Pharmaceutical combination of PARP1 inhibitor in combination with ADC and use thereof in treating tumor

Abstract

The present invention relates to a pharmaceutical combination of a PARP1 inhibitor in combination with ADC and use thereof in treating a tumor. The anti-tumor effect and the safety of the combination of the PARP1 inhibitor and ADC are significantly superior to those of ADC alone, exhibiting a significantly synergistic effect.

Description

PARP1 inhibitors combined with ADCs and their applications in cancer treatment. Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to drug combinations that can be used for anti-tumor treatment. Specifically, this invention relates to drug combinations of PARP1 inhibitors and ADCs and their use in the treatment of tumors. Background Technology

[0002] Antibody-drug conjugates (ADCs) typically consist of an antibody, a covalent linker, and a cytotoxic drug. The monoclonal antibody is covalently linked to the cytotoxic drug via a chemical linker, combining the killing effect of traditional small molecule chemotherapy with the tumor-targeting properties of antibody drugs.

[0003] Anti-cancer drug agents (ADCs) have emerged as a novel class of drugs for treating hematologic malignancies and solid tumors. However, as with most cytotoxic drugs, the duration of objective response or clinical benefit of ADCs as monotherapy remains limited due to the emergence of resistance mechanisms. Therefore, combining ADCs with other anticancer drugs has become an important direction in ADC drug development.

[0004] PARP1 is a polyADP-ribose polymerase that binds to DNA damage sites (mostly single-strand DNA breaks) and catalyzes the synthesis of polyADP-ribose chains on protein substrates. Through this catalytic action, PARP1 can recruit other DNA repair proteins to the damage site to jointly repair DNA damage. PARP1 inhibitors bind to the PARP1 catalytic site, preventing the PARP1 protein from detaching from the DNA damage site. PARP1 bound to DNA causes DNA replication fork arrest and hinders DNA replication. In this situation, cells typically activate homologous recombination repair (HRR) to correct the error. However, many tumor cells have HRR defects. When HRR function is impaired and PARP1 inhibitors are used, the other DNA repair methods employed by the cells often introduce large-scale genomic recombination, leading to tumor cell death. Summary of the Invention

[0005] The inventors unexpectedly discovered during their research that the combination therapy of PARP1 inhibitors and ADCs, compared with the monotherapy of each, has the effects of high efficiency, low toxicity, and overcoming ADC resistance.

[0006] Therefore, the present invention aims to provide a drug combination of PARP1 inhibitor and ADC and its use in the treatment of tumors.

[0007] One or more embodiments of the present invention provide a drug combination comprising: (a) a PARP1 inhibitor and (b) an ADC.

[0008] In one or more embodiments of the present invention, the pharmaceutical combination includes a PARP1 inhibitor selected from olaparib, rucaparib, niraparib, tapolaparib, fluzoparib, pamiparib, AZD-5305, AZD-9574, NMS-03305293, HRS-1167, HS-10502, IMP-1734, SNV-1521, JPI-289, or compounds of general formula (IA), their stereoisomers, pharmaceutically acceptable salts, or deuterated derivatives.

[0009] in:

[0010] R1 is selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl, the C 3-8 Heterocyclic alkyl groups may contain 1 to 4 heteroatoms selected from N, O, or S;

[0011] R0 is selected from H, halogen, or C. 1-6 Alkyl, the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from halogens;

[0012] X1, X2, and X3 are each independently selected from N or CR. X And at least one of X1, X2, and X3 is selected from N;

[0013] R X Selected from H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl;

[0014] L is selected from CH2;

[0015] A is a 4- to 12-membered heterocycle, wherein the 4- to 12-membered heterocycle is selected from 4- to 12-membered monocyclic rings, 5- to 12-membered spirocyclic rings, 4- to 12-membered fused rings, or 4- to 12-membered bridged rings, and the 4- to 12-membered heterocycle may contain 1 to 4 heteroatoms selected from N, O, or S;

[0016] Structural fragments Selected from or

[0017] R 2b They can be the same or different;

[0018] R 2c They can be the same or different;

[0019] R 2d They can be the same or different;

[0020] R 2e They can be the same or different;

[0021] R 2f They can be the same or different;

[0022] R 2b、 R 2c R 2f Each is independently selected from CN, halogen, and OR. 2a C 1-6 Alkyl, 4- to 12-membered heterocycles, wherein the C 1-6 Alkyl groups and 4- to 12-membered heterocycles may optionally be further surrounded by one or more elements selected from halogens, OH, C. 1-3 Alkyl substituents may be used to replace the 4- to 12-membered heterocycle, which may contain 1 to 4 heteroatoms selected from N, O, or S.

[0023] R 2d R 2e Each is independently selected from CN, halogen, and OR. 2a C 1-6 Alkyl, the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from halogens or OH;

[0024] R 2a Selected from H, C 1-6 Alkyl group, (CH2) n C 3-8 Cycloalkyl or (CH2) n C 3-8 Heterocyclic alkyl, the C 3-8 Heterocyclic alkyl groups may contain 1 to 4 heteroatoms selected from N, O, or S, wherein the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from halogens;

[0025] Z1, Z2, and Z3 are each independently selected from N or CH, and at least two of Z1, Z2, and Z3 are selected from N;

[0026] n is selected from 0, 1, 2, or 3;

[0027] b is selected from 1, 2, or 3;

[0028] c can be selected from 1, 2, or 3;

[0029] d is selected from 2 or 3;

[0030] e can be selected from 1, 2, or 3;

[0031] f is selected from 1 or 2;

[0032] The conditions are:

[0033] The compound represented by general formula (IA) is not: or

[0034] In one or more embodiments of the present invention, wherein:

[0035] Structural unit Selected from or

[0036] R1 is selected from C 1-6 Alkyl, C 2-6 alkenyl or C 3-8 cycloalkyl;

[0037] R0 is selected from halogens;

[0038] A is selected from

[0039] R 2b They can be the same or different, and each can be independently selected from CN, halogen, and C. 1-3 Alkoxy, C 1-3 Alkyl, 4- to 12-membered heterocycles, wherein the C 1-3 Alkyl, C 1-3 The alkoxy group and the 4- to 12-membered heterocycle may optionally be further surrounded by one or more elements selected from halogen, OH, C. 1-3 Alkyl substituents may be used to replace the 4- to 12-membered heterocycle, which may contain 1 to 4 heteroatoms selected from N, O, or S.

[0040] R 2c CN;

[0041] R 2d CN or halogen;

[0042] R 2f CN;

[0043] R 2e They can be the same or different, each independently selected from CN, halogen, OR 2a C 1-6 Alkyl, the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from halogens or OH;

[0044] R 2a Selected from C1-3 alkyl, The C 1-3 The alkyl group may optionally be further substituted with one or more substituents selected from halogens;

[0045] p is selected from 0 or 1;

[0046] q is selected from 1 or 2.

[0047] In one or more embodiments of the present invention, wherein:

[0048] Structural unit Selected from

[0049] R1 is selected from C 1-6 Alkyl or C 3-8 cycloalkyl;

[0050] A is selected from

[0051] R 2e They can be the same or different, and each can be independently selected from CN and OR. 2a C 1-3 Alkyl, the C 1-3 The alkyl group may optionally be further substituted with one or more halogens;

[0052] R 2a Selected from C 1-3 alkyl, The C 1-3 The alkyl group may optionally be further substituted with one or more substituents selected from halogens.

[0053] In one or more embodiments of the present invention, wherein:

[0054] R 2b Selected from CN, halogen, C 1-3 Alkyl, 5-membered heterocycle, the C 1-3 Alkyl groups and 5-membered heterocycles may optionally be further selected from one or more halogens, C 1-3 Alkyl substituents may be used to substitute the 5-membered heterocycle, which may contain 1 to 4 heteroatoms selected from N, O or S;

[0055] R 2e Selected from CN.

[0056] In one or more embodiments of the present invention, wherein: R 2b Selected from CN.

[0057] In one or more embodiments of the present invention, the PARP1 inhibitor is selected from olaparib, rucaparib, niraparib, tapolaparib, fluzoparib, pamiparib, AZD-5305, AZD-9574, NMS-03305293, HRS-1167, HS-10502, IMP-1734, SNV-1521, JPI-289, or compounds of general formula (I), their stereoisomers, pharmaceutically acceptable salts, or deuterated derivatives.

[0058] in:

[0059] R1 is selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl, the C 3-8 Heterocyclic alkyl groups may contain 1 to 4 heteroatoms selected from N, O, or S;

[0060] X1, X2, and X3 are each independently selected from N or CR. X ;

[0061] R X Selected from H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl;

[0062] L is selected from CH2;

[0063] A is a 4- to 12-membered heterocycle, wherein the 4- to 12-membered heterocycle is selected from 4- to 12-membered monocyclic rings, 5- to 12-membered spirocyclic rings, 4- to 12-membered fused rings, or 4- to 12-membered bridged rings, and the 4- to 12-membered heterocycle may contain 1 to 4 heteroatoms selected from N, O, or S;

[0064] R2 can be the same or different, and each can be independently selected from CN, halogen, OR. 2a Or C 1-6 alkyl;

[0065] R 2a Selected from H, C 1-6 Alkyl group, (CH2) n C 3-8 Cycloalkyl or (CH2) n C 3-8 Heterocyclic alkyl, the C 3-8 Heterocyclic alkyl groups may contain 1 to 4 heteroatoms selected from N, O, or S, wherein the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from halogens;

[0066] Z can be the same or different, and each can be independently selected from CH or N;

[0067] m is selected from 1, 2, or 3;

[0068] n is selected from 0, 1, 2, or 3;

[0069] The conditions are:

[0070] The compound represented by general formula (I) is not

[0071] In one or more embodiments of the present invention, the PARP1 inhibitor is selected from olaparib, rucaparib, niraparib, tapolaparib, fluzoparib, pamiparib, AZD-5305, AZD-9574, NMS-03305293, HRS-1167, HS-10502, IMP-1734, SNV-1521, JPI-289, or compounds of general formula (II), their stereoisomers, pharmaceutically acceptable salts, or deuterated derivatives.

[0072] in:

[0073] R1 is selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl, the C 3-8 Heterocyclic alkyl groups may contain 1 to 4 heteroatoms selected from N, O, or S;

[0074] R0 is selected from H, halogen, or C. 1-6 Alkyl, the C 1-6 Alkyl groups may optionally be further selected from one or more halogens or C 1-6 Alkyl substituents;

[0075] X1 and X2 are each independently selected from N or CR X ;

[0076] R X Selected from H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl;

[0077] L is selected from CH2;

[0078] A is a 4- to 12-membered heterocycle, wherein the 4- to 12-membered heterocycle is selected from 4- to 12-membered monocyclic rings, 5- to 12-membered spirocyclic rings, 4- to 12-membered fused rings, or 4- to 12-membered bridged rings, and the 4- to 12-membered heterocycle may contain 1 to 4 heteroatoms selected from N, O, or S;

[0079] B is selected from a 6-membered aryl group or a 6-membered heteroaryl group, wherein the heteroaryl group may contain 1 to 4 heteroatoms selected from N;

[0080] R2 can be the same or different, and each can be independently selected from CN, halogen, OR. 2a Or C 1-6 alkyl;

[0081] R 2a Selected from H, C 1-6 Alkyl group, (CH2) n C 3-8 Cycloalkyl or (CH2) n C 3-8 Heterocyclic alkyl, the C 3-8 Heterocyclic alkyl groups may contain 1 to 4 heteroatoms selected from N, O, or S, wherein the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from halogens;

[0082] m is selected from 1, 2, or 3;

[0083] n can be selected from 0, 1, 2, or 3.

[0084] In one or more embodiments of the present invention, the PARP1 inhibitor is selected from olaparib, rucaparib, niraparib, tapolaparib, fluzoparib, pamiparib, AZD-5305, AZD-9574, NMS-03305293, HRS-1167, HS-10502, IMP-1734, SNV-1521, JPI-289 or compounds shown below, their stereoisomers, pharmaceutically acceptable salts or deuterated derivatives:

[0085] In one or more embodiments of the present invention, the drug combination includes an ADC selected from one or more of T-Dxd, DS8201, Mylotarg, Adcetris, Kadcyla, Besponsa, Lumoxiti, Polivy, Padcev, Enhertu, Trodelvy, Blenrep, Zynlonta, Adrenaline, Tivdak, Elahere, Akalux, Ujvira, IBI343, SKB264, MRG004A, MRG003, 9MW2821, SHR-A1912, RC88, RC48, SYS6002, YL202 / BNT326, JSKN003, ATG-022, CMG901, HS-20093, BAT8006, BAT8007, or CS5001.

[0086] In one or more embodiments of the present invention, in the drug combination, the PARP1 inhibitor and the ADC are present in the same drug composition, or the PARP1 inhibitor and the ADC are present in different drug compositions.

[0087] In one or more embodiments of the present invention, the drug combination includes:

[0088] (i) a first pharmaceutical composition comprising a PARP1 inhibitor, a pharmaceutically acceptable carrier and / or excipient; and

[0089] (ii) A second pharmaceutical composition comprising an ADC, a pharmaceutically acceptable carrier, and / or an excipient.

[0090] Alternatively, the drug combination may include:

[0091] Single drug compositions, including PARP1 inhibitors, ADCs, pharmaceutically acceptable carriers and / or excipients.

[0092] One or more embodiments of the present invention provide the use of the pharmaceutical combinations involved in the treatment and / or prevention of tumors.

[0093] In one or more embodiments of the present invention, the PARP1 inhibitor and the ADC are administered simultaneously or separately.

[0094] In one or more embodiments of the present invention, the PARP1 inhibitor is administered orally at a frequency of three times a day, twice a day, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks, or once every four weeks, preferably twice a day or once a day.

[0095] In one or more embodiments of the present invention, the total daily dose of the PARP1 inhibitor is selected from 50-1500 mg, preferably 100-1000 mg, with the amount of free base as the measurement value.

[0096] In one or more embodiments of the present invention, the tumor is selected from solid tumors and / or hematologic malignancies.

[0097] In one or more embodiments, the solid tumor is selected from breast cancer, central nervous system cancer, uterine cancer, cervical cancer, kidney cancer, adrenal cancer, lung cancer, esophageal cancer, ovarian cancer, pancreatic cancer, liver cancer, prostate cancer, testicular cancer, gastric cancer, head and neck cancer, laryngeal cancer, urinary tract cancer, bladder cancer, colon cancer, rectal cancer, thyroid cancer, bone cancer, epithelial cancer, bile duct cancer, gallbladder cancer, skin cancer, mesothelioma, basal cell carcinoma, adenoid cystic carcinoma, leiomyosarcoma, gastrointestinal stromal tumor, Ewing sarcoma, Kaposi's sarcoma, or advanced solid tumors with PARP1 amplification.

[0098] In one or more embodiments, the hematologic malignancy is selected from leukemia, myeloma, and lymphoma. Exemplary examples include Hodgkin's lymphoma or non-Hodgkin's lymphoma, multiple myeloma, B-cell lymphoma, small lymphocytic lymphoma, T-cell lymphoma, pilocellular lymphoma, Burker's lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia.

[0099] The lung cancer is preferably non-small cell lung cancer or neuroendocrine lung cancer. The non-small cell lung cancer is preferably squamous cell carcinoma or adenocarcinoma. The breast cancer is preferably hormone receptor-positive (HR+) breast cancer. The esophageal cancer is preferably esophageal squamous cell carcinoma or adenocarcinoma. The head and neck cancer is preferably head and neck squamous cell carcinoma. The uterine cancer is preferably endometrial cancer. The central nervous system cancer is preferably glioma. The liver cancer is preferably hepatocellular carcinoma. The B-cell lymphoma is preferably diffuse large B-cell lymphoma.

[0100] Advantages of this invention:

[0101] This invention found that the antitumor efficacy and safety of PARP1 inhibitors combined with ADCs are significantly better than those of ADCs alone, indicating that the combined use of PARP1 inhibitors and ADCs has a significant synergistic effect.

[0102] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0103] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0104] "Tautomer" or "tautomer form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol isomerization, imine-enamine isomerization, lactam-lactamimide isomerization, etc. This disclosure includes tautomers of any of the compounds described.

[0105] "Pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" means that the compound of the present invention retains the bioavailability and properties of a free acid or a free base, and that the free acid is obtained by reacting with a non-toxic inorganic or organic base, and the free base is obtained by reacting with a non-toxic inorganic or organic acid.

[0106] "Optional," "optionally," "selectively," or "selectively" means that the event or condition described below may or may not occur, and the description includes both cases in which the event or condition occurs and cases in which it does not occur. For example, "selectively alkyl-substituted heterocyclic group" means that the alkyl group may or may not be present, and the description includes both cases in which the heterocyclic group is substituted with an alkyl group and cases in which the heterocyclic group is not substituted with an alkyl group. Attached Figure Description

[0107] Figure 1 shows the cell proliferation inhibition results of compound A at a fixed concentration combined with different concentrations of T-Dxd. Detailed Implementation

[0108] The following embodiments illustrate the technical solution of the present invention in detail, but the scope of protection of the present invention includes, but is not limited to, these embodiments.

[0109] The compound of formula (I) or its specific structure involved in this invention can be prepared by the method described in patent WO2023088408. Specifically, compound A used in the embodiments of this invention is selected from compound 14 in patent WO2023088408, as shown below:

[0110] The ADC drug T-Dxd used in this embodiment of the invention was purchased from Daiichi Sankyo.

[0111] Cell proliferation inhibition experiment

[0112] Human breast cancer cells KPL-4 (Shanghai Yaji Biotechnology Co., Ltd., YS1682C) were cultured in RPMI-1640 complete medium containing 10% FBS and 1% penicillin-streptomycin solution at 37℃ and 5% CO2. KPL-4 cells in logarithmic growth phase were seeded at a density of 500 cells / well in 96-well plates and cultured overnight in a cell culture incubator. The following day, cells were treated with different drugs: T-Dxd groups with different concentration gradients (6.16, 2.06, 0.69, 0.076, 0.025, 0.0084, 0.0028 μg / mL), and a combination treatment group of compound A (1 μM) with the aforementioned T-Dxd concentration gradients. A blank control group (containing only RPMI-1640 complete medium) and a negative control group (cells added, no drugs added) were also set up. The plates were then incubated for 6 days. After incubation, CellTiter-Glo working solution (Promega, G9243) was added to the well plate, and chemiluminescence readings were performed using a microplate reader. Statistical analysis and plotting were performed using Excel and Graphpad Prism. The results are shown in Figure 1.

[0113] The results show that the IC of the T-Dxd group 50 The value was 0.359 μg / mL, and the IC50 of the co-treatment group of compound A (1 μM) with different concentration gradients of T-Dxd was 0.359 μg / mL. 50 The value was 0.059 μg / mL, indicating that compound A combined with ADC had a better inhibitory effect on cell proliferation than ADC alone, demonstrating that the drug combination of the present invention has a significant synergistic effect.

[0114] This invention specification provides a detailed description of specific embodiments. Those skilled in the art should recognize that the above embodiments are exemplary and should not be construed as limiting the invention. For those skilled in the art, various improvements and modifications can be made to the invention without departing from its principles, and the resulting technical solutions also fall within the scope of protection of the claims of this invention.

Claims

1. A drug combination, characterized in that, The drug combination includes: (a) a PARP1 inhibitor and (b) an ADC.

2. The drug combination according to claim 1, characterized in that, The PARP1 inhibitor is selected from olaparib, rucaparib, niraparib, tapolaparib, fluzoparib, pamiparib, AZD-5305, AZD-9574, NMS-03305293, HRS-1167, HS-10502, IMP-1734, SNV-1521, JPI-289, or compounds of general formula (IA), their stereoisomers, pharmaceutically acceptable salts, or deuterated derivatives. in: R1 is selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl, the C 3-8 Heterocyclic alkyl groups may contain 1 to 4 heteroatoms selected from N, O, or S; R0 is selected from H, halogen, or C. 1-6 Alkyl, the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from halogens; X1, X2, and X3 are each independently selected from N or CR. X And at least one of X1, X2, and X3 is selected from N; R X Selected from H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl; L is selected from CH2; A is a 4- to 12-membered heterocycle, wherein the 4- to 12-membered heterocycle is selected from 4- to 12-membered monocyclic rings, 5- to 12-membered spirocyclic rings, 4- to 12-membered fused rings, or 4- to 12-membered bridged rings, and the 4- to 12-membered heterocycle may contain 1 to 4 heteroatoms selected from N, O, or S; Structural fragments Selected from or R 2b They can be the same or different; R 2c They can be the same or different; R 2d They can be the same or different; R 2e They can be the same or different; R 2f They can be the same or different; R 2b R 2c R 2f Each is independently selected from CN, halogen, and OR. 2a C 1-6 Alkyl, 4- to 12-membered heterocycles, wherein the C 1-6 Alkyl groups and 4- to 12-membered heterocycles may optionally be further surrounded by one or more elements selected from halogens, OH, C. 1-3 Alkyl substituents may be used to replace the 4- to 12-membered heterocycle, which may contain 1 to 4 heteroatoms selected from N, O, or S. R 2d R 2e Each is independently selected from CN, halogen, and OR. 2a C 1-6 Alkyl, the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from halogens or OH; R 2a Selected from H, C 1-6 Alkyl group, (CH2) n C 3-8 Cycloalkyl or (CH2) n C 3-8 Heterocyclic alkyl, the C 3-8 Heterocyclic alkyl groups may contain 1 to 4 heteroatoms selected from N, O, or S, wherein the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from halogens; Z1, Z2, and Z3 are each independently selected from N or CH, and at least two of Z1, Z2, and Z3 are selected from N; n is selected from 0, 1, 2, or 3; b is selected from 1, 2, or 3; c can be selected from 1, 2, or 3; d is selected from 2 or 3; e can be selected from 1, 2, or 3; f is selected from 1 or 2; The conditions are: The compound represented by general formula (IA) is not: or 3. The drug combination according to claim 2, characterized in that, Structural unit Selected from or R1 is selected from C 1-6 Alkyl, C 2-6 alkenyl or C 3-8 cycloalkyl; R0 is selected from halogens; A is selected from R 2b They can be the same or different, and each can be independently selected from CN, halogen, and C. 1-3 Alkoxy, C 1-3 Alkyl, 4- to 12-membered heterocycles, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, 4 to 12-membered heterocycles optionally further surrounded by one or more elements selected from halogen, OH, C 1-3 Alkyl substituents may be used to replace the 4- to 12-membered heterocycle, which may contain 1 to 4 heteroatoms selected from N, O, or S. R 2c CN; R 2d CN or halogen; R 2f CN; R 2e They can be the same or different, each independently selected from CN, halogen, OR 2a C 1-6 Alkyl, the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from halogens or OH; R 2a Selected from C 1-3 alkyl, The C 1-3 The alkyl group may optionally be further substituted with one or more substituents selected from halogens; p is selected from 0 or 1; q is selected from 1 or 2.

4. The drug combination according to claim 3, characterized in that, Structural unit Selected from R1 is selected from C 1-6 Alkyl or C 3-8 cycloalkyl; A is selected from R 2e They can be the same or different, and each can be independently selected from CN and OR. 2a C 1-3 Alkyl, the C 1-3 The alkyl group may optionally be further substituted with one or more halogens; R 2a Selected from C 1-3 alkyl, The C 1-3 The alkyl group may optionally be further substituted with one or more substituents selected from halogens.

5. The drug combination according to claim 4, characterized in that, R 2b Selected from CN, halogen, C 1-3 Alkyl, 5-membered heterocycle, the C 1-3 Alkyl groups and 5-membered heterocycles may optionally be further selected from one or more halogens, C 1-3 Alkyl substituents may be used to substitute the 5-membered heterocycle, which may contain 1 to 4 heteroatoms selected from N, O or S; R 2e Selected from CN.

6. The drug combination according to claim 5, characterized in that, R 2b Selected from CN.

7. The drug combination according to claim 1, characterized in that, The PARP1 inhibitor is selected from olaparib, rucaparib, niraparib, tapolaparib, fluzoparib, pamiparib, AZD-5305, AZD-9574, NMS-03305293, HRS-1167, HS-10502, IMP-1734, SNV-1521, JPI-289, or compounds of general formula (I), their stereoisomers, pharmaceutically acceptable salts, or deuterated derivatives. in: R1 is selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl, the C 3-8 Heterocyclic alkyl groups may contain 1 to 4 heteroatoms selected from N, O, or S; X1, X2, and X3 are each independently selected from N or CR. X ; R X Selected from H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl; L is selected from CH2; A is a 4- to 12-membered heterocycle, wherein the 4- to 12-membered heterocycle is selected from 4- to 12-membered monocyclic rings, 5- to 12-membered spirocyclic rings, 4- to 12-membered fused rings, or 4- to 12-membered bridged rings, and the 4- to 12-membered heterocycle may contain 1 to 4 heteroatoms selected from N, O, or S; R2 can be the same or different, and each can be independently selected from CN, halogen, OR. 2a Or C 1-6 alkyl; R 2a Selected from H, C 1-6 Alkyl group, (CH2) n C 3-8 Cycloalkyl or (CH2) n C 3-8 Heterocyclic alkyl, the C 3-8 Heterocyclic alkyl groups may contain 1 to 4 heteroatoms selected from N, O, or S, wherein the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from halogens; Z can be the same or different, and each can be independently selected from CH or N; m is selected from 1, 2, or 3; n is selected from 0, 1, 2, or 3; The conditions are: The compound represented by general formula (I) is not 8. The drug combination according to claim 1, characterized in that, The PARP1 inhibitor is selected from olaparib, rucaparib, niraparib, tapolaparib, fluzoparib, pamiparib, AZD-5305, AZD-9574, NMS-03305293, HRS-1167, HS-10502, IMP-1734, SNV-1521, JPI-289, or compounds of general formula (II), their stereoisomers, pharmaceutically acceptable salts, or deuterated derivatives. in: R1 is selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl, the C 3-8 Heterocyclic alkyl groups may contain 1 to 4 heteroatoms selected from N, O, or S; R0 is selected from H, halogen, or C. 1-6 Alkyl, the C 1-6 Alkyl groups may optionally be further selected from one or more halogens or C 1-6 Alkyl substituents; X1 and X2 are each independently selected from N or CR X ; R X Selected from H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl; L is selected from CH2; A is a 4- to 12-membered heterocycle, wherein the 4- to 12-membered heterocycle is selected from 4- to 12-membered monocyclic rings, 5- to 12-membered spirocyclic rings, 4- to 12-membered fused rings, or 4- to 12-membered bridged rings, and the 4- to 12-membered heterocycle may contain 1 to 4 heteroatoms selected from N, O, or S; B is selected from a 6-membered aryl group or a 6-membered heteroaryl group, wherein the heteroaryl group may contain 1 to 4 heteroatoms selected from N; R2 can be the same or different, and each can be independently selected from CN, halogen, OR. 2a Or C 1-6 alkyl; R 2a Selected from H, C 1-6 Alkyl group, (CH2) n C 3-8 Cycloalkyl or (CH2) n C 3-8 Heterocyclic alkyl, the C 3-8 Heterocyclic alkyl groups may contain 1 to 4 heteroatoms selected from N, O, or S, wherein the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from halogens; m is selected from 1, 2, or 3; n can be selected from 0, 1, 2, or 3.

9. The pharmaceutical combination according to any one of claims 1 to 8, characterized in that, The PARP1 inhibitor is selected from olaparib, rucaparib, niraparib, tapolaparib, fluzoparib, pamiparib, AZD-5305, AZD-9574, NMS-03305293, HRS-1167, HS-10502, IMP-1734, SNV-1521, JPI-289, or compounds listed below, their stereoisomers, pharmaceutically acceptable salts, or deuterated derivatives.

10. The pharmaceutical combination according to claim 1, characterized in that, The ADC is selected from one or more of the following: T-Dxd, DS8201, Mylotarg, Adcetris, Kadcyla, Besponsa, Lumoxiti, Polivy, Padcev, Enhertu, Trodelvy, Blenrep, Zynlonta, Aidiqi, Tivdak, Elahere, Akalux, Ujvira, IBI343, SKB264, MRG004A, MRG003, 9MW2821, SHR-A1912, RC88, RC48, SYS6002, YL202 / BNT326, JSKN003, ATG-022, CMG901, HS-20093, BAT8006, BAT8007, or CS5001.

11. The pharmaceutical combination according to claim 1, characterized in that, The PARP1 inhibitor and the ADC may be present in the same pharmaceutical composition, or the PARP1 inhibitor and the ADC may be present in different pharmaceutical compositions.

12. Use of the pharmaceutical combination according to any one of claims 1 to 11 in the treatment and / or prevention of tumors.

13. The use according to claim 12, characterized in that, The PARP1 inhibitor and the ADC may be administered simultaneously or separately.

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