Pyridinopyrazole derivative pharmaceutical composition and use thereof

Abstract

Provided in the present invention are a pyridinopyrazole derivative pharmaceutical composition as shown in formula (I), and the use thereof in the preparation of an anti-tumor drug. The pharmaceutical composition comprises a compound of formula (I) and a PARP inhibitor.

Description

A pyridopyrazole derivative pharmaceutical composition and its application Technical Field

[0001] The present invention relates to a pharmaceutical composition and an application thereof, in particular to a pyridopyrazole derivative pharmaceutical composition and an application thereof in treating tumor diseases, belonging to the technical field of pharmaceutical compositions. Background Art

[0002] Malignant tumors are serious diseases that endanger human life and health. With the rapid development of tumor biology and related disciplines in recent years, specific anti-tumor drugs that target abnormal signaling systems within tumor cells have become a focus of new drug research and development. Furthermore, the combination of multiple anti-tumor drugs for the treatment of tumors is also a hot topic in scientific research.

[0003] Maintaining genomic stability is crucial for the proper functioning of all organs in the human body. The body has a comprehensive response mechanism to DNA damage. Mutations in key proteins in the DNA damage pathway, such as BRCA1, BRCA2, and ATM, are associated with cancer susceptibility. These key proteins in the DNA damage response signaling pathway engage in numerous feedback loops and cross-talks, making the DNA damage response pathway a complex network. In eukaryotes, homologous recombination (HR) repair utilizes homologous sister chromatids as templates for new strand synthesis, thereby precisely repairing broken duplex DNA. BRCA1 and BRCA2 play crucial roles in the HR repair pathway. Mutations in these genes significantly impair HR repair capacity, leading to genomic instability. PARP plays a crucial role in the repair of single-strand breaks (SSBs). PARP inhibitors can hinder the repair of single-strand breaks in DNA. Furthermore, cells harboring BRCA1 or BRCA2 mutations are unable to repair DNA damage through the HR repair pathway, leading to cell death due to unrepaired DNA damage. Due to this synthetic lethality mechanism, PARP inhibitors have been approved for the treatment of breast or ovarian cancer with BRCA1 or BRCA2 mutations. However, studies have found that PARP inhibitors can lead to drug resistance, partially due to DNA replication fork stabilization, and thus reduce their efficacy.

[0004] USP1 is a deubiquitinase that removes ubiquitin modifications from specific proteins. Studies have shown that USP1 inhibitors increase the ubiquitination of PCNA at DNA replication forks, leading to DNA replication fork arrest and reduced fork stability. Therefore, USP1 inhibitors can address PARP inhibitor resistance caused by DNA replication fork stabilization and enhance the therapeutic efficacy of PARP inhibitors.

[0005] WO2023155866A1 describes a compound of formula (I), which has good USP1 inhibitory activity.

[0006] The present invention provides a pharmaceutical composition of a compound of formula (I) and its use in treating tumors with a sensitized PARP inhibitor. The pharmaceutical composition has a good tumor-suppressing effect. Summary of the Invention

[0007] The present invention provides a pharmaceutical composition comprising:

[0008] (i) a compound of formula (I) or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof;

[0009] (ii) PARP inhibitors;

[0010] The compound of formula (I) is:

[0011] Cy is selected from

[0012] The Cy is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, CH2F, CHF2, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or cyclopropyl;

[0013] Or Cy is selected from The Cy is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, CH2F, CHF2, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or cyclopropyl;

[0014] R 1 and R 9 Each is independently selected from H, F, Cl, Br, I, cyano, methyl or ethyl;

[0015] R 2 Selected from

[0016] R 3 and R 4 Each independently selected from H, F, Cl, Br, I, methyl, ethyl;

[0017] R 5 Selected from

[0018] or R 5 Selected from

[0019] R 8 Selected from F, Cl.

[0020] Preferably, the compound of formula (I) is selected from one of the following structures:

[0021] In some embodiments, the PARP inhibitor is selected from at least one of Olaparib, Niraparib, Talazoparib, Veliparib, Rucaparib, CEP-8983, BGB-290 or pharmaceutically acceptable salts thereof, preferably at least one of Olaparib, Niraparib, Talazoparib, Veliparib, and Rucaparib.

[0022] In some embodiments, the compound of formula (I) is selected from compound 1 having the following structure:

[0023] In some embodiments, the pharmaceutical composition further comprises:

[0024] (iii) optionally, other pharmaceutically active ingredients, such as one or more anti-tumor drugs; and

[0025] (iv) a pharmaceutically acceptable carrier.

[0026] Furthermore, the present invention also provides a pharmaceutical composition comprising:

[0027] (i) Compound 1 or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof,

[0028] (ii) Olaparib;

[0029] (iii) a pharmaceutically acceptable carrier.

[0030] In some embodiments, the unit dosage of the pharmaceutical composition is Compound 1 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in C 30 H 33The content in terms of F4N7O is selected from 1 mg-2000 mg, 20 mg-1600 mg, 20 mg-1200 mg, 20 mg-800 mg, 20 mg-400 mg, preferably 20 mg-1600 mg.

[0031] In some embodiments, the unit dosage of the pharmaceutical composition is C 24 H 23 The content calculated as FN4O3 is selected from 0.1mg-1000mg, 1mg-1000mg, 10mg-800mg, 10mg-600mg, 10mg-400mg, 10mg-200mg, preferably 10mg-400mg.

[0032] The pharmaceutical composition of the present invention has a dosage form selected from tablets, capsules, pills, granules, or injections, and the injections include injection solutions, sterile powders for injection, and concentrated solutions for injection.

[0033] The present invention also provides the use of the pharmaceutical composition in the preparation of a drug for treating tumor diseases. Optionally, it can be administered alone or in combination with one or more other anti-tumor drugs; the combined administration is selected from simultaneous administration, independent configuration and co-administration, or independent configuration and sequential administration; the administration route adopted by the combined administration is selected from oral administration, parenteral administration or transdermal administration, and the parenteral administration is selected from intravenous injection, subcutaneous injection or intramuscular injection; the tumor disease is selected from ovarian cancer, pancreatic cancer, castration-resistant prostate cancer, non-small cell lung cancer, breast cancer and other tumors with homologous recombination repair defects.

[0034] The present invention also provides a medicine packaging box, which includes the pharmaceutical composition of the present invention.

[0035] The present invention also provides the use of the above-mentioned pharmaceutical composition in the preparation of anti-tumor drugs:

[0036] Optionally, the administration frequency of (i) is once a day, twice a day, once a week, or once every two weeks, and the administration frequency of (ii) is once a day, twice a day, or once a week;

[0037] Optionally, (i) and (ii) may be administered simultaneously or separately in sequence;

[0038] Optionally, (i) and (ii) may be formulated independently and co-administered or formulated independently and administered sequentially;

[0039] Optionally, the preparations made from (i) and (ii) may be administered in combination in the same preparation or in separate different preparations.

[0040] Furthermore, the above application further includes:

[0041] (iii) other anti-tumor drugs;

[0042] Said (i), (ii) and (iii) may be administered simultaneously or separately in sequence;

[0043] Optionally, (i), (ii) and (iii) may be formulated independently and co-administered or formulated independently and administered sequentially.

[0044] The present invention also provides pharmaceutical compositions of other USP1 inhibitors and PARP inhibitors and their use in treating tumor diseases. The other USP1 inhibitors are selected from KSQ-4279, ISM3091, TNG-438, FT-3171, SJB3-019A, or pharmaceutically acceptable salts thereof; the PARP inhibitors can be selected from Olaparib, Niraparib, Talazoparib, Veliparib, Rucaparib, CEP-8983, BGB-290, or pharmaceutically acceptable salts thereof.

[0045] The present invention also provides use of (i) a compound of formula (I) or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof in combination with (ii) a PARP inhibitor for treating cancer.

[0046] The compound of formula (I) is:

[0047] Cy is selected from The Cy is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, CH2F, CHF2, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or cyclopropyl;

[0048] Or Cy is selected from The Cy is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, CH2F, CHF2, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or cyclopropyl;

[0049] R 1 and R 9 Each is independently selected from H, F, Cl, Br, I, cyano, methyl or ethyl;

[0050] R 2 Selected from

[0051] R 3 and R4 Each independently selected from H, F, Cl, Br, I, methyl, ethyl;

[0052] R 5 Selected from

[0053] or R 5 Selected from

[0054] R 8 Selected from F, Cl.

[0055] The present invention also provides the use of (i) a compound of formula (I) or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof in combination with (ii) a PARP inhibitor in the preparation of a medicament for treating cancer.

[0056] The compound of formula (I) is:

[0057] Cy is selected from The Cy is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, CH2F, CHF2, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or cyclopropyl;

[0058] Or Cy is selected from The Cy is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, CH2F, CHF2, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or cyclopropyl;

[0059] R 1 and R 9 Each is independently selected from H, F, Cl, Br, I, cyano, methyl or ethyl;

[0060] R 2 Selected from

[0061] R 3 and R 4 Each independently selected from H, F, Cl, Br, I, methyl, ethyl;

[0062] R 5 Selected from

[0063] or R 5 Selected from

[0064] R 8 Selected from F, Cl.

[0065] The present invention also provides a method for treating cancer, wherein a therapeutically effective amount of (i) a compound of formula (I) or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof and (ii) a PARP inhibitor are administered to a patient in combination.

[0066] The compound of formula (I) is:

[0067] Cy is selected from The Cy is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, CH2F, CHF2, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or cyclopropyl;

[0068] Or Cy is selected from The Cy is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, CH2F, CHF2, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or cyclopropyl;

[0069] R 1 and R 9 Each is independently selected from H, F, Cl, Br, I, cyano, methyl or ethyl;

[0070] R 2 Selected from

[0071] R 3 and R 4 Each independently selected from H, F, Cl, Br, I, methyl, ethyl;

[0072] R 5 Selected from

[0073] or R 5 Selected from

[0074] R8 Selected from F, Cl.

[0075] Furthermore, in the above uses or methods, (i) and (ii) may be administered simultaneously or separately in sequence;

[0076] Optionally, (i) and (ii) may be formulated independently and co-administered or formulated independently and administered sequentially;

[0077] Optionally, the administration frequency of (i) is once a day, twice a day, once a week, or once every two weeks, and the administration frequency of (ii) is once a day, twice a day, or once a week;

[0078] Optionally, (i) and (ii) may be administered in combination in the same formulation or in separate formulations.

[0079] Furthermore, in the above uses or methods, (i) and (ii) may be used in combination with (iii) other anti-tumor drugs;

[0080] Optionally, (i), (ii) and (iii) can be administered simultaneously or separately in sequence;

[0081] Optionally, (i), (ii) and (iii) may be formulated independently and co-administered or formulated independently and administered sequentially;

[0082] Optionally, (i), (ii) and (iii) may be administered in combination in the same formulation or in separate formulations.

[0083] Furthermore, in the above-mentioned uses or methods, when administered in combination, the route of administration adopted is selected from oral administration, parenteral administration or transdermal administration, and the parenteral administration is selected from intravenous injection, subcutaneous injection or intramuscular injection; the tumor disease is selected from ovarian cancer, pancreatic cancer, castration-resistant prostate cancer, non-small cell lung cancer, breast cancer and other tumors with homologous recombination repair defects.

[0084] Furthermore, in the above uses or methods, the compound of formula (I) is selected from one of the following structures:

[0085] Furthermore, in the above-mentioned uses or methods, the PARP inhibitor is selected from at least one of Olaparib, Niraparib, Talazoparib, Veliparib, Rucaparib, CEP-8983, BGB-290 or pharmaceutically acceptable salts thereof, preferably at least one of Olaparib, Niraparib, Talazoparib, Veliparib and Rucaparib.

[0086] Furthermore, in the above-mentioned use or method, the compound of formula (I) is selected from compound 1 having the following structure:

[0087] In the present invention, the term "combination" refers to a mode of administration, which refers to the administration of at least one dose of a USP1 inhibitor and at least one dose of a PARP inhibitor within a certain time period, wherein both administered drugs show a pharmacological effect. The time period can be within a dosing cycle, preferably within 4 weeks, within 3 weeks, within 3 weeks, within 1 week, or within 24 hours, more preferably within 12 hours. The USP1 inhibitor and the PARP inhibitor or a pharmaceutically acceptable salt thereof can be administered simultaneously or sequentially. This period includes treatments in which the USP1 inhibitor and the PARP inhibitor or a pharmaceutically acceptable salt thereof are administered by the same route of administration or different routes of administration. The combined administration mode of the present invention selects simultaneous administration, independently prepared and co-administered, or independently prepared and administered sequentially.

[0088] In the present invention, the term "optional" or "optionally" means that the event or environment described later may but need not occur, and the description includes occasions where the event or environment occurs or does not occur.

[0089] The present invention administers a USP1 inhibitor and a PARP inhibitor or a pharmaceutically acceptable salt thereof in combination, thereby enhancing anti-tumor activity and improving the therapeutic effect of tumor diseases.

[0090] Definitions of Abbreviations and Key Terms:

[0091] Beneficial effects of the present invention:

[0092] The combined use (or pharmaceutical composition) of the USP1 inhibitor and the PARP inhibitor provided by the present invention has significant synergistic effects in both in vitro and in vivo experiments, and is superior to the use of USP1 or PARP inhibitor alone. BRIEF DESCRIPTION OF THE DRAWINGS

[0093] FIG1 is a graph showing the results of USP1 inhibitors increasing the sensitivity of PARP inhibitors in an MDA-MB-436 cell growth assay in Example 1 of the present invention;

[0094] FIG2 is a graph showing the results of USP1 inhibitors increasing the sensitivity of PARP inhibitors in a CAOV3 cell growth assay in Example 2 of the present invention;

[0095] FIG3A is a graph showing the effect of the test substance in Example 3 of the present invention on the body weight of nude mice bearing human breast cancer MDA-MB-436 cells;

[0096] FIG3B is a graph showing the effect of the test substance in Example 3 of the present invention on the tumor volume of subcutaneous transplanted tumors of human breast cancer MDA-MB-436 cells. DETAILED DESCRIPTION

[0097] The drug information used in the related research of the present invention is as follows: Compound 1, prepared according to the method described in WO2023155866A1; Olaparib, purchased from Chengdu Huajieming Biotechnology Co., Ltd.

[0098] Example 1

[0099] This example studies the effect of administering Compound 1 in combination with the PARP inhibitor Olaparib on the growth of the PARP inhibitor-sensitive breast cancer cell line MDA-MB-436.

[0100] The trial was divided into three groups, including:

[0101] Control group: no drug treatment.

[0102] Olaparib group: cells were treated with different concentrations of Olaparib.

[0103] Combination group: cells were simultaneously administered with different concentrations of compound 1 and different concentrations of Olaparib.

[0104] The experimental results, shown in Figure 1, demonstrate that the USP1 inhibitor Compound 1 significantly enhances cell sensitivity to PARP inhibitors. At the same Compound 1 concentration, the combination group exhibited significantly greater cell growth inhibition than the olaparib group. For example, when Compound 1 was at a concentration of 63 nM and olaparib was at a concentration of 0.4 nM, the cell growth inhibition rate was 62.75%, while in the olaparib group, the cell growth inhibition rate at 0.4 nM was 24.79%.

[0105] It can be seen that the combination of USP1 inhibitor compound 1 and PARP inhibitor can significantly enhance the sensitivity of tumor cells to PARP inhibitors.

[0106] Example 2

[0107] This example studies the effect of administering Compound 1 in combination with Olaparib on the growth of the PARP inhibitor-resistant ovarian cancer cell line CAOV3.

[0108] The trial was divided into three groups, including:

[0109] Control group: no drug treatment.

[0110] Olaparib group: cells were treated with different concentrations of Olaparib.

[0111] Combination group: cells were simultaneously administered with different concentrations of compound 1 and different concentrations of Olaparib.

[0112] The experimental results, shown in Figure 2, demonstrate that the USP1 inhibitor Compound 1 significantly enhances cell sensitivity to PARP inhibitors. At the same Compound 1 concentration, the combination group exhibited significantly greater cell growth inhibition than the olaparib group. For example, when Compound 1 was at 8 nM and olaparib was at 938 nM, the cell growth inhibition rate was 84.5%, while in the olaparib group, the cell growth inhibition rate at 938 nM was 25.84%.

[0113] This indicates that the combination of USP1 inhibitor compound 1 and PARP inhibitors can significantly enhance the sensitivity of tumor cells to PARP inhibitors. This result is consistent with the results in the MDA-MB-436 cell line.

[0114] Example 3

[0115] Study on the pharmacodynamic effect of compound 1 combined with Olaparib on subcutaneous transplanted tumors in nude mice bearing human breast cancer MDA-MB-436 cells.

[0116] The experiment was divided into five groups as follows:

[0117] Control group: no drug treatment.

[0118] Compound 1 group: Compound 1 was administered alone at a concentration of 30 mg / kg, once a day.

[0119] Olaparib group: Olaparib was administered alone at a concentration of 50 mg / kg once a day.

[0120] Combination group I: Compound 1 and Olaparib were administered in combination at concentrations of 5 mg / kg and 50 mg / kg, respectively, once a day.

[0121] Combination group II: Compound 1 and Olaparib were co-administered at concentrations of 10 mg / kg and 50 mg / kg, respectively, once a day.

[0122] 1) Effects of the test substance on the body weight of nude mice bearing human breast cancer MDA-MB-436 cells

[0123] Animal behavior remained normal throughout the experimental period. No significant weight loss was observed in the vehicle group, the Compound 1 and Olaparib alone group, or the combination group, with no apparent toxicity attributable to the combined use. Detailed results are shown in Figure 3A.

[0124] 2) Effects of the test substance on the tumor volume of subcutaneous transplanted tumors of human breast cancer MDA-MB-436 cells

[0125] The results are shown in Figure 3B. Compared with the control group, the tumor growth rate of mice treated with either Compound 1 or Olaparib alone decreased to a certain extent. However, the combination of Compound 1 and Olaparib was more effective in inhibiting tumor growth. The tumor growth of mice was significantly inhibited after combined administration. The tumor growth inhibition rates (TGI) of 5 mg / kg or 10 mg / kg of Compound 1 combined with 50 mg / kg of Olaparib were 89.6% and 99.0%, respectively, almost completely inhibiting tumor growth.

[0126] Therefore, the combination of the USP1 inhibitor of the present invention and the PARP inhibitor exhibited significant synergistic effects in a subcutaneous xenograft tumor model. This synergistic effect allowed for a reduction in drug dosage, demonstrating robust anti-tumor effects at significantly lower doses. This result is consistent with the results of in vitro testing of tumor cell lines.

Claims

1. A pharmaceutical composition comprising: (i) a compound of formula (I) or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof; (ii) PARP inhibitors; The compound of formula (I) is: Cy is selected from The Cy is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, CH2F, CHF2, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or cyclopropyl; Or Cy is selected from The Cy is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, CH2F, CHF2, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or cyclopropyl; R 1 and R 9 Each is independently selected from H, F, Cl, Br, I, cyano, methyl or ethyl; R 2 Selected from R 3 and R 4 Each is independently selected from H, F, Cl, Br, I, methyl, ethyl; R 5 Selected from or R 5 Selected from R 8 Selected from F, Cl.

2. The pharmaceutical composition according to claim 1, further comprising: (iii) optionally, other pharmaceutically active ingredients, such as one or more anti-tumor drugs; and (iv) a pharmaceutically acceptable carrier.

3. The pharmaceutical composition according to claim 1 or 2, wherein the PARP inhibitor is selected from at least one of olaparib, niraparib, talazopanib, veliparib, rucaparib, CEP-8983, BGB-290 or a pharmaceutically acceptable salt thereof, preferably at least one of olaparib, niraparib, talazopanib, veliparib and rucaparib.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the compound of formula (I) is selected from compound 1:

5. The pharmaceutical composition according to claim 4, comprising: (i) Compound 1 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, (ii) Olaparib; (iii) a pharmaceutically acceptable carrier.

6. The composition of claim 5, wherein the unit dosage of Compound 1 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is C 30 H 33 The content in terms of F4N7O is selected from 1 mg-2000 mg, 20 mg-1600 mg, 20 mg-1200 mg, 20 mg-800 mg, 20 mg-400 mg, preferably 20 mg-1600 mg.

7. The composition of claim 5, wherein the unit dosage of Olaparib is C 24 H 23 The content of FN4O3 is selected from 0.1mg-1000mg, 1mg-1000mg, 10mg-800mg, 10mg-600mg, 10mg-400mg, 10mg-200mg, preferably 10mg-400mg.

8. The composition according to any one of claims 1 to 7, wherein the dosage form is selected from tablets, capsules, pills, granules, or injections, wherein the injections include injection solutions, sterile powders for injection, and concentrated solutions for injection.

9. Use of the composition of any one of claims 1 to 8 in the preparation of a drug for treating tumor diseases; the composition can be administered alone or in combination with one or more other anti-tumor drugs; the combined administration is selected from simultaneous administration, independently configured and co-administered, or independently configured and sequentially administered; the combined administration is selected from oral administration, parenteral administration or transdermal administration, and the parenteral administration is selected from intravenous injection, subcutaneous injection or intramuscular injection; the tumor disease is selected from ovarian cancer, pancreatic cancer, castration-resistant prostate cancer, non-small cell lung cancer, breast cancer and other tumors with homologous recombination repair defects.

10. The use according to claim 9: Optionally, the administration frequency of (i) is once a day, twice a day, once a week or once every two weeks, and the administration frequency of (ii) is once a day, twice a day or once a week; Optionally, (i) and (ii) may be administered simultaneously or separately in sequence; Optionally, (i) and (ii) may be formulated independently and co-administered or formulated independently and administered sequentially; Optionally, the preparations made from (i) and (ii) may be co-administered in the same preparation or in separate different preparations.

11. A pharmaceutical packaging box comprising the pharmaceutical composition according to any one of claims 1 to 8.

12. Use of a compound of formula (I) or its stereoisomers, tautomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals in combination with a PARP inhibitor for treating cancer, The compound of formula (I) is: Cy is selected from The Cy is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, CH2F, CHF2, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or cyclopropyl; Or Cy is selected from The Cy is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, CH2F, CHF2, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or cyclopropyl; R 1 and R 9 Each is independently selected from H, F, Cl, Br, I, cyano, methyl or ethyl; R 2 Selected from R 3 and R 4 Each is independently selected from H, F, Cl, Br, I, methyl, ethyl; R 5 Selected from or R 5 Selected from R 8 Selected from F, Cl.

13. Use of a compound of formula (I) or its stereoisomers, tautomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals in combination with a PARP inhibitor in the preparation of a medicament for treating cancer, The compound of formula (I) is: Cy is selected from The Cy is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, CH2F, CHF2, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or cyclopropyl; Or Cy is selected from The Cy is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, CH2F, CHF2, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or cyclopropyl; R 1 and R 9 Each is independently selected from H, F, Cl, Br, I, cyano, methyl or ethyl; R 2 Selected from R 3 and R 4 Each is independently selected from H, F, Cl, Br, I, methyl, ethyl; R 5 Selected from or R 5 Selected from R 8 Selected from F, Cl.

14. A method for treating cancer, wherein: administering to the patient a therapeutically effective amount of a compound of formula (I) or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof in combination with a PARP inhibitor, The compound of formula (I) is: Cy is selected from The Cy is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, CH2F, CHF2, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or cyclopropyl; Or Cy is selected from The Cy is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, CH2F, CHF2, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or cyclopropyl; R 1 and R 9 Each is independently selected from H, F, Cl, Br, I, cyano, methyl or ethyl; R 2 Selected from R 3 and R 4 Each is independently selected from H, F, Cl, Br, I, methyl, ethyl; R 5 Selected from or R 5 Selected from R 8 Selected from F, Cl.

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