Composition of piperazine compound and PD-1 inhibitor or PD-l1 inhibitor and use thereof in treating tumors

Abstract

The present application relates to a combination of a piperazine compound and a PD-1 inhibitor antibody or a PD-L1 inhibitor antibody and use thereof in treating tumors.

Description

Composition of piperazine compound and PD-1 inhibitor or PD-L1 inhibitor and use thereof in treating tumors Technical Field

[0001] This application belongs to the field of medical technology and relates to a drug combination that can be used for anti-tumor treatment. Specifically, this application relates to a composition based on a piperazine compound and a PD-1 inhibitor antibody or a PD-L1 inhibitor, and its use in treating tumors. Background Art

[0002] Programmed death 1 (PD1, Pdcd1, or CD279) is a 55KD receptor protein related to the CD28 / CTLA4 costimulatory / inhibitory receptor family. Cancer cells express PD-L1, the ligand for PD-1, which allows them to evade the host immune system. Marketed PD-1 inhibitors can significantly prolong overall survival by interfering with tumor immunosuppression mechanisms. However, this treatment approach only elicits responses in a subset of patients, or some patients may experience a favorable initial response, only to experience decreased or absent efficacy over time. Therefore, new and improved therapies are urgently needed to enhance the therapeutic effects of existing therapies.

[0003] Summary of the Invention

[0004] The applicant's PCT application PCT / CN2022 / 094124 describes the use of a piperazine derivative for the treatment of cancer. The compound described in the specification exhibits high selectivity and significant inhibitory activity against PARP7. Subsequent studies unexpectedly discovered that the piperazine derivative, when combined with a PD-1 inhibitor antibody, can significantly enhance the anti-tumor efficacy of either a PD-1 inhibitor antibody or a PD-L1 inhibitor antibody.

[0005] Therefore, the present invention provides a composition of a piperazine compound and a PD-1 inhibitor antibody or a PD-L1 inhibitor antibody and its use in treating tumors.

[0006] One or more embodiments of the present invention provide a pharmaceutical combination of at least two components, wherein component A is a PD-1 inhibitor antibody or a PD-L1 inhibitor antibody, and component B is a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof:

[0007] in:

[0008] X1 is NH, O or a 4- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N and O;

[0009] X2 is O or a single bond;

[0010] X3 and X4 are each independently C or N;

[0011] R 1a 、R 1b Each independently is H, D or C 1-6 Alkyl; or R 1a 、R 1b Together with the carbon atom to which it is attached, it forms a 3- to 5-membered cycloalkyl group;

[0012] R 2a 、R 2b Each independently is H, D or C 1-6 Alkyl; or R 2a 、R 2b Together with the carbon atom to which it is attached, it forms a 3- to 5-membered cycloalkyl group;

[0013] R3 is H, D, C 1-6 Alkyl, halogen or cyano, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens;

[0014] R4 and R5 are each independently H, D or C 1-6 Alkyl; or R4, R5 and the connected carbon atom form a 3 to 5-membered cycloalkyl;

[0015] R6 and R7 are each independently H, D or C 1-6 Alkyl; or R6, R7 and the connected carbon atom form C=O;

[0016] R8 and R9 are each independently H, D or C 1-6 Alkyl; or R8, R9 and the carbon atom to which they are connected form C=O; or R8 and R9 and the carbon atom to which they are connected form a 3- to 5-membered cycloalkyl;

[0017] 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 a 3 to 5-membered cycloalkyl group, the C 1-6 Alkyl, C 1-6 Alkoxy is optionally substituted with 1 to 3 halogens;

[0018] R 10a 、R 10b 、R 10c 、R 10d Each independently is H, D or C 1-6 alkyl;

[0019] A is R a C 1-6Alkyl, C 3-5 Cycloalkyl, halogen or cyano, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens;

[0020] B is a 5- to 10-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S;

[0021] C is a 5- to 6-membered heterocyclic ring containing 1 to 3 N heteroatoms;

[0022] m is 1, 2, or 3;

[0023] n is 0, 1, 2, or 3;

[0024] p is 0, 1, 2 or 3.

[0025] One or more embodiments of the present invention provide a pharmaceutical combination of at least two components, component A is a PD-1 inhibitor antibody, and component B is a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof, wherein:

[0026] X1 is NH, O or a 4- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N and O;

[0027] X2 is O or a single bond;

[0028] X3 and X4 are each independently C or N;

[0029] R 1a 、R 1b Each independently is H, D or C 1-6 alkyl;

[0030] R 2a 、R 2b Each independently is H, D or C 1-6 Alkyl; or R 2a 、R 2b Together with the carbon atom to which it is attached, it forms a 3- to 5-membered cycloalkyl group;

[0031] R3 is H, D, C 1-6 Alkyl, halogen or cyano, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens;

[0032] R4 and R5 are each independently H, D or C 1-6 Alkyl; or R4, R5 and the connected carbon atom form a 3 to 5-membered cycloalkyl;

[0033] R6 and R7 are each independently H, D or C 1-6 alkyl;

[0034] R8 and R9 are each independently H, D or C 1-6 Alkyl; or R8, R9 and the connected carbon atom form C=O;

[0035] 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 a 3 to 5-membered cycloalkyl group, the C 1-6 Alkyl, C 1-6 Alkoxy is optionally substituted with 1 to 3 halogens;

[0036] R 10a 、R 10b 、R 10c 、R 10d Each independently is H, D or C 1-6 alkyl;

[0037] A is R a C 1-6 Alkyl, C 3-5 Cycloalkyl, halogen or cyano, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens;

[0038] B is a 5- to 6-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S;

[0039] C is a 5- to 6-membered heterocyclic ring containing 1 to 3 N heteroatoms;

[0040] m is 1, 2, or 3;

[0041] n is 0, 1, 2, or 3;

[0042] p is 0, 1, 2 or 3.

[0043] One or more embodiments of the present invention provide a pharmaceutical combination of at least two components, wherein component A is a PD-1 inhibitor antibody, and component B is a compound of formula (I-1) or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof:

[0044] in:

[0045] X1 is NH or a 4- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N and O;

[0046] X2 is 0;

[0047] X3 and X4 are each independently C or N;

[0048] R 1a 、R 1b Each independently is H, D or C 1-6 alkyl;

[0049] R 2a 、R 2b Each independently is H, D or C 1-6 alkyl;

[0050] R3 is H, D, C 1-6 Alkyl or halogen, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens;

[0051] R4 and R5 are each independently H, D or C 1-6 alkyl;

[0052] R6 and R7 are each independently H, D or C 1-6 alkyl;

[0053] R8 and R9 are each independently H, D or C 1-6 Alkyl; or R8 and R9 form C=O with the carbon atom to which they are connected;

[0054] R 10 C 1-6 Alkyl, C 1-6 Alkoxy, cyano or SR 10d , the C 1-6 Alkyl, C 1-6 Alkoxy is optionally substituted with 1 to 3 halogens;

[0055] R 10d H, D or C 1-6 alkyl;

[0056] A is

[0057] B is a 5- to 6-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S;

[0058] C is a 5- to 6-membered heterocyclic ring containing 1 to 3 N heteroatoms;

[0059] m is 1, 2, or 3;

[0060] n is 0, 1, 2 or 3.

[0061] One or more embodiments of the present invention provide a pharmaceutical combination of at least two components, wherein component A is a PD-1 inhibitor antibody, and component B is a compound of formula (I-2) or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof:

[0062] in:

[0063] X1 is NH;

[0064] X2 is 0;

[0065] R 1a 、R 1b Each independently is H, D or C 1-6 alkyl;

[0066] R 2a 、R 2b Each independently is H, D or C 1-6 alkyl;

[0067] R3 is H, D, C 1-6 Alkyl or halogen, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens;

[0068] R4 and R5 are each independently H, D or C 1-6 alkyl;

[0069] R6 and R7 are each independently H, D or C 1-6 alkyl;

[0070] R8 and R9 are each independently H, D or C 1-6 Alkyl; or R8 and R9 and the carbon atom to which they are attached form C=O;

[0071] R 10 C 1-6 Alkyl, C 1-6 Alkoxy, cyano or SR 10d , the C 1-6 Alkyl, C 1-6 Alkoxy is optionally substituted with 1 to 3 halogens;

[0072] R 10d H, D or C 1-6 alkyl;

[0073] A is

[0074] B is a 5- to 6-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S;

[0075] m is 1, 2, or 3;

[0076] n is 0, 1, 2 or 3.

[0077] One or more embodiments of the present invention provide a pharmaceutical combination of at least two components, component A is a PD-1 inhibitor antibody, and component B is a compound of formula (I-2) or a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof, wherein:

[0078] X1 is NH;

[0079] X2 is 0;

[0080] R 1a 、R 1b Each independently is H, D or C 1-6 alkyl;

[0081] R 2a 、R 2b Each independently is H, D or C 1-6 alkyl;

[0082] R3 is H, D, C 1-6 Alkyl or halogen, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens;

[0083] R4 and R5 are each independently H, D or C 1-6 alkyl;

[0084] R6 and R7 are each independently H, D or C 1-6 alkyl;

[0085] R8 and R9 are each independently H, D or C 1-6 Alkyl, or R8 and R9 form C=O with the carbon atom to which they are connected;

[0086] R 10 C 1-6 Alkyl, cyano, or SR 10d , the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens;

[0087] R 10d H, D or C 1-6 alkyl;

[0088] A is

[0089] B is a 5- to 6-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S;

[0090] m is 1, 2, or 3;

[0091] n is 0, 1, 2 or 3.

[0092] One or more embodiments of the present invention provide a pharmaceutical combination of at least two components, component A is a PD-1 inhibitor antibody, and component B is a compound of formula (I-2) or a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof, wherein:

[0093] X1 is selected from NH;

[0094] X2 is selected from O;

[0095] R 1a 、R 1b Each independently selected from H, D or C 1-6 alkyl;

[0096] R 2a 、R 2b Each independently selected from H, D or C 1-6 alkyl;

[0097] R3 is H, D, C 1-6 Alkyl or halogen, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens;

[0098] R4 and R5 are each independently H or D;

[0099] R6 and R7 are each independently H or D;

[0100] R8 and R9 are each independently H or D;

[0101] R 10 CF3 or SR 10d ;

[0102] R 10d H, D or C 1-6 alkyl;

[0103] A is

[0104] B is

[0105] m is 1, 2, or 3;

[0106] n is 0, 1, 2 or 3.

[0107] One or more embodiments of the present invention provide a pharmaceutical combination of at least two components, component A is a PD-1 inhibitor antibody, and component B is a compound of formula (I-2) or a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof, wherein:

[0108] X1 is selected from NH;

[0109] X2 is selected from O;

[0110] R1a 、R 1b Each independently selected from H, D or C 1-3 alkyl;

[0111] R 2a 、R 2b Each independently selected from H, D or C 1-3 alkyl;

[0112] R3 is selected from H, D or CF3;

[0113] R4 and R5 are each independently selected from H or D;

[0114] R6 and R7 are each independently selected from H or D;

[0115] R8 and R9 are each independently selected from H or D;

[0116] R 10 is CF3;

[0117] A is

[0118] B is

[0119] m is 1, 2, or 3;

[0120] n is 0, 1 or 2.

[0121] One or more embodiments of the present invention provide a pharmaceutical combination of at least two components, wherein component A is a PD-1 inhibitor antibody, and component B is a compound of formula (I-3) or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof:

[0122] in:

[0123] X1 is NH or a 4- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N and O;

[0124] X2 is 0;

[0125] R 1a 、R 1b Each independently is H, D or C 1-6 alkyl;

[0126] R 2a 、R 2b Each independently is H, D or C 1-6 alkyl;

[0127] R4 and R5 are each independently H, D or C 1-6 alkyl;

[0128] R6 and R7 are each independently H, D or C 1-6 alkyl;

[0129] R8 and R9 are each independently H, D or C 1-6 Alkyl; or R8, R9 and the connected carbon atom form C=O;

[0130] R 10 C 1-6 Alkyl, C 1-6 Alkoxy, cyano or SR 10d , the C 1-6 Alkyl, C 1-6 Alkoxy is optionally substituted with 1 to 3 halogens;

[0131] R 10d H, D or C 1-6 alkyl;

[0132] A is

[0133] B is a 5- to 6-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S;

[0134] m is 1, 2, or 3;

[0135] n is 0, 1, 2 or 3.

[0136] One or more embodiments of the present invention provide a pharmaceutical combination of at least two components, component A is a PD-1 inhibitor antibody, and component B is a compound of formula (I-3) or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein:

[0137] X1 is NH or a 4- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N and O;

[0138] X2 is 0;

[0139] R 1a 、R 1b Each independently is H, D or C 1-3 alkyl;

[0140] R 2a 、R 2b Each independently is H, D or C 1-3 alkyl;

[0141] R4 and R5 are each independently H, D or C 1-3 alkyl;

[0142] R6 and R7 are each independently H, D or C 1-3 alkyl;

[0143] R8 and R9 are each independently H, D or C 1-3 Alkyl; or R8 and R9 form C=O with the carbon atom to which they are connected;

[0144] R 10 C 1-6 Alkyl, cyano or SR 10d , the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens;

[0145] R 10d H, D or C 1-6 alkyl;

[0146] A is

[0147] B is

[0148] m is 1, 2, or 3;

[0149] n is 0, 1 or 2.

[0150] One or more embodiments of the present invention provide a pharmaceutical combination of at least two components, component A is a PD-1 inhibitor antibody, and component B is a compound of formula (I-3) or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein:

[0151] X1 is NH;

[0152] X2 is 0;

[0153] R 1a 、R 1b Each independently is H, D or C 1-3 alkyl;

[0154] R 2a 、R 2b Each independently is H or D;

[0155] R4 and R5 are each independently H or D;

[0156] R6 and R7 are each independently H or D;

[0157] R8 and R9 are each independently H or D;

[0158] R 10 is CF3;

[0159] A is

[0160] B is

[0161] m is 1, 2, or 3;

[0162] n is 0, 1 or 2.

[0163] One or more embodiments of the present invention provide a pharmaceutical combination of at least two components, wherein component A is a PD-1 inhibitor antibody, and component B is selected from the following compounds or pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives thereof:

[0164] One or more embodiments of the present invention provide a drug combination of at least two components, component A is pembrolizumab, nivolumab, serolimab, pidilizumab, lambrolizumab, atezolizumab, toripalimab, sintilimab, tislelizumab, camrelizumab, penpulimab, zimberelimab, envafolimab, sugemalimab, dostarlimab, Cadonilimab, cemiplimab, retifanlimab, BMS-986213, HX-008, geptanolimab, prolgolimab, socazolimab, avelumab, adebrelimab, or durvalumab.

[0165] In one or more embodiments of the present invention, the pharmaceutical combination comprises the above-mentioned component A and the above-mentioned component B, and one or more pharmaceutically acceptable excipients, diluents or carriers.

[0166] In one or more embodiments of the present invention, the total daily dose of component B is selected from 50-1500 mg, preferably 100-1000 mg, more preferably 400-800 mg, measured as the free base.

[0167] In one or more embodiments of the present invention, the present invention relates to the use of the drug combination for treating or preventing solid tumors.

[0168] In one or more embodiments of the present invention, the solid tumor is selected from non-small cell lung cancer, head and neck squamous cell carcinoma, esophageal squamous cell carcinoma, hormone receptor-positive (HR+) breast cancer, PARP7 amplified advanced solid tumor, colon cancer or lung cancer, preferably colon cancer or lung cancer, more preferably colon cancer.

[0169] In one or more embodiments of the present invention, the above-mentioned component A and the above-mentioned component B are administered simultaneously.

[0170] In one or more embodiments of the present invention, the above-mentioned component A and the above-mentioned component B are administered sequentially. For example, component A is administered first, and then component B, or component B is administered first, and then component A. The administration interval can be several hours, several days, several weeks or several months.

[0171] In one or more embodiments of the present invention, the above-mentioned component A is administered by intravenous administration, and the administration frequency is twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, once every 3-6 months, preferably twice a week, once a week, once every two weeks or once every three weeks.

[0172] In one or more embodiments of the present invention, the above-mentioned component B is administered orally, and the dosage frequency is 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.

[0173] Advantages of the present invention

[0174] The compounds of the present invention, when used in combination with a PD-1 inhibitor or a PD-L1 inhibitor, exhibited superior in vivo anti-tumor effects compared to the PD-1 inhibitor or PD-L1 inhibitor alone, and exhibited favorable safety and tolerability, demonstrating that the drug combination of the present invention has a significant synergistic effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0175] Figure 1 is the structural formula of compound ①.

[0176] FIG2 shows the tumor volume growth curve of tumor-bearing mice.

[0177] Figure 3 shows the body weight change rate of tumor-bearing mice. DETAILED DESCRIPTION

[0178] The following describes in detail the implementation process of the present invention and the beneficial effects produced by specific embodiments, which is intended to help readers better understand the essence and characteristics of the present invention and is not intended to limit the scope of implementation of this case.

[0179] The present invention is described in further detail below with reference to the accompanying drawings:

[0180] Compound ① in the embodiment is compound 1 of PCT application PCT / CN2022 / 094124, and compound ① was prepared according to its preparation method.

[0181] Drug efficacy test in CT26 mouse tumor model

[0182] 1. Experimental steps

[0183] 1.1 Cell culture

[0184] Colon cancer cells CT26 were purchased from ATCC and cultured in DMEM supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin at 37°C in a cell culture incubator containing 5% CO 2 . When the cells reached the exponential growth phase, they were trypsinized, harvested, counted, and plated.

[0185] 1.2 Grouping and Dosing

[0186] After BALB / c mice were adapted to the laboratory environment, CT26 cell suspension was inoculated subcutaneously in the right rib of the mice, with 1×10 6 cells / mouse, the inoculation volume is 0.1mL. When the tumor grows to 30-80mm 3 Around 6:00 p.m., 32 animals were screened and divided into four groups of 8 animals each according to tumor size using a sigmoid-shaped grouping method. Grouping was designated as experimental day 0 (PG-D0), and dosing began on day 1. Grouping and dosing schedules are detailed in Table 1.

[0187] Table 1 Dosage regimen Note: ig refers to oral administration; ip refers to intraperitoneal administration; BID refers to twice-daily administration; BIW refers to twice-weekly administration.

[0188] 2. Determination method

[0189] 2.1 Tumor volume

[0190] The tumor diameter was measured with a vernier caliper twice a week, the tumor volume was calculated, and the tumor growth curve was drawn. The calculation formula for tumor volume (V) was:

[0191] V=1 / 2×a×b 2 , where a and b represent the long diameter and short diameter of the tumor, respectively.

[0192] 2.2 Mouse weight

[0193] During the drug treatment period, the mice were weighed at least twice a week.

[0194] 3. Experimental results

[0195] As shown in Figures 2 and 3 , compound ① combined with anti-PD-1 antibody exhibited a superior in vivo anti-tumor effect compared to anti-PD-1 antibody alone, and exhibited good safety and tolerability, indicating that the drug combination of the present invention has a significant synergistic effect.

[0196] The specification of the present invention describes the specific implementation scheme in detail. Those skilled in the art should recognize that the above implementation scheme is exemplary and cannot be understood as limiting the present invention. For those skilled in the art, without departing from the principles of the present invention, by making several improvements and modifications to the present invention, the technical solutions obtained by these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A pharmaceutical combination of at least two components, wherein component A is a PD-1 inhibitor antibody or a PD-L1 inhibitor antibody, and component B is a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof: in: X1 is NH, O or a 4- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N and O; X2 is 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 Together with the carbon atom to which it is attached, it forms a 3- to 5-membered cycloalkyl group; R 2a 、R 2b Each independently is H, D or C 1-6 Alkyl; or R 2a 、R 2b Together with the carbon atom to which it is attached, it forms a 3- to 5-membered cycloalkyl group; R3 is H, D, C 1-6 Alkyl, halogen or cyano, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens; R4 and R5 are each independently H, D or C 1-6 Alkyl; or R4, R5 and the connected carbon atom form a 3 to 5-membered cycloalkyl; R6 and R7 are each independently H, D or C 1-6 Alkyl; or R6, R7 and the connected carbon atom form C=O; R8 and R9 are each independently H, D or C 1-6 Alkyl; or R8, R9 and the carbon atom to which they are connected form C=O; or R8 and R9 and the carbon atom to which they are connected form a 3- to 5-membered cycloalkyl; 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 a 3 to 5-membered cycloalkyl group, the C 1-6 Alkyl, C 1-6 Alkoxy is optionally substituted with 1 to 3 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, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens; B is a 5- to 10-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S; C is a 5- to 6-membered heterocyclic ring containing 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.

2. The pharmaceutical combination according to claim 1, wherein the component B is a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof, wherein: X1 is NH, O or a 4- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N and O; X2 is 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 Together with the carbon atom to which it is attached, it forms a 3- to 5-membered cycloalkyl group; R3 is H, D, C 1-6 Alkyl, halogen or cyano, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens; R4 and R5 are each independently H, D or C 1-6 Alkyl; or R4, R5 and the connected carbon atom form a 3 to 5-membered cycloalkyl; 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; or R8, R9 and the connected carbon atom form C=O; 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 a 3 to 5-membered cycloalkyl group, the C 1-6 Alkyl, C 1-6 Alkoxy is optionally substituted with 1 to 3 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, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens; B is a 5- to 6-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S; C is a 5- to 6-membered heterocyclic ring containing 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.

3. The pharmaceutical combination according to claim 2, wherein the component B is a compound represented by formula (I-1) or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof, wherein: in: X1 is NH or a 4- to 6-membered heterocyclic ring containing 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 is H, D, C 1-6 Alkyl or halogen, the C 1-6 The alkyl group is optionally substituted with 1 to 3 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; or R8 and R9 form C=O with the carbon atom to which they are connected; R 10 C 1-6 Alkyl, C 1-6 Alkoxy, cyano or SR 10d , the C 1-6 Alkyl, C 1-6 Alkoxy is optionally substituted with 1 to 3 halogens; R 10d H, D or C 1-6 alkyl; A is B is a 5- to 6-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S; C is a 5- to 6-membered heterocyclic ring containing 1 to 3 N heteroatoms; m is 1, 2, or 3; n is 0, 1, 2 or 3.

4. The pharmaceutical combination according to claim 3, wherein the component B is a compound represented by formula (I-2) or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof, wherein: in: X1 is NH; X2 is 0; R 1a 、R 1b Each independently is H, D or C 1-6 alkyl; R 2a 、R 2b Each independently is H, D or C 1-6 alkyl; R3 is H, D, C 1-6 Alkyl or halogen, the C 1-6 The alkyl group is optionally substituted with 1 to 3 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; or R8 and R9 and the carbon atom to which they are attached form C=O; R 10 C 1-6 Alkyl, C 1-6 Alkoxy, cyano or SR 10d , the C 1-6 Alkyl, C 1-6 Alkoxy is optionally substituted with 1 to 3 halogens; R 10d H, D or C 1-6 alkyl; A is B is a 5- to 6-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S; m is 1, 2, or 3; n is 0, 1, 2 or 3.

5. The pharmaceutical combination according to claim 4, wherein the component B is a compound represented by formula (I-2) or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof, wherein: X1 is NH; X2 is 0; R 1a 、R 1b Each independently is H, D or C 1-6 alkyl; R 2a 、R 2b Each independently is H, D or C 1-6 alkyl; R3 is H, D, C 1-6 Alkyl or halogen, the C 1-6 The alkyl group is optionally substituted with 1 to 3 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, or R8 and R9 form C=O with the carbon atom to which they are connected; R 10 C 1-6 Alkyl, cyano, or SR 10d , the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens; R 10d H, D or C 1-6 alkyl; A is B is a 5- to 6-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S; m is 1, 2, or 3; n is 0, 1, 2 or 3.

6. The pharmaceutical combination according to claim 5, wherein the component B is a compound represented by formula (I-2) or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof, wherein: X1 is selected from NH; X2 is selected from O; R 1a 、R 1b Each independently selected from H, D or C 1-6 alkyl; R 2a 、R 2b Each independently selected from H, D or C 1-6 alkyl; R3 is H, D, C 1-6 Alkyl or halogen, the C 1-6 The alkyl group is optionally substituted with 1 to 3 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 CF3 or SR 10d ; R 10d H, D or C 1-6 alkyl; A is B is m is 1, 2, or 3; n is 0, 1, 2 or 3.

7. The pharmaceutical combination according to claim 6, wherein the component B is a compound represented by formula (I-2) or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof, wherein: X1 is selected from NH; X2 is selected from O; R 1a 、R 1b Each independently selected from H, D or C 1-3 alkyl; R 2a 、R 2b Each 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 is CF3; A is B is m is 1, 2, or 3; n is 0, 1 or 2.

8. The pharmaceutical combination according to claim 1, wherein the component B is a compound represented by formula (I-3) or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof, wherein: in: X1 is NH or a 4- to 6-membered heterocyclic ring containing 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; or R8, R9 and the connected carbon atom form C=O; R 10 C 1-6 Alkyl, C 1-6 Alkoxy, cyano or SR 10d , the C 1-6 Alkyl, C 1-6 Alkoxy is optionally substituted with 1 to 3 halogens; R 10d H, D or C 1-6 alkyl; A is B is a 5- to 6-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S; m is 1, 2, or 3; n is 0, 1, 2 or 3.

9. The pharmaceutical combination according to claim 8, wherein the component B is a compound represented by formula (I-3) or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof, wherein: X1 is NH or a 4- to 6-membered heterocyclic ring containing 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; or R8 and R9 form C=O with the carbon atom to which they are connected; R 10 C 1-6 Alkyl, cyano or SR 10d , the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens; R 10d H, D or C 1-6 alkyl; A is B is m is 1, 2, or 3; n is 0, 1 or 2.

10. The pharmaceutical combination according to claim 9, wherein the component B is a compound represented by formula (I-3) or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof, wherein: X1 is NH; X2 is 0; R 1a 、R 1b Each independently is H, D or C 1-3 alkyl; R 2a 、R 2b Each independently is H or D; 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 is CF3; A is B is m is 1, 2, or 3; n is 0, 1 or 2.

11. The pharmaceutical combination according to any one of claims 1 to 10, wherein the component B is selected from the following compounds or pharmaceutically acceptable salts, stereoisomers or deuterated substances thereof:

12. The pharmaceutical combination according to claim 1, wherein the component A is pembrolizumab, nivolumab, serotonin, pidilizumab, lambrolizumab, atezolizumab, toripalimab, sintilimab, tislelizumab, camrelizumab, penpulimab, sepalizumab, or zimberezumab. limab), Envafolimab, Sugemalimab, Dostarlimab, Cadonilimab, Cemiplimab, Retifanlimab, BMS-986213, HX-008, Geptanolimab, Prolgolimab, Socazolimab, Avelumab, Adebrelimab, or Durvalumab.

13. A pharmaceutical combination of at least two components according to any one of claims 1 to 12, comprising component A according to claim 12 and component B according to any one of claims 1 to 11, and one or more pharmaceutically acceptable excipients, diluents or carriers.

14. The pharmaceutical combination according to any one of claims 1 to 13, wherein the total daily dose of component B is selected from 50-1500 mg, preferably 100-1000 mg, more preferably 400-800 mg, measured as the free base.

15. Use of the pharmaceutical combination according to any one of claims 1 to 14 in treating or preventing solid tumors.

16. The use according to claim 15, characterized in that Component A according to claim 12 and component B according to any one of claims 1 to 11 are administered simultaneously.

17. The use according to claim 15, characterized in that Component A according to claim 12 and component B according to any one of claims 1 to 11 are administered sequentially.

18. The use according to any one of claims 15 to 17, characterized in that Component A according to claim 12 is administered by intravenous administration, with a frequency of twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, once every 3-6 months, preferably twice a week, once a week, once every two weeks or once every three weeks.

19. The use according to any one of claims 15 to 17, characterized in that Component B according to any one of claims 1 to 11 is administered orally at a frequency of twice a day or once a day.

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