PARP1 inhibitors

Abstract

The invention provides a PARP1 inhibitor as shown in a formula (I), or pharmaceutically acceptable salts, isotope variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates of the PARP1 inhibitor. The invention also provides a preparation method of the compound, a pharmaceutical composition containing the compound, and an effect of the compound in prevention and treatment of cancers, ischemic diseases or neurodegenerative diseases. # imgabs0 #

Description

PARP1 inhibitors

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

[0002] The present invention relates to a novel class of PARP1 inhibitors, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates thereof. The present invention also relates to methods for preparing the compounds, pharmaceutical compositions comprising the compounds, and the effects of the compounds in preventing and treating PARP1-mediated diseases such as cancer. Background Art

[0003] ADP-ribosylation is an enzymatic process that breaks down the substrate nicotinamide adenine dinucleotide (NAD+) into nicotinamide and an ADP-ribose group, which is then covalently attached to a receptor protein. ADP-ribosylation is a common, reversible post-translational modification of proteins 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) polymerases (PARPs) are a family of proteins that catalyze ADP-ribosylation. PARP1 is the most extensively studied member of this family. It is highly expressed in cells and responds rapidly, rapidly catalyzing and modifying DNA repair factors, interacting with them to participate in various DNA repair processes. In normal cells, single-strand DNA breaks are repaired through base excision. PARP1 uses NAD+ as a substrate and binds to the damage site through its zinc finger domain, causing a conformational change and catalyzing the transfer of an ADP-ribose group, ultimately completing single-strand repair. In cancer cells with double-strand breaks (DSBs), DNA breaks are primarily repaired through homologous recombination (HR). BRCA1 and BRCA2 are key proteins mediating HR. In cancer cells with BRCA1 / 2 mutations, PARP1 function is simultaneously inhibited, resulting in impaired DNA repair pathways and ultimately leading to cell death. This is the clinically validated synthetic lethality effect. Therefore, PARP1 has become a highly sought-after target for cancer therapy.

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

[0006] Recent studies have suggested that the mechanism of action of PARPi can be attributed to two distinct but interrelated mechanisms. First, by inhibiting the catalytic activity of PARP1 (PARP1 catalytic inhibition), these PARPis block the synthesis of PAR chains, thereby inhibiting poly(ADP-ribosylation) modification (PARylation) and blocking PARP1-mediated DNA damage repair signaling. Second, PARP inhibitors may also cause DNA double-strand breaks by inducing PARP1 trapping (PARP1 trapping), ultimately killing cancer cells. When the PARP1 protein undergoes PARylation modification itself, it disengages from sites of DNA damage due to steric hindrance and charge repulsion between the PAR chains. However, treatment with PARP inhibitors blocks PARP1 automodification, causing PARP1 to be trapped at DNA lesions. Long-lived PARP-DNA complexes occupy sites of DNA damage and interfere with subsequent DNA replication, leading to replication fork stalling and subsequent double-strand DNA damage, thus causing cell death. However, PARP1 trapping occurs concomitantly with the inhibition of PARP1 catalytic activity. Therefore, PARP1 catalytic activity inhibition and PARP1 trapping caused by PARP inhibitors are functionally distinct but intrinsically linked.

[0007] Based on the synthetic lethality mechanism, cell lines carrying BRCA1 / 2 mutations or homologous recombination deficiency (HRD) are extremely sensitive to PARP inhibitors, which provides a very broad therapeutic safety window for drug treatment. However, since some normal cells in the body, such as myeloid cells, are often in a state of rapid proliferation, DNA damage is inevitable. At the same time, many selected patients have germline mutations, resulting in varying degrees of blood toxicity when using approved non-selective PARP1 / 2 inhibitors, including anemia, neutropenia, and thrombocytopenia. The occurrence of grade 3 or 4 blood toxicity often leads to drug reduction, discontinuation, or interruption of medication, seriously affecting the therapeutic effect of PARP inhibitors on patients.

[0008] On the other hand, there is a potential basis for combining chemotherapy drugs with PARP inhibitors for enhanced synergy. However, because chemotherapy drugs inhibit rapidly proliferating cells and also have strong hematotoxicity, combining the two can lead to the accumulation of hematotoxicity, which greatly limits the combined use of PARP inhibitors.

[0009] Studies have shown that the anemia reaction caused by PARP inhibitors may be mainly due to the inhibition of PARP2 (Farrés J, et al. Cell Death Differ. 2015 Jul; 22(7): 1144-57.). Currently available PARPis all have inhibitory activity against PARP1 / 2. If highly selective PARP1 inhibitors can be developed to reduce the inhibition of PARP2, it may be possible to avoid the anemia toxicity caused by existing PARP1 / 2 inhibitors. WO2021013735A1 discloses a series of PARP1 selective inhibitors, such as AZD5305.

[0010] Therefore, developing more highly selective PARP1 inhibitors has important clinical application value, and there is a demand for such inhibitors in this field.

[0011] Summary of the Invention

[0012] The present invention uses PARP1 as a target and develops a new class of small molecule inhibitors that can be used to treat various cancers.

[0013] The compounds of this invention target PARP1 and possess excellent PARP1 inhibitory activity and selectivity, thereby avoiding anemic toxicity. Furthermore, the compounds of this invention exhibit varying volumes of distribution (reducing neutrophil and platelet toxicity) and varying trapping activity (facilitating dosage adjustment). While maintaining the clinical efficacy of PARP1 / 2 inhibitors, they also reduce hematotoxicity, enabling the further combination of highly selective PARP1 inhibitors with chemotherapeutic agents.

[0014] In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0015] in,

[0016] L1 is selected from CRR', O, S, NH, -C(O)-, -S(O)- or -S(O)2-;

[0017] R and R' are independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0018] A is selected from CR A or N;

[0019] E is selected from CR E or N;

[0020] G is selected from CR G or N;

[0021] R A 、R E and R G Independently selected from H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-10 Cycloalkyl or -L-3-10 membered heterocyclic group;

[0022] R1 is selected from H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0023] R 1s Independently selected from H, D, halogen, CN, OR a SR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0024] Expressed as a single or double bond;

[0025] M1 is selected from N, C or CR5;

[0026] M2 is N or CR6;

[0027] R5 and R6 are independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0028] R4 is independently selected from H, D, halogen, CN, ═O, OR a SR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 4s replace;

[0029] Or R4 and R2 located at the adjacent position of M1 together with the atoms to which they are connected form C 5-7 Cycloalkyl or 5-7 membered heterocyclic group, or R4 and Z3 located at the ortho position of M1 and the atoms to which they are connected together form C 5-7 Cycloalkyl or 5-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 4s replace;

[0030] R 4s Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group;

[0031] n is 0, 1, 2, 3 or 4;

[0032] Z1 is selected from CR7 or N;

[0033] Z2 is selected from CR8 or N;

[0034] Z3 is selected from CR9 or N;

[0035] R2, R7, R8 and R9 are independently selected from H, D, halogen, CN, OR a SR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0036] R 2s Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group;

[0037] R3 is selected from H, -L-OR a 、-L-SR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s replace;

[0038] R 3s Independently selected from H, D, halogen, CN, OR a SR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0039] L is a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, which is optionally substituted by 1, 2 or 3 atoms selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 radical substitution of alkynyl groups;

[0040] R a 、R b and R c Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group;

[0041] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0042] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, and optionally a pharmaceutically acceptable excipient, such as a carrier, adjuvant or vehicle.

[0043] In another aspect, the present invention provides use of the compound or pharmaceutical composition of the present invention in the preparation of a medicament for treating and / or preventing PARP-mediated diseases; preferably, the PARP is PARP1.

[0044] In another aspect, the present invention provides a method for treating and / or preventing a PARP-mediated disease in a subject, comprising administering to the subject a compound or a pharmaceutical composition of the present invention; preferably, the PARP is PARP1.

[0045] In another aspect, the present invention provides a compound of the present invention or a pharmaceutical composition of the present invention for use in treating and / or preventing PARP-mediated diseases; preferably, the PARP is PARP1.

[0046] In specific embodiments, the present invention is used to treat and / or prevent cancer, ischemic diseases, and neurodegenerative diseases.

[0047] In another specific embodiment, the cancer is deficient in a HR-dependent DNA DSB repair pathway.

[0048] In another specific embodiment, the cancer has a BRCA1 or BRCA2 deficient phenotype.

[0049] In another specific embodiment, the present invention is used to treat and / or prevent the following cancers: breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer, and lung cancer.

[0050] definition

[0051] Chemical definition

[0052] Definitions of specific functional groups and chemical terms are described in more detail below.

[0053] When a numerical range is listed, it is intended to include every value and sub-range within the stated range. For example, "C 1-6 "Alkyl" includes 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 、C3-4 、C 4-6 、C 4-5 and C 5-6 alkyl.

[0054] “C 1-6 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 Alkyl, C 1-3 Alkyl 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). The term “C 1-6 "Alkyl" also includes heteroalkyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2).

[0055] “C 2-6 "Alkenyl" refers to 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 is preferred. 2-6 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. The term "C 2-6 "Alkenyl" also includes heteroalkenyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). An alkenyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0056] “C 2-6 "Alkynyl" refers to 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 2-4Alkynyl is preferred. 2-6 Examples 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. The term "C 2-6 "Alkynyl" also includes heteroalkynyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkynyl groups can be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0057] “C 1-6 "Alkylene" refers to the removal of C 1-6 In some embodiments, C 1-4 Alkylene, C 2-4 Alkylene and C 1-3 Alkylene is preferred. Unsubstituted alkylene includes, but is not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylenes, for example, alkylenes substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0058] “C 2-6 "Alkenylene" refers to the removal of C 2-6 In some embodiments, C 2-4Alkenylene is particularly preferred. Exemplary unsubstituted alkenylene groups include, but are not limited to, vinylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenylene groups, for example, alkenylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted ethylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propenylene (-C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), and the like.

[0059] “C 2-6 "Alkynylidene" refers to the removal of C 2-6 In some embodiments, C 2-4 Alkyne is particularly preferred. Exemplary alkynyl includes, but is not limited to, ethynyl (-C≡C-), substituted or unsubstituted propynyl (-C≡CCH2-), and the like.

[0060] “C 0-6 "Alkylene" refers to the chemical bond and the above-mentioned "C 1-6 Alkylene", "C 0-4 "Alkylene" refers to the chemical bond and the above-mentioned "C 1-4 "Alkylene".

[0061] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0062] Therefore, “C 1-6 "Haloalkyl" refers to the above-mentioned "C 1-6 Alkyl", which is substituted by one or more halogen groups. In some embodiments, C 1-4 Halogenated alkyl is particularly preferred, more preferably C 1-3 Halogenated alkyl, more preferably C 1-2 Haloalkyl. Exemplary haloalkyl groups include, but are not limited to, -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like. The haloalkyl group can be substituted at any available point of attachment, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0063] “C 1-6"Deuterated alkyl" refers to the above-mentioned "C 1-6 Alkyl", which is substituted with one or more deuterium groups. In some embodiments, C 1-4 Deuterated alkyl is particularly preferred, more preferably C 1-2 Deuterated alkyl, more preferably C 1-2 Deuterated alkyl. Exemplary deuterated alkyl groups include, but are not limited to, -CD3, -CHD2, -CH2D, -CHDCH2D, -CH2CD3, -CD2CD3, and the like. The deuterated alkyl group can be substituted at any available point of attachment, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0064] “C 3-10 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms, optionally containing 1, 2, or 3 double or triple bonds. In some embodiments, C 5-10 Cycloalkyl, C 3-7 Cycloalkyl and C 3-6 Cycloalkyl is particularly preferred, more preferably C 5-7 Cycloalkyl and C 5-6 Cycloalkyl. Cycloalkyl also includes ring systems in which the above-mentioned cycloalkyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Cycloalkyl also includes cycloalkyl rings in which the substituents on any non-adjacent carbon atoms are linked to form a bridged ring, together forming a polycycloalkane sharing two or more carbon atoms. Cycloalkyl also includes cycloalkyl rings in which the substituents on the same carbon atom are linked to form a ring, together forming a polycycloalkane 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), and the like. A cycloalkyl group can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0065] “C 3-10 "Cycloalkylene" refers to the removal of C 3-10 In some embodiments, C 5-10 Cycloalkylene, C 5-7 Cycloalkylene, C 3-7 Cycloalkylene, C 3-6 Cycloalkylene and C 3-4Cycloalkylene is particularly preferred, and cyclopropylene is especially preferred.

[0066] "3-10 membered heterocyclyl" refers to a saturated or unsaturated radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein 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, as valence permits. In some embodiments, a 5-10 membered heterocyclyl is preferred, which is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, a 3-7 membered heterocyclyl is preferred, which is a 3-7 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; a 5-7 membered heterocyclyl is preferred, which is a 5-7 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; a 3-6 membered heterocyclyl is preferred, which is a 3-6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; a 4-6 membered heterocyclyl is preferred, which is a 4-6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; and a 5-6 membered heterocyclyl is more preferred, which is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes a ring system in which the above-mentioned heterocyclyl ring is fused to one or more cycloalkyl groups, wherein the point of attachment is on the heterocyclyl ring, or a ring system in which the above-mentioned heterocyclyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such a case, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Heterocyclyl also includes a heterocyclyl ring in which any substituents on non-adjacent carbon or nitrogen atoms are connected to form a bridged ring, together forming a polycyclic heteroalkane sharing two or more carbon or nitrogen atoms. Heterocyclyl also includes a heterocyclyl ring in which the substituents on the same carbon atom are connected to form a ring, together forming a polycyclic heteroalkane sharing one carbon atom. Exemplary 3-membered heterocyclyls containing one heteroatom include, but are not limited to, aziridine, oxirane, and thiorenyl. Exemplary 4-membered heterocyclyls containing one heteroatom include, but are not limited to, azetidinyl, oxirane, and thiidine. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, 2,5-dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, pyrazolidinyl, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.Exemplary 6-membered heterocyclyls containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyls containing three heteroatoms include, but are not limited to, hexahydrotriazinyl (triazinanyl). Exemplary 7-membered heterocyclyls containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 5-membered heterocyclyls fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclyls) include, but are not limited to, dihydroindolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary 6-membered heterocyclyls fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclyls) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Heterocyclyl also includes the above-mentioned heterocyclyl and a cycloalkyl, heterocyclyl, aryl or heteroaryl group sharing one or two atoms to form a bridged ring or spirocycle. As long as the valence permits, the shared atom can be a carbon or nitrogen atom. Heterocyclyl also includes the above-mentioned heterocyclyl and heterocyclyl groups that may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0067] “C 6-10 "Aryl" refers to 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 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 Aryl also includes ring systems in which an aryl ring as described above is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Aryl groups can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0068] "5-10 membered heteroaryl" refers to a group of a 5-10 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 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above-mentioned heteroaryl rings are fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-6 membered heteroaryl is particularly preferred, which is a 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridyl or pyridonyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azacycloheptatrienyl, oxepantatrienyl, and thiepantatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, 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, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. The heteroaryl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0069] The divalent groups formed by removing another hydrogen from the above-defined alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are collectively referred to as "subunits". The ring-forming groups such as cycloalkyl, heterocyclyl, aryl and heteroaryl groups are collectively referred to as "cyclyls".

[0070] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like are defined herein as optionally substituted groups.

[0071] Exemplary substituents on carbon atoms include, but are not limited to, 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(OR cc )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, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0072] Or the two geminal hydrogen atoms on the carbon atom are replaced by groups =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 replace;

[0073] R aa Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R aa The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0074] R bb Each of the following is independently selected from: 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, or two R bb The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0075] R cc Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R cc The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 Rdd group substitution;

[0076] R dd Each of the is independently selected from: 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)R ee 、-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, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution, or two geminal R dd Substituents may combine to form =O or =S;

[0077] R ee Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0078] R ff Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R ff The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0079] R gg Each of the independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -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 1-6Alkyl, -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, -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 1-6 Alkyl)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, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -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, -SC(=S)SC 1-6 Alkyl, -P(=O)2(C 1-6alkyl), -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, C 1-6 Halogenated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two geminal R gg Substituents may combine to form =O or =S; wherein X - For the counter ion.

[0080] Exemplary substituents on nitrogen atoms include, but are not limited to, 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, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R attached to the nitrogen atom cc The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd Group substituted, and wherein R aa 、R bb 、R cc and R dd As mentioned above.

[0081] Other definitions

[0082] The term "cancer" includes, but is not limited to, the following cancers: Heart: Sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), Myxoma, rhabdomyomas, fibromas, lipomas, and teratomas; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, hemangioma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor), Kaposi's sarcoma, leiomyomas, hemangiomas, lipomas, neurofibromas, fibromas); Colorectal: adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma; Genitourinary: 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, bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gallbladder carcinoma, ampullary carcinoma, bile duct carcinoma; bone: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, chronic exostosis of bone (osteocartilaginous exostoses), benign enchondromas, chondroblastomas, fibrochondromas, chondromyxofibromas, osteoid osteomas, and giant cell tumors; nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningiosarcomas, gliomas), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pinealomas), glioblastoma multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), Spinal neurofibroma, meningioma, glioma, sarcoma); Gynecology: uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical dysplasia, etc.), ovary (ovarian cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic 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 syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal: neuroblastoma.

[0083] In one embodiment, the term "cancer" includes, but is not limited to, the following cancers: breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer, and lung cancer.

[0084] The term "treat" as used herein relates to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such a disorder or condition. The noun "treat" as used herein relates to the action of the verb treat, which is as just defined.

[0085] As used herein, the term "pharmaceutically acceptable salt" refers to those carboxylate salts, amino acid addition salts of the compounds of the present invention that are suitable for use in contact with patient tissues within the scope of sound medical judgment, do not produce undue toxicity, irritation, allergic response, etc., are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use, including (where possible) zwitterionic forms of the compounds of the present invention.

[0086] Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.

[0087] Base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the desired base in a conventional manner to form the salt. The free acid can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this invention, the salts are equivalent to their respective free acids.

[0088] Salts can be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides prepared from inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and the like. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, methanesulfonate, glucoheptonate, lactobionate, laurylsulfonate, and isethionate, and the like. Salts can also 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, and the like. 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 and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Salts of amino acids, such as arginate, gluconate, galacturonate, and the like are also contemplated (see, e.g., Berge SM et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, incorporated herein by reference).

[0089] "Subjects" to be administered include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0090] "Disease," "disorder," and "condition" are used interchangeably herein.

[0091] As used herein, and unless otherwise indicated, the term "treating" includes actions that occur while a subject has a particular disease, disorder, or condition that reduces the severity of, or delays or slows the development of, the disease, disorder, or condition ("therapeutic treatment"), as well as actions that occur before a subject develops a particular disease, disorder, or condition ("prophylactic treatment").

[0092] Generally, an "effective amount" of a compound is an amount sufficient to elicit the desired biological response. As will be appreciated by those skilled in the art, the effective amount of a compound of the invention can vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and symptoms of the subject. An effective amount includes both a therapeutically effective amount and a prophylactically effective amount.

[0093] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic effects of other therapeutic agents.

[0094] As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or an amount to prevent the recurrence of a disease, disorder, or condition. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in preventing a disease, disorder, or condition. The term "prophylactically effective amount" can include an amount that improves overall prevention, or an amount that enhances the prophylactic effect of other prophylactic agents.

[0095] "Combination" and related terms refer to the simultaneous or sequential administration of a compound of the invention and other therapeutic agents. For example, a compound of the invention can be administered simultaneously or sequentially with the other therapeutic agents in separate unit dosage forms, or can be administered simultaneously with the other therapeutic agents in a single unit dosage form. BRIEF DESCRIPTION OF THE DRAWINGS

[0096] FIG1 is an action curve of the compound of the present invention on PARP1 / 2-DNA capture at 2 hours.

[0097] FIG2 is a time-effect curve of the compounds of the present invention on PARP1 / 2-DNA capture at different time points.

[0098] FIG3 shows the effect of the compound of the present invention on the change of tumor volume in subcutaneous transplanted tumors of MDA-MB-436 mice.

[0099] FIG4 shows the induction of DLD-1BRCA2 by the compounds of the present invention in three different experiments - / - Cell apoptosis.

[0100] Figure 5 shows the expression of cleaved Caspase-3 and Caspase-3 protein in tumor tissues.

[0101] Figure 6 shows the effects of the compound of Example 4 and reference AZD5305 on Cleaved Caspase-3 protein in tumor tissues at the same dose (*, p<0.05, by one-way ANOVA, no statistically significant differences between other groups). DETAILED DESCRIPTION

[0102] Herein, "compounds of the present invention" refers to the compounds of the following formula (I), formula (II), etc., and pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates thereof.

[0103] Herein, compounds are named using standard nomenclature. For compounds with asymmetric centers, it should be understood that (unless otherwise specified) all optical isomers and mixtures thereof are encompassed. In addition, unless otherwise specified, all isomeric compounds encompassed by the present invention may occur in both Z and E forms with carbon-carbon double bonds. Compounds that exist in different tautomeric forms are not limited to any particular tautomer, but are intended to encompass all tautomeric forms.

[0104] In one embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0105] in,

[0106] L1 is selected from CRR', O, S, NH, -C(O)-, -S(O)- or -S(O)2-;

[0107] R and R' are independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0108] A is selected from CR A or N;

[0109] E is selected from CR E or N;

[0110] G is selected from CR G or N;

[0111] R A 、R E and R G Independently selected from H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-10 Cycloalkyl or -L-3-10 membered heterocyclic group;

[0112] R1 is selected from H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0113] R 1s Independently selected from H, D, halogen, CN, OR a SR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0114] Expressed as a single or double bond;

[0115] M1 is selected from N, C or CR5;

[0116] M2 is N or CR6;

[0117] R5 and R6 are independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6alkyl halide;

[0118] R4 is independently selected from H, D, halogen, CN, ═O, OR a SR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 4s replace;

[0119] Or R4 and R2 located at the adjacent position of M1 together with the atoms to which they are connected form C 5-7 Cycloalkyl or 5-7 membered heterocyclic group, or R4 and Z3 located at the ortho position of M1 and the atoms to which they are connected together form C 5-7 Cycloalkyl or 5-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 4s replace;

[0120] R 4s Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group;

[0121] n is 0, 1, 2, 3 or 4;

[0122] Z1 is selected from CR7 or N;

[0123] Z2 is selected from CR8 or N;

[0124] Z3 is selected from CR9 or N;

[0125] R2, R7, R8 and R9 are independently selected from H, D, halogen, CN, OR a SR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0126] R 2s Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group;

[0127] R3 is selected from H, -L-OR a、-L-SR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s replace;

[0128] R 3s Independently selected from H, D, halogen, CN, OR a SR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0129] L is a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, which is optionally substituted by 1, 2 or 3 atoms selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 radical substitution of alkynyl groups;

[0130] R a 、R b and R c Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group;

[0131] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0132] L1

[0133] In one embodiment, L1 is CRR', such as 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-.

[0134] In a 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.

[0135] R and R'

[0136] 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 Alkyl; in another embodiment, R is C 1-6 Haloalkyl, such as C 1-3 Halogenated alkyl.

[0137] 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 Alkyl; in another embodiment, R' is C 1-6 Haloalkyl, such as C 1-3 Halogenated alkyl.

[0138] In a more specific embodiment, R and R' are independently selected from H, D, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R and R' are independently selected from H, D, C 1-3 Alkyl or C 1-3 haloalkyl; in another more specific embodiment, R and R' are independently H or D; in another more specific embodiment, R and R' are H.

[0139] A, E and G

[0140] In one embodiment, A is CR A ; In another embodiment, A is N.

[0141] In one embodiment, E is CR E ; In another embodiment, E is N.

[0142] In one embodiment, G is CR G ; In another embodiment, G is N.

[0143] In a more specific embodiment, A is N; in another more specific embodiment, E is CR E In another more specific embodiment, G is CR G In another more specific embodiment, for

[0144] R A 、R E and R G

[0145] In one embodiment, R A is H; in another embodiment, R A is D; in another embodiment, R A is halogen; in another embodiment, R A is CN; in another embodiment, R A For-L-OR a , preferably OR a In another embodiment, R A For-L-SR a , preferably SR a In another embodiment, R A -L-NR b R c , preferably NR b R c In another embodiment, R A C 1-6 Alkyl; in another embodiment, R A C 1-6 haloalkyl; in another embodiment, R A C 2-6 alkenyl; in another embodiment, R A C 2-6 Alkynyl; in another embodiment, R A For-LC 3-10 Cycloalkyl, preferably C 3-10 Cycloalkyl, preferably C 3-7 Cycloalkyl; in another embodiment, R A It is -L-3-10 membered heterocyclic group, preferably 3-10 membered heterocyclic group, preferably 3-7 membered heterocyclic group.

[0146] In one embodiment, RE is H; in another embodiment, R E is D; in another embodiment, R E is halogen; in another embodiment, R E is CN; in another embodiment, R E For-L-OR a , preferably OR a In another embodiment, R E For-L-SR a , preferably SR a In another embodiment, R E -L-NR b R c , preferably NR b R c In another embodiment, R E C 1-6 Alkyl; in another embodiment, R E C 1-6 haloalkyl; in another embodiment, R E C 2-6 alkenyl; in another embodiment, R E C 2-6 Alkynyl; in another embodiment, R E For-LC 3-10 Cycloalkyl, preferably C 3-10 Cycloalkyl, preferably C 3-7 Cycloalkyl; in another embodiment, R E It is -L-3-10 membered heterocyclic group, preferably 3-10 membered heterocyclic group, preferably 3-7 membered heterocyclic group.

[0147] In one embodiment, R G is H; in another embodiment, R G is D; in another embodiment, R G is halogen; in another embodiment, R G is CN; in another embodiment, R G For-L-OR a , preferably OR a In another embodiment, R G For-L-SR a , preferably SR a In another embodiment, R G -L-NR b R c , preferably NR b R c In another embodiment, RG C 1-6 Alkyl; in another embodiment, R G C 1-6 haloalkyl; in another embodiment, R G C 2-6 alkenyl; in another embodiment, R G C 2-6 Alkynyl; in another embodiment, R G For-LC 3-10 Cycloalkyl, preferably C 3-10 Cycloalkyl, preferably C 3-7 Cycloalkyl; in another embodiment, R G It is -L-3-10 membered heterocyclic group, preferably 3-10 membered heterocyclic group, preferably 3-7 membered heterocyclic group.

[0148] In a more specific embodiment, R A 、R E and R G Independently selected from H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 3-7 Cycloalkyl or -L-3-7 membered heterocyclyl; In another more specific embodiment, R A 、R E and R G Independently selected from H, D, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclyl; in another more specific embodiment, R A 、R E and R G Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R A 、R E and R G are independently H or D; in another more specific embodiment, R A 、R E and R G For H.

[0149] R1

[0150] 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 , preferably OR a In another embodiment, R1 is -L-SR a , preferably SR a In another embodiment, R1 is -L-NR b R c , preferably NR b R c In another embodiment, R1 is C 1-6 Alkyl, such as Me, such as Et; In another embodiment, R1 is C 1-6 In another embodiment, R1 is C 2-6 In another embodiment, R1 is C 2-6 Alkynyl; in another embodiment, R1 is -LC 3-10 Cycloalkyl, preferably C 3-10 Cycloalkyl, preferably C 3-7 Cycloalkyl; in another embodiment, R1 is -L-3-10 membered heterocyclyl, preferably 3-10 membered heterocyclyl, preferably 3-7 membered heterocyclyl; in another embodiment, R1 is -LC 6-10 Aryl, preferably C 6-10 In another embodiment, R1 is -L-5-10 membered heteroaryl, preferably 5-10 membered heteroaryl, preferably 5-6 membered heteroaryl; In another embodiment, R1 is optionally replaced by 1, 2 or 3 R 1s replace.

[0151] In a more specific embodiment, R1 is selected from H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl; In another more specific embodiment, R1 is selected from H, D, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; In another more specific embodiment, R1 is selected from H, D, halogen, CN, OR a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclyl; In another more specific embodiment, R1 is selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R1 is C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably Et.

[0152] R 1s

[0153] In one embodiment, R 1s is H; in another embodiment, R 1s is D; in another embodiment, R 1s is halogen; in another embodiment, R 1s is CN; in another embodiment, R 1s OR a In another embodiment, R 1s SR a In another embodiment, R 1s NR b R c In another embodiment, R 1s C 1-6 Alkyl; in another embodiment, R 1s C 1-6 haloalkyl; in another embodiment, R 1s C 2-6 alkenyl; in another embodiment, R 1s C 2-6 Alkynyl; in another embodiment, R 1s C 3-10 Cycloalkyl, preferably C 3-7 Cycloalkyl; in another embodiment, R 1s is a 3-10 membered heterocyclic group, preferably a 3-7 membered heterocyclic group; in another embodiment, R 1s C 6-10 Aryl, preferably phenyl; in another embodiment, R 1sIt is a 5-10 membered heteroaryl group, preferably a 5-6 membered heteroaryl group.

[0154] In a more specific embodiment, R 1s Independently selected from H, D, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; in another more specific embodiment, R 1s Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclyl; in another more specific embodiment, R 1s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R 1s Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0155] In one embodiment, is a single bond; in another embodiment, For double bonds.

[0156] M1 and M2

[0157] In one embodiment, M1 is N; in another embodiment, M1 is C; in another embodiment, M1 is CR5.

[0158] In one embodiment, M2 is N; in another embodiment, M2 is CR6.

[0159] In a more specific embodiment, M1 is selected from N or CR5; in another more specific embodiment, M1 is N; in another more specific embodiment, M2 is N; in another more specific embodiment, for

[0160] R5 and R6

[0161] In one embodiment, R5 is H; in another embodiment, R5 is D; in another embodiment, R5 is halogen; in another embodiment, R5 is C 1-6Alkyl; in another embodiment, R5 is C 1-6 Halogenated alkyl.

[0162] 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 Alkyl; in another embodiment, R6 is C 1-6 Halogenated alkyl.

[0163] In a more specific embodiment, R5 and R6 are independently selected from H, D, C 1-6 Alkyl or C 1-6 haloalkyl; in another more specific embodiment, R5 and R6 are H or D; in another more specific embodiment, R5 and R6 are H.

[0164] R4

[0165] 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 In another embodiment, R4 is SR a In another embodiment, R4 is NR b R c In another embodiment, R4 is C 1-6 Alkyl; in another embodiment, R4 is C 1-6 In another embodiment, R4 is C 3-7 In another embodiment, R4 is a 3-7 membered heterocyclyl; In another embodiment, R4 is optionally substituted by 1, 2 or 3 R 4s replace.

[0166] In one embodiment, R4 and R2 located in the ortho position of M1 together with the atoms to which they are attached form C 5-7 In another embodiment, R4 and R2 located at the ortho position of M1 and the atoms to which they are attached together form a 5-7 membered heterocyclic group; In another embodiment, R4 and Z3 located at the ortho position of M1 and the atoms to which they are attached together form a C 5-7 In another embodiment, R4 and Z3 located at the ortho position of M1 together with the atoms to which they are attached form a 5-7 membered heterocyclic group; In another embodiment, the ring structure formed by R4 and R2 or Z3 is optionally substituted by 1, 2 or 3 R 4s replace.

[0167] In a more specific embodiment, R4 is independently selected from H, D, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclyl; In another more specific embodiment, R4 is independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclyl; In another more specific embodiment, R4 is independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R4 is independently selected from H, D, C 1-6 Alkyl or C 1-6 haloalkyl; in another more specific embodiment, R4 is independently H or D; in another more specific embodiment, R4 is H.

[0168] In a more specific embodiment, R4 located at an ortho position of M1 and R2 together with the atoms to which they are attached form a 5-7 membered heterocyclic group, or R4 located at an ortho position of M1 and Z3 together with the atoms to which they are attached form a 5-7 membered heterocyclic group; in another more specific embodiment, R4 located at an ortho position of M1 and R2 together with the atoms to which they are attached form a 5-7 membered heterocyclic group.

[0169] R 4s

[0170] In one embodiment, R 4s is H; in another embodiment, R 4s is D; in another embodiment, R 4s is halogen; in another embodiment, R 4s is CN; in another embodiment, R 4s C 1-6 Alkyl; in another embodiment, R 4s C 1-6 haloalkyl; in another embodiment, R 4s C 3-7 Cycloalkyl; in another embodiment, R 4s It is a 3-7 membered heterocyclic group.

[0171] In a more specific embodiment, R 4s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0172] n

[0173] In one embodiment, n is 0; in another embodiment, n is 1; in another embodiment, n is 2; in another embodiment, n is 3; in another embodiment, n is 4.

[0174] In a more specific embodiment, n is selected from 0, 1 or 2; in another more specific embodiment, n is 0.

[0175] Z1, Z2, and Z3

[0176] In one embodiment, Z1 is CR7; in another embodiment, Z1 is N.

[0177] In one embodiment, Z2 is CR8; in another embodiment, Z2 is N;

[0178] In one embodiment, Z3 is CR9; in another embodiment, Z3 is N.

[0179] In a more specific embodiment, Z1 is N; in another more specific embodiment, Z2 is CR8; in another more specific embodiment, Z3 is CR9; in another more specific embodiment, for

[0180] R7, R8, and R9

[0181] 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 Alkyl; in another embodiment, R7 is C 1-6 In another embodiment, R7 is C 3-7 In another embodiment, R7 is a 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 2s replace.

[0182] 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 aIn another embodiment, R8 is SR a In another embodiment, R8 is NR b R c In another embodiment, R8 is C 1-6 Alkyl; in another embodiment, R8 is C 1-6 In another embodiment, R8 is C 3-7 In another embodiment, R8 is a 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 2s replace.

[0183] 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 In another embodiment, R9 is SR a In another embodiment, R9 is NR b R c In another embodiment, R9 is C 1-6 Alkyl; in another embodiment, R9 is C 1-6 In another embodiment, R9 is C 3-7 In another embodiment, R9 is a 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 2s replace.

[0184] In a more specific embodiment, R7, R8 and R9 are independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclyl; In another more specific embodiment, R7, R8 and R9 are independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R7, R8 and R9 are independently selected from H, D, C 1-6 Alkyl or C 1-6 haloalkyl; 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.

[0185] R2

[0186] In one embodiment, R2 is H; in another embodiment, R2 is D; in another embodiment, R2 is halogen, such as F; in another embodiment, R2 is CN; in another embodiment, R2 is ORa In another embodiment, R2 is SR a In another embodiment, R2 is NR b R c In another embodiment, R2 is C 1-6 Alkyl; in another embodiment, R2 is C 1-6 In another embodiment, R2 is C 3-7 In another embodiment, R2 is a 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 2s replace.

[0187] In a more specific embodiment, R2 is selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclyl; In another more specific embodiment, R2 is selected from H, D, halogen, CN, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R2 is selected from H, D, halogen, C 1-6 Alkyl 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.

[0188] In a more specific embodiment, R2 is halogen, preferably F, Cl or Br, preferably F.

[0189] R 2s

[0190] In one embodiment, R 2s is H; in another embodiment, R 2s is D; in another embodiment, R 2s is halogen; in another embodiment, R 2s is CN; in another embodiment, R 2s C 1-6 Alkyl; in another embodiment, R 2s C 1-6 haloalkyl; in another embodiment, R 2s C 3-7 Cycloalkyl; in another embodiment, R 2s It is a 3-7 membered heterocyclic group.

[0191] In a more specific embodiment, R 2s Independently selected from H, D, halogen, C 1-6 Alkyl or C1-6 Halogenated alkyl.

[0192] R3

[0193] In one embodiment, R3 is H; in another embodiment, R3 is -L-OR a , preferably OR a , such as OMe; in another embodiment, R3 is -L-SR a , preferably SR a In another embodiment, R3 is -L-NR b R c , preferably NR b R c In another embodiment, R3 is C 1-6 Alkyl, such as Me; in another embodiment, R3 is C 1-6 In another embodiment, R3 is C 2-6 In another embodiment, R3 is C 2-6 Alkynyl; in another embodiment, R3 is -LC 3-10 Cycloalkyl, preferably C 3-10 Cycloalkyl, preferably C 3-7 Cycloalkyl; in another embodiment, R3 is -L-3-10 membered heterocyclyl, preferably 3-10 membered heterocyclyl, preferably 3-7 membered heterocyclyl; in another embodiment, R3 is -LC 6-10 Aryl, preferably C 6-10 Aryl, preferably phenyl; in another embodiment, R3 is -L-5-10 membered heteroaryl, preferably 5-10 membered heteroaryl, preferably 5-6 membered heteroaryl; in another embodiment, R3 is optionally replaced by 1, 2 or 3 R 3s Substitution, for example, R3 is C 1-6 Deuterated alkyl groups, such as CD3.

[0194] In a more specific embodiment, R3 is selected from H, -L-OR a 、-L-SR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl; In another more specific embodiment, R3 is selected from H, OR a NR b R c 、C 1-6 Alkyl, C1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; In another more specific embodiment, R3 is selected from H, OR a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclyl; In another more specific embodiment, R3 is selected from H, OR a 、C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Deuterated alkyl; in another more specific embodiment, R3 is selected from OR a 、C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Deuterated alkyl; in another more specific embodiment, R3 is selected from Me, CD3 or OMe.

[0195] In a more specific embodiment, R3 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 In another more specific embodiment, R3 is C 1-6 deuterated alkyl; in another more specific embodiment, R3 is selected from Me and CD3; in another more specific embodiment, R3 is CD3.

[0196] R 3s

[0197] In one embodiment, R 3s is H; in another embodiment, R 3s is D; in another embodiment, R 3s is halogen; in another embodiment, R 3s is CN; in another embodiment, R 3s OR a In another embodiment, R 3s SR a In another embodiment, R 3s NR b R c In another embodiment, R 3s C 1-6 Alkyl; in another embodiment, R 3s C 1-6 haloalkyl; in another embodiment, R 3s C 2-6alkenyl; in another embodiment, R 3s C 2-6 Alkynyl; in another embodiment, R 3s C 3-10 Cycloalkyl, preferably C 3-7 Cycloalkyl; in another embodiment, R 3s is a 3-10 membered heterocyclic group, preferably a 3-7 membered heterocyclic group; in another embodiment, R 3s C 6-10 Aryl, preferably phenyl; in another embodiment, R 3s It is a 5-10 membered heteroaryl group, preferably a 5-6 membered heteroaryl group.

[0198] In a more specific embodiment, R 3s Independently selected from H, D, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; in another more specific embodiment, R 3s Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclyl; in another more specific embodiment, R 3s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R 3s Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0199] L

[0200] In one embodiment, L is a chemical bond; in another embodiment, L is C 1-6 Alkylene; in another embodiment, L is C 2-6 Alkenylene; in another embodiment, L is C 2-6 Alkyne; In another embodiment, L is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 In another embodiment, L is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C1-6 Alkyl or C 1-6 The haloalkyl group is substituted.

[0201] In a more specific embodiment, L is independently selected from a chemical bond or C 1-6 Alkylene, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl or C 1-6 The haloalkyl group is substituted.

[0202] R a 、R b and R c

[0203] In one embodiment, R a 、R b and R c are independently H; in another embodiment, R a 、R b and R c Independently C 1-6 Alkyl, such as Me; in another embodiment, R a 、R b and R c Independently C 1-6 haloalkyl; in another embodiment, R a 、R b and R c Independently C 3-10 Cycloalkyl, preferably C 3-7 Cycloalkyl; in another embodiment, R a 、R b and R c are independently 3-10 membered heterocyclic groups, preferably 3-7 membered heterocyclic groups; in another embodiment, R b 、R c Together with the atoms to which they are attached, they form a 5-10 membered heterocyclic group, preferably a 5-7 membered heterocyclic group.

[0204] In a more specific embodiment, R a 、R b and R c Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclyl; in another more specific embodiment, R a 、R b and R c Each independently selected from H, C 1-6 Alkyl or C 1-6 In another more specific embodiment, Ra 、R b and R c is H or Me; in another more specific embodiment, R a 、R b and R c is Me; in another more specific embodiment, R b 、R c and the atoms to which they are attached together form a 5-7 membered heterocyclic group.

[0205] 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 of 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 of these technical solutions, which are not listed one by one due to space limitations.

[0206] In a more specific embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0207] in,

[0208] L1 is selected from CRR', O, S, NH, -C(O)-, -S(O)- or -S(O)2-;

[0209] R and R' are independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0210] A is selected from CR A or N;

[0211] E is selected from CR E or N;

[0212] G is selected from CR G or N;

[0213] R A 、RE and R G Independently selected from H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-10 Cycloalkyl or -L-3-10 membered heterocyclic group;

[0214] R1 is selected from H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0215] R 1s Independently selected from H, D, halogen, CN, OR a SR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0216] Expressed as a single or double bond;

[0217] M1 is selected from N, C or CR5;

[0218] M2 is N or CR6;

[0219] R5 and R6 are independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0220] R4 is independently selected from H, D, halogen, CN, ═O, OR a SRa NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 4s replace;

[0221] Or R4 and R2 located at the adjacent position of M1 together with the atoms to which they are connected form C 5-7 Cycloalkyl or 5-7 membered heterocyclic group, or R4 and Z3 located at the ortho position of M1 and the atoms to which they are connected together form C 5-7 Cycloalkyl or 5-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 4s replace;

[0222] R 4s Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group;

[0223] n is 0, 1, 2, 3 or 4;

[0224] Z1 is selected from CR7 or N;

[0225] Z2 is selected from CR8 or N;

[0226] Z3 is selected from CR9 or N;

[0227] R2, R7, R8 and R9 are independently selected from H, D, halogen, CN, OR a SR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0228] R 2s Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group;

[0229] R3 is selected from H, -L-OR a 、-L-SR a 、-L-NR b R c 、C 1-6 Alkyl, C1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s replace;

[0230] R 3s Independently selected from H, D, halogen, CN, OR a SR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0231] L is a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, which is optionally substituted by 1, 2 or 3 atoms selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 radical substitution of alkynyl groups;

[0232] R a 、R b and R c Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group;

[0233] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0234] In a more specific embodiment, the present invention provides a compound of the above formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, 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.

[0235] 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, polymorph, hydrate or solvate thereof, wherein R and R' are independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, C 1-3 Alkyl or C 1-3 Halogenated alkyl; preferably H or D; preferably H.

[0236] 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, polymorph, hydrate or solvate thereof, wherein A is N;

[0237] Preferably, E is CR E ;

[0238] Preferably, G is CR G ;

[0239] Preferably, for

[0240] 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, polymorph, hydrate or solvate thereof, wherein R A 、R E and R G Independently selected from H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 3-7 Cycloalkyl or -L-3-7 membered heterocyclic group; preferably selected from H, D, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably H or D; preferably H.

[0241] In a more specific embodiment, the present invention provides a compound of formula (I) as described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R1 is selected from H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl; preferably selected from H, D, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; preferably selected from H, D, halogen, CN, OR a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably Et.

[0242] 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, polymorph, hydrate or solvate thereof, wherein R 1s Independently selected from H, D, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from H, D, halogen, C1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0243] 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, polymorph, hydrate or solvate thereof, wherein M1 is selected from N or CR5, preferably N;

[0244] Preferably, M2 is N;

[0245] Preferably, for

[0246] 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, polymorph, hydrate or solvate thereof, wherein R5 and R6 are independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably H or D; preferably H.

[0247] 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, polymorph, hydrate or solvate thereof, wherein R4 is independently selected from H, D, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably H or D; preferably H;

[0248] Preferably, n is 0, 1 or 2, preferably 0.

[0249] In a more specific embodiment, the present invention provides a compound of formula (I) as described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R4 located at the ortho position of M1 and R2 together with the atoms to which they are attached form a 5-7 membered heterocyclic group, or R4 located at the ortho position of M1 and Z3 together with the atoms to which they are attached form a 5-7 membered heterocyclic group;

[0250] Preferably, R4 located at the ortho position of M1 forms a 5-7 membered heterocyclic group together with R2 and the atoms to which they are attached.

[0251] 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, polymorph, hydrate or solvate thereof, wherein R 4s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0252] 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, polymorph, hydrate or solvate thereof, wherein Z1 is N;

[0253] Preferably, Z2 is CR8;

[0254] Preferably, Z3 is CR9;

[0255] Preferably, for

[0256] 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, polymorph, hydrate or solvate thereof, wherein R7, R8 and R9 are independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably H or D; preferably H.

[0257] 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, polymorph, hydrate or solvate thereof, wherein R2 is selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from H, D, halogen, CN, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl; preferably selected from H, D or halogen; preferably H or F.

[0258] 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, polymorph, hydrate or solvate thereof, wherein R 2s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0259] 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, polymorph, hydrate or solvate thereof, wherein R3 is selected from H, -L-OR a 、-L-SR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl; preferably selected from H, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; preferably selected from H, OR a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from H, OR a 、C 1-6 Alkyl, C 1-6 Haloalkyl or C1-6 Deuterated alkyl; preferably selected from OR a 、C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Deuterated alkyl; preferably selected from Me, CD3 or OMe.

[0260] 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, polymorph, hydrate or solvate thereof, wherein R 3s Independently selected from H, D, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0261] 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, polymorph, hydrate or solvate thereof, wherein L is independently selected from a chemical bond or C 1-6 Alkylene, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl or C 1-6 The haloalkyl group is substituted.

[0262] 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, polymorph, hydrate or solvate thereof, wherein R a 、R b and R c Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably C 1-6Alkyl or C 1-6 Halogenated alkyl; preferably H or Me; more preferably Me;

[0263] or R b 、R c and the atoms to which they are attached together form a 5-7 membered heterocyclic group.

[0264] 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, polymorph, hydrate or solvate thereof, which has the following structural formula:

[0265] wherein each group is as defined above.

[0266] 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, polymorph, hydrate or solvate thereof, wherein,

[0267] R1 is selected from H, D, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0268] R2 is selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0269] R3 is selected from H, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s replace;

[0270] R4 is selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7Cycloalkyl or 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 4s replace;

[0271] Alternatively, R4 located at the N-ortho position to the pyridine bond, together with R2 and the atoms to which they are attached, forms a 5-7 membered heterocyclic group;

[0272] R 1s and R 3s Each independently selected from H, D, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0273] R 2s and R 4s are independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0274] n is 0, 1, 2, 3 or 4;

[0275] R a 、R b and R c Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; or R b 、R c and the atoms to which they are attached together form a 5-7 membered heterocyclic group;

[0276] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0277] 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, polymorph, hydrate or solvate thereof, wherein,

[0278] R1 is selected from H, D, halogen, CN, OR a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0279] R2 is selected from H, D, halogen, CN, C 1-6Alkyl or C 1-6 Haloalkyl, optionally substituted by 1, 2 or 3 R 2s replace;

[0280] R3 is selected from H, OR a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 3s replace;

[0281] R4 is selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl, optionally substituted by 1, 2 or 3 R 4s replace;

[0282] R 1s and R 3s Each independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group;

[0283] R 2s and R 4s are independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0284] n is 0, 1, 2, 3 or 4;

[0285] R a Independently selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0286] 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, polymorph, hydrate or solvate thereof, wherein,

[0287] R1 is selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0288] R2 is selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0289] R3 is selected from H, OR a 、C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl;

[0290] R4 is selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0291] n is 0, 1, 2, 3 or 4;

[0292] R a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0293] 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, polymorph, hydrate or solvate thereof, wherein,

[0294] R1 is C 1-6 Alkyl or C 1-6 Haloalkyl, preferably Et;

[0295] R2 is selected from H, D or halogen, preferably H or F;

[0296] R3 is selected from OR a 、C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Deuterated alkyl, preferably selected from Me, CD3 or OMe;

[0297] R4 is H or D, preferably H;

[0298] n is 0, 1 or 2, preferably 0;

[0299] R a C 1-6 Alkyl or C 1-6 Haloalkyl, preferably Me;

[0300] Preferably, R3 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Deuterated alkyl, preferably C 1-6 Deuterated alkyl, preferably selected from Me and CD3, preferably CD3;

[0301] Preferably, R2 is halogen, preferably F, Cl or Br, preferably F.

[0302] 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, polymorph, hydrate or solvate thereof, wherein the compound is selected from the following:

[0303] The compounds of the present invention may include one or more asymmetric centers and may therefore exist in a variety of stereoisomeric forms, for example, enantiomers and / or diastereomeric forms. For example, the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0304] The compounds of the present invention may exist as tautomers. Tautomers are functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Tautomers are a special type of functional group isomer. A pair of tautomers can convert between each other, but the more stable isomer usually predominates. The most prominent examples are the enol and keto tautomers.

[0305] Those skilled in the art will appreciate that organic compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. These complexes are referred to as "solvates." When the solvent is water, the complex is referred to as a "hydrate." The present invention encompasses all solvates of the compounds of the present invention.

[0306] The term "solvate" refers to a form of a compound or its salt that is associated with a solvent, typically formed by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein can be prepared, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be capable of separation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes solvates in solution and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0307] The term "hydrate" refers to a compound that is combined with water. Generally, the ratio of the number of water molecules contained in the hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Therefore, the hydrate of a compound can be represented by the general formula R·x H2O, for example, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, for example, hemihydrate (R·0.5H2O)) and polyhydrates (x is a number greater than 1, for example, dihydrates (R·2H2O) and hexahydrates (R·6H2O)).

[0308] The compounds of the present invention can be in amorphous or crystalline form (polymorph). In addition, the compounds of the present invention can exist in one or more crystalline forms. Therefore, the present invention includes all amorphous or crystalline forms of the compounds of the present invention within its scope. The term "polymorph" refers to the crystalline form (or its salt, hydrate or solvate) of a compound with a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, photoelectric properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature and other factors can cause one crystalline form to dominate. The various polymorphs of a compound can be prepared by crystallization under different conditions.

[0309] The present invention also includes isotopically labeled compounds (isotopic variants) which are identical to those described in formula (I) but for which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, for example 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 Cl. Compounds of the present invention containing the above-mentioned isotopes and / or other isotopes of other atoms, their prodrugs and pharmaceutically acceptable salts of the compounds or prodrugs are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those in which radioactive isotopes (e.g. 3 H and 14 C) can be used in drug and / or substrate tissue distribution assays. 3 H and carbon-14, i.e.14 C isotopes are particularly preferred because they are easy to prepare and detect. 2 H, because greater metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, and thus may be preferred in some cases. Isotopically labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents when carrying out the processes disclosed in the following schemes and / or the Examples and Preparations.

[0310] In addition, prodrugs are also included in the context of the present invention. The term "prodrug" as used herein refers to a compound that is converted in vivo, for example by hydrolysis in the blood, into its active form that has a medical effect. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, 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.

[0311] A prodrug is any covalently bonded compound of the present invention that releases the parent compound in vivo when such a prodrug is administered to a patient. Prodrugs are typically prepared by modifying functional groups in such a way that the modification can be cleaved to produce the parent compound by conventional manipulation or in vivo. Prodrugs include, for example, compounds of the present invention in which a hydroxyl, amino, or sulfhydryl group is bonded to any group that, when administered to a patient, can be cleaved to form a hydroxyl, amino, or sulfhydryl group. Thus, representative examples of prodrugs include, but are not limited to, acetate / amide, formate / amide, and benzoate / amide derivatives of the hydroxyl, sulfhydryl, 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. Esters themselves can be active and / or can be hydrolyzed under human in vivo conditions. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those that readily decompose in the human body to release the parent acid or its salt.

[0312] The present invention also provides a pharmaceutical preparation comprising 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 of these forms belong to the present invention.

[0313] Pharmaceutical compositions and kits

[0314] In another aspect, the present invention provides pharmaceutical compositions comprising 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.

[0315] Pharmaceutically acceptable excipients used in the present invention refer to non-toxic carriers, adjuvants or vehicles that do not destroy the pharmacological activity of the compound formulated together. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

[0316] Suitable formulations for administering the compounds of the present invention will be readily apparent to those skilled in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, solutions (particularly solutions for injection (subcutaneous, intravenous, intramuscular) and infusion (injection)), elixirs, syrups, cachets, emulsions, inhalants, or dispersible powders. The content of the one or more pharmaceutically active compounds should be in the range of 0.1 to 90% by weight, preferably 0.5 to 50% by weight, of the composition as a whole, i.e., an amount sufficient to achieve the dosage range specified below. If necessary, the specified dosage may be administered several times a day.

[0317] The present invention also includes kits (e.g., pharmaceutical packaging). The kits provided may include a compound of the invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the compound of the invention and other therapeutic agents. In some embodiments, the kit provided may also optionally include a third container containing a pharmaceutical excipient for diluting or suspending the compound of the invention and / or other therapeutic agents. In some embodiments, the compound of the invention and other therapeutic agents provided in the first and second containers are combined to form a unit dosage form.

[0318] Drug administration

[0319] Pharmaceutical compositions provided by the invention can be administered by many routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration by implant or other modes of administration. For example, parenteral administration used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration, intrathecal administration, intralesional administration, and intracranial injection or infusion technology.

[0320] Typically, an effective amount of the compounds provided herein is administered. The amount of compound actually administered can be determined by a physician based on the relevant circumstances, including the condition being treated, the route of administration selected, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0321] When used to prevent the conditions described herein, the compounds provided herein are administered to a subject at risk of developing the condition, typically based on the advice and under the supervision of a physician, at dosage levels as described above. Subjects at risk of developing a particular condition typically include those with a family history of the condition, or those identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0322] The pharmaceutical compositions provided herein can also be administered long-term ("chronic administration"). Long-term administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or administration can continue indefinitely, e.g., for the remainder of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of the compound in the blood over an extended period of time, e.g., within the therapeutic window.

[0323] Various methods of administration can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by injection, for example, in order to increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active ingredient by the body, for example, an intramuscular or subcutaneous bolus dose slowly releases the active ingredient, and the bolus (for example, by IV intravenous drip) delivered directly to the vein can be delivered more quickly so that the concentration of the active ingredient in the blood is rapidly increased to an effective level. In other embodiments, the pharmaceutical composition can be given in a continuous infusion form, for example, by IV intravenous drip, so as to provide a steady-state concentration of the active ingredient in the subject's body. In addition, in other embodiments, the pharmaceutical composition of the bolus dose can be first given, and then continuous infusion.

[0324] Oral compositions can be in the form of bulk liquid solutions or suspensions or bulk powders. However, more generally, in order to facilitate accurate dosing, the compositions are provided in unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined amount of active substance suitable for producing the desired therapeutic effect and a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc. in the case of solid compositions. In such compositions, the compound is typically a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various carriers or excipients and processing aids useful for forming the desired dosage form.

[0325] For oral dosage, a representative regimen is one to five oral doses per day, particularly two to four oral doses, typically three oral doses. Using these dosage administration modes, each dose provides about 0.01 to about 20 mg / kg of the compound of the invention, with preferred doses each providing about 0.1 to about 10 mg / kg, particularly about 1 to about 5 mg / kg.

[0326] To provide blood levels similar to, or lower than, those obtained with an injectable dose, a transdermal dose is typically selected in an amount of 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.

[0327] From about 1 to about 120 hours, and particularly from 24 to 96 hours, the injected dose level is in the range of about 0.1 mg / kg / hour to at least 10 mg / kg / hour. To achieve adequate steady-state levels, a preload bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered. For a 40 to 80 kg human patient, the maximum total dose may not exceed about 2 g / day.

[0328] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous carrier and buffers, suspending and dispersing agents, colorants, flavorings, etc. Solid forms may include, for example, any of the following components, or compounds of a similar nature: binders such as microcrystalline cellulose, tragacanth, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavor.

[0329] Injectable compositions are typically based on sterile saline or phosphate buffered saline for injection, or other injectable excipients known in the art. As previously mentioned, in such compositions, the active compound is typically a minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.

[0330] Typically, transdermal compositions are formulated as topical ointments or creams containing the active ingredient. When formulated as an ointment, the active ingredient is typically combined with a paraffin or water-miscible ointment base. Alternatively, the active ingredient can be formulated into a cream together with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and typically include other components that enhance the stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope provided by the present invention.

[0331] The compounds of the present invention may also be administered by transdermal devices.Thus, transdermal administration may be achieved using patches of the reservoir or porous membrane type, or various solid matrices.

[0332] The above components for oral administration, injection or topical administration are representative only. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0333] The compounds of the invention can also be administered in sustained release form or from a sustained release delivery system. Descriptions of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0334] The present invention also relates to pharmaceutically acceptable formulations of the compounds of the present invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins consisting of 6, 7, and 8 α-1,4-linked glucose units, respectively, which optionally include one or more substituents on the linked sugar portion, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitutions. In some embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, for example, US5,376,645. In some embodiments, the formulation includes hexapropyl-β-cyclodextrin (e.g., in water, 10-50%).

[0335] Indications

[0336] For tumors lacking the HR-dependent DNA DSB repair pathway or other DNA repair mechanisms, the development of highly selective PARP1 inhibitors could provide therapeutic benefits to a large number of cancer patients. The compounds of this invention exert their therapeutic effects by highly selectively negatively regulating PARP1 activity in tumor cells, particularly those lacking the HR-dependent DNA DSB repair pathway or other DNA repair mechanisms, or various tumor cells with BRCA1 or BRCA2 deficient phenotypes.

[0337] In some embodiments, the PARP1 inhibitors described herein can treat various cancers, ischemic diseases, and neurodegenerative diseases.

[0338] More specifically, these compounds can be used to treat: Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, etc.), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma, etc.), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma, etc.), stomach (tumor, lymphoma, leiomyosarcoma, etc.), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, hemangioma etc.), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, etc.), Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma, etc.), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma, etc.); genitourinary tract: kidney (adenocarcinoma, Wilms' tumor, etc.), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, etc.), prostate (adenocarcinoma, sarcoma, etc.), testicle (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma, etc.); liver: hepatocellular carcinoma, bile duct carcinoma, hepatoblastoma, angiosarcoma, Hepatocellular adenoma, hemangioma; Biliary tract: gallbladder cancer, ampullary cancer, bile duct cancer, etc.; Bone: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (reticular cell sarcoma, etc.), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteocartilaginous exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor of bone; Nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, deforming osteitis, etc.), meninges (meningiomas, meningiosarcomas, gliomas, etc.), brain (astrocytomas, medulloblastomas, gliomas, ependymomas Gynecology: uterus (endometrial cancer, etc.), cervix (cervical cancer, preneoplastic cervical dysplasia, etc.), ovary (ovarian cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, etc.), granulosa cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma, etc.), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma, etc.), vagina (clear cell carcinoma, squamous cell carcinoma, Botryoid sarcoma (embryonic 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 diseases, 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, nevus dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, etc.; Adrenal gland: neuroblastoma, etc.;

[0339] More specifically, these compounds are useful in treating: breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer (eg, gastric cancer and colorectal cancer), and lung cancer.

[0340] Combination therapy

[0341] The PARP1 inhibitor of the present invention can be combined with other drugs to treat cancer, including at least one target 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 (such as carboplatin), radiotherapy, STING agonists or immune checkpoint inhibitors / modulators, etc.

[0342] Example

[0343] The starting materials and reagents used herein are either commercially available or prepared by synthetic methods generally known in the art.

[0344] Example 1

[0345] 5-(4-((8-amino-7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide

[0346] Step 1

[0347] 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-dicyclohexylphosphino-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 hours. LCMS (RT = 1.700 min) showed complete consumption of the starting material. The reaction mixture was cooled and filtered through celite. 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 yield Intermediate 2 (3.00 g, crude) as a yellow oil.

[0348] LCMS (ESI) m / z: 322.0 [M+H] + .

[0349] Step 2

[0350] Intermediate 2 (3.00 g) was dissolved in methanol (21.0 mL), and methylamine solution (7.25 g, 40% purity) was added. After addition, the reaction mixture was stirred at 20°C for 4 hours. LCMS (RT = 1.376 min) showed complete consumption of the starting material. The reaction mixture 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 afford Intermediate 3 (2.90 g, crude) as a yellow oil.

[0351] LCMS (ESI) m / z: 321.2 [M+H] + .

[0352] Step 3

[0353] Intermediate 3 (2.90 g) was dissolved in hydrochloric acid / methanol (21.0 mL, 4 M). After addition, the reaction solution 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) showed that the starting material was completely consumed. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was added to tertiary methyl ether (4.00 mL) and purified by slurrying to obtain yellow oily intermediate 4 (2.00 g, yield 86.0%, HCl).

[0354] Step 4

[0355] 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 addition, the reaction mixture was stirred at 50°C for 2 hours. LCMS (RT = 1.355 min) showed complete consumption of the starting material. After cooling, the reaction mixture 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 afford Intermediate 6 (3.00 g, 31.2% yield) as a yellow oil.

[0356] LCMS (ESI) m / z: 268.0 [M+H] + .

[0357] Step 5

[0358] 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]palladium dichloride in dichloromethane (456 mg) were added. After addition, the reaction mixture was stirred at 80°C under a carbon monoxide atmosphere (50 psi) for 12 hours. LCMS (RT = 1.213 min) showed complete consumption of the starting material. The reaction mixture was cooled and filtered through celite. 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 yield Intermediate 7 (2.00 g, crude) as a yellow solid.

[0359] LCMS (ESI) m / z: 248.1 [M+H] + .

[0360] Step 6

[0361] Intermediate 7 (2.30 g) was dissolved in dichloromethane (15.0 mL). Diisobutylaluminum hydride (13.9 mL, 1 M) was added at -78°C. After addition, the reaction mixture was stirred at 20°C for 1 hour. LCMS (RT = 0.58 min) showed complete consumption of the starting material. Water (10.0 mL) and dichloromethane (10.0 mL, 8.00 mL) were added to the reaction mixture for extraction. 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 HPLC (column: Phenomenex C18 250*50 mm*10 μm; mobile phase: [water (ammonia)-acetonitrile]; B%: 3%-30%, 20 min) to afford Intermediate 8 (300 mg, 14.7% yield) as a yellow solid.

[0362] LCMS (ESI) m / z: 220.1 [M+H] + .

[0363] Step 7

[0364] 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 addition, the reaction mixture was stirred at 20°C for 2 hours. LCMS (RT = 1.43 min) showed complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure to afford Intermediate 9 (80.0 mg, 92.2% yield) as a yellow solid.

[0365] LCMS (ESI) m / z: 238.0 [M+H] + .

[0366] Step 8

[0367] Intermediate 9 (80.0 mg) and Intermediate 4 (111 mg, HCl) were dissolved in N,N-dimethylformamide (1.00 mL), and potassium carbonate (139 mg) was added. After the addition was complete, the reaction mixture was stirred at 60°C for 2 hours. LCMS (RT = 1.287 min) showed complete consumption of the starting material. After cooling, the reaction mixture 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 HPLC (column: Phenomenex luna C18 80*40 mm*3 μm; mobile phase: [water (hydrochloric acid)-acetonitrile]; B%: 5%-35%, 7 min) to obtain Example 1 as a white solid (74.3 mg, 100% purity, HCl).

[0368] LCMS (ESI) m / z: 422.2 [M+H] + ;

[0369] 1 H NMR (400MHz, DMSO-d6) δppm 1.01 (t, J = 7.32Hz, 3H), 2.53-2.59 (m, 2H), 2.77-2.87 (m, 3H), 3.17-3.55 (m, 6H), 4.02-4.18 (m, 2H), 4.52 (br s,2H),,7.47-7.58(m,1H)7.73(d,J=1.60Hz,1H),7.86-7.99(m,1H),8.29-8.41(m,1H),8.50(br d,J=4.80Hz,1H),8.61-8.70(m,1H),11.18-11.30(m,1H),11.32-11.51(m,1H).

[0370] Example 2

[0371] 5-(4-((8-amino-7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-fluoro-N-methoxypicolinamide

[0372] Step 1

[0373] 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 solution 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) indicating complete consumption of the starting material. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (silica, petroleum ether / ethyl acetate = 50 / 1 to 1 / 1) to obtain a yellow solid intermediate 11 (9.30 g, yield 61.3%).

[0374] Step 2

[0375] Intermediate 11 (4.30 g) was dissolved in toluene (43 mL), and 1-tert-butyloxycarbonyl-piperazine (4.11 g), cesium carbonate (19.4 g), 2-dicyclohexylphosphine-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) indicated complete consumption of the starting material. After cooling, the reaction solution was filtered through celite. Water (50.0 mL) and ethyl acetate (50.0 mL, 30.0 mL) were added to the filtrate for extraction. 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 to 0 / 1) to obtain intermediate 12 (2.70 g, 43.3% yield) as a yellow solid.

[0376] 1 H NMR (400MHz, CDCl3) δppm 1.49 (s, 9H) 3.15-3.26 (m, 4H) 3.56-3.67 (m, 4H) 3.96 (s, 3H) 7.23-7.27 (m, 1H) 7.97 (dd, J=8.00, 1.06Hz, 1H).

[0377] Step 3

[0378] 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 solution 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) indicating complete consumption of the starting material. Dilute hydrochloric acid (10.0 mL, 2 M) was added to the reaction solution to quench the reaction, and ethyl acetate (30.0 mL, 20.0 mL) was added for extraction. 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 obtain intermediate 13 (2.10 g, 81.1% yield) as a yellow oil.

[0379] 1 H NMR (400MHz, CDCl3) δppm 1.35-1.60 (m, 9H) 2.63-3.13 (m, 4H) 3.28-3.68 (m, 4H) 6.81-7.16 (m, 1H) 7.65-8.00 (m, 1H).

[0380] Step 4

[0381] 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 hexafluorophosphonate (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) indicating complete consumption of the starting material. Water (10.0 mL) and ethyl acetate (10.0 mL, 8.00 mL) were added to the reaction solution for extraction. 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 obtain intermediate 14 (500 mg, 65.5% yield) as a yellow solid.

[0382] Step 5

[0383] Intermediate 14 (100 mg) was dissolved in hydrochloric acid / methanol (2.00 mL, 4 M). After the addition was complete, the reaction solution 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) showed that the starting material was completely consumed. The reaction solution was concentrated under reduced pressure to obtain yellow solid intermediate 15 (50.0 mg, yield 69.6%, HCl).

[0384] Step 6

[0385] 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 solution was stirred at 60°C for 2 hours. LCMS (RT = 0.892 min) showed that the starting material was completely consumed. After the reaction solution was cooled, water (3.00 mL) and ethyl acetate (5.00 mL, 3.00 mL) were added to the reaction solution for extraction. 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*30mm*3um; mobile phase: [water (hydrochloric acid)-acetonitrile]; B%: 5%-35%, 8 min) to obtain Example 2 as a white solid compound (13.0 mg, purity 96.4%, HCl).

[0386] LCMS (ESI) m / z: 456.1 [M+H] + ;

[0387] 1 H NMR (400MHz, DMSO-d6) δppm 1.01 (t, J = 7.20Hz, 3H) 2.56 (br.s, 2H) 3.13-3.33 (m, 6H) 3.67 (s, 3H) 3.73 (br.d, J = 12.0Hz, 2H) 4.54 (br.s, 2H) 6.36-6.50 (m, 1H) 7.65-7.74 (m, 2H) 7.88 (d, J=8.00Hz, 1H) 8.52 (br.s, 1H) 10.51 (br.d, J=3.60Hz, 1H) 11.24 (br.s, 1H) 11.82 (s, 1H).

[0388] The same experimental method as that of Examples 1 and 2 was used to synthesize Examples 3 and 4.

[0389] Example 3

[0390] 5-(4-((8-amino-7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide

[0391] LCMS (ESI) m / z: 440.1 [M+H] + ;

[0392] 1 H NMR (400MHz, DMSO-d6) δppm 1.01 (t, J = 7.20Hz, 3H) 2.54-2.58 (m, 2H) 2.74-2.82 (m, 3H) 3.14-3.38 (m, 6H) 3.72 (br.d, J = 12.0Hz, 2H) 4.54 (br.s, 2H) 6.31-6 .53 (m, 1H) 7.65-7.73 (m, 2H) 7.89 (d, J=7.80Hz, 1H) 8.43-8.48 (m, 1H) 8.50-8.55 (m, 1H) 10.28-10.68 (m, 1H) 11.25 (br.s, 1H).

[0393] Example 4

[0394] 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

[0395] LCMS (ESI) m / z: 443.1 [M+H] + ;

[0396] 1 H NMR (400MHz, DMSO-d6) δppm 0.96-1.05(m,3H)2.29-2.41(m,4H)2.54(br.s,2H)3.11-3.25(m,4H)3.63-3.80(m,2H)4.54(br.s,2H)6.42(br. s, 2H) 7.68-7.72 (m, 1H) 7.89 (d, J=8.00Hz, 1H) 8.42 (s, 1H) 8.51 (br.s, 1H) 10.28-10.54 (m, 1H) 11.24 (br.s, 1H).

[0397] Experimental Example 1 Inhibitory Effect of Compounds on PARP1 / PARP2 Enzyme Activity

[0398] PARP1 / PARP2 enzyme activity was detected by chemiluminescence. First, histone (Active Motif, 81126) was incubated on a 384-well plate for 2 hours. Then, different dilutions of the example compounds and PARP1 working solution (Abcam, ab279663) or PARP2 working solution (BPS, 80502) were added. The Max control wells were only added with PARP1 working solution or PARP2 working solution, and the Min control wells were only added with assay buffer. The plates were incubated at room temperature for 15 minutes. Then, the biotin-labeled substrate NAD was added. + (BPS, 80610), incubated at room temperature for 2 hours. After the substrate is catalyzed by the enzyme, the ADP-ribosylation group binds to the histone and still carries the biotin label. Streptavidin-HRP solution (Abcam, ab7403) is added to develop the biotin color. The values ​​are read on the EnSight (PE) instrument. The inhibition rate is calculated using the fluorescence values ​​of the Max and Min wells. The analysis software GraphPad Prism 5 is used to fit the dose-effect curve to obtain the IC value of each compound on the enzyme activity. 50 value.

[0399] The results are shown in Table 1 below. Examples 1, 2, 3, and 4 exhibited dose-dependent inhibitory effects on the PARP1 enzyme, with significant inhibitory activity reaching picomolar concentrations, and exhibited similar activity to the reference compounds AZD5305 and Olaparib. In terms of PARP2 selectivity, Example 1 exhibited a 3-fold improvement in selectivity over the reference AZD5305, while Examples 2, 3, and 4 exhibited similar selectivity to the reference AZD5305. In terms of PARP2 selectivity, Example 1 exhibited a 3-fold improvement in selectivity over the control AZD5305, while Examples 2, 3, and 4 exhibited similar selectivity to the positive control. Compared to the currently marketed PARPi Olaparib, Examples 1, 2, 3, and 4 exhibited significantly improved selectivity for PARP2, with selectivity increases ranging from 16-83 fold, while maintaining inhibition of PARP1 activity.

[0400] Table 1 Inhibition of PARP1 / PARP2 enzyme activity by compounds

[0401] Experimental Example 2 Compounds Induce DNA Capture Ability of PARP1 / PARP2

[0402] The DNA capture ability of PARP1 / PARP2 was detected using HTRF (homogeneous time-resolved fluorescence). First, PARP1 (BPS, 80501) or PARP2 (BPS, 80502) was labeled with Mab anti-GST-Tb crypate (cisbio, 61GSTTLA), and a DNA damage labeling probe (Generay) was added. Different concentrations of the example compounds were added. 50 μM AZD2281 was added to the Max control wells, and medium buffer was added to the Min wells. The cells were incubated at room temperature for 1 hour, and the substrate NAD was added. + (Sigma, 10127965001) was incubated for 10 minutes, during which PARP exerted its enzymatic activity, causing PARP to be released from damaged DNA. At this time, only a fluorescent signal with an emission wavelength of 615 nm could be detected. When PARP was inhibited, PARP was induced to bind to damaged DNA, causing energy transfer. Two emission wavelengths could be detected, one from the damaged DNA probe itself, with an emission wavelength of 615 nm, and the other from the energy transfer that occurred after PARP bound to damaged DNA, with an emission wavelength of 665 nm. The fluorescence ratio of 665 nm to 615 nm was calculated to represent the amount of the PARP-DNA-captured complex. The capture capacity induced by each compound was calculated using the fluorescence values ​​of the Max and Min wells, and the dose-effect curve was fitted using the analysis software GraphPad Prism 5 to obtain the EC value of each compound's ability to induce PARP enzyme DNA capture. 50 value (required concentration to achieve 50% capture).

[0403] The results are shown in Table 2 below. Examples 1, 2, 3, and 4 induced PARP to capture DNA at single-digit nanomolar concentrations, demonstrating significant capture capabilities, similar to the activity of the reference compound AZD53305 and superior to Olaparib. In terms of PARP2 selectivity, Example 3 achieved a 64-fold selectivity, similar to that of the reference compound AZD5305; Examples 1, 2, and 4 achieved approximately 100-fold selectivity, superior to the reference compound AZD5305. Compared to the currently marketed PARPi Olaparib, Examples 1, 2, 3, and 4 all significantly enhanced their activity against PARP1 and selectivity for PARP2, with activity increased by 3-7 times and selectivity increased by 213-333 times.

[0404] Table 2 DNA capture ability of compounds inducing PARP

[0405] Experimental Example 3 Inhibitory Effect of Compounds on PARP1 / PARP2 Enzyme Activity at the Cellular Level

[0406] High-content imaging was used to assess the inhibitory effects of compounds on PARP1 / PARP2 enzyme activity at the cellular level. A549WT, PARP1-KO, and PARP2-KO cell lines were established and revived. After stabilization, sufficient cells were harvested and 100 μL of the cell suspension was plated in a 96-well plate. The next day, a series of isocratic dilutions of the example compounds were added. The Max control wells received buffer alone, while the Min control wells received 500 nM AZD5305 (A549WT and PARP2-KO cell lines) or 1 μM AZD2281 (PARP1-KO cell line). The plates were incubated for 1.5 hours (A549WT 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 lines) to induce extensive DNA damage. The supernatant was removed and the cells were fixed with 4% paraformaldehyde for 20 minutes, followed by treatment with 0.5% Triton X-100 for 20 minutes to increase cell membrane permeability. The cells were then incubated with 3% BSA for 1 hour to prevent nonspecific binding. A 1:500 dilution of the primary antibody Poly (ADP-ribose) monoclonal antibody (CST, 83732S) was added. After overnight incubation, a 1:500 dilution of the secondary antibody Goat anti-Rabbit IgG, Alexa Fluor TM488 (invitrogen, A-11034) for 1 hour. 50 μL DAPI (invitrogen, R37606) was added to stain the cell nucleus for 30 minutes. After washing twice with PBS, the cells were placed in OPERETTA CLS TM (PE) was photographed and the cells were scanned under a 20x water objective lens in non-confocal mode, with 5 areas captured for each well. When analyzing the data, the DAPI-stained cell nucleus group was selected to distinguish the cell nucleus from the cytoplasm, and the average intensity value of Alexa 488 in the cell nucleus of each well was calculated. The inhibition rate was calculated using the fluorescence values ​​of the Max and Min wells, and the dose-effect curve was fitted using the analysis software GraphPad Prism 5 to obtain the IC value of each compound on the enzyme activity. 50 value.

[0407] The results, as shown in Table 3, show dose-dependent, significant inhibition of enzyme activity in both A549WT and PARP2-KO cell lines. Example 4 exhibited similar inhibitory activity at single-digit nanomolar concentrations, indicating that the primary cellular enzyme activity is derived from PARP1. Examples 1, 2, 3, and 4 exhibited similar inhibitory activity against PARP1 compared to the reference AZD5305. The example compounds all exhibited relatively weak inhibitory activity in the A549 PARP1-KO cell line. Examples 2, 3, and 4 showed no detectable inhibition of enzyme activity at the highest concentration of 40 μM, indicating that after PARP1 knockout, the example compounds exhibited little inhibition of cellular PARylation and little inhibitory activity against enzymes other than PARP1. Compared to the reference AZD5305, Examples 1 and 2 exhibited similar selectivity, while Examples 3 and 4 exhibited selectivity improvements of >3-6 times that of the reference AZD5305, demonstrating superior selectivity.

[0408] Table 3 Compounds inhibit PARP1 / PARP2 enzyme-mediated PARylation activity at the cellular level

[0409] Experimental Example 4: Anti-proliferative activity test of compounds on tumor cells

[0410] The anti-proliferation test of the compound on tumor cells uses the most widely used ATP concentration detection method. MDA-MB-231 and MDA-MB-436 cell lines are from ATCC, DLD-1 human colorectal adenocarcinoma epithelial cells and DLD-1BRCA2 - / -Cells were obtained from Horizon, and recovered. After the cells were stable, they were harvested. When the viable cell count was greater than 90%, 450-500 cells were seeded into a 384-well plate. On the second day, a series of isocratic dilutions of the example compounds were added. Only buffer was added to the Max wells, and 50 μM AZD2281 was added to the Min wells. The cells were incubated for 7 days. On the 8th day, AZD2281 was added. Reagent (Promega, G7573), incubate at room temperature for 30 minutes, and read the value on Envision (PE). The inhibition rate was calculated using the fluorescence values ​​of the Max and Min wells, and the analysis software GraphPad Prism 5 was used to fit the dose-effect curve to obtain the IC value of each compound on the enzyme activity. 50 value.

[0411] The results are shown in Table 4 below. In both 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 compounds of the Examples exhibited dose-dependent anti-proliferative activity against the BRCA1-mutated MDA-MB-436. The inhibitory activity of Examples 2, 3, and 4 against these cancer cells reached single-digit nanomolar concentrations, similar to that of the reference AZD5305. For the BRCA1-normal MDA-MB-231, no inhibitory activity was detected at the highest concentration of 10 μM for Examples 1, 2, and 4, consistent with the reference AZD5305. The IC values ​​of Example 3 were 0.1, 0.2, and 0.3, respectively. 50 At 7.4 μM, Examples 1, 2, 3, and 4 demonstrated significant selectivity between BRCA1-mutated cell lines and BRCA1-normal cells, with selectivity reaching hundreds or thousands of times. Compared to the marketed PARPi Olaparib, Examples 1, 2, 3, and 4 demonstrated 18-235-fold increased anti-proliferative activity against BRCA1-mutated MDA-MB-436 and 55-530-fold increased selectivity for PARP2, significantly enhancing PARP1 inhibitory activity and PARP2 selectivity.

[0412] As shown in Table 5, in the case of BRCA2 mutation DLD-1BRCA2 - / -In the DLD-1 human colorectal adenocarcinoma epithelial cell line with and normal BRCA2 expression, the compounds of the Examples all exhibited dose-dependent antiproliferative activity against the BRCA2 mutant cell line. Examples 2, 3, and 4 all demonstrated inhibitory activity against these cancer cells at single-digit nanomolar concentrations, similar to that of the reference AZD5305. In the DLD-1 cell line with normal BRCA2 expression, no inhibitory activity was detected for Examples 1, 2, 3, and 4 at the highest concentration of 10 μM, consistent with that of the reference AZD5305. This demonstrates that Examples 1, 2, 3, and 4 exhibit significant selectivity between BRCA2 mutant cell lines and BRCA2 normal cells, with selectivity reaching hundreds or thousands of times.

[0413] The anti-proliferative activities of the example compounds on BRCA1 mutation and normal, BRCA2 mutation and normal cancer cell lines indicate that the example compounds have strong anti-proliferative activity on target cells and are targeted and safe for clinical treatment.

[0414] Table 4 Antiproliferative ability of compounds against BRCA1 mutation and BRCA1 normal cancer cells

[0415] Table 5 Antiproliferative ability of compounds against BRCA2 mutant and BRCA2 normal cancer cells

[0416] Taking into account the enzymatic activities at the molecular and cellular levels, the ability of induced PARP to capture damaged DNA, and the anti-proliferative activity of cancer cells, Examples 1, 2, 3, and 4 have excellent PARP1 selective inhibitory activity and target cell anti-proliferative ability, and are significantly superior to the marketed PARPi Olaparib in both PARP1 activity and selectivity for PARP2. Compared with the reference compound AZD5305, the selectivity for PARP1 at the cellular level is significantly improved.

[0417] Experimental Example 5: Pharmacokinetic study of single-dose administration in mice

[0418] Male CD-1 mice were used as test subjects to determine plasma drug concentrations and evaluate pharmacokinetic parameters after a single dose. Healthy adult male CD-1 mice were selected. The candidate compound was dissolved in 10% DMSO by vortexing and sonication. After thorough dissolution, 30% PEG400 was added, vortexed and sonicated, and 60% double-distilled water was added to prepare a clear solution for later use. Mice were dosed with 2 mg / kg intravenously and 10 mg / kg orally. Whole blood was collected at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration to prepare plasma. The samples were processed and analyzed for drug concentration by LC-MS / MS, and pharmacokinetic parameters were calculated.

[0419] The results are shown in Table 6 below, which indicate that the compound of Example 1 has good bioavailability and good pharmacokinetic properties.

[0420] Table 6 Pharmacokinetic parameters of compounds in CD-1 mice

[0421] The above experiments demonstrate that the compounds of the present invention exhibit high selectivity for PARP1 inhibition, with inhibitory activity against PARP1 and PARP2 at both the cellular and cellular levels 10-100 times greater than that observed against PARP2. This higher selectivity is expected to lead to greater clinical safety, reduced toxic side effects, and improved patient acceptance, thus increasing their therapeutic value.

[0422] Experimental Example 6: Selectivity of Compounds for PARP Family PARP3, 5a, 6, 7, and 11

[0423] The enzyme activity of the PARP family was detected by chemiluminescence. First, histone (Active Motif, 81126) was incubated on a 384-well plate for 2 hours.

[0424] Add different dilutions of the example compounds and PARP3 working solution (BPS, 80503), add only PARP working solution to the Max control wells, and add only assay buffer to the Min control wells. Incubate at room temperature for 15 minutes, then add biotin-labeled substrate NAD + (BPS, 80610), PARP3 activating DNA (Generay), incubated at room temperature for 2 hours. After the substrate is catalyzed by the enzyme, the ADP-ribosylation group binds to the histone and still carries the biotin label. Streptavidin-HRP solution (Abcam, ab7403) is added to develop the biotin color, and the value is read on the EnSight (PE) instrument.

[0425] Add different dilutions of the example compounds and PARP5a working solution (BPS, 80504), add only PARP working solution to the Max control wells, and add only assay buffer to the Min control wells. Incubate at room temperature for 15 minutes, then add biotin-labeled substrate NAD + (BPS, 80610), incubate at room temperature for 2 hours. After the substrate is catalyzed by the enzyme, the ADP-ribosylation group binds to the histone and still carries the biotin label. Streptavidin-HRP solution (Abcam, ab7403) is added to develop the biotin color, and the value is read on the EnSight (PE) instrument.

[0426] Add different dilutions of the example compounds and PARP6 working solution (BPS, 80506), add only PARP working solution to the Max control wells, and add only assay buffer to the Min control wells. Incubate at room temperature for 15 minutes, then add biotin-labeled substrate NAD + (BPS, 80610), incubate at room temperature for 2 hours. After the substrate is catalyzed by the enzyme, the ADP-ribosylation group binds to the histone and still carries the biotin label. Streptavidin-HRP solution (Abcam, ab7403) is added to develop the biotin color, and the value is read on the EnSight (PE) instrument.

[0427] Using the PARP7 Chemiluminescent assay kit (BPS, 79729), different dilutions of the example compounds and PARP7 working solution (BPS, 80527) were added. Max control wells were added with only the PARP working solution, and Min control wells were added with only the assay buffer. The cells were incubated at room temperature for 15 minutes. The substrate mixture provided in the assay kit (BPS, 78371) was added and incubated at room temperature for 1 hour. After enzyme-catalyzed ADP-ribosylation of the substrate, the ADP-ribosylation group bound to the histone still carried the biotin label. Treptavidin-HRP solution (BPS, 80611) was added to visualize the biotin, and the values ​​were read on the EnSight (PE) instrument.

[0428] Using the PARP11 Chemiluminescent assay kit (BPS, 80561), different dilutions of the example compounds and PARP11 working solution (BPS, 80511) were added. Max control wells were added with only the PARP working solution, and Min control wells were added with only the assay buffer. The cells were incubated at room temperature for 15 minutes. The substrate mixture provided in the assay kit (BPS, 78371) was added and incubated at room temperature for 1 hour. After enzyme-catalyzed ADP-ribosylation of the substrate, the ADP-ribosylation group bound to the histone still carried the biotin label. Treptavidin-HRP solution (BPS, 80611) was added to visualize the biotin, and the values ​​were read on the EnSight (PE) instrument.

[0429] The inhibition rate was calculated using the fluorescence values ​​of the Max and Min wells, and the dose-effect curve was fitted using the analysis software GraphPad Prism 5 to obtain the IC value of each compound on the enzyme activity. 50 value.

[0430] The results are shown in Table 7 below. The inhibitory effect of Example 4 on each PARP enzyme is weaker than that on the PARP1 enzyme activity. The values ​​in the brackets of Table 7 represent the ratio relative to the PARP1 enzyme activity. Compared with the marketed PARPi Olaparib, Example 4 has significantly improved selectivity for other enzymes, except for slightly weaker selectivity for PARP11. Compared with the reference AZD5305, Example 4 has significantly improved selectivity for the tested PARP enzymes.

[0431] This shows that Example 4 is a PARP1-specific selective inhibitor, which is more selective than AZD5305 for PARP3, PARP5a, PARP6, PARP7 and PARP11, and has a particularly significant selectivity advantage for PARP11; it is more selective than Olaparib for PARP3, PARP5a, PARP6 and PARP7, and has a particularly significant selectivity advantage for PARP3.

[0432] Table 7 Inhibition of PARP3 / PARP5a / PARP6 / PARP7 / PARP11 Enzyme Activity by Compounds (nM)

[0433] Experimental Example 7 Effect of Compounds on Inducing PARP1 / 2 Capture of DNA in FP Experiment

[0434] In order to further explore the effect of Example 4 on the capture of PARP1-DNA and PARP2-DNA, as well as the difference between the two, the fluorescence polarization (FP) method was used for further evaluation. PARP1 / 2 enzymes bind to fluorescently labeled DNA to form a larger complex, causing the fluorescently labeled DNA to rotate slower, thereby emitting a higher polarization value. + Afterwards, the PARP1 / 2 enzyme undergoes autoribosylation and accumulates negative charges. When the negative charges accumulate to a certain level, the fluorescently labeled DNA will dissociate, causing the fluorescently labeled DNA to rotate faster and the polarization value to decrease. The addition of PARP inhibitors affects PARP-DNA capture, and the extent of the effect can be detected by changes in polarization intensity. First, 25nL of different concentrations of compounds at 1000 times the final concentration are transferred to a 384-well plate. 25nL of 100% DMSO is added to the Min well and Max well, respectively. 5μL of enzyme solution containing 10nM PARP1 (BPS, 80501) and 1nM FAM-PARP1-DNA (Generay, customized) or 10nM PARP2 (BPS, 80502) and 1nM FAM-PARP2-DNA (Generay, customized) is added. The plate is centrifuged at 1000rpm for 1 minute, then incubated at room temperature for 30 minutes. 5μL of 1mM substrate NAD is added.+ (MCE, HY-B0445), add 5 μL of 1 mM substrate NAD into the Min well + , add Assay buffer to the Max well, centrifuge at 1000 rpm for 1 minute, react at 25°C, and test at the following time points:

[0435] For the PARP1 capture assay, the values ​​were read using a plate reader (Envision) at 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, 30 hours, 48 ​​hours, and 54 hours.

[0436] For the PARP2 capture assay, the plate reader was read at 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, and 48 hours.

[0437] The compound-induced capture capacity was calculated using the fluorescence values ​​of the Max and Min wells, and the dose-effect curve was fitted using the analysis software GraphPad Prism 5 to obtain the EC value of each compound's ability to induce PARP enzyme DNA capture. 50 value.

[0438] The results are shown in Table 8 and Figure 1. At the 2-hour time point, Example 4 demonstrated a 48-fold increase in PARP1 DNA capture compared to the marketed PARPi Olaparib, and similar activity to the reference AZD5305. Example 4 showed almost no PARP2 DNA capture, similar to the reference AZD5305. Meanwhile, the marketed PARPi Olaparib exhibited similar PARP2 DNA capture to that of PARP1 DNA, demonstrating a lack of selectivity.

[0439] This indicates that Example 4 has much higher selectivity for PARP1 than PARP2, and is expected to significantly reduce the blood toxicity caused by PARP2.

[0440] As shown in Table 8 and Figure 2, further comparison of the PARP1-DNA capture abilities of Example 4 and reference AZD5305 reveals that Example 4 maintains its activity for more than 54 hours over time, and is 14 times more active than reference AZD5305 at 54 hours, suggesting superior anti-tumor activity.

[0441] Table 8 Effects of compounds on PARP1 / 2-DNA capture

[0442] Experimental Example 8 Antitumor Effect of Compounds on Human Breast Cancer Cell MDA-MB-436 Transplanted Tumor Mouse Model

[0443] Example 4 was further validated in vivo using a mouse subcutaneous xenograft tumor model of the BRCA1 mutant MDA-MB-436 cell line. Human breast cancer MDA-MB-436 cells (ATCC, HTB-130) were cultured in monolayers 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. Twice a week, cells were routinely digested and passaged using trypsin-EDTA. When the cell saturation reached 80%-90%, the cells were harvested, counted, and 0.2 mL of 1×10 7 MDA-MB-436 cells were subcutaneously inoculated into the right back of each mouse (PBS:Matrigel=1:1). The average tumor volume reached 152 mm 3 The grouping and drug administration began at 14:00, which was set as Day 0. The tumor volume and mouse body weight were monitored twice a week for 28 days.

[0444] The tumor diameter was measured with a vernier caliper. The tumor volume was calculated as follows: V = 0.5a × b 2 , a and b represent the long diameter and short diameter of the tumor, respectively. The anti-tumor efficacy of the compound is evaluated by the relative tumor shrinkage rate Reg%. Reg% reflects the ratio of tumor volume reduction after treatment. Reg% = (V0-V t ) / V0×100%, where V0 is the tumor volume measured at the time of group administration (i.e., d0), V t is the tumor volume at a certain measurement.

[0445] The compound response criteria in the mouse model were modified from mRECIST (revised response criteria in solid tumors) (Gao et al, 2015) and are defined as follows:

[0446] CR (complete remission): BestResponse <-95% and BestAvgResponse <-40%;

[0447] PR (partial response): BestResponse < -50% and BestAvgResponse < -20%;

[0448] SD (stable disease): BestResponse < 35% and BestAvgResponse < 30%;

[0449] PD (progressive disease): other classifications;

[0450] ORR% is equal to the sum of the proportions of complete response (CR) and partial response (PR).

[0451] Statistical analysis was performed using Prism software, including the mean (mean) and standard error (SEM) of tumor volume at each time point for each group. For statistical analysis of TV, the raw TV data for each measurement were used to compare differences between groups. Two-way ANOVA was performed, incorporating both drug administration and time into the analysis. Tukey's multiple comparisons test was used for testing. A p < 0.05 was considered statistically significant.

[0452] The results are shown in FIG3 . At the same dose, both Example 4 and reference AZD5305 promoted tumor regression. The degree of tumor regression achieved by Example 4 was superior to that achieved by reference AZD5305, with an ORR of 60%, while the ORR of the reference was 20%.

[0453] This indicates that in the subcutaneous transplant tumor model of human breast cancer MDA-MB-436 mice, the anti-tumor growth effect of Example 4 is superior to that of the reference AZD5305.

[0454] Experimental Example 9: Effect of Compounds on Promoting Apoptosis in BRCA2-Deficient Cell Lines

[0455] The mechanism of the compound's anti-proliferative effect on BRCA-mutated tumors was analyzed, and the apoptotic effect of the compound on BRCA2-mutated cell lines was analyzed by flow cytometry. BRCA2-deficient human colon cancer DLD-1 cells (ATCC, HTB-130) were adherently cultured in RPMI1640 medium supplemented with 1% fetal bovine serum and 100 μg / mL hygromycin B. When the cells entered the logarithmic phase, the cells were harvested and plated in 6-well plates 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 plated in 96-well plates. 195 μL of Annexin V-FITC binding buffer was added to each well to resuspend the cells. 5 μL of Annexin V-FITC (beyotime, C1052) was then added and gently mixed. The cells were incubated at room temperature for 30 minutes, washed twice with PBS, centrifuged at 300 g for 5 minutes, 500 μL of PBS was added to each well to resuspend the cells, and 5 μL of Gently mix with PI (beyotime, C1052) and stain at room temperature for 30 minutes. Wash once with PBS and centrifuge at 300g for 5 minutes. Resuspend the cells in 500μL of PBS. Remove 300μL of cells and transfer to a flow cytometer (BD Bioscience, FACSVerse) for analysis. Data collected by the flow cytometer were analyzed using FlowJo software.

[0456] Apoptosis analysis: Drag the apoptotic sample into FlowJo and double-click the raw data to open the graph window. Select FSC-A on the X-axis and SSC-A on the Y-axis. For analysis of apoptotic cells, select the cell population shown in the figure above. Cell debris will not be analyzed. Double-click "Analyzed Cell Population" in the SSC / FSC graph, select FITC on the X-axis to represent AnnexinV-FITC. Select PerCP on the Y-axis to represent PI. Use the four-point gate tool to define live cells and apoptotic cells. AnnexinV-positive cells are apoptotic cells, AnnexinV-positive cells are PI-negative cells are early apoptotic cells, and AnnexinV-positive cells are PI-positive cells are late apoptotic cells. PRISM was used for graphical analysis, and two-way ANOVA was used for statistical analysis to include different compounds and different concentrations in the analysis. Tukey's multiple comparisons test was used for testing, and p<0.05 was considered to be statistically significant.

[0457] The results are shown in Figure 4. Three repeated experiments were performed. Example 4 induced a higher percentage of cell apoptosis at different concentrations than the reference AZD5305, with some concentrations showing statistically significant differences. This suggests that Example 4 is superior to the reference AZD5305 in inducing apoptosis in BRCA2-deficient human colon cancer DLD-1 cells.

[0458] Experimental Example 10: Effect of Compounds on Promoting Apoptosis of BRCA1 Mutated Human Breast Cancer Transplants

[0459] To further validate the pro-apoptotic effects of the compounds in vivo, immunoblotting was used to detect changes in cleaved caspase-3 in subcutaneous xenografts of MDA-MB-436 mice. After 10 days of treatment with the different compounds, animals were euthanized 0.25 and 24 hours after the last dose, and tumor tissue was harvested for analysis. Quick-frozen tumor tissue was placed on dry ice, and 350 μL of complete cell lysis buffer (containing 1% protease and phosphatase inhibitors) was added. The tissue was disrupted using a tissue grinder for 5 minutes, and the tissue lysis buffer was placed on ice for 30 minutes. The supernatant was then centrifuged at 12,000 rpm and 4°C for 10 minutes. The supernatant was transferred to a new 1.5 mL centrifuge tube and protein quantified using a BCA assay kit. Based on the quantification results, the sample protein concentration was adjusted to 2 μg / μL. LDS loading buffer (4X) and sample reducing agent (10X) were added, and the samples were heated at 100°C for 10 minutes. Western blotting was performed by loading 10 μL of sample per well on an SDS-PAGE gel at 80 V for 30 min, followed by electrophoresis at 120 V for 90 min. The membrane was transferred using the iBlot2 transfer kit and a transfer apparatus for 7 min. The membrane was cut according to the molecular weight of the desired protein and washed three times with 1xTBST for 5 min each time. 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 min each time. Secondary antibody Goat anti-Rabbit IgG-HRP (Thermo Fisher, 31462) was added and incubated at room temperature for 1 h. The membrane was washed three times with 1xTBST for 10 min each time. Western blotting was performed by adding the secondary antibody Goat anti-Rabbit IgG-HRP (Thermo Fisher, 31462). Chemiluminescence was performed using the HRP substrate in the Femto Ultrasensitive Chemiluminescence Kit. Chemiluminescence was detected on a Tanon 5200 Multi instrument and photographed for storage. Alpha View software was used for quantitative analysis to determine the relative density intensities of immunoblot luminescence bands. β-Actin is a housekeeping protein, and sample loading consistency was monitored during immunoblotting. The density intensity of the cleaved caspase-3 band was normalized to that of the total caspase-3 band. The relative density intensity of cleaved caspase-3 in the vehicle control group was set as 1, and the relative expression levels of cleaved caspase-3 in each treatment group were converted and plotted.Prism software was used to generate and analyze the values, including the mean and standard error (SEM) of the relative expression of cleaved caspase-3 at each time point for each group. Differences between groups were compared. Multiple group comparisons were analyzed using one-way ANOVA. If there was no significant difference in the F value, the Games-Howell test was used. If there was no significant difference in the F value, the Tukey's multiple comparisons test was used for further analysis. A p value < 0.05 was considered statistically significant.

[0460] The results, as shown in Figures 5 and 6, show that Example 4 promoted the increase of cleaved caspase-3 in subcutaneous xenograft tumor tissues of MDA-MB-436 mice. At both 0.25 and 24 hours after the last administration, the degree of increase was superior to that of the reference AZD5305. This suggests that Example 4 has a better effect in promoting tumor cell apoptosis than the reference AZD5305 in BRCA1-mutant MDA-MB-436 tumors in vivo, which is consistent with its superior tumor inhibition effect.

[0461] In summary, the compound of the present invention is a highly selective PARP1 inhibitor, superior to AZD5305 in inhibiting tumor growth in the BRCA1 MDA-MB-436 human breast cancer model. This superiority is further demonstrated by comparisons of PARP1 DNA capture and apoptosis induction. Compared with marketed PARP inhibitors, it exhibits significantly improved selectivity for PARP2, and compared with the reference AZD5305, it exhibits significantly improved selectivity for other PARP family members. This suggests that the compound of the present invention, such as Example 4, has the potential to become a safer, more effective, and highly selective PARP1 inhibitor, potentially providing higher-quality treatment options for clinical patients.

[0462] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof: in, L1 is selected from CRR', O, S, NH, -C(O)-, -S(O)- or -S(O)2-; R and R' are independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; A is selected from CR A or N; E is selected from CR E or N; G is selected from CR G or N; R A 、R E and R G Independently selected from H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-10 Cycloalkyl or -L-3-10 membered heterocyclic group; R1 is selected from H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace; R 1s Independently selected from H, D, halogen, CN, OR a SR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; Expressed as a single or double bond; M1 is selected from N, C or CR5; M2 is N or CR6; R5 and R6 are independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R4 is independently selected from H, D, halogen, CN, ═O, OR a SR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 4s replace; Or R4 and R2 located at the adjacent position of M1 together with the atoms to which they are connected form C 5-7 Cycloalkyl or 5-7 membered heterocyclic group, or R4 and Z3 located at the ortho position of M1 and the atoms to which they are connected together form C 5-7 Cycloalkyl or 5-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 4s replace; R 4s Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic 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 selected from H, D, halogen, CN, OR a SR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 2s replace; R 2s Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; R3 is selected from H, -L-OR a 、-L-SR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s replace; R 3s Independently selected from H, D, halogen, CN, OR a SR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; L is a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, which is optionally substituted by 1, 2 or 3 atoms selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 radical substitution of alkynyl groups; R a 、R b and R c Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, 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.

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

4. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: A is N; Preferably, E is CR E ; Preferably, G is CR G ; Preferably, for 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, polymorph, hydrate or solvate thereof, wherein: R A 、R E and R G Independently selected from H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 3-7 Cycloalkyl or -L-3-7 membered heterocyclic group; preferably selected from H, D, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably H or D; preferably H.

6. A compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R1 is selected from H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl; preferably selected from H, D, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; preferably selected from H, D, halogen, CN, OR a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably Et.

7. A compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 1s Independently selected from H, D, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

8. A compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: M1 is selected from N or CR5, preferably N; Preferably, M2 is N; Preferably, for 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, polymorph, hydrate or solvate thereof, wherein: R5 and R6 are independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably H or D; preferably H.

10. A compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R4 is independently selected from H, D, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably H or D; preferably H; Preferably, n is 0, 1 or 2, preferably 0.

11. A compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R4 located at the ortho position of M1 and R2 together with the atoms to which they are attached form a 5-7 membered heterocyclic group, or R4 located at the ortho position of M1 and Z3 together with the atoms to which they are attached form a 5-7 membered heterocyclic group; Preferably, R4 located at the ortho position of M1 forms a 5-7 membered heterocyclic group together with R2 and the atoms to which they are attached.

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, polymorph, hydrate or solvate thereof, wherein: R 4s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

13. A compound of formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: Z1 is N; Preferably, Z2 is CR8; Preferably, Z3 is CR9; Preferably, for 14. A compound of formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R7, R8 and R9 are independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably H or D; preferably H.

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, polymorph, hydrate or solvate thereof, wherein: R2 is selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from H, D, halogen, CN, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl; preferably selected from H, D or halogen; preferably H or F.

16. A compound of formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 2s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

17. A compound of formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R3 is selected from H, -L-OR a 、-L-SR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl; preferably selected from H, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; preferably selected from H, OR a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from H, OR a 、C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Deuterated alkyl; preferably selected from OR a 、C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Deuterated alkyl; preferably selected from Me, CD3 or OMe.

18. A compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 3s Independently selected from H, D, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

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

20. A compound of formula (I) according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R a 、R b and R c Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably H or Me; more preferably Me; or R b 、R c and the atoms to which they are attached together form a 5-7 membered heterocyclic group.

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, polymorph, hydrate or solvate thereof, having the following structural formula: wherein each group is as defined in claims 1 to 20.

22. The compound of formula (II) according to claim 21, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R1 is selected from H, D, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace; R2 is selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 2s replace; R3 is selected from H, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s replace; R4 is selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 4s replace; Alternatively, R4 located at the N-ortho position to the pyridine bond, together with R2 and the atoms to which they are attached, forms a 5-7 membered heterocyclic group; R 1s and R 3s Each independently selected from H, D, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; R 2s and R 4s are each independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; n is 0, 1, 2, 3 or 4; R a 、R b and R c Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; or R b 、R c and the atoms to which they are attached together form a 5-7 membered heterocyclic group; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

23. The compound of formula (II) according to claim 21 or 22, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R1 is selected from H, D, halogen, CN, OR a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1s replace; R2 is selected from H, D, halogen, CN, C 1-6 Alkyl or C 1-6 Haloalkyl, optionally substituted by 1, 2 or 3 R 2s replace; R3 is selected from H, OR a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 3s replace; R4 is selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl, optionally substituted by 1, 2 or 3 R 4s replace; R 1s and R 3s Each independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; R 2s and R 4s are each independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; n is 0, 1, 2, 3 or 4; R a Independently selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

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, polymorph, hydrate or solvate thereof, wherein R1 is selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide; R2 is selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R3 is selected from H, OR a 、C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl; R4 is selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide; n is 0, 1, 2, 3 or 4; R a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

25. The compound of formula (II) according to any one of claims 21 to 24, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R1 is C 1-6 Alkyl or C 1-6 Haloalkyl, preferably Et; R2 is selected from H, D or halogen, preferably H or F; R3 is selected from OR a 、C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Deuterated alkyl, preferably selected from Me, CD3 or OMe; R4 is H or D, preferably H; n is 0, 1 or 2, preferably 0; R a C 1-6 Alkyl or C 1-6 Haloalkyl, preferably Me; Preferably, R3 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Deuterated alkyl, preferably C 1-6 Deuterated alkyl, preferably selected from Me and CD3, preferably CD3; Preferably, R2 is halogen, preferably F, Cl or Br, preferably F.

26. The compound of formula (I) of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: The compound is selected from the following:

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, polymorph, hydrate or solvate thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle, optionally with another therapeutic agent.

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

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

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

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

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

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

34. 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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