Pharmaceutical combination of PARP7 inhibitor in combination with ADC and use thereof in treating tumor

Abstract

The present application relates to a pharmaceutical combination of a PARP7 inhibitor in combination with ADC and use thereof in treating a tumor.

Description

PARP7 inhibitors combined with ADCs and their use in cancer treatment

[0001] This application claims priority to Chinese patent application 2025101068508, filed on January 23, 2025; Chinese patent application 2025101582614, filed on February 13, 2025; and Chinese patent application 2026100722142, 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 ADCs and their use in the treatment of tumors. Background Technology

[0003] Antibody-drug conjugates (ADCs) typically consist of an antibody, a covalent linker, and a cytotoxic drug. The monoclonal antibody is covalently linked to the cytotoxic drug via a chemical linker, combining the killing effect of traditional small molecule chemotherapy with the tumor-targeting properties of antibody drugs.

[0004] Anti-cancer drug agents (ADCs) have emerged as a novel class of drugs for treating hematologic malignancies and solid tumors. However, as with most cytotoxic drugs, the duration of objective response or clinical benefit of ADCs as monotherapy remains limited due to the emergence of resistance mechanisms. Therefore, combining ADCs with other anticancer drugs has become an important direction in ADC drug development.

[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 ADCs, compared with the monotherapy of each, has the effects of high efficacy, low toxicity, and overcoming ADC resistance.

[0007] Therefore, the present invention aims to provide a drug combination of a PARP7 inhibitor and an ADC, 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 ADC.

[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 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 1-6The 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. 1-6Alkyl 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 1-6The 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 C1-6 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 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 drug combination includes an ADC selected from DS-1062, DS8201, Mylotarg (gem-tuzumab), Adcetris (bentuximab), Kadcyla (trastuzumab-metazine conjugate), Besponsa (oligotuzumab), Lumoxicillin, Polivy, Padcev, Trodelvy, Blenrep, Zynlonta, Idixin, T... One or more combinations of ivdak, Elahere, Akalux, Ujvira, IBI343, SKB264, MRG004A, MRG003, 9MW2821, SHR-A1912, RC88, RC48, SYS6002, YL202 / BNT326, JSKN003, ATG-022, CMG901, HS-20093, BAT8006, BAT8007 or CS5001.

[0170] In one or more embodiments of the present invention, the drug combination includes an ADC selected from DS-1062 (DS-1062a; datopotamab deruxtecan; Dato-DXd; Datroway; datopotamab deruxtecan-dlnk; Dato-1062; Dato-1062).

[0171] In one or more embodiments of the present invention, the drug combination includes an ADC selected from DS8201 (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki; Enhertu; trastuzumab deruxtecan-nxki; DS-8201a; T-DXd; Dextromethorphan trastuzumab; Dextromethorphan trastuzumab; Enhertu).

[0172] In one or more embodiments of the present invention, the drug combination, wherein the PARP7 inhibitor and the ADC are present in the same drug composition, or the PARP7 inhibitor and the ADC are present in different drug compositions.

[0173] In one or more embodiments of the present invention, the drug combination includes:

[0174] (i) a first pharmaceutical composition comprising a PARP7 inhibitor, a pharmaceutically acceptable carrier and / or excipient; and

[0175] (ii) A second pharmaceutical composition comprising an ADC, a pharmaceutically acceptable carrier, and / or an excipient.

[0176] Alternatively, the drug combination may include:

[0177] A single pharmaceutical composition comprising a PARP7 inhibitor, an ADC, a pharmaceutically acceptable carrier, and / or an excipient.

[0178] One or more embodiments of the present invention provide the use of the pharmaceutical combinations involved in the treatment and / or prevention of tumors.

[0179] 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.

[0180] 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.

[0181] 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.

[0182] 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.

[0183] In one or more embodiments of the present invention, the PARP7 inhibitor and the RDC are the active pharmaceutical ingredients in the pharmaceutical composition.

[0184] 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.

[0185] 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.

[0186] 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 ADC are administered simultaneously or separately.

[0187] 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.

[0188] 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.

[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 tumor is selected from solid tumors and / or hematologic malignancies.

[0190] 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.

[0191] 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.

[0192] 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.

[0193] 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.

[0194] In one or more embodiments (e.g., embodiments of drug combination, drug composition, use or method of treating tumor), the breast cancer is preferably hormone receptor positive (HR+) breast cancer.

[0195] 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.

[0196] 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.

[0197] In one or more embodiments (e.g., embodiments of drug combination, drug composition, use or method of treating tumor), the uterine cancer is preferably endometrial cancer.

[0198] 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.

[0199] In one or more embodiments (e.g., embodiments of drug combinations, drug compositions, uses, or methods of treating tumors), the liver cancer is preferably hepatocellular carcinoma.

[0200] 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.

[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 drug combinations have a superior antitumor effect compared to using PARP7 inhibitors and / or ADCs alone.

[0202] 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.

[0203] 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 tumor volume is reduced by 0% or more, preferably by 40% or more, more preferably by 50% or more, for example by 60% or more, compared to the use of a PARP7 inhibitor alone. The subject is preferably a mouse.

[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 drug combinations have a better antitumor effect than ADCs alone.

[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 drug combination is administered to a subject suffering from a tumor, and the tumor volume is reduced by 40% or more, preferably by 50% or more, more preferably by 60% or more, such as by 70% or more, compared to ADC alone. The subject is preferably a mouse.

[0206] 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.

[0207] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0208] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0209] "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.

[0210] "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.

[0211] "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

[0212] Figure 1 shows the tumor growth curves of each group in Example 1.

[0213] Figure 2 shows the rate of weight change in each group in Example 1.

[0214] Figure 3 shows the tumor growth curves of each group in Example 2.

[0215] Figure 4 shows the rate of weight change for each group in Example 2. Detailed Implementation

[0216] 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.

[0217] 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.

[0218] Example 1: Pharmacodynamic test in a CT26 mouse tumor-bearing model

[0219] B-hHER2 CT26.WT cells (obtained by Biocytogen (Beijing) Pharmaceutical Technology Co., Ltd. through genetic modification of CT26.WT cells derived from ATCC) were cultured in RPMI 1640 medium containing 10% fetal bovine serum. When the cells reached the exponential growth phase, they were trypsinized, collected, counted, resuspended in PBS, and subcutaneously inoculated into the right back of 60 female Balb / c mice at a cell density of 1 × 10⁶ cells / year. 5 Inoculate one tumor per animal, with an inoculation volume of 100 μL. Wait until the average tumor volume reaches 40–80 mm. 3Around [time period missing], 24 mice were selected based on tumor volume and body weight and randomly assigned to four experimental groups (n=6 per group): G1 - blank control group, G2 - compound A monotherapy group (125 mg / kg, BID), G3 - DS8201 monotherapy group, and G4 - compound A (125 mg / kg, BID) + DS8201 combination group. 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. DS8201 was prepared using 0.9% sodium chloride injection and administered by intravenous injection at a dose of 10 mL / kg. Both the DS8201 monotherapy group and the compound A (125 mg / kg, BID) + DS8201 combination group received a single dose of 5 mg / kg DS8201 on day 0, and single doses of 10 mg / kg DS8201 on days 6, 11, and 15. Both the compound A monotherapy group (125 mg / kg, BID) and the compound A (125 mg / kg, BID) + DS8201 combination group were administered compound A continuously for 15 days.

[0220] During the drug administration period, tumor volume was measured and tumor growth curves were plotted. Mouse body weight was measured to calculate the rate of weight change. Figure 1 shows the tumor growth curves for each group in Example 1. Figure 2 shows the rate of weight change for each group in Example 1. Table 1 shows the D... 15 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%.

[0221] Table 1

[0222] The results showed that the tumor volume of the experimental animals treated with compound A and DS8201 was small, and the tumor volume of the compound A and DS8201 combination group was significantly smaller than that of other groups. The combination of compound A and DS8201 had a significant synergistic anti-tumor effect. The experimental animals in the single-drug group and the combination group showed stable weight gain, indicating that the test substance was safe.

[0223] Example 2: Pharmacodynamic test in MC38 mouse tumor-bearing model

[0224] MC38-hTrop2 Hucell cells were cultured in DMEM medium containing 10% fetal bovine serum and 1.5 μg / mL puromycin. When the cells reached the exponential growth phase, they were trypsinized, collected, counted, resuspended in PBS, and subcutaneously seeded onto the right back of 40 female C57BL / 6-Trop2HuGEMM mice at a density of 1 × 10⁻⁶ cells. 6 One tumor per animal, with an inoculation volume of 100 μL. Inoculate until the average tumor volume reaches 97 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 monotherapy group (75 mg / kg, BID), a datopotamab deruxtecan monotherapy group (10 mg / kg, QW), and a combination group of compound A (75 mg / kg, BID) and datopotamab deruxtecan (10 mg / kg, QW). 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. Datopotamab deruxtecan was prepared using PBS and administered by intravenous injection at a dose of 10 mL / kg. Administration continued for 17 days. During the administration period, tumor volume was measured and tumor growth curves were plotted, and mouse body weight was measured to calculate the rate of change in body weight.

[0225] During the drug administration period, tumor volume was measured and tumor growth curves were plotted. Mouse body weight was measured to calculate the rate of weight change. Figure 3 shows the tumor growth curves for each group in Example 2. Figure 4 shows the rate of weight change for each group in Example 2. Table 2 shows the D... 17 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%.

[0226] Table 2

[0227] The results showed that the tumor volume of the experimental animals treated with compound A and Datopotamab deruxtecan was small, and the tumor volume of the compound A and Datopotamab deruxtecan combination group was significantly smaller than that of other groups. The combination of compound A and Datopotamab deruxtecan had a significant synergistic anti-tumor effect. The experimental animals in both the single-drug group and the combination group showed stable weight gain, indicating that the test substance had good safety.

[0228] In summary, the combination of compound A and ADC exhibits better antitumor efficacy and safety compared to ADC alone. This demonstrates that the drug combination of the present invention has a significant synergistic effect.

[0229] 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.

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