Pharmaceutical combination of PARP7 inhibitor with bispecific antibody and use thereof in treating tumors

Abstract

The present application relates to a pharmaceutical combination of a PARP7 inhibitor with a bispecific antibody and use thereof in treating tumors. Compared with the monotherapies, the combination therapy of the PARP7 inhibitor with the bispecific antibody has a good anti-cancer effect and can overcome the drug resistance to the bispecific antibody.

Description

PARP7 inhibitors combined with bispecific antibodies and their applications in cancer treatment.

[0001] This application claims priority to Chinese patent applications 2025101067488 (filed January 23, 2025), 2025111922557 (filed August 25, 2025), 2025120050745 (filed December 29, 2025), and 2026100764395 (filed January 20, 2026). The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This application belongs to the field of pharmaceutical technology and relates to drug combinations that can be used for anti-tumor treatment. Specifically, this application relates to drug combinations of PARP7 inhibitors and bispecific antibodies, and their use in the treatment of tumors. Background Technology

[0003] Bispecific antibodies (abbreviated as biantibodies) are special antibodies that can simultaneously bind to two different antigens or different epitopes of a single antigen. Compared to monoclonal antibodies (MSBs), bispecific antibodies have stronger specificity and targeting, and can reduce off-target toxicity; compared to combination therapy with monoclonal antibodies, they can also effectively reduce treatment costs. They have broad application prospects in cancer treatment.

[0004] Bispecific antibodies have emerged as a novel class of drugs for treating hematologic malignancies and solid tumors. However, as with most anti-tumor drugs, the duration of objective response or clinical benefit produced by bispecific antibodies as monotherapy remains limited due to the emergence of drug resistance mechanisms. Therefore, combining bispecific antibodies with other anticancer drugs has become an important direction in the development of bispecific antibody drugs.

[0005] 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly(ADP-ribose) polymerase (PARP7) is a member of the MonoPARP family. TCDD activates the aryl hydrocarbon receptor (AHR), upregulating its expression. PARP7 interacts with the kinase TBK1 and ADP-ribosylates it, leading to inhibition of TBK1 activity and downregulation of IFN-I (type I interferon) response, thereby suppressing the body's antiviral and tumor immune responses. As a negative regulator of nucleic acid sensing in tumor cells, inhibiting PARP7 has shown the effect of restoring the IFN-I signaling pathway's response to nucleic acids in tumor models. This restoration of signaling can directly inhibit cell proliferation and activate the immune system, both of which contribute to tumor regression. Summary of the Invention

[0006] During the research, the applicant unexpectedly discovered that the combination therapy of PARP7 inhibitors and bispecific antibodies is more effective and less toxic than the individual monotherapy, and can overcome bispecific antibody resistance.

[0007] Therefore, the present invention aims to provide a pharmaceutical combination of a PARP7 inhibitor and a bispecific antibody, and its use in the treatment of tumors.

[0008] One or more embodiments of the present invention provide a drug combination comprising: (a) a PARP7 inhibitor and (b) a bispecific antibody.

[0009] In one or more embodiments of the present invention, the pharmaceutical combination includes a PARP7 inhibitor selected from RBN-2397, ONO-7119, QLS1103, JAB-26766, NSP-5020, NSP-5033, EB400, or a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, or deuterated thereof:

[0010] in:

[0011] X1 is NH, O, or a 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle contains 1 to 3 heteroatoms selected from N and O;

[0012] X2 is an O or a single bond;

[0013] X3 and X4 are each independently C or N;

[0014] R 1a R 1b Each independently is H, D, or C. 1-6 Alkyl; or R 1a R 1b It forms 3- to 5-membered cycloalkyl groups with the attached carbon atom;

[0015] R 2a R 2b Each independently is H, D, or C. 1-6 Alkyl; or R 2a R 2b It forms 3- to 5-membered cycloalkyl groups with the attached carbon atom;

[0016] R3 represents H, D, and C. 1-6 Alkyl, halogen, or cyano, wherein the C 1-6 The alkyl group may optionally be substituted with one to three halogens;

[0017] R4 and R5 are each independently H, D, or C. 1-6 Alkyl group; or R4 and R5 form a 3- to 5-membered cycloalkyl group with the attached carbon atom;

[0018] R6 and R7 are each independently H, D, or C. 1-6 Alkyl group; or R6 and R7 form C=O with the attached carbon atom;

[0019] R8 and R9 are each independently H, D, or C. 1-6 Alkyl group; or R8 and R9 form C=O with the attached carbon atom; or R8 and R9 form 3- to 5-membered cycloalkyl groups with the attached carbon atom;

[0020] R 10 Each independently is C 1-6 Alkyl, C 1-6 Alkoxy, CONR 10a R 10b Halogen, cyano, S(O)2R 10c SR 10d Or 3- to 5-membered cycloalkyl groups, wherein the C 1-6 Alkyl, C 1-6 The alkoxy group may optionally be replaced by one to three halogens;

[0021] R 10a R 10b R 10c R 10d Each independently is H, D, or C. 1-6 alkyl;

[0022] A is R a C 1-6 Alkyl, C 3-5 Cycloalkyl, halogen, or cyano, wherein the C 1-6 The alkyl group may optionally be substituted with one to three halogens;

[0023] B is a 5- to 10-membered carbon ring or heterocycle, wherein the heterocycle contains 1 to 3 heteroatoms selected from N, O and S;

[0024] C is a 5- to 6-membered heterocycle, wherein the heterocycle contains 1 to 3 N heteroatoms;

[0025] m is 1, 2, or 3;

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

[0027] p can be 0, 1, 2, or 3.

[0028] In one or more embodiments of the present invention, the pharmaceutical combination includes a PARP7 inhibitor selected from RBN-2397, ONO-7119, QLS1103, JAB-26766, NSP-5020, NSP-5033, EB400, or a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, or deuterated thereof, wherein:

[0029] X1 is NH, O, or a 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle contains 1 to 3 heteroatoms selected from N and O;

[0030] X2 is an O or a single bond;

[0031] X3 and X4 are each independently C or N;

[0032] R 1a R 1b Each independently is H, D, or C. 1-6 alkyl;

[0033] R 2a R 2b Each independently is H, D, or C. 1-6 Alkyl; or R 2a R 2b It forms 3- to 5-membered cycloalkyl groups with the attached carbon atom;

[0034] R3 represents H, D, and C. 1-6 Alkyl, halogen, or cyano, wherein the C 1-6 The alkyl group is optionally replaced by one to three halogens;

[0035] R4 and R5 are each independently H, D, or C. 1-6 Alkyl group; or R4 and R5 form a 3- to 5-membered cycloalkyl group with the attached carbon atom;

[0036] R6 and R7 are each independently H, D, or C. 1-6 alkyl;

[0037] R8 and R9 are each independently H, D, or C. 1-6 Alkyl groups; or R8 and R9 forming C=O with the attached carbon atom;

[0038] R 10 Each independently is C 1-6 Alkyl, C 1-6 Alkoxy, CONR 10a R 10b Halogen, cyano, S(O)2R 10c SR 10d Or 3- to 5-membered cycloalkyl groups, wherein the C 1-6 Alkyl, C 1-6 The alkoxy group may optionally be replaced by one to three halogens;

[0039] R 10a R 10b R 10c R 10d Each independently is H, D, or C. 1-6 alkyl;

[0040] A is R a C 1-6 Alkyl, C 3-5 Cycloalkyl, halogen, or cyano, wherein the C 1-6 The alkyl group may optionally be substituted with one to three halogens;

[0041] B is a 5- to 6-membered carbon ring or heterocycle, wherein the heterocycle contains 1 to 3 heteroatoms selected from N, O and S;

[0042] C is a 5- to 6-membered heterocycle, wherein the 5- to 6-membered heterocycle contains 1 to 3 N heteroatoms;

[0043] m is 1, 2, or 3;

[0044] n is 0, 1, 2, or 3;

[0045] p can be 0, 1, 2, or 3.

[0046] In one or more embodiments of the present invention, the drug combination includes a PARP7 inhibitor selected from RBN-2397, ONO-7119, QLS1103, JAB-26766, NSP-5020, NSP-5033, EB400, or a compound of formula (I-1) or a pharmaceutically acceptable salt, stereoisomer, or deuterated thereof.

[0047] in:

[0048] X1 is NH or a 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle contains 1 to 3 heteroatoms selected from N and O;

[0049] X2 is 0;

[0050] X3 and X4 are each independently C or N;

[0051] R 1a R 1b Each independently is H, D, or C. 1-6 alkyl;

[0052] R 2a R 2b Each independently is H, D, or C. 1-6 alkyl;

[0053] R3 represents H, D, and C. 1-6 Alkyl or halogen, the C 1-6 The alkyl group may optionally be substituted with one to three halogens;

[0054] R4 and R5 are each independently H, D, or C. 1-6 alkyl;

[0055] R6 and R7 are each independently H, D, or C. 1-6 alkyl;

[0056] R8 and R9 are each independently H, D, or C. 1-6 Alkyl groups; or R8 and R9 forming C=O with the attached carbon atom;

[0057] R 10 C 1-6 Alkyl, C 1-6 Alkoxy, cyano or SR 10d The C 1-6 Alkyl, C 1-6 The alkoxy group may optionally be replaced by one to three halogens;

[0058] R 10d For H, D or C 1-6 alkyl;

[0059] A is

[0060] B is a 5- to 6-membered carbon ring or heterocycle, wherein the heterocycle contains 1 to 3 heteroatoms selected from N, O and S;

[0061] C is a 5- to 6-membered heterocycle, wherein the 5- to 6-membered heterocycle contains 1 to 3 N heteroatoms;

[0062] m is 1, 2, or 3;

[0063] n can be 0, 1, 2, or 3.

[0064] In one or more embodiments of the present invention, the drug combination includes a PARP7 inhibitor selected from RBN-2397, ONO-7119, QLS1103, JAB-26766, NSP-5020, NSP-5033, EB400, or compounds of formula (I-2), or their pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives.

[0065] in:

[0066] X1 is NH;

[0067] X2 is 0;

[0068] R 1a R 1b Each independently is H, D, or C. 1-6 alkyl;

[0069] R 2a R 2b Each independently is H, D, or C. 1-6 alkyl;

[0070] R3 represents H, D, and C. 1-6 Alkyl or halogen, the C 1-6 The alkyl group may optionally be substituted with one to three halogens;

[0071] R4 and R5 are each independently H, D, or C. 1-6 alkyl;

[0072] R6 and R7 are each independently H, D, or C. 1-6 alkyl;

[0073] R8 and R9 are each independently H, D, or C. 1-6 Alkyl groups; or R8 and R9 forming C=O with the carbon atom they are attached to;

[0074] R 10 C 1-6 Alkyl, C 1-6 Alkoxy, cyano or SR 10d The C 1-6 Alkyl, C 1-6 The alkoxy group may optionally be replaced by one to three halogens;

[0075] R 10d For H, D or C 1-6 alkyl;

[0076] A is

[0077] B is a 5- to 6-membered carbon ring or heterocycle, wherein the heterocycle contains 1 to 3 heteroatoms selected from N, O and S;

[0078] m is 1, 2, or 3;

[0079] n can be 0, 1, 2, or 3.

[0080] In one or more embodiments of the present invention, the pharmaceutical combination includes a PARP7 inhibitor selected from RBN-2397, ONO-7119, QLS1103, JAB-26766, NSP-5020, NSP-5033, EB400, or a compound of formula (I-2) or a pharmaceutically acceptable salt, stereoisomer, or deuterated thereof, wherein:

[0081] X1 is NH;

[0082] X2 is 0;

[0083] R 1a R 1b Each independently is H, D, or C. 1-6 alkyl;

[0084] R 2a R 2bEach independently is H, D, or C. 1-6 alkyl;

[0085] R3 represents H, D, and C. 1-6 Alkyl or halogen, the C 1-6 The alkyl group may optionally be substituted with one to three halogens;

[0086] R4 and R5 are each independently H, D, or C. 1-6 alkyl;

[0087] R6 and R7 are each independently H, D, or C. 1-6 alkyl;

[0088] R8 and R9 are each independently H, D, or C. 1-6 Alkyl groups, or R8 and R9, form C=O with the attached carbon atom;

[0089] R 10 C 1-6 Alkyl, cyano, or SR 10d The C 1-6 The alkyl group may optionally be substituted with one to three halogens;

[0090] R 10d For H, D or C 1-6 alkyl;

[0091] A is

[0092] B is a 5- to 6-membered carbon ring or heterocycle, wherein the heterocycle contains 1 to 3 heteroatoms selected from N, O and S;

[0093] m is 1, 2, or 3;

[0094] n can be 0, 1, 2, or 3.

[0095] In one or more embodiments of the present invention, the pharmaceutical combination includes a PARP7 inhibitor selected from RBN-2397, ONO-7119, QLS1103, JAB-26766, NSP-5020, NSP-5033, EB400, or a compound of formula (I-2) or a pharmaceutically acceptable salt, stereoisomer, or deuterated thereof, wherein:

[0096] X1 is selected from NH;

[0097] X2 is selected from O;

[0098] R 1a R 1b Each is independently selected from H, D, or C. 1-6 alkyl;

[0099] R 2a R2b Each is independently selected from H, D, or C. 1-6 alkyl;

[0100] R3 represents H, D, and C. 1-6 Alkyl or halogen, the C 1-6 The alkyl group may optionally be substituted with one to three halogens;

[0101] R4 and R5 are each independently H or D;

[0102] R6 and R7 are each independently H or D;

[0103] R8 and R9 are each independently H or D;

[0104] R 10 For CF3 or SR 10d ;

[0105] R 10d For H, D or C 1-6 alkyl;

[0106] A is

[0107] B is

[0108] m is 1, 2, or 3;

[0109] n can be 0, 1, 2, or 3.

[0110] In one or more embodiments of the present invention, the pharmaceutical combination includes a PARP7 inhibitor selected from RBN-2397, ONO-7119, QLS1103, JAB-26766, NSP-5020, NSP-5033, EB400, or a compound of formula (I-2) or a pharmaceutically acceptable salt, stereoisomer, or deuterated thereof, wherein:

[0111] X1 is selected from NH;

[0112] X2 is selected from O;

[0113] R 1a R 1b Each is independently selected from H, D, or C. 1-3 alkyl;

[0114] R 2a R 2b Each is independently selected from H, D, or C. 1-3 alkyl;

[0115] R3 is selected from H, D, or CF3;

[0116] R4 and R5 are each independently selected from H or D;

[0117] R6 and R7 are each independently selected from H or D;

[0118] R8 and R9 are each independently selected from H or D;

[0119] R 10 For CF3;

[0120] A is

[0121] B is

[0122] m is 1, 2, or 3;

[0123] n is 0, 1, or 2.

[0124] In one or more embodiments of the present invention, the drug combination includes a PARP7 inhibitor selected from RBN-2397, ONO-7119, QLS1103, JAB-26766, NSP-5020, NSP-5033, EB400, or compounds of formula (I-3), or their pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives.

[0125] in:

[0126] X1 is NH or a 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle contains 1 to 3 heteroatoms selected from N and O;

[0127] X2 is 0;

[0128] R 1a R 1b Each independently is H, D, or C. 1-6 alkyl;

[0129] R 2a R 2b Each independently is H, D, or C. 1-6 alkyl;

[0130] R4 and R5 are each independently H, D, or C. 1-6 alkyl;

[0131] R6 and R7 are each independently H, D, or C. 1-6 alkyl;

[0132] R8 and R9 are each independently H, D, or C. 1-6 Alkyl groups; or R8 and R9 forming C=O with the attached carbon atom;

[0133] R 10 C 1-6 Alkyl, C 1-6Alkoxy, cyano or SR 10d The C 1-6 Alkyl, C 1-6 The alkoxy group may optionally be replaced by one to three halogens;

[0134] R 10d For H, D or C 1-6 alkyl;

[0135] A is

[0136] B is a 5- to 6-membered carbon ring or heterocycle, wherein the heterocycle contains 1 to 3 heteroatoms selected from N, O and S;

[0137] m is 1, 2, or 3;

[0138] n can be 0, 1, 2, or 3.

[0139] In one or more embodiments of the present invention, the pharmaceutical combination includes a PARP7 inhibitor selected from RBN-2397, ONO-7119, QLS1103, JAB-26766, NSP-5020, NSP-5033, EB400, or a compound of formula (I-3) or a pharmaceutically acceptable salt, stereoisomer, or deuterated thereof, wherein:

[0140] X1 is NH or a 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle contains 1 to 3 heteroatoms selected from N and O;

[0141] X2 is 0;

[0142] R 1a R 1b Each independently is H, D, or C. 1-3 alkyl;

[0143] R 2a R 2b Each independently is H, D, or C. 1-3 alkyl;

[0144] R4 and R5 are each independently H, D, or C. 1-3 alkyl;

[0145] R6 and R7 are each independently H, D, or C. 1-3 alkyl;

[0146] R8 and R9 are each independently H, D, or C. 1-3 Alkyl groups; or R8 and R9 forming C=O with the attached carbon atom;

[0147] R 10 C 1-6 Alkyl, cyano or SR 10d The C1-6 The alkyl group may optionally be substituted with one to three halogens;

[0148] R 10d For H, D or C 1-6 alkyl;

[0149] A is

[0150] B is

[0151] m is 1, 2, or 3;

[0152] n is 0, 1, or 2.

[0153] In one or more embodiments of the present invention, the pharmaceutical combination includes a PARP7 inhibitor selected from RBN-2397, ONO-7119, QLS1103, JAB-26766, NSP-5020, NSP-5033, EB400, or a compound of formula (I-3) or a pharmaceutically acceptable salt, stereoisomer, or deuterated thereof, wherein:

[0154] X1 is NH;

[0155] X2 is 0;

[0156] R 1a R 1b Each independently is H, D, or C. 1-3 alkyl;

[0157] R 2a R 2b Each can be H or D independently;

[0158] R4 and R5 are each independently H or D;

[0159] R6 and R7 are each independently H or D;

[0160] R8 and R9 are each independently H or D;

[0161] R 10 For CF3;

[0162] A is

[0163] B is

[0164] m is 1, 2, or 3;

[0165] n is 0, 1, or 2.

[0166] In one or more embodiments of the present invention, the pharmaceutical combination includes a PARP7 inhibitor selected from RBN-2397, ONO-7119, QLS1103, JAB-26766, NSP-5020, NSP-5033, EB400, or compounds shown below, or their pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives:

[0167] In one or more embodiments of the present invention, the PARP7 inhibitor is

[0168] In one or more embodiments of the present invention, the PARP7 inhibitor is

[0169] In one or more embodiments of the present invention, the bispecific antibody is selected from PD-1 / VEGF bispecific antibodies, PD-L1 / VEGF-A bispecific antibodies, PD-1 / CTLA-4 bispecific antibodies, CD3 / EpCAM / FcγR triple antibodies, CD3 / CD19 bispecific antibodies, EGFR / c-Met bispecific antibodies, IL-17A / IL-17F bispecific antibodies, Ang2 / VEGF-A bispecific antibodies, PD-1 / CTLA-4 bispecific antibodies, CD3 / CD20 bispecific antibodies, CD3 / BCMA bispecific antibodies, CD3 / One or more combinations of GPRC5D bispecific antibody, CD3 / BCMA bispecific antibody, CD3 / gp100 bispecific antibody, CD3 / DLL3 bispecific antibody, HER2 / HER3 bispecific antibody, HER2 bispecific antibody, PD-1 / CTLA-4 bispecific antibody, EGFR / HER3 bispecific antibody, CD3 / GPC3 bispecific antibody, Claudin18.2 / CD3 bispecific antibody, CD3 / CD19 bispecific antibody, PD-L1 / TGF-β bispecific antibody, PD-1 / TIGIT bispecific antibody, and TGF-β / VEGF bispecific antibody.

[0170] In one or more embodiments of the present invention, the bispecific antibody is selected from PD-1 / VEGF bispecific antibodies.

[0171] In one or more embodiments of the present invention, the bispecific antibody is selected from AK112, SSGJ-707, Catuxomab, Blinatumomab, Amivantamab, Bimekizumab, Faricimab, Cadonilimab, Mosunetuzumab, Glofitamab, Epcoritamab, Teclistamab, Talquetamab, Elranatamab, etc. b (Enatuzumab), Tebentafusp, Tarlatamab, Odronextamab, Zenocutuzumab, Zanidatamab, Linvoseltamab, Volrustomig, Izalontamab, Velinotamig, Danvilostomig, Bafisontamab, CMD011, HBM7022, YK012, TQB2934, BA1201, AZD2936, ICP-B02, or Y332, or one or more combinations thereof.

[0172] In one or more embodiments of the present invention, the bispecific antibody is selected from AK112 (AK-112; evokimib; SMT112; ivonescimab; VP101; edafen) or SSGJ-707.

[0173] In one or more embodiments of the present invention, the drug combination comprises: (a) a PARP7 inhibitor and (b) an RDC; the PARP7 inhibitor is The bispecific antibody is selected from AK112 or SSGJ-707.

[0174] In one or more embodiments of the present invention, the drug combination comprises: (a) a PARP7 inhibitor and (b) an RDC; the PARP7 inhibitor is The bispecific antibody is selected from AK112.

[0175] In one or more embodiments of the present invention, the drug combination, wherein the PARP7 inhibitor and the bispecific antibody are present in the same drug composition, or the PARP7 inhibitor and the bispecific antibody are present in different drug compositions.

[0176] In one or more embodiments of the present invention, the drug combination includes:

[0177] (i) a first pharmaceutical composition comprising a PARP7 inhibitor, a pharmaceutically acceptable carrier and / or excipient; and

[0178] (ii) A second pharmaceutical composition comprising a bispecific antibody, a pharmaceutically acceptable carrier, and / or an excipient.

[0179] Alternatively, the drug combination may include:

[0180] A single pharmaceutical composition comprising a PARP7 inhibitor, a bispecific antibody, a pharmaceutically acceptable carrier, and / or an excipient.

[0181] One or more embodiments of the present invention provide the use of the pharmaceutical combinations involved in the treatment and / or prevention of tumors.

[0182] One or more embodiments of the present invention provide a method for treating tumors, comprising administering the drug combination of the present invention to a subject in need of such treatment.

[0183] One or more embodiments of the present invention provide a method for treating tumors, comprising administering a therapeutically effective amount of the drug combination of the present invention to a subject in need of such treatment.

[0184] One or more embodiments of the present invention provide a pharmaceutical composition for treating and / or preventing tumors, comprising the pharmaceutical composition involved in the present invention.

[0185] In one or more embodiments of the present invention, the pharmaceutical composition comprises a therapeutically effective amount of the pharmaceutical composition involved in the present invention.

[0186] In one or more embodiments of the present invention, the PARP7 inhibitor and the RDC are the active pharmaceutical ingredients in the pharmaceutical composition.

[0187] One or more embodiments of the present invention provide the pharmaceutical combinations involved in the present invention for the treatment and / or prevention of tumors.

[0188] One or more embodiments of the present invention provide the use of the pharmaceutical combination involved in the present invention in the preparation of medicaments for treating and / or preventing tumors.

[0189] In one or more embodiments of the present invention (e.g., embodiments of drug combinations, drug compositions, uses, or methods of treating tumors), the PARP7 inhibitor and the bispecific antibody are administered simultaneously or separately.

[0190] In one or more embodiments of the present invention (e.g., embodiments of drug combinations, drug compositions, uses, or methods of treating tumors), the PARP7 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, once every four weeks, preferably twice a day or once a day.

[0191] In one or more embodiments of the present invention (e.g., embodiments of drug combinations, drug compositions, uses, or methods of treating tumors), the total daily dose of the PARP7 inhibitor is selected from 50-1500 mg, preferably 100-1000 mg, measured in terms of the amount of free base.

[0192] In one or more embodiments of the present invention (e.g., embodiments of drug combinations, drug compositions, uses, or methods of treating tumors), the tumor is selected from solid tumors and / or hematologic malignancies.

[0193] In one or more embodiments (e.g., embodiments of drug combinations, drug compositions, uses, or methods of treating tumors), 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 PARP7 amplification.

[0194] In one or more embodiments (e.g., embodiments of drug combinations, drug compositions, uses, or methods of treating tumors), 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.

[0195] In one or more embodiments (e.g., embodiments of drug combinations, drug compositions, uses, or methods of treating tumors), the lung cancer is preferably non-small cell lung cancer or neuroendocrine lung cancer.

[0196] In one or more embodiments (e.g., embodiments of drug combinations, drug compositions, uses, or methods of treating tumors), the non-small cell lung cancer is preferably squamous cell carcinoma or adenocarcinoma of the lung.

[0197] In one or more embodiments (e.g., embodiments of drug combinations, drug compositions, uses, or methods of treating tumors), the breast cancer is preferably hormone receptor-positive (HR+) breast cancer.

[0198] In one or more embodiments (e.g., embodiments of drug combinations, drug compositions, uses, or methods of treating tumors), the esophageal cancer is preferably esophageal squamous cell carcinoma or esophageal adenocarcinoma.

[0199] In one or more embodiments (e.g., embodiments of drug combination, drug composition, use or method of treating tumor), the head and neck cancer is preferably head and neck squamous cell carcinoma.

[0200] In one or more embodiments (e.g., embodiments of drug combinations, drug compositions, uses, or methods of treating tumors), the uterine cancer is preferably endometrial cancer.

[0201] In one or more embodiments (e.g., embodiments of drug combinations, drug compositions, uses, or methods of treating tumors), the central nervous system cancer is preferably a glioma.

[0202] In one or more embodiments (e.g., embodiments of drug combination, drug composition, use or method of treating tumor), the liver cancer is preferably hepatocellular carcinoma.

[0203] In one or more embodiments (e.g., embodiments of drug combination, drug composition, use or method of treating tumor), the B-cell lymphoma is preferably diffuse large B-cell lymphoma.

[0204] In one or more embodiments (e.g., embodiments of a drug combination, a pharmaceutical composition, a use or a method of treating a tumor), the total daily dose of the bispecific antibody is selected from 1-50 mg / kg.

[0205] In one or more embodiments (e.g., embodiments of drug combination, pharmaceutical composition, use or method of treating tumor), the total daily dose of the bispecific antibody is preferably 10-30 mg / kg.

[0206] In one or more embodiments (e.g., embodiments of drug combination, pharmaceutical composition, use or method of treating tumor), the total daily dose of the bispecific antibody is more preferably from 18-22 mg / kg.

[0207] In one or more embodiments (e.g., embodiments of a drug combination, a pharmaceutical composition, a use or a method of treating a tumor), the total daily dose of the PARP7 inhibitor is selected from 50-1500 mg, measured as the amount of free base.

[0208] In one or more embodiments (e.g., embodiments of drug combination, drug composition, use or method of treating tumor), the total daily dose of the PARP7 inhibitor is preferably from 100-1000 mg, measured in terms of the amount of free base.

[0209] In one or more embodiments (e.g., embodiments of a drug combination, a pharmaceutical composition, a use or a method of treating a tumor), the total daily dose of the PARP7 inhibitor is more preferably from 100-400 mg, measured in terms of the amount of free base.

[0210] In one or more embodiments (e.g., embodiments of drug combination, drug composition, use or method of treating tumor), the total daily dose of the PARP7 inhibitor is more preferably 100-400 mg, measured as the amount of free base; the total daily dose of the bispecific antibody is more preferably 18-22 mg / kg.

[0211] In one or more embodiments (e.g., embodiments of drug combination, drug composition, use or method of treating tumor), the bispecific antibody is administered intravenously at frequencies of twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every 3-6 months.

[0212] In one or more embodiments (e.g., embodiments of drug combination, drug composition, use or method of treating tumor), the bispecific antibody is administered intravenously, preferably once a week, once every two weeks, once every three weeks or once every four weeks.

[0213] In one or more embodiments (e.g., embodiments of drug combination, drug composition, use or method of treating tumor), the PARP7 inhibitor is administered orally 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.

[0214] In one or more embodiments (e.g., embodiments of drug combination, drug composition, use or method of treating tumor), the PARP7 inhibitor is administered orally, preferably three times a day, twice a day or once a day.

[0215] In one or more embodiments of the present invention (e.g., embodiments of drug combinations, pharmaceutical compositions, uses, or methods of treating tumors), the drug combinations have a superior antitumor effect compared to using PARP7 inhibitors and / or bispecific antibodies alone.

[0216] In one or more embodiments of the present invention (e.g., embodiments of drug combinations, drug compositions, uses, or methods of treating tumors), the drug combinations have a better anti-tumor effect than PARP7 inhibitors alone.

[0217] In one or more embodiments of the present invention (e.g., embodiments of drug combinations, pharmaceutical compositions, uses, or methods of treating tumors), the drug combination is administered to a subject with a tumor, and the tumor volume is reduced by 10% or more, preferably by 20% or more, more preferably by 30% or more, compared to the use of a PARP7 inhibitor alone.

[0218] In one or more embodiments of the present invention (e.g., embodiments of drug combinations, drug compositions, uses, or methods of treating tumors), the drug combinations have a better antitumor effect than bispecific antibodies alone.

[0219] In one or more embodiments of the present invention (e.g., embodiments of drug combination, pharmaceutical composition, use, or method of treating tumors), the drug combination is administered to a subject with a tumor, and the tumor volume is reduced by 10% or more, preferably by 20% or more, more preferably by 30% or more, compared to the use of bispecific antibody alone.

[0220] In one or more embodiments of the present invention (e.g., embodiments of drug combinations, pharmaceutical compositions, uses, or methods of treating tumors), the safety profile of the drug combinations is superior to that of PAPR7 inhibitors and / or bispecific antibodies used alone.

[0221] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0222] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0223] "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.

[0224] "Pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" means that the compound of this application 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.

[0225] "Optional" or "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

[0226] Figure 1 shows the tumor volume change curve of Example 1.

[0227] Figure 2 shows the tumor volume change curve in Example 2. Detailed Implementation

[0228] 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.

[0229] The compound of formula (I) or its specific structure involved in this invention can be prepared by the method of patent WO2022242750. Specifically, the compound A used in the embodiments of this invention is selected from compound 1 in patent WO2022242750.

[0230] Example 1: In vivo pharmacodynamic experiment using a subcutaneous humanized model of MDA-MB-231.

[0231] MDA-MB-231 cells were cultured in Leibovitz's L-15 medium containing 10% fetal bovine serum, 1% penicillin-streptomycin solution, and 0.01 mg / mL insulin. When the cells reached the exponential growth phase, they were trypsinized, collected, counted, resuspended in DPBS, gel-coated, and subcutaneously seeded onto the right back of 54 female C-NKG mice at a density of 1 × 10⁶ cells / mL. 7 5 × 10⁶ cells / mouse, with an inoculation volume of 200 μL. Frozen PBMCs were resuscitated, resuspended in DPBS, and inoculated into the tail vein of mice at a cell density of 5 × 10⁶ cells / mouse. 6 Inoculate one tumor per animal, with an inoculation volume of 200 μL. Wait until the average tumor volume reaches 80–120 mm. 3Around 10:00 AM, 24 mice were selected based on tumor volume and body weight and randomly assigned to four experimental groups (n=6 per group): a blank control group, a compound A (125 mg / kg, BID) monotherapy group, an AK112 (3 mg / kg, BIW) monotherapy group, and a combination of compound A (125 mg / kg, BID) and AK112 (3 mg / kg, BIW). Compound A was prepared using DMSO + 30% HP-β-CD (5:95, v / v) and administered by gavage at a dose of 10 mL / kg. AK112 (Kangfang Biotechnology, batch number: BA112P202405004) was prepared using DPBS and administered by intraperitoneal injection at a dose of 10 mL / kg. During the administration period, tumor volume was measured twice weekly and tumor growth curves were plotted. Mouse body weight was also measured twice weekly to calculate the rate of weight change. At the end of the experiment, mouse tumors were removed, weighed, and photographed.

[0232] The results showed that: Figure 1 is the tumor volume change curve. It can be seen from the figure that compound A combined with AK112 has better anti-tumor effect and safety than AK112 alone, and shows a significant synergistic effect in anti-tumor treatment.

[0233] Example 2: In vivo pharmacodynamic experiment using a subcutaneous humanized HCC827 model.

[0234] HCC827 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum, 1% penicillin-streptomycin solution, and 0.01 mg / mL insulin. When the cells reached the exponential growth phase, they were trypsinized, collected, counted, resuspended in DPBS, gel-coated, and subcutaneously seeded onto the right back of 54 female B-NDG mice at a density of 1 × 10⁻⁶ cells. 7 Each mouse was inoculated with 1 × 10⁶ cells at a volume of 200 μL. Frozen PBMCs were resuscitated, resuspended in DPBS, and then inoculated into the tail vein of mice at a density of 1 × 10⁶ cells. 7 Inoculate one tumor per animal, with an inoculation volume of 200 μL. Wait until the average tumor volume reaches 80–120 mm. 3Around 10:00 AM, 24 mice were selected based on tumor volume and body weight and randomly assigned to four experimental groups (n=6 per group): a blank control group, a compound A (125 mg / kg, BID) monotherapy group, an AK112 (4 mg / kg, BIW) monotherapy group, and a combination of compound A (125 mg / kg, BID) and AK112 (4 mg / kg, BIW). Compound A was prepared using DMSO + 30% HP-β-CD (5:95, v / v) and administered by gavage at a dose of 10 mL / kg. AK112 (Kangfang Biotechnology, batch number: BA112P202405004) was prepared using DPBS and administered by intraperitoneal injection at a dose of 10 mL / kg. During the administration period, tumor volume was measured twice weekly and tumor growth curves were plotted.

[0235] The results showed that: Figure 2 is the tumor volume change curve of Example 2. It can be seen from the figure that compound A combined with AK112 has a better anti-tumor effect than AK112 alone, and shows a significant synergistic effect in anti-tumor.

[0236] Example 3 Clinical Assessment

[0237] Trial objective: To evaluate the safety, tolerability, pharmacokinetic characteristics, and preliminary efficacy of compound A in combination with PD-1 / VEGF bispecific antibodies in patients with malignant solid tumors.

[0238] Clinical participants were aged 18 to 75 years (minimum age); male or female; and had locally advanced, metastatic malignant solid tumors that were not eligible for radical treatment, as confirmed by histology or cytology. At least one measurable lesion was present according to RECIST 1.1 criteria.

[0239] Test protocol:

[0240] Dosage and administration: 100mg QD, 200mg QD, 300mg QD, 400mg QD. The dose escalation study includes four phases: screening, monotherapy pretreatment, combination therapy, and safety follow-up. The first cycle of the combination therapy phase (C1D1–C1D21) is the DLT observation period. During the monotherapy pretreatment phase (C0D1–C0D7), compound A is administered twice daily at a fixed dose of 300mg each time (before breakfast and dinner, with at least a 1-hour interval between doses). During the combination therapy phase (21 days per cycle starting from C1D1), compound A is administered once daily (before breakfast, with at least a 1-hour interval between doses), and the PD-1 / VEGF bispecific antibody (AK112) is administered at a fixed dose of 20mg / kg via intravenous infusion on the first day of each cycle starting from C1, with each cycle lasting 3 weeks. Duration of treatment: until the subject experiences disease progression, intolerable toxicity, death, or meets other criteria for discontinuation of treatment.

[0241] Endpoint Indicator:

[0242] Table 3 Endpoint Indicators

[0243] Clinical trial results showed that tumor growth was effectively suppressed in patients during the clinical trial period, and the treatment was safe. This indicates that PARP7 inhibitors and PD-1 / VEGF bispecific antibodies have a significant synergistic effect in the treatment of tumors.

[0244] In summary, the combination of compound A and bispecific antibody has a better anti-tumor effect than the bispecific antibody alone, demonstrating a significant synergistic effect in anti-tumor activity.

[0245] 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 PARP7 inhibitor and (b) a bispecific antibody.

2. The drug combination according to claim 1, characterized in that, The PARP7 inhibitor is selected from RBN-2397, ONO-7119, QLS1103, JAB-26766, NSP-5020, NSP-5033, EB400, or compounds of formula (I) or their pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives. in: X1 is NH, O, or a 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle contains 1 to 3 heteroatoms selected from N and O; X2 is an O or a single bond; X3 and X4 are each independently C or N; R 1a R 1b Each independently is H, D, or C. 1-6 Alkyl; or R 1a R 1b It forms 3- to 5-membered cycloalkyl groups with the attached carbon atom; R 2a R 2b Each independently is H, D, or C. 1-6 Alkyl; or R 2a R 2b It forms 3- to 5-membered cycloalkyl groups with the attached carbon atom; R3 represents H, D, and C. 1-6 Alkyl, halogen, or cyano, wherein the C 1-6 The alkyl group may optionally be substituted with one to three halogens; R4 and R5 are each independently H, D, or C. 1-6 Alkyl group; or R4 and R5 form a 3- to 5-membered cycloalkyl group with the attached carbon atom; R6 and R7 are each independently H, D, or C. 1-6 Alkyl group; or R6 and R7 form C=O with the attached carbon atom; R8 and R9 are each independently H, D, or C. 1-6 Alkyl group; or R8 and R9 form C=O with the attached carbon atom; or R8 and R9 form 3- to 5-membered cycloalkyl groups with the attached carbon atom; R 10 Each independently is C 1-6 Alkyl, C 1-6 Alkoxy, CONR 10a R 10b Halogen, cyano, S(O)2R 10c SR 10d Or 3- to 5-membered cycloalkyl groups, wherein the C 1-6 Alkyl, C 1-6 The alkoxy group may optionally be replaced by one to three halogens; R 10a R 10b R 10c R 10d Each independently is H, D, or C. 1-6 alkyl; A is R a C 1-6 Alkyl, C 3-5 cycloalkyl, halogen or cyano, wherein C 1-6 The alkyl group may optionally be substituted with one to three halogens; B is a 5- to 10-membered carbon ring or heterocycle, wherein the heterocycle contains 1 to 3 heteroatoms selected from N, O and S; C is a 5- to 6-membered heterocycle, wherein the heterocycle contains 1 to 3 N heteroatoms; m is 1, 2, or 3; n is 0, 1, 2, or 3; p can be 0, 1, 2, or 3.

3. The pharmaceutical combination according to claim 2, wherein: X1 is NH, O, or a 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle contains 1 to 3 heteroatoms selected from N and O; X2 is an O or a single bond; X3 and X4 are each independently C or N; R 1a R 1b Each independently is H, D, or C. 1-6 alkyl; R 2a R 2b Each independently is H, D, or C. 1-6 Alkyl; or R 2a R 2b It forms 3- to 5-membered cycloalkyl groups with the attached carbon atom; R3 represents H, D, and C. 1-6 Alkyl, halogen, or cyano, wherein the C 1-6 The alkyl group is optionally replaced by one to three halogens; R4 and R5 are each independently H, D, or C. 1-6 Alkyl group; or R4 and R5 form a 3- to 5-membered cycloalkyl group with the attached carbon atom; R6 and R7 are each independently H, D, or C. 1-6 alkyl; R8 and R9 are each independently H, D, or C. 1-6 Alkyl groups; or R8 and R9 forming C=O with the attached carbon atom; R 10 Each independently is C 1-6 Alkyl, C 1-6 Alkoxy, CONR 10a R 10b Halogen, cyano, S(O)2R 10c SR 10d Or 3- to 5-membered cycloalkyl groups, wherein the C 1-6 Alkyl, C 1-6 The alkoxy group may optionally be replaced by one to three halogens; R 10a R 10b R 10c R 10d Each independently is H, D, or C. 1-6 alkyl; A is R a C 1-6 Alkyl, C 3-5 cycloalkyl, halogen, or cyano, wherein the C 1-6 The alkyl group may optionally be substituted with one to three halogens; B is a 5- to 6-membered carbon ring or heterocycle, wherein the heterocycle contains 1 to 3 heteroatoms selected from N, O and S; C is a 5- to 6-membered heterocycle, wherein the 5- to 6-membered heterocycle contains 1 to 3 N heteroatoms; m is 1, 2, or 3; n is 0, 1, 2, or 3; p can be 0, 1, 2, or 3.

4. The drug combination according to claim 2, characterized in that, The PARP7 inhibitor is selected from RBN-2397, ONO-7119, QLS1103, JAB-26766, NSP-5020, NSP-5033, EB400, or compounds of formula (I-1) or their pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives, wherein: in: X1 is NH or a 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle contains 1 to 3 heteroatoms selected from N and O; X2 is 0; X3 and X4 are each independently C or N; R 1a R 1b Each independently is H, D, or C. 1-6 alkyl; R 2a R 2b Each independently is H, D, or C. 1-6 alkyl; R3 represents H, D, and C. 1-6 Alkyl or halogen, the C 1-6 The alkyl group may optionally be substituted with one to three halogens; R4 and R5 are each independently H, D, or C. 1-6 alkyl; R6 and R7 are each independently H, D, or C. 1-6 alkyl; R8 and R9 are each independently H, D, or C. 1-6 Alkyl groups; or R8 and R9 forming C=O with the attached carbon atom; R 10 C 1-6 Alkyl, C 1-6 Alkoxy, cyano or SR 10d The C 1-6 Alkyl, C 1-6 The alkoxy group may optionally be replaced by one to three halogens; R 10d For H, D or C 1-6 alkyl; A is B is a 5- to 6-membered carbon ring or heterocycle, wherein the heterocycle contains 1 to 3 heteroatoms selected from N, O and S; C is a 5- to 6-membered heterocycle, wherein the 5- to 6-membered heterocycle contains 1 to 3 N heteroatoms; m is 1, 2, or 3; n can be 0, 1, 2, or 3.

5. The drug combination according to claim 2, characterized in that, The PARP7 inhibitor is selected from RBN-2397, ONO-7119, QLS1103, JAB-26766, NSP-5020, NSP-5033, EB400, or compounds of formula (I-2), or their pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives, wherein: in: X1 is NH; X2 is 0; R 1a R 1b Each independently is H, D, or C. 1-6 alkyl; R 2a R 2b Each independently is H, D, or C. 1-6 alkyl; R3 represents H, D, and C. 1-6 Alkyl or halogen, the C 1-6 The alkyl group may optionally be substituted with one to three halogens; R4 and R5 are each independently H, D, or C. 1-6 alkyl; R6 and R7 are each independently H, D, or C. 1-6 alkyl; R8 and R9 are each independently H, D, or C. 1-6 Alkyl groups; or R8 and R9 forming C=O with the carbon atom they are attached to; R 10 C 1-6 Alkyl, C 1-6 Alkoxy, cyano or SR 10d The C 1-6 Alkyl, C 1-6 The alkoxy group may optionally be replaced by one to three halogens; R 10d For H, D or C 1-6 alkyl; A is B is a 5- to 6-membered carbon ring or heterocycle, wherein the heterocycle contains 1 to 3 heteroatoms selected from N, O and S; m is 1, 2, or 3; n can be 0, 1, 2, or 3.

6. The pharmaceutical combination according to claim 5, wherein: X1 is NH; X2 is 0; R 1a R 1b Each independently is H, D, or C. 1-6 alkyl; R 2a R 2b Each independently is H, D, or C. 1-6 alkyl; R3 represents H, D, and C. 1-6 Alkyl or halogen, the C 1-6 The alkyl group may optionally be substituted with one to three halogens; R4 and R5 are each independently H, D, or C. 1-6 alkyl; R6 and R7 are each independently H, D, or C. 1-6 alkyl; R8 and R9 are each independently H, D, or C. 1-6 Alkyl groups, or R8 and R9, form C=O with the attached carbon atom; R 10 C 1-6 Alkyl, cyano, or SR 10d The C 1-6 The alkyl group may optionally be substituted with one to three halogens; R 10d For H, D or C 1-6 alkyl; A is B is a 5- to 6-membered carbon ring or heterocycle, wherein the heterocycle contains 1 to 3 heteroatoms selected from N, O and S; m is 1, 2, or 3; n can be 0, 1, 2, or 3.

7. The pharmaceutical combination according to claim 6, wherein: X1 is selected from NH; X2 is selected from O; R 1a R 1b Each is independently selected from H, D, or C. 1-6 alkyl; R 2a R 2b Each is independently selected from H, D, or C. 1-6 alkyl; R3 represents H, D, and C. 1-6 Alkyl or halogen, the C 1-6 The alkyl group may optionally be substituted with one to three halogens; R4 and R5 are each independently H or D; R6 and R7 are each independently H or D; R8 and R9 are each independently H or D; R 10 For CF3 or SR 10d ; R 10d For H, D or C 1-6 alkyl; A is B is m is 1, 2, or 3; n can be 0, 1, 2, or 3.

8. The pharmaceutical combination according to claim 7, wherein: X1 is selected from NH; X2 is selected from O; R 1a R 1b Each is independently selected from H, D, or C. 1-3 alkyl; R 2a R 2b Each is independently selected from H, D, or C. 1-3 alkyl; R3 is selected from H, D, or CF3; R4 and R5 are each independently selected from H or D; R6 and R7 are each independently selected from H or D; R8 and R9 are each independently selected from H or D; R 10 For CF3; A is B is m is 1, 2, or 3; n is 0, 1, or 2.

9. The drug combination according to claim 2, characterized in that, The PARP7 inhibitor is selected from RBN-2397, ONO-7119, QLS1103, JAB-26766, NSP-5020, NSP-5033, EB400, or compounds of formula (I-3) or their pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives, wherein: in: X1 is NH or a 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle contains 1 to 3 heteroatoms selected from N and O; X2 is 0; R 1a R 1b Each independently is H, D, or C. 1-6 alkyl; R 2a R 2b Each independently is H, D, or C. 1-6 alkyl; R4 and R5 are each independently H, D, or C. 1-6 alkyl; R6 and R7 are each independently H, D, or C. 1-6 alkyl; R8 and R9 are each independently H, D, or C. 1-6 Alkyl groups; or R8 and R9 forming C=O with the attached carbon atom; R 10 C 1-6 Alkyl, C 1-6 Alkoxy, cyano or SR 10d The C 1-6 Alkyl, C 1-6 The alkoxy group may optionally be replaced by one to three halogens; R 10d For H, D or C 1-6 alkyl; A is B is a 5- to 6-membered carbon ring or heterocycle, wherein the heterocycle contains 1 to 3 heteroatoms selected from N, O and S; m is 1, 2, or 3; n can be 0, 1, 2, or 3.

10. The pharmaceutical combination according to claim 9, wherein: X1 is NH or a 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle contains 1 to 3 heteroatoms selected from N and O; X2 is 0; R 1a R 1b Each independently is H, D, or C. 1-3 alkyl; R 2a R 2b Each independently is H, D, or C. 1-3 alkyl; R4 and R5 are each independently H, D, or C. 1-3 alkyl; R6 and R7 are each independently H, D, or C. 1-3 alkyl; R8 and R9 are each independently H, D, or C. 1-3 Alkyl groups; or R8 and R9 forming C=O with the attached carbon atom; R 10 C 1-6 Alkyl, cyano or SR 10d The C 1-6 The alkyl group may optionally be substituted with one to three halogens; R 10d For H, D or C 1-6 alkyl; A is B is m is 1, 2, or 3; n is 0, 1, or 2.

11. The pharmaceutical combination according to claim 10, wherein: X1 is NH; X2 is 0; R 1a R 1b Each independently is H, D, or C. 1-3 alkyl; R 2a R 2b Each can be H or D independently; R4 and R5 are each independently H or D; R6 and R7 are each independently H or D; R8 and R9 are each independently H or D; R 10 For CF3; A is B is m is 1, 2, or 3; n is 0, 1, or 2.

12. The pharmaceutical combination according to any one of claims 1 to 11, characterized in that, The PARP7 inhibitor is selected from RBN-2397, ONO-7119, QLS1103, JAB-26766, NSP-5020, NSP-5033, EB400, or compounds listed below, or their pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives:

13. The drug combination according to any one of claims 1 to 12, wherein the PARP7 inhibitor is 14. The pharmaceutical combination according to any one of claims 1 to 12, characterized in that, The bispecific antibody is selected from PD-1 / VEGF bispecific antibody, PD-L1 / VEGF-A bispecific antibody, PD-1 / CTLA-4 bispecific antibody, CD3 / EpCAM / FcγR triple antibody, CD3 / CD19 bispecific antibody, EGFR / c-Met bispecific antibody, IL-17A / IL-17F bispecific antibody, Ang2 / VEGF-A bispecific antibody, PD-1 / CTLA-4 bispecific antibody, CD3 / CD20 bispecific antibody, CD3 / BCMA bispecific antibody, and CD3 / GPRC5D bispecific antibody. One or more combinations of CD3 / BCMA bispecific antibodies, CD3 / gp100 bispecific antibodies, CD3 / DLL3 bispecific antibodies, HER2 / HER3 bispecific antibodies, HER2 bispecific antibodies, PD-1 / CTLA-4 bispecific antibodies, EGFR / HER3 bispecific antibodies, CD3 / GPC3 bispecific antibodies, Claudin18.2 / CD3 bispecific antibodies, CD3 / CD19 bispecific antibodies, PD-L1 / TGF-β bispecific antibodies, PD-1 / TIGIT bispecific antibodies, and TGF-β / VEGF bispecific antibodies.

15. The pharmaceutical combination according to any one of claims 1 to 12, characterized in that, The bispecific antibody is selected from PD-1 / VEGF bispecific antibodies.

16. The pharmaceutical combination according to any one of claims 1 to 13, characterized in that, The bispecific antibody is selected from one or more combinations of AK112, SSGJ-707, Catumaxomab, Blinatumomab, Amivantamab, Bimekizumab, Faricimab, Cadonilimab, Mosunetuzumab, Glofitamab, Epcoritamab, Teclistamab, Talquetamab, Elranatamab, Tebentafusp, Tarlatamab, Odronextamab, Zenocutuzumab, Zanidatamab, Linvoseltamab, Volrustomig, Izalontamab, Velinotamig, Danvilostomig, Bafisontamab, CMD011, HBM7022, YK012, TQB2934, BA1201, AZD2936, ICP-B02, or Y332.

17. The pharmaceutical combination according to any one of claims 1 to 13, characterized in that, The bispecific antibody is selected from AK112 or SSGJ-707.

18. The pharmaceutical combination according to any one of claims 1 to 16, characterized in that, The PARP7 inhibitor and the bispecific antibody may be present in the same pharmaceutical composition, or the PARP7 inhibitor and the bispecific antibody may be present in different pharmaceutical compositions.

19. Use of the pharmaceutical combination according to any one of claims 1 to 18 in the preparation of a medicament for treating and / or preventing tumors.

20. The use according to claim 19, characterized in that, The PARP7 inhibitor and the bispecific antibody may be administered simultaneously or separately.

21. The use according to claim 20 or 19, wherein the total daily dose of the bispecific antibody is selected from 1-50 mg / kg, preferably 10-30 mg / kg, more preferably 18-22 mg / kg.

22. The use according to claim 20 or 19, wherein the total daily dose of the PARP7 inhibitor is selected from 50-1500 mg, preferably 100-1000 mg, more preferably 100-400 mg, measured in terms of the amount of free base.

23. The use according to any one of claims 19 to 22, characterized in that, The bispecific antibody is administered intravenously at frequencies of twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every 3-6 months, preferably once a week, once every two weeks, once every three weeks, or once every four weeks.

24. The use according to any one of claims 19 to 22, characterized in that, The PARP7 inhibitor is administered orally 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 three times a day, twice a day, or once a day.

Images