Pharmaceutical combination of PARP7 inhibitor combined with RDC and use thereof in tumor treatment

Abstract

The present application relates to a pharmaceutical combination of a PARP7 inhibitor combined with an RDC and use thereof in tumor treatment. Radionuclide drug conjugates (RDCs) are a new targeted radiotherapy technology. The combination therapy of the PARP7 inhibitor with the RDC exhibits good anticancer efficacy and overcomes RDC drug resistance compared to monotherapy with either agent alone.

Description

PARP7 inhibitors combined with RDC and their use in cancer treatment

[0001] This application claims priority to Chinese patent application 2025101066451, filed on January 23, 2025; Chinese patent application 2025103397891, filed on March 21, 2025; and Chinese patent application 2026100724294, filed on 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 RDCs, and their use in the treatment of tumors. Background Technology

[0003] 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.

[0004] 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.

[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 with RDC has the effects of high efficacy, low toxicity, and overcoming RDC resistance compared to the individual monotherapy.

[0007] The present invention provides a drug combination of PARP7 inhibitor and RDC 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) an RDC.

[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 R2b 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 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 1-6Alkoxy, 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 2b Each 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 R 2b 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 1-6 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;

[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 C 1-6 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 any of the following compounds, or their pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives:

[0167] In one or more embodiments of the present invention, the drug combination includes a PARP7 inhibitor.

[0168] In one or more embodiments of the present invention, the drug combination includes a PARP7 inhibitor.

[0169] In one or more embodiments of the present invention, the RDC included in the drug combination may be selected from Pluvicto (i.e., 177 Lu-PSMA-617), Lutathera (lutetium oxide octreotide), RYZ-101, 177 Lu-PSMA-I&T 177 Lu-PNT2002 225 Ac-PSMA-617 177 Lu-edotreotide (lutetium-177-edotreotide), iodine [ 131[I] Metuximab, Locametz, Illuccix, Pylarify, Gallium GA-68 Gozetotide, Detectnet, Gallium DOTATOC Ga-68, Netspot, or radium chloride [ 223 Ra] injection solution contains one or more combinations of radionuclides. Common radionuclides in RDCs may include... 68 Ga、 177 Lu、 161 Tb, 225 Ac、 226 Ra et al.

[0170] In one or more embodiments of the present invention, the drug combination includes an RDC of: 177 Lu-PSMA-617 and / or 225 Ac-PSMA-617.

[0171] In one or more embodiments of the present invention, the drug combination includes an RDC of: 177 Lu-PSMA-617(Pluvicto; lutetium Lu 177; vipivotide tetraxetan; 177Lu-DKFZ-617PSMA; (177)Lu-DKFZ-617PSMA; (177)Lu-DKFZ-PSMA-617; 177Lu-PSMA-D KFZ-617; lutetium-177-PSMA-617; (177Lu)-PSMA-617; 177Lu-DKFZ-PSMA-617; lutetium[177Lu]tersivirpitide; Pavilion).

[0172] In one or more embodiments of the present invention, the drug combination includes an RDC of: 225 Ac-PSMA-617.

[0173] In one or more embodiments of the present invention, the drug combination is drug combination I or drug combination II, wherein,

[0174] The drug combination I comprises: (a) a PARP7 inhibitor and (b) RDC; the PARP7 inhibitor is The RDC is 177 Lu-PSMA-617;

[0175] The drug combination II comprises: (a) a PARP7 inhibitor and (b) RDC; the PARP7 inhibitor is The RDC is 225 Ac-PSMA-617.

[0176] In one or more embodiments of the present invention, in the drug combination I, the PARP7 inhibitor is The RDC is 177 Lu-PSMA-617.

[0177] In one or more embodiments of the present invention, in the drug combination II, the PARP7 inhibitor is The RDC is 225 Ac-PSMA-617.

[0178] In one or more embodiments of the present invention, the drug combination, wherein the PARP7 inhibitor and the RDC are present in the same drug composition, or the PARP7 inhibitor and the RDC are present in different drug compositions.

[0179] In one or more embodiments of the present invention, the drug combination includes:

[0180] (i) a first pharmaceutical composition comprising a PARP7 inhibitor, a pharmaceutically acceptable carrier and / or excipient; and

[0181] (ii) A second pharmaceutical composition comprising an RDC, a pharmaceutically acceptable carrier, and / or an excipient.

[0182] Alternatively, the drug combination may include:

[0183] A single pharmaceutical composition comprising a PARP7 inhibitor, an RDC, a pharmaceutically acceptable carrier, and / or an excipient.

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

[0190] 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.

[0191] 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.

[0192] In one or more embodiments of the present invention (e.g., embodiments of drug combinations, pharmaceutical compositions, uses, or methods of treating tumors), the subject of the drug combination is a mammal, preferably selected from one or more of humans, non-human primates, and laboratory animals, such as laboratory animals.

[0193] In one or more embodiments of the present invention (e.g., embodiments of drug combinations, drug compositions, uses, or methods of treating tumors), the laboratory animal is selected from one or more of rats, mice, and guinea pigs, preferably mice.

[0194] 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 RDC are administered simultaneously or separately.

[0195] 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.

[0196] 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 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.

[0197] 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 twice daily.

[0198] In one or more embodiments of the present invention (e.g., embodiments of pharmaceutical 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, or once every four weeks, preferably twice a day or once a day.

[0199] 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 twice daily.

[0200] 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 for a period of five days or more, such as five days, one week, ten days, two weeks, twenty days, three weeks, four weeks, one month, two months, three months, four months, five months, six months, one year, two years, or longer.

[0201] In one or more embodiments of the present invention (e.g., embodiments of drug combinations, pharmaceutical compositions, uses, or methods of treating tumors), the PARP7 inhibitor is administered over a period of twenty days.

[0202] In one or more embodiments of the present invention (e.g., embodiments of pharmaceutical compositions, uses, or methods of treating tumors), the PARP7 inhibitor is administered orally twice daily for a period of twenty days.

[0203] 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, more preferably 100-400 mg, with the amount of free base as the measurement value.

[0204] 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.

[0205] In one or more embodiments of the present invention (e.g., embodiments of drug combinations, pharmaceutical compositions, uses, or methods of treating tumors), the total daily dose of the PARP7 inhibitor is selected from 50-1500 mg, measured as the amount of free base.

[0206] 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 100-1000 mg, measured as the amount of free base.

[0207] 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 100-400 mg, measured as the amount of free base.

[0208] In one or more embodiments of the present invention (e.g., embodiments of drug combinations, pharmaceutical compositions, uses, or methods of treating tumors), the single-dose dose of the PARP7 inhibitor is selected from 10-100 mg / kg, preferably 50-75 mg / kg, based on the weight of the subject to which it is administered. The subject is preferably a mouse.

[0209] In one or more embodiments of the present invention (e.g., embodiments of drug combinations, pharmaceutical compositions, uses, or methods of treating tumors), the PARP7 inhibitor is administered orally twice daily for a period of twenty days, with a single dose of 50-75 mg / kg based on the weight of the subject. The subject is preferably a mouse.

[0210] In one or more embodiments of the present invention (e.g., embodiments of drug combinations, drug compositions, uses, or methods of treating tumors), the RDC is administered by intravenous injection or intravenous infusion, preferably by intravenous injection.

[0211] In one or more embodiments of the present invention (e.g., embodiments of drug combinations, drug compositions, uses, or methods of treating tumors), the RDC is administered at a frequency of single dose, once daily, once every two days, once every three days, once every four days, once every five days, once every six days, once weekly, once every two weeks, once every three weeks, or once every four weeks, preferably as a single dose.

[0212] In one or more embodiments of the present invention (e.g., embodiments of drug combinations, drug compositions, uses, or methods of treating tumors), the single dose of the RDC is 0.05-110 MBq, for example 0.111 MBq or 100 MBq.

[0213] In one or more embodiments of the present invention (e.g., embodiments of drug combinations, pharmaceutical compositions, uses, or methods of treating tumors), the RDC is administered via intravenous injection at a single-dose frequency, with a single-dose dose of 0.111 MBq or 100 MBq. The subject is preferably a mouse.

[0214] In one or more embodiments of the present invention (e.g., embodiments of drug combinations, pharmaceutical compositions, uses, or methods of treating tumors), when the drug combination is drug combination I, the single dose of the PARP7 inhibitor is 50 mg / kg, and the single dose of the RDC is 100 MBq. The subject is preferably a mouse. The tumor is preferably colon cancer.

[0215] In one or more embodiments of the present invention (e.g., embodiments of drug combinations, pharmaceutical compositions, uses, or methods of treating tumors), when the drug combination is drug combination II, the single dose of the PARP7 inhibitor is 75 mg / kg, and the single dose of the RDC is 0.111 MBq. The subject is preferably a mouse. The tumor is preferably prostate cancer.

[0216] In one or more embodiments of the present invention (e.g., embodiments of drug combinations, drug compositions, uses, or methods of treating tumors), when the drug combination is drug combination I or drug combination II, the PARP7 inhibitor is administered orally twice daily or once daily for a period of 18-25 days, with a single dose of 40-80 mg / kg; the RDC is administered intravenously, with a single dose on day 0, at a dose of 90-110 MBq or 0.05-0.5 MBq. The subject is preferably a mouse. The tumor is preferably colon cancer or prostate cancer.

[0217] In one or more embodiments of the present invention (e.g., embodiments of drug combinations, pharmaceutical compositions, uses, or methods of treating tumors), when the drug combination is drug combination I, the PARP7 inhibitor is administered orally twice daily or once daily for a period of 18–25 days, with a single dose of 40–60 mg / kg. The RDC is administered intravenously, with a single dose on day 0, at a dose of 90–110 MBq. The subject is preferably a mouse. The tumor is preferably colon cancer.

[0218] In one or more embodiments of the present invention (e.g., embodiments of drug combinations, drug compositions, uses, or methods of treating tumors), when the drug combination is drug combination I, the PARP7 inhibitor is administered orally twice daily at 6-hour intervals for a 20-day period, with a single dose of 50 mg / kg. The RDC is administered intravenously as a single dose on day 0 at a dose of 100 MBq. The subject is preferably a mouse. The tumor is preferably colon cancer.

[0219] In one or more embodiments of the present invention (e.g., embodiments of drug combinations, drug compositions, uses, or methods of treating tumors), when the drug combination is drug combination II, the PARP7 inhibitor is administered orally twice daily or once daily for a period of 18–25 days, with a single dose of 70–80 mg / kg. The RDC is administered intravenously, with a single dose on day 0, at a dose of 0.05–0.5 MBq. The subject is preferably a mouse. The tumor is preferably prostate cancer.

[0220] In one or more embodiments of the present invention (e.g., embodiments of drug combinations, pharmaceutical compositions, uses, or methods of treating tumors), when the drug combination is drug combination II, the PARP7 inhibitor is administered orally twice daily at 6-hour intervals for a 20-day period, with a single dose of 75 mg / kg. The RDC is administered intravenously as a single dose on day 0, at a dose of 0.111 MBq. The subject is preferably a mouse. The tumor is preferably prostate cancer.

[0221] 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.

[0222] In one or more embodiments (e.g., embodiments of a drug combination, a drug composition, a use or a method of treating a tumor), the tumor is selected from malignant solid tumors; preferably, the tumor is selected from advanced malignant solid tumors.

[0223] 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.

[0224] 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.

[0225] 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.

[0226] In one or more embodiments (e.g., embodiments of drug combinations, drug compositions, uses, or methods of treating tumors), the lung cancer is selected from non-small cell lung cancer or neuroendocrine lung cancer; preferably, the non-small cell lung cancer is selected from squamous cell carcinoma of the lung or adenocarcinoma of the lung; the breast cancer is selected from hormone receptor-positive (HR+) breast cancer; the head and neck cancer is selected from head and neck squamous cell carcinoma; and the uterine cancer is selected from endometrial cancer.

[0227] In one or more embodiments (e.g., embodiments of drug combinations, drug compositions, uses, or methods of treating tumors), the lung cancer is non-small cell lung cancer or neuroendocrine lung cancer; the non-small cell lung cancer is squamous cell carcinoma or adenocarcinoma of the lung; the breast cancer is hormone receptor-positive (HR+) breast cancer; the esophageal cancer is squamous cell carcinoma or adenocarcinoma of the esophagus; the head and neck cancer is squamous cell carcinoma of the head and neck; the uterine cancer is endometrial cancer; the central nervous system cancer is glioma; the liver cancer is hepatocellular carcinoma; and the B-cell lymphoma is diffuse large B-cell lymphoma.

[0228] 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 tumor is colon cancer or prostate cancer.

[0229] In one or more embodiments of the present invention (e.g., embodiments of a drug combination, pharmaceutical composition, use, or method of treating a tumor), the drug combination is administered to a subject suffering from a tumor, and the tumor inhibition rate is 40% or higher, preferably 50% or higher, more preferably 60% or higher. The subject is preferably a mouse. The tumor is preferably colon cancer or prostate cancer.

[0230] 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 RDCs alone.

[0231] 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.

[0232] 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 suffering from a tumor, resulting in a reduction in tumor volume of 20% or more, preferably 30% or more, and more preferably 40% or more, compared to the use of a PARP7 inhibitor alone. The subject is preferably a mouse. The tumor is preferably colon cancer or prostate cancer.

[0233] 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 RDC alone.

[0234] 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 suffering from a tumor, resulting in a reduction in tumor volume of 40% or more, preferably 50% or more, and more preferably 60% or more, compared to RDC alone. The subject is preferably a mouse. The tumor is preferably colon cancer or prostate cancer.

[0235] 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 RDCs alone.

[0236] 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 combination is superior to that of RDC alone.

[0237] 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 suffering from a tumor, and the subject's weight change is reduced by 40% or more, preferably by 50% or more, more preferably by 60% or more, such as 70% or more, compared to RDC alone. The subject is preferably a mouse. The tumor is preferably colon cancer or prostate cancer.

[0238] 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 has a synergistic anti-tumor effect. The tumor is preferably colon cancer or prostate cancer.

[0239] 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 has a synergistic anti-tumor effect. For example, when the drug combination is administered to a subject with a tumor, the tumor inhibition rate in the subject is 10% or more higher than the sum of the tumor inhibition rates of PARP7 inhibitors alone and RDCs alone, preferably 15% or more, more preferably 20% or more, and more preferably 30% or more. The subject is preferably a mouse. The tumor is preferably colon cancer or prostate cancer. Beneficial effects:

[0240] The antitumor efficacy and safety of the PARP7 inhibitor combined with RDC in this invention are significantly better than those of RDC alone. This indicates that the combined use of the PARP7 inhibitor and RDC in this invention has a significant synergistic effect.

[0241] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0242] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0243] "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.

[0244] "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.

[0245] "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

[0246] Figure 1 is a line graph of tumor volume in each group in Example 1.

[0247] Figure 2 is a line graph showing the rate of change in body weight for each group in Example 1.

[0248] Figure 3 is a line graph of tumor volume in each group in Example 2.

[0249] Figure 4 is a line graph showing the rate of change in body weight for each group in Example 2. Detailed Implementation

[0250] The present invention will be described in detail below with reference to embodiments, but this does not imply any adverse limitation on the invention. The present invention has been described in detail, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the concept and scope of the invention.

[0251] 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.

[0252] Example 1: In vivo efficacy test of hPSMA-MC38 subcutaneous tumor-bearing hPSMA mice.

[0253] 1. Animals and materials

[0254] The B-hPSMA-MC38 subcutaneous tumor model in B-hPSMA mice was provided by Biocytogen (Beijing) Pharmaceutical Technology Co., Ltd. The B-hPSMA MC38 cells were cultured in Dulbecco's Modified Eagle's Medium (DMEM) containing 10% inactivated fetal bovine serum at 37°C and 5% CO2.

[0255] 2. Experimental Design

[0256] Modeling: The seeding density of B-hPSMA MC38 cells was 5 × 10⁻⁶. 5 Forty-two male B-hPSMA mice (6-7 weeks old, C57 / BL6 strain) were subcutaneously inoculated with 0.1 mL of the drug on the right back of each mouse. Two days after tumor inoculation, the animals were airlifted to Tongrui Biopharmaceutical (Chengdu) Co., Ltd. for efficacy testing. The efficacy was determined when the average tumor volume reached 200 mm². 3 Around 10:00 AM, 24 mice were selected for the group based on tumor volume and mouse weight.

[0257] Grouping: Animals were randomly assigned to four experimental groups, with six animals in each group. The groups were: G1 - blank control, G2 - compound A alone (50 mg / kg, BID), G3 - ... 177 Lu-PSMA-617 monotherapy (100 MBq / vial), G4-compound A+ 177 Lu-PSMA-617 group (50mg / kg, BID + 100MBq / animal).

[0258] Administration method: Compound A is administered by gavage twice a day, with an interval of 6 hours, for a period of 20 days; 177 Lu-PSMA-617 was administered intravenously in a single dose on day 0.

[0259] Experimental Results: Figure 1 is a line graph of tumor volume in each group of Example 1. Figure 2 is a line graph of body weight change rate in each group of Example 1. Table 1 shows the results for D. 20 The tumor inhibition rate of each group is calculated using the following formula: Tumor inhibition rate = (G1 - average tumor volume of the blank group - average tumor volume of the experimental group) / G1 - average tumor volume of the blank group × 100%.

[0260] Table 1

[0261] The results showed that compound A combined with 177 Lu-PSMA-617 exhibits significant synergistic anti-tumor effects and demonstrates good safety.

[0262] Example 2: In vivo efficacy test of hPSMA-RM1 cell-bearing tumor-bearing mice

[0263] All efficacy studies were conducted at Tongrui Biopharmaceutical (Chengdu) Co., Ltd. h-PSMA-RM1 cells were cultured in RPMI 1640 medium containing 10% FBS and 2 μL / mg puromycin. When the h-PSMA-RM1 cells were in the exponential growth phase, the cells were collected and resuspended in PBS to a suitable concentration for subcutaneous tumor inoculation in mice. The inoculation density of h-PSMA-RM1 cells was 5 × 10⁶ cells / year. 6 Thirty-two male C57BL / 6J mice (6-8 weeks old) were subcutaneously inoculated with 0.1 mL of the solution into the right back (near the forelimb) of each mouse. The inoculation continued until the average tumor volume reached 73.8 mm. 3 Around 10:00 AM, 24 mice were selected based on tumor volume and body weight and randomly assigned to 4 experimental groups, with 6 mice in each group. The groups were designated as G1-blank group, G2-... 225 Ac-PSMA-617 monotherapy (3 μCi (0.111 MBq) / animal), G3-compound A monotherapy (75 mg / kg, BID), G4-compound A+ 225Ac-PSMA-617 group (75 mg / kg, BID + 3 μCi (0.111 MBq) / animal). Administration method: 225 Ac-PSMA-617 was administered intravenously once on day D0; compound A was administered by gavage twice daily, with a dosing interval of 6 hours, for a period of 20 days. Figure 3 shows a line graph of tumor volume in each group in Example 2. Figure 4 shows a line graph of body weight change rate in each group in Example 2.

[0264] The results showed that compound A combined with 225 Ac-PSMA-617 exhibits significant synergistic anti-tumor effects and demonstrates good safety.

[0265] In summary, the combination of compound A and RDC exhibits better antitumor efficacy and safety compared to RDC alone. This demonstrates that the drug combination of the present invention has a significant synergistic effect.

[0266] 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) RDC.

2. The drug combination according to claim 1, characterized in that, The PARP7 inhibitor is 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: In the compound shown in formula (I): 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 is 0, 1, 2 or 3; Preferably, in the compound represented by formula (I): 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.

3. The drug combination according to claim 2, characterized in that, The PARP7 inhibitor is 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, wherein: In the compound shown by formula (I-1): 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.

4. The drug combination according to claim 2, characterized in that, The PARP7 inhibitor is 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: In the compound shown in formula (I-2): 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 is 0, 1, 2, or 3; Preferably, in the compound represented by formula (I-2): 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 is 0, 1, 2, or 3; More preferably, in the compound represented by formula (I-2): 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 is 0, 1, 2, or 3; More preferably, in the compound shown in formula (I-2): 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.

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-3) or their pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives, wherein: In the compound shown in formula (I-3): 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 is 0, 1, 2, or 3; Preferably, in the compound represented by formula (I-3): 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; Further preferred, in the compound shown in formula (I-3): 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.

6. The pharmaceutical combination according to any one of claims 1 to 5, characterized in that, The PARP7 inhibitor is selected from RBN-2397, ONO-7119, QLS1103, JAB-26766, NSP-5020, NSP-5033, EB400, or any of the following compounds, or their pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives: Preferably, the PARP7 inhibitor is More preferably, PARP7 inhibitors are 7. The drug combination according to claim 1, characterized in that, The RDC is selected from 177 Lu-PSMA-617, Lutathera, RYZ-101, 177 Lu-PSMA-I&T 177 Lu-PNT2002 225 Ac-PSMA-617 177 Lu-edotreotide, iodine [ 131 [I] Metuximab, Locametz, Illuccix, Pylarify, Gallium GA-68 Gozetotide, Detectnet, Gallium DOTATOC Ga-68, Netspot, and radium chloride [ 223 Ra] injection solution, preferably one or more combinations thereof. 177 Lu-PSMA-617 and / or 225 Ac-PSMA-617.

8. The drug combination according to claim 1, characterized in that, The drug combination is either drug combination I or drug combination II, wherein, The drug combination I comprises: (a) a PARP7 inhibitor and (b) RDC; the PARP7 inhibitor is (For example The RDC is... 177 Lu-PSMA-617; The drug combination II comprises: (a) a PARP7 inhibitor and (b) RDC; the PARP7 inhibitor is (For example The RDC is... 225 Ac-PSMA-617.

9. The pharmaceutical combination according to any one of claims 1 to 8, characterized in that, The PARP7 inhibitor and the RDC are present in the same pharmaceutical composition, or the PARP7 inhibitor and the RDC are present in different pharmaceutical compositions. Preferably, the drug combination comprises: (i) a first pharmaceutical composition comprising the PARP7 inhibitor and a pharmaceutically acceptable carrier and / or excipient; and (ii) a second pharmaceutical composition comprising the RDC and a pharmaceutically acceptable carrier and / or excipient; Alternatively, the drug combination may include: A single pharmaceutical composition comprising the aforementioned PARP7 inhibitor, the aforementioned RDC, and a pharmaceutically acceptable carrier and / or excipient.

10. The pharmaceutical combination according to any one of claims 1 to 9, characterized in that, It meets one or more of the following conditions: (1) The subject of the drug combination is a mammal, preferably selected from one or more of humans, non-human primates and laboratory animals, such as laboratory animals; the laboratory animals are preferably selected from one or more of rats, mice and guinea pigs; (2) The PARP7 inhibitor and the RDC are administered simultaneously or separately; (3) The PARP7 inhibitor is administered orally; (4) The PARP7 inhibitor is administered 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. (5) The administration period of the PARP7 inhibitor is five days or more, such as five days, one week, ten days, two weeks, twenty days, three weeks, four weeks, one month, two months, three months, four months, five months, half a year, one year, two years or longer; (6) The total daily dose of the PARP7 inhibitor is 50-1500 mg, measured by the amount of free base; (7) The RDC is administered by intravenous injection or intravenous infusion; (8) The administration frequency of the RDC is 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.

11. The pharmaceutical combination according to claim 10, characterized in that, It meets one or more of the following conditions: (1) The subjects of the drug combination were mice; (2) The PARP7 inhibitor is administered twice daily or once daily, preferably twice daily; (3) The dosing cycle of the PARP7 inhibitor is twenty days; (4) The total daily dose of the PARP7 inhibitor is 100-1000 mg, preferably 100-400 mg, with the amount of free base as the measurement value; (5) The RDC is administered via intravenous injection; (6) The RDC is administered once.

12. Use of the pharmaceutical combination according to any one of claims 1 to 11 in the preparation of a medicament for treating and / or preventing tumors.

13. The use according to claim 12, characterized in that, The tumor is a solid tumor and / or a hematologic malignancy; Preferably, the tumor is a malignant solid tumor; more preferably, the tumor is an advanced malignant solid tumor; even more preferably, the tumor is colon cancer or prostate cancer.

14. The use according to claim 13, characterized in that, It meets one or more of the following conditions: (1) The solid tumor is breast cancer, central nervous system cancer, uterine cancer, cervical cancer, kidney cancer, adrenal cancer, lung cancer, esophageal cancer, head and neck cancer, ovarian cancer, pancreatic cancer, liver cancer, prostate cancer, endometrial 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 tumor with PARP7 amplification; 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 head and neck cancer is preferably squamous cell carcinoma of the head and neck; the uterine cancer is preferably endometrial cancer; the esophageal cancer is preferably squamous cell carcinoma or adenocarcinoma of the esophagus; the central nervous system cancer is preferably glioma; the liver cancer is preferably hepatocellular carcinoma. (2) The hematologic malignancy is selected from leukemia, myeloma and lymphoma; preferably, the hematologic malignancy is Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, B-cell lymphoma, small lymphocytic lymphoma, T-cell lymphoma, pilocellular lymphoma, Burkert's lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia or chronic myeloid leukemia; the B-cell lymphoma is preferably diffuse large B-cell lymphoma.

15. The use according to any one of claims 12 to 14, characterized in that, It meets one or more of the following conditions: (1) The drug combination has a better anti-tumor effect than PARP7 inhibitors alone. For example, when the drug combination is administered to a subject with a tumor, the tumor volume is reduced by 20% or more, preferably by 30% or more, and more preferably by 40% or more compared to PARP7 inhibitors alone. (2) The drug combination has a better anti-tumor effect than RDC alone. For example, when the drug combination is administered to a subject with a tumor, the tumor volume is reduced by 40% or more, preferably by 50% or more, and more preferably by 60% or more compared with RDC alone. (3) The safety of the drug combination is better than that of RDC alone. For example, when the drug combination is administered to a subject with a tumor, the subject’s weight change range is reduced by 40% or more, preferably by 50% or more, more preferably by 60% or more, such as by 70% or more. (4) The combination of drugs is administered to a subject with a tumor, and the tumor inhibition rate is 40% or higher, preferably 50% or higher, more preferably 60% or higher; (5) The drug combination has a synergistic anti-tumor effect. For example, when the drug combination is administered to a subject with a tumor, the tumor inhibition rate of the subject is 10% or more higher than the sum of the tumor inhibition rates of PARP7 inhibitor alone and RDC alone, preferably 15% or more, more preferably 20% or more, and more preferably 30% or more.

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