 1-6 Haloalkyl groups, such as C1-3 It is a haloalkyl group.

[0064] In one embodiment, R' is H, in another embodiment, R' is D, in another embodiment, R' is halogen, in another embodiment, R' is C 1-6 Alkyl groups, such as C 1-3 In another embodiment, R' is C 1-6 Haloalkyl groups, such as C 1-3 It is a haloalkyl group.

[0065] In one more specific embodiment, R and R′ are independently H, D, C 1-6 Alkyl group or C 1-6 In another more specific embodiment, R and R′ are independently selected from H, D, C 1-3 Alkyl group or C 1-3 haloalkyl groups; in another more specific embodiment, R and R' are independently H or D; and in another more specific embodiment, R and R' are H.

[0066] A, E and G In one embodiment, A is CR A and in another embodiment, A is N.

[0067] In one embodiment, E is CR E and in another embodiment, E is N.

[0068] In one embodiment, G is CR G and in another embodiment, G is N.

[0069] In one more specific embodiment, A is N, and in another more specific embodiment, E is CR E and in another more specific embodiment, G is CR G and in another more specific embodiment, [ka] teeth, [ka] is.

[0070] R A , R E and R G In one embodiment, R A is H, and in another embodiment, R A is D, and in another embodiment, R A is halogen, and in another embodiment, R A is CN, and in another embodiment, R A -L-OR a and preferably OR a and in another embodiment, R A -L-SR a and preferably SR a and in another embodiment, R A -L-NR b R c and preferably NR b R c and in another embodiment, R A is C 1-6 is an alkyl group, and in another embodiment, R A is C 1-6 haloalkyl group, and in another embodiment, R A is C 2-6 alkenyl group, and in another embodiment, R A is C 2-6 In another embodiment, R A -LC 3-10 is a cycloalkyl group, preferably C 3-10 is a cycloalkyl group, preferably C 3-7 is a cycloalkyl group, and in another embodiment, R A represents an -L-3 to 10-membered heterocyclyl group, preferably a 3 to 10-membered heterocyclyl group, and preferably a 3 to 7-membered heterocyclyl group.

[0071] In one embodiment, R E is H, and in another embodiment, R E is D, and in another embodiment, R E is halogen, and in another embodiment, R E is CN, and in another embodiment, R E -L-OR a and preferably OR a and in another embodiment, R E -L-SR a and preferably SR a and in another embodiment, R E -L-NR b R c and preferably NR b R c and in another embodiment, R E is C 1-6 is an alkyl group, and in another embodiment, R E is C 1-6 haloalkyl group, and in another embodiment, R E is C 2-6 alkenyl group, and in another embodiment, R E is C 2-6 In another embodiment, R E -LC 3-10 is a cycloalkyl group, preferably C 3-10 is a cycloalkyl group, preferably C 3-7 is a cycloalkyl group, and in another embodiment, R E represents an -L-3 to 10-membered heterocyclyl group, preferably a 3 to 10-membered heterocyclyl group, and preferably a 3 to 7-membered heterocyclyl group.

[0072] In one embodiment, R G is H, and in another embodiment, R G is D, and in another embodiment, R G is halogen, and in another embodiment, R Gis CN, and in another embodiment, R G -L-OR a and preferably OR a and in another embodiment, R G -L-SR a and preferably SR a and in another embodiment, R G -L-NR b R c and preferably NR b R c and in another embodiment, R G is C 1-6 is an alkyl group, and in another embodiment, R G is C 1-6 haloalkyl group, and in another embodiment, R G is C 2-6 alkenyl group, and in another embodiment, R G is C 2-6 In another embodiment, R G -LC 3-10 is a cycloalkyl group, preferably C 3-10 is a cycloalkyl group, preferably C 3-7 is a cycloalkyl group, and in another embodiment, R G represents an -L-3 to 10-membered heterocyclyl group, preferably a 3 to 10-membered heterocyclyl group, and preferably a 3 to 7-membered heterocyclyl group.

[0073] In one more specific embodiment, R A , R E and R G are independently H, D, halogen, CN, -L-OR a , -L-SR a , -L-NR b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, -LC 3-7 In another more specific embodiment, R A , R Eand R G are independently H, D, halogen, CN, OR a , N.R. b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 In another more specific embodiment, R A , R E and R G are independently H, D, halogen, C 1-6 Alkyl group or C 1-6 haloalkyl groups, and in another more specific embodiment, R A , R E and R G is independently H or D, and in another more specific embodiment, R A , R E and R G is H.

[0074] R1 In one embodiment, R1 is H; in another embodiment, R1 is D; in another embodiment, R1 is halogen; in another embodiment, R1 is CN; in another embodiment, R1 is -L-OR a and preferably OR a and in another embodiment, R1 is -L-SR a and preferably SR a and in another embodiment, R1 is -L-NR b R c and preferably NR b R c In another embodiment, R is C 1-6 In another embodiment, R is an alkyl group such as Me, for example Et, 1-6 In another embodiment, R is a haloalkyl group. 2-6 In another embodiment, R is an alkenyl group. 2-6 In another embodiment, R1 is -LC 3-10is a cycloalkyl group, preferably C 3-10 is a cycloalkyl group, preferably C 3-7 In another embodiment, R1 is -LC-C-cycloalkyl group, and in another embodiment, R1 is -LC-C-3 to 10-membered heterocyclyl group, and preferably a 3 to 10-membered heterocyclyl group, and preferably a 3 to 7-membered heterocyclyl group. 6-10 An aryl group, preferably C 6-10 In another embodiment, R1 is an -L-5 to 10 membered heteroaryl group, preferably a 5 to 10 membered heteroaryl group, preferably a 5 to 6 membered heteroaryl group, in another embodiment, R1 is optionally selected from 1, 2 or 3 R 1s is replaced by

[0075] In one more specific embodiment, R1 is H, D, halogen, CN, -L-OR a , -L-SR a , -L-NR b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, -LC 3-10 Cycloalkyl group, -L-3 to 10-membered heterocyclyl group, -LC 6-10 In another more specific embodiment, R is selected from H, D, halogen, CN, OR a , N.R. b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-10 Cycloalkyl groups, 3- to 10-membered heterocyclyl groups, C 6-10 In another more specific embodiment, R is selected from H, D, halogen, CN, OR a , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7In another more specific embodiment, R is selected from H, D, halogen, C 1-6 Alkyl group or C 1-6 haloalkyl groups, preferably H, D, C 1-6 Alkyl group or C 1-6 In another more specific embodiment, R is a haloalkyl group. 1-6 Alkyl group or C 1-6 It is a haloalkyl group, preferably Et.

[0076] R 1s In one embodiment, R 1s is H, and in another embodiment, R 1s is D, and in another embodiment, R 1s is halogen, and in another embodiment, R 1s is CN, and in another embodiment, R 1s is OR a and in another embodiment, R 1s is SR a and in another embodiment, R 1s is NR b R c and in another embodiment, R 1s is C 1-6 is an alkyl group, and in another embodiment, R 1s is C 1-6 haloalkyl group, and in another embodiment, R 1s is C 2-6 alkenyl group, and in another embodiment, R 1s is C 2-6 In another embodiment, R 1s is C 3-10 Cycloalkyl groups, preferably C 3-7 is a cycloalkyl group, and in another embodiment, R 1s is a 3- to 10-membered heterocyclyl group, preferably a 3- to 7-membered heterocyclyl group, and in another embodiment, R 1s is C 6-10is an aryl group, preferably a phenyl group, and in another embodiment, R 1s is a 5- to 10-membered heteroaryl group, preferably a 5- or 6-membered heteroaryl group.

[0077] In one more specific embodiment, R 1s are independently H, D, halogen, CN, OR a , N.R. b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-10 Cycloalkyl groups, 3- to 10-membered heterocyclyl groups, C 6-10 In another more specific embodiment, R 1s are independently H, D, halogen, CN, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 In another more specific embodiment, R 1s are independently H, D, halogen, C 1-6 Alkyl group or C 1-6 haloalkyl groups, and in another more specific embodiment, R 1s are independently H, D, and C 1-6 Alkyl group or C 1-6 haloalkyl groups. [ka]

[0078] In one embodiment, [ka] is a single bond, and in another embodiment, [ka] is a double bond.

[0079] M1 and M2 In one embodiment, M1 is N, in another embodiment, M1 is C, and in another embodiment, M1 is CR5.

[0080] In one embodiment, M2 is N, and in another embodiment, M2 is CR6.

[0081] In one more specific embodiment, M is selected from N or CR; in another more specific embodiment, M is N; in another more specific embodiment, M is N; in another more specific embodiment, [ka] teeth, [ka] is.

[0082] R5 and R6 In one embodiment, R5 is H, in another embodiment, R5 is D, in another embodiment, R5 is halogen, in another embodiment, R5 is C 1-6 In another embodiment, R is an alkyl group. 1-6 It is a haloalkyl group.

[0083] In one embodiment, R6 is H; in another embodiment, R6 is D; in another embodiment, R6 is halogen; in another embodiment, R6 is C 1-6 In another embodiment, R6 is C 1-6 It is a haloalkyl group.

[0084] In one more specific embodiment, R5 and R6 are independently H, D, C 1-6 Alkyl group or C 1-6 In another more specific embodiment, R5 and R6 are selected from haloalkyl groups; in another more specific embodiment, R5 and R6 are H or D; and in another more specific embodiment, R5 and R6 are H.

[0085] R4 In one embodiment, R4 is H; in another embodiment, R4 is D; in another embodiment, R4 is halogen; in another embodiment, R4 is CN; in another embodiment, R4 is ═O; in another embodiment, R4 is OR a and in another embodiment, R4 is SR a and in another embodiment, R4 is NR b R c In another embodiment, R4 is C 1-6 In another embodiment, R is an alkyl group. 1-6 In another embodiment, R is a haloalkyl group. 3-7 In another embodiment, R4 is a 3- to 7-membered heterocyclyl group, and in another embodiment, R4 is optionally 1, 2, or 3 R 4s is replaced by

[0086] In one embodiment, R4 and R2 in the ortho positions of M1 and the atoms connected thereto together form C 5-7 In another embodiment, R4 and R2 in the ortho positions to M1 and the atoms connected thereto together form a 5- to 7-membered heterocyclyl group; in another embodiment, R4 and Z3 in the ortho positions to M1 and the atoms connected thereto together form a C 5-7 In another embodiment, R and Z and the atoms connected thereto in the ortho positions of M together form a 5- to 7-membered heterocyclyl group, and in another embodiment, the ring structure formed by R and R or Z optionally contains 1, 2, or 3 R 4s is replaced by

[0087] In a more specific embodiment, R4 is independently H, D, halogen, CN, OR a , N.R. b R c , C 1-6 Alkyl group, C 1-6Haloalkyl group, C 3-7 In another more specific embodiment, R4 is independently selected from H, D, halogen, CN, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 In another more specific embodiment, R4 is independently selected from H, D, halogen, C 1-6 Alkyl group or C 1-6 In another more specific embodiment, R4 is independently selected from H, D, C 1-6 Alkyl group or C 1-6 haloalkyl groups; in another more specific embodiment, R 4 is independently H or D; in another more specific embodiment, R 4 is H.

[0088] In one more specific embodiment, R4 and R2 in the ortho positions of M1 and the atoms connected thereto together form a 5- to 7-membered heterocyclyl group; or R4 and Z3 in the ortho positions of M1 and the atoms connected thereto together form a 5- to 7-membered heterocyclyl group; in another more specific embodiment, R4 and R2 in the ortho positions of M1 and the atoms connected thereto together form a 5- to 7-membered heterocyclyl group.

[0089] R 4s In one embodiment, R 4s is H, and in another embodiment, R 4s is D, and in another embodiment, R 4s is halogen, and in another embodiment, R 4s is CN, and in another embodiment, R 4s is C 1-6 is an alkyl group, and in another embodiment, R 4s is C 1-6 haloalkyl group, and in another embodiment, R 4s is C 3-7 is a cycloalkyl group, and in another embodiment, R4s is a 3- to 7-membered heterocyclyl group.

[0090] In one more specific embodiment, R 4s are independently H, D, halogen, C 1-6 Alkyl group or C 1-6 haloalkyl groups.

[0091] n In one embodiment, n is 0; in another embodiment, n is 1; in another embodiment, n is 2; in another embodiment, n is 3; and in another embodiment, n is 4.

[0092] In one more specific embodiment, n is selected from 0, 1, or 2; in another more specific embodiment, n is 0.

[0093] Z1, Z2 and Z3 In one embodiment, Z1 is CR7; in another embodiment, Z1 is N.

[0094] In one embodiment, Z2 is CR8, and in another embodiment, Z2 is N; In one embodiment, Z3 is CR9; in another embodiment, Z3 is N.

[0095] In one more specific embodiment, Z1 is N, in another more specific embodiment, Z2 is CR8, in another more specific embodiment, Z3 is CR9, and in another more specific embodiment, [ka] teeth, [ka] is.

[0096] R7, R8 and R9 In one embodiment, R7 is H; in another embodiment, R7 is D; in another embodiment, R7 is halogen; in another embodiment, R7 is CN; in another embodiment, R7 is OR a In another embodiment, R7 is SR a In another embodiment, R7 is NR b R c In another embodiment, R7 is C 1-6 In another embodiment, R7 is C 1-6 In another embodiment, R7 is C 3-7 In another embodiment, R7 is a 3- to 7-membered heterocyclyl group, which optionally contains 1, 2, or 3 R 2s is replaced by

[0097] In one embodiment, R8 is H; in another embodiment, R8 is D; in another embodiment, R8 is halogen; in another embodiment, R8 is CN; in another embodiment, R8 is OR a and in another embodiment, R8 is SR a and in another embodiment, R8 is NR b R c In another embodiment, R8 is C 1-6 In another embodiment, R is C 1-6 In another embodiment, R is a haloalkyl group. 3-7 In another embodiment, R is a 3- to 7-membered heterocyclyl group, which optionally contains 1, 2, or 3 R 2s is replaced by

[0098] In one embodiment, R9 is H, in another embodiment, R9 is D, in another embodiment, R9 is halogen, in another embodiment, R9 is CN, in another embodiment, R9 is OR a and in another embodiment, R9 is SR aand in another embodiment, R9 is NR b R c In another embodiment, R9 is C 1-6 In another embodiment, R is an alkyl group. 1-6 In another embodiment, R is a haloalkyl group. 3-7 In another embodiment, R is a 3- to 7-membered heterocyclyl group, which optionally contains 1, 2, or 3 R 2s is replaced by

[0099] In one more specific embodiment, R7, R8 and R9 are independently H, D, halogen, CN, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 In another more specific embodiment, R7, R8, and R9 are independently selected from H, D, halogen, C 1-6 Alkyl group or C 1-6 In another more specific embodiment, R7, R8, and R9 are independently selected from H, D, C 1-6 Alkyl group or C 1-6 haloalkyl groups; in another more specific embodiment, R7, R8, and R9 are independently H or D; in another more specific embodiment, R7, R8, and R9 are H.

[0100] R2 In one embodiment, R2 is H, in another embodiment, R2 is D, in another embodiment, R2 is halogen, for example, F, in another embodiment, R2 is CN, in another embodiment, R2 is OR a and in another embodiment, R2 is SR a and in another embodiment, R2 is NR b R c In another embodiment, R2 is C 1-6 In another embodiment, R is an alkyl group. 1-6In another embodiment, R is a haloalkyl group. 3-7 In another embodiment, R2 is a 3- to 7-membered heterocyclyl group, which optionally contains 1, 2, or 3 R 2s is replaced by

[0101] In one more specific embodiment, R2 is H, D, halogen, CN, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 In another more specific embodiment, R2 is selected from H, D, halogen, CN, C 1-6 Alkyl group or C 1-6 In another more specific embodiment, R2 is selected from H, D, halogen, C 1-6 Alkyl group or C 1-6 In another more specific embodiment, R2 is selected from H, D, or halogen; in another more specific embodiment, R2 is H or F.

[0102] In one more specific embodiment, R2 is halogen, preferably F, Cl or Br, preferably F.

[0103] R 2s In one embodiment, R 2s is H, and in another embodiment, R 2s is D, and in another embodiment, R 2s is halogen, and in another embodiment, R 2s is CN, and in another embodiment, R 2s is C 1-6 is an alkyl group, and in another embodiment, R 2s is C 1-6 haloalkyl group, and in another embodiment, R 2s is C 3-7 is a cycloalkyl group, and in another embodiment, R 2s is a 3- to 7-membered heterocyclyl group.

[0104] In one more specific embodiment, R 2s are independently H, D, halogen, C 1-6 Alkyl group or C 1-6 haloalkyl groups.

[0105] R3 In one embodiment, R3 is H, and in another embodiment, R3 is -L-OR a and preferably OR a , for example, OMe, and in another embodiment, R3 is -L-SR a and preferably SR a and in another embodiment, R3 is -L-NR b R c and preferably NR b R c In another embodiment, R3 is C 1-6 In another embodiment, R is an alkyl group such as Me; 1-6 In another embodiment, R is a haloalkyl group. 2-6 In another embodiment, R is an alkenyl group. 2-6 In another embodiment, R3 is -LC 3-10 is a cycloalkyl group, preferably C 3-10 is a cycloalkyl group, preferably C 3-7 In another embodiment, R3 is -LC-C-cycloalkyl group, and in another embodiment, R3 is -LC-C-3 to 10-membered heterocyclyl group, preferably a 3 to 10-membered heterocyclyl group, and preferably a 3 to 7-membered heterocyclyl group. 6-10 is an aryl group, preferably C 6-10 In another embodiment, R3 is an -L-5 to 10 membered heteroaryl group, preferably a 5 to 10 membered heteroaryl group, preferably a 5 to 6 membered heteroaryl group, in another embodiment, R3 is optionally substituted with 1, 2 or 3 R 3s For example, R3 is substituted with C1-6 Deuterated alkyl groups, for example, CD3.

[0106] In one more specific embodiment, R3 is H, -L-OR a , -L-SR a , -L-NR b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, -LC 3-10 Cycloalkyl group, -L-3 to 10-membered heterocyclyl group, -LC 6-10 In another more specific embodiment, R3 is selected from H, OR a , N.R. b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-10 Cycloalkyl groups, 3- to 10-membered heterocyclyl groups, C 6-10 In another more specific embodiment, R3 is selected from H, OR a , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 In another more specific embodiment, R3 is selected from H, OR a , C 1-6 Alkyl group, C 1-6 haloalkyl group or C 1-6 In another more specific embodiment, R is selected from a deuterated alkyl group, and in ... a , C 1-6 Alkyl group, C 1-6 haloalkyl group or C 1-6 In another more specific embodiment, R3 is selected from Me, CD3, or OMe.

[0107] In one more specific embodiment, R3 is C 1-6 Alkyl group, C 1-6 Haloalkyl groups and C 1-6In another more specific embodiment, R is selected from deuterated alkyl groups. 1-6 In another more specific embodiment, R3 is a deuterated alkyl group, and in another more specific embodiment, R3 is selected from Me and CD3, and in another more specific embodiment, R3 is CD3.

[0108] R 3s In one embodiment, R 3s is H, and in another embodiment, R 3s is D, and in another embodiment, R 3s is halogen, and in another embodiment, R 3s is CN, and in another embodiment, R 3s is OR a and in another embodiment, R 3s is SR a and in another embodiment, R 3s is NR b R c and in another embodiment, R 3s is C 1-6 is an alkyl group, and in another embodiment, R 3s is C 1-6 haloalkyl group, and in another embodiment, R 3s is C 2-6 alkenyl group, and in another embodiment, R 3s is C 2-6 In another embodiment, R 3s is C 3-10 is a cycloalkyl group, preferably C 3-7 is a cycloalkyl group, and in another embodiment, R 3s is a 3- to 10-membered heterocyclyl group, preferably a 3- to 7-membered heterocyclyl group, and in another embodiment, R 3s is C 6-10 is an aryl group, preferably a phenyl group, and in another embodiment, R 3s is a 5- to 10-membered heteroaryl group, preferably a 5- or 6-membered heteroaryl group.

[0109] In one more specific embodiment, R 3s are independently H, D, halogen, CN, OR a , N.R. b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-10 Cycloalkyl groups, 3- to 10-membered heterocyclyl groups, C 6-10 In another more specific embodiment, R 3s are independently H, D, halogen, CN, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 In another more specific embodiment, R 3s are independently H, D, halogen, C 1-6 Alkyl group or C 1-6 haloalkyl groups, and in another more specific embodiment, R 3s are independently H, D, and C 1-6 Alkyl group or C 1-6 haloalkyl groups.

[0110] L In one embodiment, L is a chemical bond, and in another embodiment, L is C 1-6 In another embodiment, L is an alkylene group. 2-6 In another embodiment, L is an alkenylene group. 2-6 In another embodiment, L is an alkynylene group, and in another embodiment, L is optionally selected from H, D, halogen, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group or C 2-6 In another embodiment, L is optionally substituted with 1, 2, or 3 groups selected from alkynyl groups, H, D, halogen, C 1-6 Alkyl group or C 1-6 It is substituted with 1, 2 or 3 groups selected from haloalkyl groups.

[0111] In a more specific embodiment, L is independently a chemical bond or C 1-6 alkylene groups, which are optionally selected from H, D, halogen, C 1-6 Alkyl group or C 1-6 It is substituted with 1, 2 or 3 groups selected from haloalkyl groups.

[0112] R a , R b and R c In one embodiment, R a , R b and R c is independently H, and in another embodiment, R a , R b and R c independently C 1-6 In another embodiment, R a , R b and R c independently C 1-6 haloalkyl group, and in another embodiment, R a , R b and R c independently C 3-10 is a cycloalkyl group, preferably C 3-7 is a cycloalkyl group, and in another embodiment, R a , R b and R c are independently a 3- to 10-membered heterocyclyl group, preferably a 3- to 7-membered heterocyclyl group, and in another embodiment, R b , R c and the atoms to which they are linked, taken together, form a 5- to 10-membered heterocyclyl group, preferably a 5- to 7-membered heterocyclyl group.

[0113] In one more specific embodiment, R a , R b and R c are independently H, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7In another more specific embodiment, R a , R b and R c are independently H, C 1-6 Alkyl group or C 1-6 haloalkyl groups, and in another more specific embodiment, R a , R b and R c is H or Me, and in another more specific embodiment, R a , R b and R c is Me, and in another more specific embodiment, R b , R c and the atoms to which they are connected, taken together, form a 5- to 7-membered heterocyclyl group.

[0114] Any technical solution or any combination thereof in any of the above specific embodiments can be combined with any technical solution or any combination thereof in other specific embodiments. For example, any technical solution or any combination thereof in ring A can be combined with L1, R, R', A, E, G, R A , R E , R G , R1, R 1s , M1, M2, R5, R6, R4, R 4s , n, Z1, Z2, Z3, R2, R7, R8, R9, R 2s , R3, R 3s , L, R a , R b and R c The present invention is intended to include all combinations of these technical solutions, but due to space limitations, it is not possible to list them all comprehensively.

[0115] In a more specific embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate, or solvate thereof: [ka] where: L1 is selected from CRR′, O, S, NH, —C(O)—, —S(O)—, or —S(O)2—; R and R' are independently H, D, halogen, or C 1-6 Alkyl group or C 1-6 haloalkyl groups, A is CR A or N, E is CR E or N, G is CR G or N, R A , R E and R G are independently H, D, halogen, CN, -L-OR a , -L-SR a , -L-NR b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -LC 3-10 a cycloalkyl group or an -L-3 to 10-membered heterocyclyl group; R1 is H, D, halogen, CN, -L-OR a , -L-SR a , -L-NR b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -LC 3-10 Cycloalkyl group, -L-3 to 10-membered heterocyclyl group, -LC 6-10 an -L-aryl group or an -L-5 to 10 membered heteroaryl group, which optionally has one, two or three R 1s is replaced by R 1s are independently H, D, halogen, CN, OR a , S.R. a , N.R. b R c, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-10 Cycloalkyl groups, 3- to 10-membered heterocyclyl groups, C 6-10 selected from an aryl group or a 5- to 10-membered heteroaryl group; [ka] represents a single bond or a double bond, M1 is selected from N, C, or CR5; M2 is N or CR6; R5 and R6 are independently H, D, halogen, or C 1-6 Alkyl group or C 1-6 haloalkyl groups, R4 independently represents H, D, halogen, CN, =O, OR a , S.R. a , N.R. b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 cycloalkyl or 3- to 7-membered heterocyclyl group, which optionally contains 1, 2, or 3 R 4s is replaced by Or R4 and R2 in the ortho position of M1 and the atoms connected thereto together form C 5-7 R4 and Z3 in the ortho position of M1 and the atoms connected thereto together form a cycloalkyl group or a 5- to 7-membered heterocyclyl group, or C 5-7 Forming a cycloalkyl group or a 5- to 7-membered heterocyclyl group, which optionally contains one, two, or three R 4s is replaced by R 4s are independently H, D, halogen, CN, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 selected from a cycloalkyl group or a 3- to 7-membered heterocyclyl group; n is 0, 1, 2, 3 or 4; Z1 is selected from CR7 or N; Z2 is selected from CR8 or N; Z3 is selected from CR9 or N; R2, R7, R8 and R9 are independently H, D, halogen, CN, OR a , S.R. a , N.R. b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 cycloalkyl or 3- to 7-membered heterocyclyl group, which optionally contains 1, 2, or 3 R 2s is replaced by R 2s are independently H, D, halogen, CN, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 selected from a cycloalkyl group or a 3- to 7-membered heterocyclyl group; R3 is H, -L-OR a , -L-SR a , -L-NR b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -LC 3-10 Cycloalkyl group, -L-3 to 10-membered heterocyclyl group, -LC 6-10 aryl group or -L-5 to 10 membered heteroaryl group, which optionally has 1, 2 or 3 R 3s is replaced by R 3s are independently H, D, halogen, CN, OR a , S.R. a , N.R. b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-10 Cycloalkyl groups, 3- to 10-membered heterocyclyl groups, C 6-10an aryl group or a 5- to 10-membered heteroaryl group; L is a chemical bond, C 1-6 Alkylene group, C 2-6 Alkenylene group or C 2-6 Alkynylene groups, which may optionally be H, D, halogen, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group or C 2-6 alkynyl groups; R a , R b and R c are independently H, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-10 cycloalkyl group or 3- to 10-membered heterocyclyl group, or R b , R c and the atoms to which they are connected, taken together, form a 5- to 10-membered heterocyclyl group; Here, each of the above group definitions is optionally deuterated until fully deuterated.

[0116] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein L1 is selected from CRR', O, S, NH or -C(O)-, preferably CRR' or -C(O)-, preferably CRR', preferably CH2.

[0117] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein R and R' are independently H, D, C ... 1-6 Alkyl group or C 1-6 haloalkyl groups, preferably H, D, C 1-3 Alkyl group or C 1-3It is selected from haloalkyl groups, preferably H or D, and preferably H.

[0118] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein A is N; Preferably, E is CR E and Preferably, G is CR G and Preferably, [ka] teeth, [ka] is.

[0119] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein R A , R E and R G are independently H, D, halogen, CN, -L-OR a , -L-SR a , -L-NR b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, -LC 3-7 cycloalkyl group or -L-3 to 7-membered heterocyclyl group, preferably H, D, halogen, CN, OR a , N.R. b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 A cycloalkyl group or a 3- to 7-membered heterocyclyl group is preferably selected from H, D, halogen, C 1-6 Alkyl group or C 1-6It is selected from haloalkyl groups, preferably H or D, and preferably H.

[0120] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein R is H, D, halogen, CN, -L-OR a , -L-SR a , -L-NR b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, -LC 3-10 Cycloalkyl group, -L-3 to 10-membered heterocyclyl group, -LC 6-10 aryl group or -L-5 to 10-membered heteroaryl group, preferably H, D, halogen, CN, OR a , N.R. b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-10 Cycloalkyl groups, 3- to 10-membered heterocyclyl groups, C 6-10 aryl group or 5- to 10-membered heteroaryl group, preferably H, D, halogen, CN, OR a , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 A cycloalkyl group or a 3- to 7-membered heterocyclyl group is preferably selected from H, D, halogen, C 1-6 Alkyl group or C 1-6 haloalkyl groups, preferably H, D, C 1-6 Alkyl group or C 1-6 haloalkyl groups, preferably C 1-6 Alkyl group or C 1-6 It is a haloalkyl group, preferably Et.

[0121] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein R 1s are independently H, D, halogen, CN, OR a , N.R. b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-10 Cycloalkyl groups, 3- to 10-membered heterocyclyl groups, C 6-10 aryl group or 5- to 10-membered heteroaryl group, preferably H, D, halogen, CN, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 A cycloalkyl group or a 3- to 7-membered heterocyclyl group is preferably selected from H, D, halogen, C 1-6 Alkyl group or C 1-6 haloalkyl groups, preferably H, D, C 1-6 Alkyl group or C 1-6 haloalkyl groups.

[0122] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein M is selected from N or CR, preferably N; Preferably, M2 is N, Preferably, [ka] teeth, [ka] is.

[0123] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein R5 and R6 are independently H, D, C ... 1-6 Alkyl group or C 1-6 It is selected from haloalkyl groups, preferably H or D, and preferably H.

[0124] In more specific embodiments, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate, or solvate thereof, wherein R4 is independently H, D, halogen, CN, OR a , N.R. b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 A cycloalkyl group or a 3- to 7-membered heterocyclyl group is preferably selected from H, D, halogen, CN, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 A cycloalkyl group or a 3- to 7-membered heterocyclyl group is preferably selected from H, D, halogen, C 1-6 Alkyl group or C 1-6 haloalkyl groups, preferably H, D, C 1-6 Alkyl group or C 1-6 is a haloalkyl group, preferably H or D, preferably H; Preferably, n is 0, 1 or 2, preferably 0.

[0125] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein R4 and R2 in the ortho position to M1 and the atoms connected thereto together form a 5- to 7-membered heterocyclyl group, or R4 and Z3 in the ortho position to M1 and the atoms connected thereto together form a 5- to 7-membered heterocyclyl group; Preferably, R4 and R2 in the ortho positions of M1 and the atoms connected thereto together form a 5- to 7-membered heterocyclyl group.

[0126] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein R 4s are independently H, D, halogen, C 1-6 Alkyl group or C 1-6 haloalkyl groups.

[0127] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein Z is N; Preferably, Z2 is CR8, Preferably, Z3 is CR9, Preferably, [ka] teeth, [ka] is.

[0128] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein R7, R8 and R9 are independently H, D, halogen, CN, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 A cycloalkyl group or a 3- to 7-membered heterocyclyl group is preferably selected from H, D, halogen, C 1-6 Alkyl group or C 1-6 haloalkyl groups, preferably H, D, C 1-6 Alkyl group or C 1-6 It is selected from haloalkyl groups, preferably H or D, and preferably H.

[0129] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein R2 is H, D, halogen, CN, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 A cycloalkyl group or a 3- to 7-membered heterocyclyl group is preferably selected from H, D, halogen, CN, C 1-6 Alkyl group or C 1-6 haloalkyl groups, preferably H, D, halogen, C 1-6 Alkyl group or C 1-6 It is selected from haloalkyl groups, preferably H, D or halogen, preferably H or F.

[0130] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein R 2s are independently H, D, halogen, C 1-6 Alkyl group or C 1-6 haloalkyl groups.

[0131] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein R3 is H, -L-OR a , -L-SR a , -L-NR b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, -LC 3-10 Cycloalkyl group, -L-3 to 10-membered heterocyclyl group, -LC 6-10 aryl group or -L-5 to 10-membered heteroaryl group, preferably H, OR a , N.R. b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-10 Cycloalkyl groups, 3- to 10-membered heterocyclyl groups, C 6-10 aryl group or 5- to 10-membered heteroaryl group, preferably H, OR a , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 A cycloalkyl group or a 3- to 7-membered heterocyclyl group is preferably selected from H, OR a , C 1-6 Alkyl group, C 1-6 haloalkyl group or C 1-6 deuterated alkyl groups, preferably OR a , C 1-6 Alkyl group, C 1-6 haloalkyl group or C 1-6 It is selected from deuterated alkyl groups, preferably selected from Me, CD3 or OMe.

[0132] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein R 3s are independently H, D, halogen, CN, OR a , N.R.b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-10 Cycloalkyl groups, 3- to 10-membered heterocyclyl groups, C 6-10 aryl group or 5- to 10-membered heteroaryl group, preferably H, D, halogen, CN, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 A cycloalkyl group or a 3- to 7-membered heterocyclyl group is preferably selected from H, D, halogen, C 1-6 Alkyl group or C 1-6 haloalkyl groups, preferably H, D, C 1-6 Alkyl group or C 1-6 haloalkyl groups.

[0133] In more specific embodiments, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate, or solvate thereof, wherein L is independently a chemical bond or C 1-6 alkylene groups, which are optionally selected from H, D, halogen, C 1-6 Alkyl group or C 1-6 It is substituted with 1, 2 or 3 groups selected from haloalkyl groups.

[0134] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein R a , R b and R c are independently H, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 A cycloalkyl group or a 3- to 7-membered heterocyclyl group is preferably selected from H, C 1-6 Alkyl group or C 1-6 haloalkyl groups, preferably C 1-6 Alkyl group or C1-6 is a haloalkyl group, preferably H or Me, more preferably Me; or R b , R c and the atoms to which they are connected, taken together, form a 5- to 7-membered heterocyclyl group.

[0135] In a more specific embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate, or solvate thereof, having the following structural formula: [ka] Here, each group is as defined above.

[0136] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein: R1 is H, D, halogen, CN, OR a , N.R. b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-10 Cycloalkyl groups, 3- to 10-membered heterocyclyl groups, C 6-10 aryl group or a 5- to 10-membered heteroaryl group, which optionally has one, two, or three R 1s is replaced by R2 is H, D, halogen, CN, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 cycloalkyl or 3- to 7-membered heterocyclyl group, which optionally has one, two, or three R 2s is replaced by R3 is H, OR a , N.R. b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C3-10 Cycloalkyl groups, 3- to 10-membered heterocyclyl groups, C 6-10 aryl group or a 5- to 10-membered heteroaryl group, which optionally has one, two, or three R 3s is replaced by R4 is H, D, halogen, CN, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 cycloalkyl or 3- to 7-membered heterocyclyl group, which optionally contains 1, 2, or 3 R 4s is replaced by or R4 and R2 at the N-ortho positions connected to the pyridine and the atoms connected thereto together form a 5- to 7-membered heterocyclyl group; R 1s and R 3s are each independently H, D, halogen, CN, or OR a , N.R. b R c , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-10 Cycloalkyl groups, 3- to 10-membered heterocyclyl groups, C 6-10 selected from an aryl group or a 5- to 10-membered heteroaryl group; R 2s and R 4s are independently H, D, halogen, C 1-6 Alkyl group or C 1-6 haloalkyl groups, n is 0, 1, 2, 3 or 4; R a , R b and R c are independently H, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 cycloalkyl group or 3- to 7-membered heterocyclyl group, or R b , R c and the atoms to which they are connected, taken together, form a 5- to 7-membered heterocyclyl group; Here, each of the above group definitions is optionally deuterated until fully deuterated.

[0137] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein: R1 is H, D, halogen, CN, OR a , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 cycloalkyl or 3- to 7-membered heterocyclyl group, which optionally contains 1, 2, or 3 R 1s is replaced by R2 is H, D, halogen, CN, C 1-6 Alkyl group or C 1-6 haloalkyl groups, which optionally have one, two or three R 2s is replaced by R3 is H, OR a , C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 cycloalkyl or 3- to 7-membered heterocyclyl group, which optionally contains 1, 2, or 3 R 3s is replaced by R4 is H, D, halogen, C 1-6 Alkyl group or C 1-6 haloalkyl groups, which optionally have one, two or three R 4s is replaced by R 1s and R 3s are independently H, D, halogen, CN, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-7 selected from a cycloalkyl group or a 3- to 7-membered heterocyclyl group; R 2s and R 4s are independently H, D, halogen, C 1-6 Alkyl group or C 1-6 haloalkyl groups, n is 0, 1, 2, 3 or 4; Ra are independently H, C 1-6 Alkyl group or C 1-6 haloalkyl groups.

[0138] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein: R1 is H, D, C 1-6 Alkyl group or C 1-6 haloalkyl groups, R2 is H, D, halogen, C 1-6 Alkyl group or C 1-6 haloalkyl groups, R3 is H, OR a , C 1-6 Alkyl group, C 1-6 haloalkyl group or C 1-6 deuterated alkyl groups, R4 is H, D, C 1-6 Alkyl group or C 1-6 haloalkyl groups, n is 0, 1, 2, 3 or 4; R a is H, C 1-6 Alkyl group or C 1-6 haloalkyl groups.

[0139] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein: R1 is C 1-6 Alkyl group or C 1-6 is a haloalkyl group, preferably Et; R2 is selected from H, D or halogen, preferably H or F; R3 is OR a , C 1-6 Alkyl group, C 1-6 haloalkyl group or C 1-6deuterated alkyl groups, preferably Me, CD3 or OMe; R4 is H or D, preferably H; n is 0, 1 or 2, preferably 0; R a is C 1-6 Alkyl group or C 1-6 is a haloalkyl group, preferably Me; Preferably, R3 is C 1-6 Alkyl group, C 1-6 Haloalkyl groups and C 1-6 deuterated alkyl groups, preferably C 1-6 a deuterated alkyl group, preferably selected from Me and CD3, preferably CD3; Preferably, R2 is halogen, preferably F, Cl or Br, preferably F.

[0140] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein said compound is [ka] is selected from.

[0141] The compounds of the present invention may contain one or more asymmetric centers and therefore may exist in multiple stereoisomeric forms, e.g., enantiomeric and / or diastereomeric forms. For example, the compounds of the present invention may be a single enantiomer, diastereomer, or geometric isomer (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis.

[0142] The compounds of the present invention can exist in tautomeric forms. Tautomers are functional isomers formed by the rapid movement of an atom in a molecule between two positions. Tautomers are special functional isomers. A pair of tautomers can be converted into each other, but the more stable isomer usually exists as the predominant form. The most prominent examples are enol tautomers and keto tautomers.

[0143] As will be understood by those skilled in the art, organic compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. These complexes are called "solvates." When the solvent is water, the complex is called a "hydrate." The present invention encompasses all solvates of the compounds of the present invention.

[0144] The term "solvate" refers to a form of a compound or its salt associated with a solvent, usually formed by a solvation reaction. This physical association may involve hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ethyl ether, and the like. The compounds described herein may be prepared, for example, in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate may be separable, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes solution-state and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0145] The term "hydrate" refers to a compound associated with an aqueous phase. Typically, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Thus, a hydrate of a compound can be represented, for example, by the general formula R·xH2O, where R is the compound and x is a number greater than 0. A given compound can form one or more hydrate types, including, for example, a monohydrate (x is 1), a lower hydrate (x is a number greater than 0 and less than 1, e.g., a hemihydrate (R·0.5H2O)), and a polyhydrate (x is a number greater than 1, e.g., a dihydrate (R·2H2O) and a hexahydrate (R·6H2O)).

[0146] The compounds of the present invention may be in amorphous or crystalline form (polymorphs). The compounds of the present invention may exist in one or more crystalline forms. Therefore, the present invention includes within its scope all amorphous or crystalline forms of the compounds of the present invention. The term "polymorph" refers to a crystalline form of a compound (or its salts, hydrates, or solvates) that is a stacked arrangement of specific crystals. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystalline shape, optical and electrical properties, stability, and solubility. Depending on the recrystallization solvent, crystallization rate, storage temperature, and other factors, one crystalline form may predominate. Various polymorphs of a compound can be produced by crystallization under different conditions.

[0147] The present invention further includes isotopically labeled compounds (isotopic variants), which are equivalent to those set forth in formula (I), except that one or more atoms are replaced by atoms whose atomic mass or mass number differs from the atomic mass or mass number commonly found in nature. Examples of isotopes that may be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, e.g., 2 H, 3 H, 13 C. 11 C. 14 C. 15 N, 18 O. 17 O.31 P, 32 P, 35 S, 18 F and 36 The compound of the present invention, its prodrugs, and pharmaceutically acceptable salts of said compounds or said prodrugs, which contain the above isotopes and / or other isotopes of other atoms, are all within the scope of the present invention. Some compounds of the present invention are isotopically labeled, e.g., containing a radioactive isotope (e.g., 3 H and 14 C) can be used to measure the tissue distribution of drugs and / or substrates. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred because they are easily produced and detectable. Furthermore, more significant isotopes, such as deuterium, i.e. 2 H substitution and high metabolic stability may provide therapeutic benefits, such as increased in vivo half-life or reduced dose requirements, and may be preferred in some circumstances. Isotopically labeled compounds of formula (I) of the present invention and prodrugs thereof can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents when performing the procedures below and / or the processes disclosed in the Examples and Preparations.

[0148] It should be noted that prodrugs are also included in the context of the present invention. As used herein, the term "prodrug" refers to a compound that is converted into its active form, which has medical effects, in vivo, for example, by hydrolysis in blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, "Prodrugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, Edward B. Roche, ed., "Bioreversible Carriers in Drug Design," American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon, and H. Barbra, "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs," Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each of which is incorporated herein by reference.

[0149] A prodrug is any compound of the present invention covalently bonded to a compound that releases the parent compound in the body when administered to a patient. Prodrugs are typically prepared by modifying functional groups in a manner that allows the modification to yield the parent compound through conventional manipulation or in vivo degradation. Prodrugs include, for example, compounds of the present invention in which a hydroxyl, amino, or mercapto group is bonded to any group that, when administered to a patient, can be decomposed to form a hydroxyl, amino, or mercapto group. Thus, representative examples of prodrugs include, but are not limited to, acetate / amide, formate / amide, and benzoate / amide derivatives of the hydroxyl, mercapto, and amino functional groups of compounds of Formula (I). Additionally, in the case of carboxylic acids (—COOH), esters, such as methyl esters, ethyl esters, and the like, can be used. The esters themselves are active and / or can be hydrolyzed under conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include groups that readily decompose in the human body to release the parent acid or its salt.

[0150] The present invention further provides a pharmaceutical formulation, which comprises a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. All these forms belong to the present invention.

[0151] Pharmaceutical compositions and kits In another aspect, the present invention provides pharmaceutical compositions, which comprise a compound of the present invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the present invention.

[0152] The pharmaceutically acceptable excipient used in the present invention refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound combined with it.The pharmaceutically acceptable carrier, adjuvant or vehicle that can be used in the composition of the present invention includes (but is not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphate), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

[0153] Suitable formulations for administration with the compounds of the present invention will be apparent to those skilled in the art and include, for example, tablets, pills, capsules, suppositories, troches, lozenges, solutions (especially solutions for injection (subcutaneous, intravenous, intramuscular) and infusion (injectable)), elixirs, syrups, wafers, emulsions, inhalants, or dispersible powders. The content of one or more pharmaceutically active compounds should be in the range of 0.1 to 90 wt% of the total composition, preferably 0.5 to 50 wt%, i.e., the amount is sufficient to achieve the dose range specified below. If necessary, the specified dose may be administered several times a day.

[0154] The present invention further includes kits (e.g., pharmaceutical packages). The provided kits may include a compound of the invention, another therapeutic agent, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packages or other suitable containers) containing the compound of the invention and the other therapeutic agent. In some embodiments, the provided kits may optionally further include a third container, which contains a pharmaceutical excipient for diluting or suspending the compound of the invention and / or the other therapeutic agent. In some embodiments, the compound of the invention and the other therapeutic agent provided in the first container and the second container combine to form a single unit dosage form.

[0155] Administration The pharmaceutical compositions according to the present invention can be administered by many routes, including, but not limited to, oral, parenteral, inhalation, topical, rectal, nasal, buccal, vaginal, implant, or other modes of administration. For example, parenteral administration as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrathoracic, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0156] Typically, an effective amount of a compound according to the present invention is administered. The amount of compound actually administered can be determined by a physician depending on the relevant circumstances, including the condition being treated, the selected route of administration, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0157] When used to prevent the conditions described in this invention, the compounds herein are administered to subjects at risk of developing the condition, typically at the dosage levels described above, based on a physician's recommendations and under the supervision of a physician. Subjects at risk of developing a particular condition usually include those subjects who have a family history of the condition, or who have been determined by genetic testing or screening to be particularly susceptible to developing the condition.

[0158] Pharmaceutical compositions according to the present invention may also be administered chronically ("chronic administration"). Chronic administration refers to administering a compound or pharmaceutical composition thereof for an extended period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or continuing to administer indefinitely, for example, for the remainder of the subject's life. In some embodiments, chronic administration is intended to provide a constant level of the compound in the blood for an extended period of time, for example, within a therapeutic window.

[0159] Various administration methods can be used to further deliver the pharmaceutical compositions of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered as a bolus, e.g., to raise the blood concentration of the compound to an effective level. The bolus dose depends on the target systemic level of the active ingredient through the body; for example, an intramuscular or subcutaneous bolus dose will slowly release the active ingredient, whereas a bolus delivered directly into a vein (e.g., via IV infusion) can deliver the active ingredient more quickly, thereby quickly raising the blood concentration of the active ingredient to an effective level. In other embodiments, the pharmaceutical composition can be administered in the form of a continuous infusion, e.g., via IV infusion, to provide a stable concentration of the active ingredient in the subject's body. In yet other embodiments, a bolus dose of the pharmaceutical composition can be administered first, followed by a continuous infusion.

[0160] Orally administered compositions can take the form of bulk liquid solutions or suspensions or bulk powders. However, more commonly, the compositions are provided in unit dose form to facilitate precise administration. "Unit dosage form" refers to a physically discrete unit suitable as a unitary dose for a human patient or other mammal, each unit containing a predetermined number of active ingredients and appropriate excipients appropriate for producing a desired therapeutic effect. Typical unit dose forms include prefilled, premeasured ampoules or syringes for liquid compositions, or pills, tablets, capsules, etc. for solid compositions. In such compositions, the compound is typically the minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder consisting of various carriers or excipients and processing aids useful for forming the desired dosage form.

[0161] For oral administration, a typical regimen is 1 to 5 oral doses, particularly 2 to 4 oral doses, typically 3 oral doses per day. Using these dosage regimens, each dose provides about 0.01 to about 20 mg / kg of the compound of the present invention, with preferred doses being about 0.1 to about 10 mg / kg, particularly about 1 to about 5 mg / kg.

[0162] To provide blood levels similar to or lower than the injection dose used, the transdermal dose is typically selected to be about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight.

[0163] Injection dose levels range from about 0.1 mg / kg / hour to at least 10 mg / kg / hour for about 1 to about 120 hours, particularly 24 to 96 hours. A preloading bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to obtain adequate steady-state levels. For a 40-80 kg human patient, the maximum total dose should not exceed about 2 g / day.

[0164] Liquid forms suitable for oral administration may include suitable aqueous or nonaqueous carriers and buffers, suspending and dispersing agents, colorants, flavors, etc. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: binders such as microcrystalline cellulose, gum tragacanth or gelatin, excipients such as starch or lactose, disintegrants such as alginic acid, Primogel or corn starch, lubricants such as magnesium stearate, flow aids such as colloidal silica, sweeteners such as sucrose or saccharin, or flavors such as mint, methyl salicylate, orange flavoring.

[0165] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline, or other injectable vehicles known in the art. As noted above, in such compositions, the active compound is typically the minor component, usually about 0.05-10% by weight, with the remainder being the injectable vehicle, etc.

[0166] Typically, transdermal compositions are formulated as a topical ointment or cream containing the active ingredient. When formulated as an ointment, the active ingredient is typically combined with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and typically include other ingredients to enhance consistent skin penetration of the active ingredient or formulation. All such transdermal formulations and ingredients are within the scope of the present invention.

[0167] The compounds of the present invention can also be administered by a transdermal device. Thus, transdermal administration can be accomplished using a reservoir or porous membrane type patch or a multiple solid base patch.

[0168] The above components of compositions for oral, injectable, or topical administration are merely representative. Other materials, processing techniques, and the like are described in Section 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0169] The compounds of this invention can also be administered in sustained release forms or from sustained release delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0170] The present invention further relates to pharmaceutically acceptable formulations of the compounds of the present invention. In one embodiment, the formulation contains water. In another embodiment, the formulation contains a cyclodextrin derivative. Common cyclodextrins are α-, β-, and γ-cyclodextrins, which consist of six, seven, and eight α-1,4-linked glucose units, respectively, which optionally contain one or more substituents on the linked sugar moieties, including, but not limited to, methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution. In some embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, also known as Captisol. See, e.g., U.S. Pat. No. 5,376,645. In some embodiments, the formulation contains hexapropyl-β-cyclodextrin (e.g., 10-50% in water).

[0171] Indications The development of highly selective PARP1 inhibitors for tumors lacking the HR-dependent DNA DSB repair pathway or other DNA repair mechanisms could provide therapeutic benefits to many tumor patients. The compounds of the present invention exert their therapeutic effects by negatively regulating PARP1 activity in tumor cells, particularly tumor cells lacking the HR-dependent DNA DSB repair pathway or other DNA repair mechanisms, or various tumor cells with a BRCA1 or BRCA2-deficient phenotype, due to their high selectivity. In some embodiments, PARP1 inhibitors according to the present invention can treat multiple cancers, ischemic diseases and neurodegenerative diseases.

[0172] More specifically, these compounds are effective in treating heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, etc.), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung: bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, etc.), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, hamartoma, and mesothelioma; gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma, etc.); stomach (tumor, lymphoma, leiomyosarcoma, etc.); pancreas (tubular adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, hemangioma, etc.); small intestine (adenocarcinoma, lymphoma, carcinoma, etc.); leiomyoma, hemangioma, lipoma, neurofibroma, fibroma, etc.), colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma, etc.), genitourinary tract: kidney (adenocarcinoma, nephroblastoma, etc.), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, etc.), prostate (adenocarcinoma, sarcoma, etc.), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma, etc.), liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, biliary tract: gallbladder carcinoma, ampulla carcinoma, cholangiocarcinoma, etc., bone: osteosarcoma, fibrosarcoma, malignant fibrous tissue Myeloma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma, etc.), multiple myeloma, malignant giant cell chordoma, osteochondroma (osteochondroid exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor, nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans, etc.), meninges (meningiomas, meningeal sarcomas, gliomas, etc.), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumors (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, etc.), spinal neurofibromas, meningiomas, gliomas, sarcomas, etc.), gynecology: uterus (endometrial cancer) etc.), Cervix (cervical cancer, precancerous cervical dysplasia, etc.), Ovary (ovarian cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, etc.), Granulosa cell tumor, suspensory stromal cell tumor, dysgerminoma, malignant teratoma, etc.), Vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma, etc.), Vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma, etc.), Fallopian tube cancer, etc., Hematology: Blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma (MCL), follicular lymphoma, myeloproliferative disorders,It can be used to treat multiple myeloma, myelodysplastic syndrome, etc.), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma), etc., skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, adrenal gland: neuroblastoma, etc.

[0173] More specifically, these compounds may be used to treat breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, hematological cancer, gastrointestinal cancer (eg, gastric cancer and colorectal cancer), and lung cancer.

[0174] Combination administration The PARP1 inhibitors described in the present invention can be used in combination with other drugs to treat cancer, including at least one targeted drug / cell activity modulator, including CDK4 / 6 inhibitors, MAT2A inhibitors, MAPK1 / MAPK3 inhibitors, Type I PRMT inhibitors, EGFR inhibitors, SHP2 inhibitors, pan-KRAS inhibitors, KRASG12C inhibitors, RAF inhibitors, MEK inhibitors, ERK inhibitors, Bcl-2 inhibitors, SOS1 inhibitors, PARP inhibitors, MALT1 inhibitors, MALT2 inhibitors, BTK inhibitors, PI3K inhibitors, AKT inhibitors, FGFR inhibitors, DNA methyltransferase (DNMT) inhibitors, EZH1 / 2 inhibitors, EZH2 inhibitors, Menin-MLL inhibitors, IDH1 inhibitors, IDH2 inhibitors, IDH1 / 2 inhibitors, chemotherapy drugs (e.g., carboplatin), radiation therapy, STING agonists, or immune checkpoint inhibitors / modulators.

[0175] Example The raw materials or reagents used herein are either commercially available or can be prepared by synthetic methods known in the art.

[0176] Example 1 5-(4-((8-amino-7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide [ka]

[0177] Step 1 Intermediate 1 (2.00 g) was dissolved in toluene (14.0 mL) and 1-Boc-piperazine (1.72 g), cesium carbonate (9.05 g), 2-bicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl (432 mg), and bis(dibenzylideneacetone)palladium (133 mg) were added. After the addition was complete, the reaction mixture was stirred at 100 °C for 12 h. LCMS (RT = 1.700 min) indicated complete consumption of the starting material. The reaction mixture was cooled and then filtered through diatomaceous earth. The filtrate was extracted with water (15.0 mL) and ethyl acetate (20.0 mL, 10.0 mL). The organic phase was washed with saturated sodium chloride solution (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Intermediate 2 (3.00 g, crude) as a yellow oil. LCMS (ESI) m / z: 322.0[M+H] + .

[0178] Step 2 Intermediate 2 (3.00 g) was dissolved in methanol (21.0 mL), and methylamine solution (7.25 g, 40% purity) was added. The mixture was heated and stirred at 20 °C for 4 h. LCMS (RT = 1.376 min) indicated complete consumption of the starting material. The reaction was quenched with dilute hydrochloric acid (20.0 mL, 2 M) and extracted with dichloromethane (20.0 mL, 10.0 mL). The organic phase was washed with saturated sodium chloride solution (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Intermediate 3 (2.90 g, crude) as a yellow oil. LCMS (ESI) m / z: 321.2[M+H] + .

[0179] Step 3 Intermediate 3 (2.90 g) was dissolved in hydrochloric acid / methanol (21.0 mL, 4 M). After the addition was complete, the reaction mixture was stirred at 20° C. for 2 hours. TLC (petroleum ether / ethyl acetate=0 / 1, product: R f =0.02, raw material: R f= 0.43) indicated that the starting material had been completely consumed. The reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was added to methyl tert-ether (4.00 mL) and triturated to obtain intermediate 4 (2.00 g, yield 86.0%, HCl) as a yellow oil.

[0180] Step 4 Intermediate 5 (5.00 g) was dissolved in toluene (35.0 mL), and ethyl n-butyrate (5.87 g, 6.74 mL) and potassium tert-butoxide (8.50 g) were added. After the addition was complete, the reaction mixture was stirred at 50 °C for 2 h. LCMS (RT = 1.355 min) indicated complete consumption of the starting material. After the reaction mixture was cooled, it was extracted with water (15.0 mL) and ethyl acetate (20.0 mL, 15.0 mL). The organic phase was washed with saturated sodium chloride solution (15.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give intermediate 6 (3.00 g, 31.2% yield) as a yellow oil. LCMS (ESI) m / z: 268.0[M+H] + .

[0181] Step 5 Intermediate 6 (3.00 g) was dissolved in dioxane (18.0 mL) and methanol (3.00 mL). Triethylamine (3.40 g, 4.67 mL) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane (456 mg) were added. After the addition was complete, the reaction mixture was stirred at 80 °C under a carbon monoxide atmosphere (50 Psi). LCMS (RT = 1.213 min) indicated complete consumption of the starting material. The reaction mixture was cooled and then filtered through diatomaceous earth. The filtrate was extracted with water (10.0 mL) and ethyl acetate (10.0 mL, 8.00 mL). The organic phase was washed with saturated sodium chloride solution (5.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Intermediate 7 (2.00 g, crude) as a yellow solid. LCMS (ESI) m / z: 248.1[M+H] + .

[0182] Step 6 Intermediate 7 (2.30 g) was dissolved in dichloromethane (15.0 mL) and diisobutylaluminum hydride (13.9 mL, 1 M) was added at -78 °C. After the addition was complete, the reaction mixture was stirred at 20 °C for 1 h. LCMS (RT = 0.58 min) indicated complete consumption of the starting material. The reaction mixture was extracted with water (10.0 mL) and dichloromethane (10.0 mL, 8.00 mL). The organic phase was washed with saturated sodium chloride solution (5.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance liquid chromatography (chromatographic column: Phenomenex C18 250 x 50 mm x 10 μm; mobile phase: [water (aqueous ammonia)-acetonitrile]; B%: 3%-30%, 20 min) to obtain Intermediate 8 (300 mg, 14.7% yield) as a yellow solid. LCMS (ESI) m / z: 220.1[M+H] + .

[0183] Step 7 Intermediate 8 (80.0 mg) was dissolved in dichloromethane (2.00 mL) and thionyl chloride (217 mg, 132 μL) was added at 0°C. After the addition was complete, the reaction mixture was stirred at 20°C for 2 hours. LCMS (RT = 1.43 min) indicated that the starting material had been completely consumed. The reaction mixture was concentrated under reduced pressure to give Intermediate 9 (80.0 mg, 92.2% yield) as a yellow solid. LCMS (ESI) m / z: 238.0[M+H] + .

[0184] Step 8 Intermediate 9 (80.0 mg) and Intermediate 4 (111 mg, HCl) were dissolved in N,N-dimethylformamide (1.00 mL), potassium carbonate (139 mg) was added, and the reaction mixture was stirred at 60 °C for 2 h. LCMS (RT = 1.287 min) indicated complete consumption of the starting material. After the reaction mixture was cooled, it was extracted with water (3.00 mL) and ethyl acetate (5.00 mL, 3.00 mL). The organic phase was washed with saturated sodium chloride solution (5.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance liquid chromatography (chromatographic column: Phenomenex luna C18 80*40mm*3um; mobile phase: [water (hydrochloric acid)-acetonitrile]; B%: 5%-35%, 7 min) to obtain the white solid compound of Example 1 (74.3 mg, purity 100%, HCl). LCMS (ESI) m / z: 422.2[M+H] + ; 1 H NMR (400MHz,DMSO-d6) δ ppm 1.01 (t,J=7.32Hz,3 H),2.53 - 2.59 (m,2 H),2.77 - 2.87 (m,3 H),3.17 - 3.55 (m,6 H),4.02 - 4.18 (m,2 H),4.52 (br s,2 H),,7.47 - 7.58 (m,1 H) 7.73 (d,J=1.60Hz,1 H),7.86 - 7.99 (m,1 H),8.29 - 8.41 (m,1 H),8.50 (br d,J=4.80Hz,1 H),8.61 - 8.70 (m,1 H),11.18 - 11.30 (m,1 H),11.32 - 11.51 (m,1 H).

[0185] Example 2 5-(4-((8-amino-7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-fluoro-N-methoxypicolinamide [ka]

[0186] Step 1 Intermediate 10 (14.0 g) was dissolved in acetonitrile (140 mL), and silver(II) fluoride (24.6 g) was added. After the addition was complete, the reaction mixture was stirred at 20° C. for 12 hours. TLC (petroleum ether / ethyl acetate=2 / 1, product: R f =0.54, raw material: R f =0.43) indicated complete consumption of the starting material. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (silica, petroleum ether / ethyl acetate = 50 / 1 to 1 / 1) to give Intermediate 11 (9.30 g, 61.3% yield) as a yellow solid.

[0187] Step 2 Intermediate 11 (4.30 g) was dissolved in toluene (43 mL), and 1-tert-butoxycarbonyl-piperazine (4.11 g), cesium carbonate (19.4 g), 2-bicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl (857 mg), and bis(dibenzylideneacetone)palladium (504 mg) were added. After the addition was complete, the reaction mixture was stirred at 100° C. for 12 hours. TLC (petroleum ether / ethyl acetate = 2 / 1, product: R f =0.24, raw material: R f = 0.54), indicating complete consumption of the starting material. After cooling, the reaction mixture was filtered through diatomaceous earth. The filtrate was extracted with water (50.0 mL) and ethyl acetate (50.0 mL, 30.0 mL). The organic phase was washed with saturated sodium chloride solution (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica, petroleum ether / ethyl acetate = 50 / 1-0 / 1) to obtain Intermediate 12 (2.70 g, 43.3% yield) as a yellow solid. 1H NMR (400MHz,CDCl3) δ ppm 1.49 (s,9 H) 3.15 - 3.26 (m,4 H) 3.56 - 3.67 (m,4 H) 3.96 (s,3 H) 7.23 - 7.27 (m,1 H) 7.97 (dd,J=8.00,1.06Hz,1 H).

[0188] Step 3 Intermediate 12 (2.70 g) was dissolved in tetrahydrofuran (14.0 mL), methanol (2.70 mL), and water (7.00 mL), and lithium hydroxide (700 mg) was added. After the addition was complete, the reaction mixture was stirred at 20° C. for 12 hours. TLC (petroleum ether / ethyl acetate=1 / 1, product: R f =0.02, raw material: R f =0.43) indicated complete consumption of the raw materials. The reaction mixture was quenched by adding dilute hydrochloric acid (10.0 mL, 2 M), extracted with ethyl acetate (30.0 mL, 20.0 mL), and the organic phase was washed with saturated sodium chloride solution (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give intermediate 13 (2.10 g, 81.1% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ ppm 1.35 - 1.60 (m, 9 H) 2.63 - 3.13 (m, 4 H) 3.28 - 3.68 (m, 4 H) 6.81 - 7.16 (m, 1 H) 7.65 - 8.00 (m, 1 H).

[0189] Step 4 Intermediate 13 (700 mg) was dissolved in N,N-dimethylformamide (7.00 mL), and N,N-diisopropylethylamine (556 mg, 749 μL), methoxyamine hydrochloride (179 mg), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (818 mg) were added. After the addition was complete, the reaction mixture was stirred at 20°C for 12 hours. TLC (petroleum ether / ethyl acetate = 1 / 1, product: R f =0.24, raw material: R f= 0.02) indicated that the starting material had been completely consumed. The reaction mixture was extracted with water (10.0 mL) and ethyl acetate (10.0 mL, 8.00 mL). The organic phase was washed with saturated sodium chloride solution (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Intermediate 14 (500 mg, 65.5% yield) as a yellow solid.

[0190] Step 5 Intermediate 14 (100 mg) was dissolved in hydrochloric acid / methanol (2.00 mL, 4 M). After the addition was complete, the reaction mixture was stirred at 20° C. for 2 hours. TLC (petroleum ether / ethyl acetate=1 / 1, product: R f =0.02, raw material: R f =0.43) indicated that the starting material had been completely consumed. The reaction mixture was concentrated under reduced pressure to give Intermediate 15 (50.0 mg, 69.6% yield, HCl) as a yellow solid.

[0191] Step 6 Intermediate 9 (50.0 mg) and Intermediate 15 (56.3 mg, HCl) were dissolved in N,N-dimethylformamide (1.00 mL), and N,N-diisopropylethylamine (81.5 mg) was added. After the addition was complete, the reaction mixture was stirred at 60 °C for 2 h. LCMS (RT = 0.892 min) indicated complete consumption of the starting material. After the reaction mixture was cooled, it was extracted with water (3.00 mL) and ethyl acetate (5.00 mL, 3.00 mL). The organic phase was washed with saturated sodium chloride solution (5.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance liquid chromatography (chromatography column: Phenomenex luna C18 80*30mm*3um; mobile phase: [water (hydrochloric acid)-acetonitrile]; B%: 5%-35%, 8 min) to obtain the white solid compound of Example 2 (13.0 mg, purity 96.4%, HCl). LCMS (ESI) m / z: 456.1[M+H] + ; 1H NMR (400MHz,DMSO-d6) δ ppm 1.01 (t,J=7.20Hz,3 H) 2.56 (br. s,2 H) 3.13 - 3.33 (m,6 H) 3.67 (s,3 H) 3.73 (br. d,J=12.0Hz,2 H) 4.54 (br. s,2 H) 6.36 - 6.50 (m,1 H) 7.65 - 7.74 (m,2 H) 7.88 (d,J=8.00Hz,1 H) 8.52 (br. s,1 H) 10.51 (br. d,J=3.60Hz,1 H) 11.24 (br. s,1 H) 11.82 (s,1 H).

[0192] Examples 3 and 4 were synthesized using the same experimental methods as in Examples 1 and 2.

[0193] Example 3 5-(4-((8-amino-7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide [ka] LCMS (ESI) m / z: 440.1[M+H] + ; 1 H NMR (400MHz,DMSO-d6) δ ppm 1.01 (t,J=7.20Hz,3 H) 2.54 - 2.58 (m,2 H) 2.74 - 2.82 (m,3 H) 3.14 - 3.38 (m,6 H) 3.72 (br. d,J=12.0Hz,2 H) 4.54 (br. s,2 H) 6.31 - 6.53 (m,1 H) 7.65 - 7.73 (m,2 H) 7.89 (d,J=7.80Hz,1 H) 8.43 - 8.48 (m,1 H) 8.50 - 8.55 (m,1 H) 10.28 - 10.68 (m,1 H) 11.25 (br. s,1 H).

[0194] Example 4 5-(4-((8-amino-7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-fluoro-N-(methyl-d3)picolinamide [ka] LCMS (ESI) m / z: 443.1[M+H] + ; 1 H NMR (400MHz,DMSO-d6) δ ppm 0.96 - 1.05 (m,3 H) 2.29 - 2.41 (m,4 H) 2.54 (br. s,2 H) 3.11 - 3.25 (m,4 H) 3.63 - 3.80 (m,2 H) 4.54 (br. s,2 H) 6.42 (br. s,2 H) 7.68 - 7.72 (m,1 H) 7.89 (d,J=8.00Hz,1 H) 8.42 (s,1 H) 8.51 (br. s,1 H) 10.28 - 10.54 (m,1 H) 11.24 (br. s,1 H).

[0195] Experimental Example 1: Inhibitory effect of compounds on PARP1 / PARP2 enzyme activity PARP1 / PARP2 enzyme activity was detected using chemiluminescence. First, histone (Active Motif, 81126) was incubated in a 384-well plate for 2 hours, and then various dilutions of the example compound and PARP1 working solution (Abcam, ab279663) or PARP2 working solution (BPS, 80502) were added. Only the PARP1 working solution or PARP2 working solution was added to the Max control wells, and only the assay buffer was added to the Min control wells. The plate was then incubated at room temperature for 15 minutes, and the biotin-labeled substrate NAD +After the enzyme catalyzed conversion of the substrate, the ADP-ribosylated group retained the biotin label even when bound to histone. Streptavidin-HRP solution (Abcam, ab7403) was added to develop the biotin. The values ​​were read using an EnSight (PE) instrument, and the inhibition rate was calculated using the fluorescence values ​​of the Max and Min wells. The dose-effect curves were fitted using the analytical software GraphPad Prism 5, which allowed for the IC value of each compound relative to the enzyme activity. 50 got the value.

[0196] The results are shown in Table 1 below. Examples 1, 2, 3, and 4 had dose-dependent effects on the PARP1 enzyme, exhibiting significant inhibitory activity, reaching picomolar concentrations, and exhibiting similar activity to the reference compounds AZD5305 and olaparib. Regarding PARP2 selectivity, the selectivity of Example 1 was three-fold superior to that of the reference AZD5305, while Examples 2, 3, and 4 were similar to that of the reference AZD5305. Regarding PARP2 selectivity, the selectivity of Example 1 was three-fold superior to that of the control AZD5305, while Examples 2, 3, and 4 were similar to that of the positive control. Compared to the currently commercially available PARPi olaparib, Examples 1, 2, 3, and 4 exhibited significantly improved selectivity for PARP2 while maintaining inhibitory activity against the PARP1 enzyme, with selectivity fold improvements of 16-83 fold.

[0197] [Table 1]

[0198] Experimental Example 2: Compound-induced DNA trapping ability of PARP1 / PARP2 The DNA trapping ability of PARP1 / PARP2 was detected using HTRF (homogeneous time-resolved fluorescence). First, MAb anti-GST-Tb crypate (cisbio, 61GSTTLA) labeled PARP1 (BPS, 80501) or PARP2 (BPS, 80502) and damaged DNA labeled probe (Generay) were used. Various concentrations of the example compounds were added. 50 μM AZD2281 was added to the Max control well, and medium buffer was added to the Min well. The wells were incubated at room temperature for 1 hour, and the substrate NAD + The solution was incubated for 10 minutes with PARP (Sigma, 10127965001) and allowed to undergo enzymatic activity, resulting in the release of PARP from the damaged DNA. Only a fluorescent signal with an emission wavelength of 615 nm was detected. After PARP was inhibited, binding of PARP to the damaged DNA was induced, resulting in energy transfer, resulting in two emission wavelengths: a fluorescent signal with an emission wavelength of 615 nm from the damaged DNA probe itself, and a fluorescent signal with an emission wavelength of 665 nm from PARP binding to DNA, resulting in energy transfer. The fluorescence ratio between 665 nm and 615 nm was calculated to represent the amount of PARP-DNA trapping complex. The trapping capacity induced by each compound was calculated using the Max and Min fluorescence values. A dose-effect curve was fitted using GraphPad Prism 5 analysis software, which determined the EC2 value for the DNA trapping capacity of the PARP isoform induced by each compound. 50 The values ​​(trapping required concentration reached 50%) were obtained.

[0199] The results are shown in Table 2 below. The DNA trapping ability of PARP induced by Examples 1, 2, 3, and 4 reached single-digit nanomolar concentrations, demonstrating remarkable trapping ability, similar to the activity of the reference compound AZD53305 and superior to that of olaparib. Regarding PARP2 selectivity, Example 3 achieved 64-fold selectivity, similar to that of reference AZD5305, while Examples 1, 2, and 4 achieved approximately 100-fold selectivity, superior to that of reference AZD5305. Compared to the currently commercially available PARPi olaparib, Examples 1, 2, 3, and 4 all significantly improved PARP1 activity and PARP2 selectivity, with activity improved 3-7 fold and selectivity improved 213-333 fold.

[0200] [Table 2]

[0201] Experimental Example 3: Inhibitory effect of compounds on PARP1 / PARP2 enzyme activity at the cellular level High-content imaging was used to detect the inhibitory effects of compounds on PARP1 / PARP2 enzymes at the cellular level. A549 WT, PARP1-KO, and PARP2-KO cell lines were prepared and resuscitated. After the cells stabilized, a sufficient number of cells were harvested. 100 μL of the cell suspension was then seeded into a 96-well plate. The next day, proportionally diluted series of the example compounds were added. The Max control wells were treated with buffer alone, and the Min control wells were treated with 500 nM AZD5305 (A549 WT and PARP2-KO cell lines) or 1 μM AZD2281 (PARP1-KO cell line). The cells were then incubated for 1.5 hours (A549 WT and PARP2-KO cell lines) or 2 hours (PARP1-KO cell line). The supernatant was removed, and the cells were incubated with 0.4 mM H2O2 for 10 minutes (A549 WT and PARP2-KO cell lines) or 1.5 mM H2O2 for 15 minutes (PARP1-KO cell line) to induce extensive DNA damage. The supernatant was removed, and the cells were fixed with 4% paraformaldehyde for 20 minutes. Then, the cells were treated with 0.5% Triton X-100 for 20 minutes to permeabilize the cell membrane. Then, the cells were incubated with 3% BSA for 1 hour to prevent nonspecific binding. The primary antibody, Poly(ADP-ribose) monoclonal antibody (CST, 83732S) diluted 1:500 was added, followed by overnight incubation with the secondary antibody, Goat anti-Rabbit IgG, Alexa Fluor ® ELISA, diluted 1:500. TM 488 (Invitrogen, A-11034) was added and incubated for 1 hour. 50 μL of DAPI (Invitrogen, R37606) was added and cell nuclei were stained for 30 minutes. After washing twice with PBS, OPERETTA CLS TMImages were taken in non-confocal mode using a 20x water-immersion objective, with five fields captured for each well. For data analysis, the DAPI-stained nuclear population was selected to distinguish between nuclei and cytoplasm, and the average Alexa 488 intensity in the nuclei of each well was calculated. The Max and Min well fluorescence values ​​were used to calculate the inhibition rate, and dose-effect curves were fitted using GraphPad Prism 5 analysis software, thereby determining the IC value for each compound's enzyme activity. 50 got the value.

[0202] As shown in Table 3, the example compounds exhibited dose-dependent enzyme activity inhibition in both A549 WT and PARP2-KO cell lines, demonstrating significant inhibitory activity. Example 4 reached single-digit nanomolar concentrations, demonstrating that the cellular enzyme activity was primarily derived from PARP1. Examples 1, 2, 3, and 4 exhibited similar inhibitory activity against the PARP1 enzyme compared to the reference AZD5305. The example compounds all exhibited fairly weak inhibitory activity in the A549 PARP1-KO cell line, with Examples 2, 3, and 4 showing no detectable enzyme activity inhibition at concentrations up to 40 μM. This indicates that the example compounds did not significantly inhibit cellular PARylation after PARP1 knockout, and that the compounds did not exhibit any significant inhibitory activity against enzymes other than PARP1. Compared to reference AZD5305, Examples 1 and 2 exhibited similar selectivity, while Examples 3 and 4 exhibited superior selectivity, with selectivity folds improved by 3-6 times over reference AZD5305.

[0203] [Table 3]

[0204] Experimental Example 4: Test of the compound's growth inhibitory activity against tumor cells The most widely used ATP concentration detection method was used to test the compounds for tumor cell growth inhibition. MDA-MB-231 and MDA-MB-436 cell lines were derived from ATCC DLD-1 human colorectal cancer epithelial cells. DLD-1 BRCA2 - / - The cells were derived from Horizon. They were resuscitated and harvested after the cell condition stabilized. The viable cell count was greater than 90%. 450-500 cells were seeded into a 384-well plate. The next day, a series of equally diluted concentrations of the example compounds were added. Buffer alone was added to the Max well, and 50 μM AZD2281 was added to the Min well. The cells were incubated for 7 days, and on the 8th day, the cells were analyzed by CellTiter-Glo. (R) The reagent (Promega, G7573) was added, and the mixture was incubated at room temperature for 30 minutes. The values ​​were then read on an Envision (PE) instrument. The fluorescence values ​​of the Max and Min wells were used to calculate the inhibition rate, and dose-effect curves were fitted using the analytical software GraphPad Prism 5, thereby determining the IC value for each compound on the enzyme activity. 50 got the value.

[0205] The results are shown in Table 4 below. In the BRCA1-mutated MDA-MB-436 human triple-negative breast cancer cell line and the BRCA1-normal MDA-MB-231 human triple-negative breast cancer cell line, the example compounds exhibited dose-dependent growth inhibitory activity against the BRCA1-mutated MDA-MB-436, and the growth inhibitory activity of Examples 2, 3, and 4 against these cancer cells all reached single-digit nanomolar concentrations, similar to that of the reference AZD5305. In the case of the BRCA1-normal MDA-MB-231, Examples 1, 2, and 4 did not exhibit any growth inhibitory activity at the highest concentration of 10 μM, consistent with that of the reference AZD5305, and the IC of Example 3 was higher. 50The β-amylindrical activity of Examples 1, 2, 3, and 4 was 7.4 μM, demonstrating that Examples 1, 2, 3, and 4 exhibited clear selectivity between BRCA1 mutant cell lines and BRCA1 normal cells, with selectivity reaching hundreds or even thousands of times. Compared to the commercially available PARPi olaparib, Examples 1, 2, 3, and 4 exhibited 18- to 235-fold improved growth inhibitory activity against BRCA1 mutant MDA-MB-436 and 55- to 530-fold improved selectivity against PARP2, significantly improving activity against PARP1 and selectivity against PARP2.

[0206] As shown in Table 5, BRCA2 mutation DLD-1 BRCA2 - / - In the BRCA2-normal DLD-1 human colorectal cancer epithelial cell line, all of the example compounds exhibited dose-dependent growth inhibitory activity against the BRCA2-mutated cell line, and the growth inhibitory potency of Examples 2, 3, and 4 against these cancer cells reached single-digit nanomolar concentrations, similar to that of reference AZD5305. In the BRCA2-normal DLD-1 cell line, Examples 1, 2, 3, and 4 did not show any growth inhibitory activity at the highest concentration of 10 μM, consistent with that of reference AZD5305. This indicates that Examples 1, 2, 3, and 4 have clear selectivity between BRCA2-mutated cell lines and BRCA2-normal cells, with selection folds reaching hundreds or thousands of times.

[0207] The growth inhibitory activity of the example compounds in BRCA1 mutated and normal, and BRCA2 mutated and normal cancer cell lines demonstrated that the example compounds have potent growth inhibitory activity against target cells and are clear and safe when used in clinical treatment.

[0208] [Table 4]

[0209] [Table 5]

[0210] By combining enzymatic activities at the molecular and cellular levels, the damaged DNA trapping ability of PARP and the proliferation inhibitory activity against cancer cells were induced. Examples 1, 2, 3, and 4 have excellent PARP1 selective inhibitory activity and proliferation inhibitory activity against target cells, and are significantly superior to the commercially available PARPi olaparib in both PARP1 activity and PARP2 selectivity, and have significantly improved PARP1 selectivity at the cellular level compared to the reference compound AZD5305.

[0211] Experimental Example 5: Single-dose pharmacokinetic study in mice Male CD-1 mice were used as test animals. After a single dose, plasma drug concentrations of the compounds were measured and pharmacokinetic parameters were evaluated. Healthy adult male CD-1 mice were selected. 10% DMSO was added to the candidate compounds, followed by vortexing and sonication to dissolve them thoroughly. 30% PEG 400 was added, vortexing, sonication, and 60% double-distilled water was added to obtain a clear solution. The mice were administered 2 mg / kg intravenously and 10 mg / kg orally. Whole blood was collected at 5, 15, and 30 minutes, 1, 2, 4, 8, and 24 hours after administration. Plasma was then obtained and the samples were processed using LC-MS / MS to analyze drug concentrations and calculate pharmacokinetic parameters.

[0212] The results are shown in Table 6 below, and demonstrate that the compound of Example 1 has excellent bioavailability and good pharmacokinetic properties.

[0213] [Table 6]

[0214] As can be seen from the above experiments, the compounds of the present invention have high selectivity for inhibiting the PARP1 enzyme, and their inhibitory activity at the PARP1 enzyme and cellular level is 10 to 100 times or more greater than their inhibitory activity against the PARP2 enzyme. Higher selectivity is expected to lead to higher clinical safety, fewer toxic side effects, and easier patient acceptance, thereby increasing their medical value.

[0215] Experimental Example 6 Selectivity of compounds against PARP family PARP3, 5a, 6, 7, and 11 PARP family enzyme activity was detected by chemiluminescence. Histones (Active Motif, 81126) were first incubated in a 384-well plate for 2 hours. The example compounds and PARP3 working solution (BPS, 80503) at different dilutions were added, and only the PARP working solution was added to the Max control wells, and only the assay buffer was added to the Min control wells. The wells were incubated at room temperature for 15 minutes, and the biotin-labeled substrate NAD + (BPS, 80610), PARP3 activating DNA (Generay) was added and incubated at room temperature for 2 hours. After the substrate was catalyzed by the enzyme, the ADP-ribosylated group retained the biotin label even when bound to histones. Streptavidin-HRP solution (Abcam, ab7403) was added to develop the biotin, and the value was read using an EnSight (PE) instrument.

[0216] The example compounds and PARP5a working solution (BPS, 80504) at different dilutions were added, and only the PARP working solution was added to the Max control wells, and only the assay buffer was added to the Min control wells. The wells were incubated at room temperature for 15 minutes, and the biotin-labeled substrate NAD + (BPS, 80610) was added and incubated at room temperature for 2 hours. After the substrate was catalyzed by the enzyme, the ADP-ribosylated group still had a biotin label even when bound to histone. Streptavidin-HRP solution (Abcam, ab7403) was added to develop the biotin, and the value was read using an EnSight (PE) instrument.

[0217] The example compounds and PARP6 working solution (BPS, 80506) at different dilutions were added, and only the PARP working solution was added to the Max control wells, and only the assay buffer was added to the Min control wells. The wells were incubated at room temperature for 15 minutes, and the biotin-labeled substrate NAD + (BPS, 80610) was added and incubated at room temperature for 2 hours. After the substrate was catalyzed by the enzyme, the ADP-ribosylated group still had a biotin label even when bound to histone. Streptavidin-HRP solution (Abcam, ab7403) was added to develop the biotin, and the value was read using an EnSight (PE) instrument.

[0218] Using a PARP7 chemiluminescent assay kit (BPS, 79729), various dilutions of the example compounds and PARP7 working solution (BPS, 80527) were added. Only the PARP working solution was added to the Max control wells, and only the assay buffer was added to the Min control wells. These were then incubated at room temperature for 15 minutes. The substrate mixture (BPS, 78371) from the assay kit was then added and incubated at room temperature for 1 hour. After the substrate was catalyzed by the enzyme, the ADP-ribosylated group, even when bound to histone, retained the biotin label. Streptavidin-HRP solution (BPS, 80611) was added to develop the biotin, and the values ​​were read using an EnSight (PE) instrument.

[0219] Using a PARP11 chemiluminescent assay kit (BPS, 80561), various dilutions of the example compounds and PARP11 working solution (BPS, 80511) were added. Only the PARP working solution was added to the Max control wells, and only the assay buffer was added to the Min control wells. The wells were then incubated at room temperature for 15 minutes. The substrate mixture (BPS, 78371) from the assay kit was then added and incubated at room temperature for 1 hour. After the substrate was catalyzed by the enzyme, the ADP-ribosylated group, even when bound to histone, retained the biotin label. Streptavidin-HRP solution (BPS, 80611) was added to develop the biotin, and the values ​​were read using an EnSight (PE) instrument.

[0220] The fluorescence values ​​of the Max and Min wells were used to calculate the inhibition rate, and dose-effect curves were fitted using the analytical software GraphPad Prism 5, thereby determining the IC value for each compound on the enzyme activity. 50 got the value.

[0221] The results are as shown in Table 7 below. The inhibitory effects of Example 4 on each PARP enzyme were all weaker than its activity against the PARP1 enzyme, and the values ​​in parentheses in Table 7 represent the ratio to PARP1 enzyme activity. Compared to the commercially available PARPi Olaparib, Example 4 had slightly weaker selectivity for PARP11, but also significantly improved selectivity for all other enzymes. Compared to the reference AZD5305, Example 4 had significantly improved selectivity for all tested PARP enzymes.

[0222] According to this, Example 4 is a PARP1-specific selective inhibitor, and its selectivity against PARP3, PARP5a, PARP6, PARP7 and PARP11 is superior to AZD5305, with its selectivity against PARP11 being particularly notable, and its selectivity against PARP3, PARP5a, PARP6 and PARP7 is superior to olaparib, with its selectivity against PARP3 being particularly notable.

[0223] [Table 7]

[0224] Experimental Example 7: Effect of compounds on DNA trapping by PARP1 / 2 induced in FP experiments To further investigate the effect of Example 4 on PARP1-DNA and PARP2-DNA trapping and the difference between them, we further evaluated them using the fluorescence polarization (FP) method. PARP1 / 2 enzymes bind to fluorescently labeled DNA to form a large complex, which slows down the rotation of the fluorescently labeled DNA, emitting higher polarization values ​​and increasing NAD. +After the addition of PARP inhibitors, PARP1 / 2 enzymes self-ribosylated, accumulating negative charges. After a certain amount of negative charge accumulation, the fluorescently labeled DNA dissociated, which accelerated the rotation of the fluorescently labeled DNA and reduced the polarization value. Adding PARP inhibitors affected PARP-DNA trapping, and the extent of this effect could be detected by changes in polarization intensity. First, 25 nL of compounds at 1000x final concentration were transferred to a 384-well plate. 25 nL of 100% DMSO was added to the Min and Max wells, respectively. 5 μL of enzyme solution containing 10 nM PARP1 (BPS, 80501) and 1 nM FAM-PARP1-DNA (Generay, customized) or 10 nM PARP2 (BPS, 80502) and 1 nM FAM-PARP2-DNA (Generay, customized) was added. The mixture was centrifuged at 1000 rpm for 1 minute and incubated at room temperature for 30 minutes. Then, 5 μL of 1 mM substrate NAD was added. + (MCE, HY-B0445) and 5 μL of 1 mM substrate NAD + The assay buffer was added to the Maxwell, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C. The following tests were performed at different time points: For PARP1 trapping studies, readings were taken using a plate reader (Envision) at 0.25, 0.5, 1, 2, 4, 8, 24, 30, 48 and 54 hours.

[0225] For PARP2 trapping studies, readings were taken using a plate reader at 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours and 48 hours.

[0226] The compound-induced trapping capacity was calculated using the fluorescence values ​​of the Max and Min wells, and a dose-effect curve was fitted using the analytical software GraphPad Prism 5, thereby determining the EC of the DNA trapping capacity of the PARP enzyme induced by each compound. 50 got the value.

[0227] The results are shown in Table 8 and Figure 1. Taking the 2-hour time point as an example, the ability of Example 4 to induce PARP1-DNA trapping was 48-fold improved compared to the commercially available PARPi Olaparib and similar to the reference AZD5305. Example 4 had almost no ability to trap PARP2-DNA, similar to the reference AZD5305, whereas the commercially available PARPi Olaparib showed similar trapping of PARP2-DNA and PARP1-DNA, lacking selectivity.

[0228] Example 4 was shown to have much higher selectivity for PARP1 than for PARP2, and was expected to significantly reduce hematotoxicity caused by PARP2.

[0229] As shown in Table 8 and Figure 2, the PARP1-DNA trapping ability of Example 4 and reference AZD5305 was further compared. Over time, the activity of Example 4 could be maintained for more than 54 hours, and its activity at 54 hours was 14-fold stronger than that of reference AZD5305, demonstrating its better tumor growth inhibitory activity.

[0230] [Table 8]

[0231] Experimental Example 8 Antitumor effect of the compound on a mouse model transplanted with human breast cancer cells MDA-MB-436 For further in vivo validation of Example 4, a mouse subcutaneous tumor model of the BRCA1 mutant MDA-MB-436 cell line was selected. Human breast cancer MDA-MB-436 cells (ATCC, HTB-130) were cultured in vitro as a monolayer in L-15 medium supplemented with 10% fetal bovine serum, 1% penicillin / streptomycin solution, and 0.01 mg / mL bovine insulin in a 37°C CO2-free incubator. Pancreatin-EDTA was used for general digestion and passage twice a week. When cell saturation reached 80%-90%, the cells were harvested, counted, and cultured in 0.2 mL of 1 x 107 MDA-MB-436 cells were inoculated subcutaneously into the right back of each mouse (PBS:Matrigel = 1:1). The average tumor volume was 152 mm 3 When the tumor volume reached 100 mg / kg, the mice were divided into groups and administration was initiated. The day of administration was designated as Day 0, and tumor volume and mouse body weight were monitored twice a week. Administration treatment was continued for 28 days.

[0232] The tumor diameter was measured using a vernier. The tumor volume was calculated using the following formula: V = 0.5a × b 2 , a and b represent the long and short diameters of the tumor, respectively. The tumor-inhibiting effect of the compound was evaluated by the relative tumor shrinkage rate (Reg%). Reg% represents the volume shrinkage rate of the tumor itself after tumor treatment. Reg% = (V0 - V t ) / V0×100%, where V0 is the tumor volume measured specifically at the time of administration (i.e., d0), and V t is the tumor volume at a given measurement.

[0233] The compound response criteria in mouse models were modified from mRECIST (modified solid tumor response criteria) (Gao et al., 2015), and the specific definitions are as follows: CR (complete remission): Best Response <-95% and Best Avg Response <-40% PR (partial response): Best Response < -50% and Best Avg Response < -20% SD (stable disease): Best Response < 35% and Best Avg Response < 30% PD (progressive disease): other classifications; ORR% is equal to the sum of the rates of complete response (CR) and partial response (PR).

[0234] Statistical analysis was performed using Prism software, and included the mean (Mean) and standard error (SEM) of tumor volume for each group at each time point. For statistical analysis of TV, the raw TV data measured at each time were used to compare differences between groups, and two-way ANOVA was used to analyze the effects of administration and time. A p<0.05 was considered statistically significant.

[0235] The results are shown in Figure 3. At the same dose, both Example 4 and reference AZD5305 were able to induce tumor regression, with the tumor regression rate of Example 4 being superior to that of reference AZD5305, with an ORR of 60% compared to the reference ORR of 20%.

[0236] In a mouse subcutaneously transplanted human breast cancer MDA-MB-436 tumor model, the tumor growth inhibitory effect of Example 4 was shown to be superior to that of the reference compound AZD5305.

[0237] Experimental Example 9: Pro-apoptotic effect of compounds on BRCA2-deficient cell lines The mechanism of growth inhibitory action of the compounds on BRCA mutant tumors was analyzed, and the apoptotic effect of the compounds on BRCA2 mutant cell lines was analyzed by flow cytometry. BRCA2-deficient human colon cancer DLD-1 cells (ATCC, HTB-130) were cultured in adherent culture in RPMI 1640 medium supplemented with 1% fetal bovine serum and 100 μg / mL hygromycin B. When the cells reached logarithmic growth phase, they were harvested and placed in a 6-well plate at 600,000 cells per well. The cells were allowed to adhere overnight in a 37°C / 5% CO2 incubator. Different concentrations of compounds were added to each well and incubated in the incubator. After 7 days, the cells were harvested and placed in a 96-well plate. 195 μL of Annexin V-FITC binding buffer was added to each well, the cells were resuspended, and 5 μL of Annexin V-FITC (Beyotime, C1052) was added. The cells were gently mixed and incubated at room temperature for 30 minutes. The cells were then selected twice in PBS and centrifuged at 300 g for 5 minutes. 500 μL of PBS was added to each well, the cells were resuspended, and 5 μL of Annexin V-FITC (Beyotime, C1052) was added. PI (Beyotime, C1052) was added, mixed gently, and stained for 30 minutes at room temperature. Following selection with PBS, the cells were centrifuged at 300 g for 5 minutes, and then 500 μL of PBS was added to resuspend the cells. 300 μL of cells were removed and placed in a flow tube for analysis using a Flow-On Machine (BD Bioscience, FACS Verse). Data collected by the flow meter was analyzed using FlowJo software.

[0238] Cell apoptosis analysis: Apoptosis samples were dragged into FlowJo and double-clicked on the raw data to open the graph window. FSC-A was selected for the X-axis, and SSC-A for the Y-axis. The cell populations shown in the figure above were selected for apoptosis analysis. Cell debris was not analyzed. Double-clicking on "Cell Populations Analyzed" in the SSC / FSC graph allowed FITC to be selected for the X-axis, representing Annexin V-FITC. PerCP was selected for the Y-axis, representing PI. A quadrant gating tool was used to define live and apoptotic cells. Annexin V positivity indicates apoptotic cells, Annexin V positive PI negative indicates early apoptotic cells, and Annexin V positive PI positive indicates late apoptotic cells. Data were plotted and analyzed using PRISM. Statistical analysis was performed using two-way ANOVA, incorporating different compounds and different concentrations, with Tukey's multiple comparisons test. A p<0.05 was considered statistically significant.

[0239] The results are shown in Figure 4. The experiment was repeated three times, and the cell apoptosis rate induced by Example 4 at different concentrations was higher than that of the reference AZD5305, with some concentrations showing statistically significant differences. This indicates that Example 4 is superior to the reference AZD5305 in inducing apoptosis in BRCA2-deficient human colon cancer DLD-1 cells.

[0240] Experimental Example 10: Pro-apoptotic effect of compounds on BRCA1 mutant human breast cancer xenograft tumors The pro-apoptotic effects of the compounds were further verified in vivo by immunoblotting to detect changes in cleaved caspase-3 expression in subcutaneously implanted tumor tissues in MDA-MB-436 mice. After 10 days of treatment with different compounds, animals were euthanized 0.25 and 24 hours after the final dose, and tumor tissues were collected for analysis. Snap-frozen tumor tissues were placed on dry ice and 350 μL of complete cell lysis solution (containing 1% protease and phosphatase inhibitors) was added. The tissues were ground in a tissue grinder for 5 minutes, and then lysed in the tissue lysis solution on ice for 30 minutes. The mixture was centrifuged at 12,000 rpm and 4°C for 10 minutes, and the supernatant was collected and placed in a new 1.5 mL centrifuge tube. Protein quantification was performed using a BCA quantification kit. Based on the quantification results, the sample protein concentration was uniformly adjusted to 2 μg / μL. LDS loading buffer (4X) and sample reducing agent (10X) were added, and the sample was heated at a constant temperature of 100°C for 10 minutes. Protein blotting was performed on an SDS-PAGE gel. 10 μL was loaded into each well and electrophoresed at 80 volts for 30 minutes, then at 120 volts for 90 minutes. The membrane was transferred for 7 minutes using the iBlot2 transfer set and transfer device. The membrane was cut according to the molecular weight of the protein to be detected. The membrane was washed three times with 1xTBST for 5 minutes each. The primary antibodies Cleaved Caspase-3 (Asp175) (5A1E) Rabbit mAb (CST, 9664), Caspase-3 Antibody (CST, 9662), and β-Actin Antibody (CST, 4967) were added and incubated overnight at 4°C. The membrane was washed three times with 1xTBST for 10 minutes each. The secondary antibody Goat anti-Rabbit IgG-HRP (Thermo Fisher, 31462) was added and incubated at room temperature for 1 hour. The membrane was washed three times with 1xTBST for 10 minutes each. The West The HRP substrate from the Femto Hypersensitive Chemiluminescence Kit was added, and the chemiluminescence was detected, photographed, and saved on a Tanon 5200 Multi machine. Quantitative analysis was performed using Alpha View software to quantify the relative density intensity of immunoblot luminescent bands.β-Actin was used as a housekeeping protein to confirm consistency of loading levels in immunoblotting. The density intensity of the cleaved caspase-3 band was compared with that of the total caspase-3 band and normalized. The relative density intensity of cleaved caspase-3 in the vehicle control group was set to 1, and the relative expression levels of cleaved caspase-3 in each treatment group were converted and plotted. The plots were analyzed using Prism software. The mean and standard error of the mean (SEM) of the relative expression levels of cleaved caspase-3 at each time point in each group were used to compare differences between groups. Comparisons between multiple groups were analyzed using one-way ANOVA. If variances were not equal (significant differences in F values), the Games-Howell test was used to verify the significance. If the F values ​​were not significant, the Tukey's multiple comparisons test was used. A p<0.05 was considered statistically significant.

[0241] The results are shown in Figures 5 and 6. Example 4 promoted the elevation of cleaved caspase-3 in subcutaneously implanted tumor tissues in MDA-MB-436 mice, with the degree of elevation at 0.25 hours and 24 hours after the last administration being superior to that of the reference AZD5305. This suggests that Example 4 has a more potent tumor cell apoptosis-promoting effect than the reference AZD5305 in BRCA1-mutated MDA-MB-436 tumors in vivo, which is consistent with its better antitumor effect.

[0242] As described above, the compounds of the present invention are highly selective PARP1 inhibitors, and their tumor growth inhibitory effects in the BRCA1 MDA-MB-436 human breast cancer tumor model are superior to those of AZD5305. This superiority is further demonstrated by comparison of the promotion of PARP1 DNA trapping and the induction of cell apoptosis. Compared with commercially available PARP inhibitors, the compounds exhibit significantly improved selectivity for PARP2, and compared with the reference compound AZD5305, they exhibit significantly improved selectivity for other PARP family members. The compounds of the present invention, such as Example 4, are expected to be safer and more effective highly selective PARP1 inhibitors, suggesting that they can provide higher quality treatments for clinical patients.

[0243] Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the present invention, and the scope of the present invention is limited by the appended claims and their equivalents.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, 【Chemistry 1】 where: L １ is CRR', O, S, NH, -C(O)-, -S(O)- or -S(O) ２ - is selected from, R and R' are independently H, D, halogen, C １－６ Alkyl group or C １－６ haloalkyl groups, A is CR Ａ or N, E is CR Ｅ or N, G is CR Ｇ or N, R Ａ , R Ｅ and R Ｇ are independently H, D, halogen, CN, -L-OR ａ , -L-SR ａ , -L-NR ｂ R ｃ , C １－６ Alkyl group, C １－６ Haloalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, -L-C ３－１０ a cycloalkyl group or an -L-3 to 10 membered heterocyclyl group; R １ is H, D, halogen, CN, -L-OR ａ , -L-SR ａ , -L-NR ｂ R ｃ , C １－６ Alkyl group, C １－６ Haloalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, -L-C ３－１０ Cycloalkyl group, -L-3 to 10-membered heterocyclyl group, -L-C ６－１０ aryl group or -L-5 to 10 membered heteroaryl group, which optionally has 1, 2 or 3 R １ｓ is replaced by R １ｓ are independently H, D, halogen, CN, OR ａ , S.R. ａ , N.R. ｂ R ｃ , C １－６ Alkyl group, C １－６ Haloalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１０ Cycloalkyl group, 3- to 10-membered heterocyclyl group, C ６－１０ selected from an aryl group or a 5- to 10-membered heteroaryl group; 【Chemistry 2】 represents a single bond or a double bond, M １ is N, C or CR ５ is selected from M ２ is N or CR ６ and R ５ and R ６ are independently H, D, halogen, C １－６ Alkyl group or C １－６ haloalkyl groups, R ４ are independently H, D, halogen, CN, ═O, OR ａ , S.R. ａ , N.R. ｂ R ｃ , C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－７ cycloalkyl or 3- to 7-membered heterocyclyl group, which optionally has one, two, or three R ４ｓ is replaced by or M １ R in the ortho position of ４ and R ２ and the atoms connected thereto together form C ５－７ forming a cycloalkyl group or a 5- to 7-membered heterocyclyl group, or M １ R in the ortho position of ４ and Z ３ and the atoms connected thereto together form C ５－７ Forms a cycloalkyl group or a 5- to 7-membered heterocyclyl group, which optionally contains 1, 2, or 3 R ４ｓ is replaced by R ４ｓ are independently H, D, halogen, CN, C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－７ selected from a cycloalkyl group or a 3- to 7-membered heterocyclyl group; n is 0, 1, 2, 3 or 4; Z １ is CR ７ or N, Z ２ is CR ８ or N, Z ３ is CR ９ or N, R ２ , R ７ , R ８ and R ９ are independently H, D, halogen, CN, OR ａ , S.R. ａ , N.R. ｂ R ｃ , C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－７ cycloalkyl or 3- to 7-membered heterocyclyl group, which optionally has one, two, or three R ２ｓ is replaced by R ２ｓ are independently H, D, halogen, CN, C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－７ selected from a cycloalkyl group or a 3- to 7-membered heterocyclyl group; R ３ is H, -L-OR ａ , -L-SR ａ , -L-NR ｂ R ｃ , C １－６ Alkyl group, C １－６ Haloalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, -L-C ３－１０ Cycloalkyl group, -L-3 to 10-membered heterocyclyl group, -L-C ６－１０ aryl group or -L-5 to 10 membered heteroaryl group, which optionally has 1, 2 or 3 R ３ｓ is replaced by R ３ｓ are independently H, D, halogen, CN, OR ａ , S.R. ａ , N.R. ｂ R ｃ , C １－６ Alkyl group, C １－６ Haloalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１０ Cycloalkyl group, 3- to 10-membered heterocyclyl group, C ６－１０ selected from an aryl group or a 5- to 10-membered heteroaryl group; L is a chemical bond, C １－６ Alkylene group, C ２－６ Alkenylene group or C ２－６ Alkynylene groups, which may optionally be H, D, halogen, C １－６ Alkyl group, C １－６ Haloalkyl group, C ２－６ Alkenyl group or C ２－６ alkynyl groups; R ａ , R ｂ and R ｃ are each independently H, C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－１０ cycloalkyl group or a 3- to 10-membered heterocyclyl group, or R ｂ , R ｃ and the atoms to which they are connected, taken together, form a 5- to 10-membered heterocyclyl group; wherein the definitions of each of the above groups refer to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, optionally deuterated to be fully deuterated.

2. L １ is selected from CRR′, O, S, NH or —C(O)—, preferably CRR′ or —C(O)—, preferably CRR′, preferably CH ２ 2. The compound of formula (I) according to claim 1, wherein:

3. R and R' are independently H, D, C １－６ Alkyl group or C １－６ haloalkyl groups, preferably H, D, C １－３ Alkyl group or C １－３ 3. The compound of formula (I) according to claim 1 or 2, wherein the haloalkyl group is selected from H or D, preferably H, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof.

4. A is N, Preferably, E is CR Ｅ and Preferably, G is CR Ｇ and Preferably, 【Transformation 3】 teeth, 【Chemistry 4】 4. The compound of formula (I) according to claim 1, wherein:

5. R Ａ , R Ｅ and R Ｇ are independently H, D, halogen, CN, -L-OR ａ , -L-SR ａ , -L-NR ｂ R ｃ , C １－６ Alkyl group, C １－６ haloalkyl group, -L-C ３－７ cycloalkyl group or -L-3 to 7-membered heterocyclyl group, preferably H, D, halogen, CN, OR ａ , N.R. ｂ R ｃ , C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－７ cycloalkyl groups or 3- to 7-membered heterocyclyl groups, preferably H, D, halogen, C １－６ Alkyl group or C １－６ 5. The compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein haloalkyl group is selected from haloalkyl groups, preferably H or D, preferably H.

6. R １ is H, D, halogen, CN, -L-OR ａ , -L-SR ａ , -L-NR ｂ R ｃ , C １－６ Alkyl group, C １－６ haloalkyl group, -L-C ３－１０ Cycloalkyl group, -L-3 to 10-membered heterocyclyl group, -L-C ６－１０ aryl group or -L-5 to 10 membered heteroaryl group, preferably H, D, halogen, CN, OR ａ , N.R. ｂ R ｃ , C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－１０ Cycloalkyl group, 3- to 10-membered heterocyclyl group, C ６－１０ aryl group or 5- to 10-membered heteroaryl group, preferably H, D, halogen, CN, OR ａ , C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－７ cycloalkyl groups or 3- to 7-membered heterocyclyl groups, preferably H, D, halogen, C １－６ Alkyl group or C １－６ haloalkyl groups, preferably H, D, C １－６ Alkyl group or C １－６ haloalkyl groups, preferably C １－６ Alkyl group or C １－６ A compound of formula (I) according to any one of claims 1 to 5, wherein R is a haloalkyl group, preferably Et, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof.

7. R １ｓ are independently H, D, halogen, CN, OR ａ , N.R. ｂ R ｃ , C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－１０ Cycloalkyl group, 3- to 10-membered heterocyclyl group, C ６－１０ aryl group or 5- to 10-membered heteroaryl group, preferably H, D, halogen, CN, C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－７ cycloalkyl groups or 3- to 7-membered heterocyclyl groups, preferably H, D, halogen, C １－６ Alkyl group or C １－６ haloalkyl groups, preferably H, D, C １－６ Alkyl group or C １－６ 7. The compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein the aryl group is selected from haloalkyl groups.

8. M １ is N or CR ５ is selected from, preferably N; Preferably, M ２ is N, Preferably, 【Transformation 5】 teeth, 【Transformation 6】 8. The compound of formula (I) according to any one of claims 1 to 7, wherein:

9. R ５ and R ６ are independently H, D, C １－６ Alkyl group or C １－６ 9. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein haloalkyl group is selected from haloalkyl groups, preferably H or D, preferably H.

10. R ４ are independently H, D, halogen, CN, OR ａ , N.R. ｂ R ｃ , C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－７ cycloalkyl groups or 3- to 7-membered heterocyclyl groups, preferably H, D, halogen, CN, C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－７ cycloalkyl groups or 3- to 7-membered heterocyclyl groups, preferably H, D, halogen, C １－６ Alkyl group or C １－６ haloalkyl groups, preferably H, D, C １－６ Alkyl group or C １－６ haloalkyl groups, preferably H or D, preferably H; Preferably, n is 0, 1 or 2, preferably 0. The compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof.

11. M １ R in the ortho position of ４ and R ２ and the atoms to which they are connected, taken together, form a 5- to 7-membered heterocyclyl group, or M １ R in the ortho position of ４ and Z ３ and the atoms to which they are connected, taken together, form a 5- to 7-membered heterocyclyl group; Preferably, M １ R in the ortho position of ４ and R ２ and the atoms to which they are linked, taken together, form a 5- to 7-membered heterocyclyl group, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof.

12. R ４ｓ are independently H, D, halogen, C １－６ Alkyl group or C １－６ 12. The compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein the aryl group is selected from haloalkyl groups.

13. Z １ is N, Preferably, Z ２ is CR ８ and Preferably, Z ３ is CR ９ and Preferably, 【Transformation 7】 teeth, 【Transformation 8】 13. The compound of formula (I) according to any one of claims 1 to 12, wherein:

14. R ７ , R ８ and R ９ are independently H, D, halogen, CN, C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－７ cycloalkyl groups or 3- to 7-membered heterocyclyl groups, preferably H, D, halogen, C １－６ Alkyl group or C １－６ haloalkyl groups, preferably H, D, C １－６ Alkyl group or C １－６ 14. The compound of formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein haloalkyl group is selected from haloalkyl groups, preferably H or D, preferably H.

15. R ２ H, D, halogen, CN, C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－７ cycloalkyl groups or 3- to 7-membered heterocyclyl groups, preferably H, D, halogen, CN, C １－６ Alkyl group or C １－６ haloalkyl groups, preferably H, D, halogen, C １－６ Alkyl group or C １－６ 15. The compound of formula (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein the haloalkyl group is selected from haloalkyl groups, preferably selected from H, D or halogen, preferably H or F.

16. R ２ｓ are independently H, D, halogen, C １－６ Alkyl group or C １－６ 16. The compound of formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein the aryl group is selected from haloalkyl groups.

17. R ３ is H, -L-OR ａ , -L-SR ａ , -L-NR ｂ R ｃ , C １－６ Alkyl group, C １－６ haloalkyl group, -L-C ３－１０ Cycloalkyl group, -L-3 to 10-membered heterocyclyl group, -L-C ６－１０ aryl group or -L-5 to 10 membered heteroaryl group, preferably H, OR ａ , N.R. ｂ R ｃ , C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－１０ Cycloalkyl group, 3- to 10-membered heterocyclyl group, C ６－１０ aryl group or 5- to 10-membered heteroaryl group, preferably H, OR ａ , C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－７ cycloalkyl groups or 3- to 7-membered heterocyclyl groups, preferably H, OR ａ , C １－６ Alkyl group, C １－６ haloalkyl group or C １－６ deuterated alkyl groups, preferably OR ａ , C １－６ Alkyl group, C １－６ haloalkyl group or C １－６ Deuterated alkyl groups are selected from the group consisting of Me, CD ３ or OMe, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof.

18. R ３ｓ are independently H, D, halogen, CN, OR ａ , N.R. ｂ R ｃ , C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－１０ Cycloalkyl group, 3- to 10-membered heterocyclyl group, C ６－１０ aryl group or 5- to 10-membered heteroaryl group, preferably H, D, halogen, CN, C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－７ cycloalkyl groups or 3- to 7-membered heterocyclyl groups, preferably H, D, halogen, C １－６ Alkyl group or C １－６ haloalkyl groups, preferably H, D, C １－６ Alkyl group or C １－６ 18. The compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein the compound is selected from haloalkyl groups.

19. L is independently a chemical bond or C １－６ alkylene groups, which are optionally selected from H, D, halogen, C １－６ Alkyl group or C １－６ 19. The compound of formula (I) according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, substituted with 1, 2 or 3 groups selected from haloalkyl groups.

20. R ａ , R ｂ and R ｃ are each independently H, C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－７ is selected from a cycloalkyl group or a 3- to 7-membered heterocyclyl group, preferably H, C １－６ Alkyl group or C １－６ haloalkyl groups, preferably C １－６ Alkyl group or C １－６ haloalkyl groups, preferably H or Me, more preferably Me; or R ｂ , R ｃ and the atoms to which they are linked, taken together, form a 5- to 7-membered heterocyclyl group; or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof.

21. having the following structural formula: 【Chemistry 9】 21. A compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein each group is as defined in claims 1 to 20.

22. R １ is H, D, halogen, CN, OR ａ , N.R. ｂ R ｃ , C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－１０ Cycloalkyl group, 3- to 10-membered heterocyclyl group, C ６－１０ aryl group or a 5- to 10-membered heteroaryl group, which optionally has one, two, or three R １ｓ is replaced by R ２ H, D, halogen, CN, C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－７ cycloalkyl or 3- to 7-membered heterocyclyl group, which optionally has one, two, or three R ２ｓ is replaced by R ３ is H, OR ａ , N.R. ｂ R ｃ , C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－１０ Cycloalkyl group, 3- to 10-membered heterocyclyl group, C ６－１０ aryl group or a 5- to 10-membered heteroaryl group, which optionally has one, two, or three R ３ｓ is replaced by R ４ H, D, halogen, CN, C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－７ cycloalkyl or 3- to 7-membered heterocyclyl group, which optionally has one, two, or three R ４ｓ is replaced by or R at the N ortho position linked to the pyridine ４ and R ２ and the atoms to which they are connected, taken together, form a 5- to 7-membered heterocyclyl group; R １ｓ and R ３ｓ are each independently H, D, halogen, CN, OR ａ , N.R. ｂ R ｃ , C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－１０ Cycloalkyl group, 3- to 10-membered heterocyclyl group, C ６－１０ selected from an aryl group or a 5- to 10-membered heteroaryl group; R ２ｓ and R ４ｓ are each independently H, D, halogen, or C １－６ Alkyl group or C １－６ haloalkyl groups, n is 0, 1, 2, 3 or 4; R ａ , R ｂ and R ｃ are each independently H, C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－７ cycloalkyl group or a 3- to 7-membered heterocyclyl group, or R ｂ , R ｃ and the atoms to which they are connected, taken together, form a 5- to 7-membered heterocyclyl group; 22. The compound of formula (II) according to claim 21, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein each of the above group definitions is optionally deuterated until fully deuterated.

23. R １ is H, D, halogen, CN, OR ａ , C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－７ cycloalkyl or 3- to 7-membered heterocyclyl group, which optionally has one, two, or three R １ｓ is replaced by R ２ H, D, halogen, CN, C １－６ Alkyl group or C １－６ haloalkyl groups, which optionally have one, two or three R ２ｓ is replaced by R ３ is H, OR ａ , C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－７ cycloalkyl or 3- to 7-membered heterocyclyl group, which optionally has one, two, or three R ３ｓ is replaced by R ４ H, D, halogen, C １－６ Alkyl group or C １－６ haloalkyl groups, which optionally have one, two or three R ４ｓ is replaced by R １ｓ and R ３ｓ are each independently H, D, halogen, CN, or C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－７ selected from a cycloalkyl group or a 3- to 7-membered heterocyclyl group; R ２ｓ and R ４ｓ are each independently H, D, halogen, or C １－６ Alkyl group or C １－６ haloalkyl groups, n is 0, 1, 2, 3 or 4; R ａ are independently H, C １－６ Alkyl group or C １－６ 23. The compound of formula (II) according to claim 21 or 22, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein the compound is selected from haloalkyl groups.

24. R １ H, D, C １－６ Alkyl group or C １－６ haloalkyl groups, R ２ H, D, halogen, C １－６ Alkyl group or C １－６ haloalkyl groups, R ３ is H, OR ａ , C １－６ Alkyl group, C １－６ haloalkyl group or C １－６ deuterated alkyl groups, R ４ H, D, C １－６ Alkyl group or C １－６ haloalkyl groups, n is 0, 1, 2, 3 or 4; R ａ is H, C １－６ Alkyl group or C １－６ 24. The compound of formula (II) according to any one of claims 21 to 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, wherein the aryl group is selected from haloalkyl groups.

25. R １ is C １－６ Alkyl group or C １－６ a haloalkyl group, preferably Et; R ２ is selected from H, D or halogen, preferably H or F; R ３ is OR ａ , C １－６ Alkyl group, C １－６ haloalkyl group or C １－６ Deuterated alkyl groups are selected from the group consisting of Me, CD ３ or OMe, R ４ is H or D, preferably H, n is 0, 1 or 2, preferably 0; R ａ is C １－６ Alkyl group or C １－６ is a haloalkyl group, preferably Me; Preferably, R ３ is C １－６ Alkyl group, C １－６ Haloalkyl groups and C １－６ deuterated alkyl groups, preferably C １－６ Deuterated alkyl groups, preferably Me and CD ３ Preferably, CD ３ and Preferably, R ２ is halogen, preferably F, Cl or Br, preferably F; or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof.

26. The compound is 【Chemistry 10】 2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, selected from:

27. 27. A pharmaceutical composition comprising a compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle, and optionally other therapeutic agents.

28. Use of a compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, or a pharmaceutical composition according to claim 27, in the manufacture of a medicament for treating or preventing a PARP-mediated disease, wherein preferably the PARP is PARP1.

29. 27. A method for treating or preventing a PARP-mediated disease in a subject, comprising administering to the subject a compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, or a pharmaceutical composition according to claim 27, wherein preferably the PARP is PARP1.

30. The compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, crystalline polymorph, hydrate or solvate thereof, or the pharmaceutical composition according to claim 27, for treating or preventing a PARP-mediated disease, wherein the PARP is preferably PARP1.

31. 31. The use of claim 28 or the method of claim 29 or the use of the compound or pharmaceutical composition of claim 30, wherein the disease is selected from cancer, ischemic diseases and neurodegenerative diseases.

32. 32. The use or method of claim 31 , wherein the cancer is deficient in the HR dependent DNA DSB repair pathway.

33. 32. The use or method of claim 31 , wherein the cancer has a BRCA1 or BRCA2 deficient phenotype.

34. 32. The use or method of claim 31 , wherein the cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer and lung cancer.

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