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

Abstract

Provided are a pharmaceutical combination of a PARP1 inhibitor in combination with a radionuclide drug conjugate (RDC) and use thereof in treating a tumor. The anti-tumor effect and safety of the combination of the PARP1 inhibitor and the RDC are superior to those of the RDC alone and the PARP1 inhibitor alone, exhibiting a synergistic effect.

Description

PARP1 inhibitors combined with RDC and their use 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 RDCs and their use in the treatment of tumors. Background Technology

[0002] Radiotherapy is one of the important methods in the comprehensive treatment of malignant tumors. Among them, radionuclide drug conjugates (RDC) is a new targeted radiotherapy technology, which mainly consists of four parts: a targeting ligand (antibody, peptide, nucleic acid, small molecule and nanoparticle, etc.), a linker, a chelator, and a radioisotope.

[0003] In RDC treatment strategies, although many studies have attempted to deliver more radiopharmaceuticals to the tumor for greater therapeutic efficacy, it is clearly impossible to target all injected drugs directly to the tumor. Furthermore, distributing drugs to all cells within the tumor is also challenging, depending on tumor size and vascular distribution, i.e., influenced by tumor heterogeneity. In addition, cells that are not completely killed can survive, leading to tumor regrowth. To overcome the limitations of radiation-tolerant cells and tumor heterogeneity in RDC and achieve more effective treatment without damaging normal tissue, further exploration of combination therapy strategies is needed.

[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 RDCs, compared with the monotherapy of each, has the effects of high efficiency, low toxicity, and overcoming RDC drug resistance.

[0006] Therefore, the present invention aims to provide a drug combination of PARP1 inhibitor and RDC 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) RDC.

[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 selected from one or more 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 by 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, each independently selected from CN, halogen, 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 constituting 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 C 1-3 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 1-3Alkyl 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), or 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, C1-6 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 RDC included in the drug combination may be selected from Pluvicto (i.e., 177One or more of the following: Lu-PSMA-617, Lutathera, RYZ-101, 177Lu-PSMA-I&T, 177Lu-PNT2002, 225Ac-PSMA-617, 177Lu-edotreotide, iodine [131I] metuximab, Locametz, Illuccix, Pylarify, Gallium GA-68 Gozetotide, Detectnet, Gallium DOTATOC Ga-68, Netspot, or radium chloride [223Ra] injection. Common radionuclides in RDCs may include... 68 Ga、 177 Lu、 161 Tb, 225 Ac、 226 Ra et al.

[0086] In one or more embodiments of the present invention, in the drug combination, the PARP1 inhibitor and the RDC are present in the same drug composition, or the PARP1 inhibitor and the RDC 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 RDC, a pharmaceutically acceptable carrier, and / or an excipient.

[0090] Alternatively, the drug combination may include:

[0091] Single pharmaceutical compositions, including PARP1 inhibitors, RDCs, 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, in the described use, the PARP1 inhibitor and the RDC are administered simultaneously or separately.

[0094] In one or more embodiments of the present invention, in the described use, 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, in the described use, 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 PARP7 inhibitors combined with RDC are significantly better than those of RDC alone or PARP7 inhibitor alone, indicating that the combined use of PARP7 inhibitors and RDC 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 a fixed concentration. 177 Figure showing the cell proliferation inhibition results of Lu-PSMA-617 in combination with different concentrations of compound A.

[0108] Figure 2 shows the results of compound A at a fixed concentration and at different concentrations. 177 Figure showing the cell proliferation inhibition results of Lu-PSMA-617 in combination. Detailed Implementation

[0109] 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.

[0110] 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:

[0111] RDC drugs used in the embodiments of the present invention 177 Lu-PSMA-617 was provided by Wuxi Saifu Guotong Pharmaceutical Technology Co., Ltd.

[0112] Cell proliferation inhibition experiment

[0113] Human prostate cancer cells LNCaP clone FGC (Nanjing Kebai Biotechnology Co., Ltd., CBP60342) were cultured in RPMI-1640 medium containing 10% FBS, 1% penicillin-streptomycin, 1% glutamine, and 1% sodium pyruvate solution at 37°C and 5% CO2. Logarithmic growth phase LNCaP cells were seeded at a density of 4500 cells / well in 96-well plates (1× poly-L-lysine coated overnight) and incubated overnight. The following day, corresponding drug treatments were applied to the wells, with different gradients set up in the single-drug experiments. 177 The Lu-PSMA-617 group (starting concentration 10 MBq / mL, 2-fold dilution, 10 concentrations, duplex wells, solvent 0.005 M NaAC) and the compound A group (starting concentration 10 μM, 3-fold dilution, 9 concentrations, duplex wells, solvent 0.5% DMSO) were also prepared, along with Vehicel (solvent for compound A). 177 Lu-PSMA-617Vehicel ( 177 Lu-PSMA-617 solvent) and Cell control (cells and culture medium only). Cells with... 177 After co-incubating the cells with Lu-PSMA-617 medium for 8 hours, the medium was discarded and replaced with fresh medium, and incubation continued for another 88 hours. The cells were co-incubated with the medium containing compound A for 4 days without any treatment. In the combined experiments, 7.492 MBq / mL was selected. 177 Lu-PSMA-617 was used in combination with different concentrations of compound A. Compound A at 5.985 μM was selected in combination with different concentrations of... 177 Lu-PSMA-617 was used in combination, with a concentration of 7.492 MBq / mL selected simultaneously. 177 Lu-PSMA-617 concentration point and compound A concentration point at 5.985 μM, as well as Cell control (cells and culture medium only), Vehicel+ 177 Lu-PSMA-617Vehicel control (solvent for compound A and) 177 (The solvent for Lu-PSMA-617). After incubation for 8 hours, all drug solution was discarded. Fresh culture medium was then added, containing either a concentration gradient of compound A corresponding to the initial group or a fixed concentration of compound A, for a subsequent 88 hours of incubation. After incubation, CTG solution (Beyotime, Cat No. C0056M) was added, and after shaking and standing, the values ​​were read using a microplate reader. The IC50 was calculated using Graphpad Prism to plot the inhibition rate curve. 50 Values. The results are shown in Figures 1 and 2.

[0114] The results show that, in Figure 1, the IC50 values ​​of compounds in group A at different gradients... 50 The value was 9.197 μM, 7.492 MBq / mL. 177 IC50 of Lu-PSMA-617 + different gradients of compound A 50 The value is 3.917 μM; in Figure 2, different gradients 177 Lu-PSMA-617 group IC 50 The value was 8.949 MBq / mL, at different gradients 177 IC50 of the combination therapy group of Lu-PSMA-617 + compound A (5.985 μM) 50 The value was 5.666 MBq / mL. This indicates that compound A, in combination with RDC, exhibits better cell proliferation inhibition than either RDC alone or compound A alone, demonstrating the significant combined effect of the drug combination of this invention.

[0115] 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 pharmaceutical combination, characterized in that, The drug combination includes: (a) a PARP1 inhibitor and (b) RDC.

2. The pharmaceutical 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, X3are each independently selected from N or CR X , and at least one of X1, X2, X3is 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 fragment selected from the group consisting of or R 2b may be the same or different; R 2c may be the same or different; R 2d may be the same or different; R 2e may be the same or different; R 2f may 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 independently is selected from the group consisting of CN, halogen, OR 2a , C 1-6 alkyl, said C 1-6 alkyl is optionally further substituted with 1 or more substituents selected from halogen 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: Compounds of the general formula (I-A) are not: or 3. The drug combination according to claim 2, characterized in that, Structural unit selected from the group consisting of 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 the group consisting of 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 pharmaceutical combination according to claim 5, characterized in that, R 2b selected from CN.

7. The pharmaceutical combination according to claim 1, wherein 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) or 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; R2may be the same or different, each independently selected from the group consisting of 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: Compounds of general formula (I) are not 8. The pharmaceutical 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) or 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; R0is selected from H, halogen or C 1-6 alkyl, said C 1-6 alkyl is optionally further substituted with 1 or more substituents selected from halogen or C 1-6 alkyl; X1, X2are 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; R2may be the same or different, each independently selected from the group consisting of 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 RDC is selected from Pluvicto (i.e. 177 One or a combination of Lu-PSMA-617), Lutathera, RYZ-101, 177Lu-PSMA-I&T, 177Lu-PNT2002, 225Ac-PSMA-617, 177Lu-edotreotide, iodine [131I] metuximab, Locametz, Illuccix, Pylarify, Gallium GA-68Gozetotide, Detectnet, Gallium DOTATOC Ga-68, Netspot, or radium chloride [223Ra] injection.

11. The pharmaceutical combination according to claim 1, characterized in that, The PARP1 inhibitor and the RDC may be present in the same pharmaceutical composition, or the PARP1 inhibitor and the RDC 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. Use according to claim 12, characterized in that, The PARP1 inhibitor and the RDC can be administered simultaneously or separately.

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