Compositions of piperazine compounds with PD-1 or PD-L1 inhibitors and their use in tumor treatment

Abstract

The present application relates to combinations of piperazine compounds with PD-1 inhibitor antibodies or PD-L1 inhibitor antibodies and their use in the treatment of tumors. [Formula 1] JPEG2025526003000051.jpg37169

Description

Detailed Description of the Invention

[0001] [Technical field] The present application belongs to the field of medicine and relates to pharmaceutical combinations that can exert antitumor effects. Specifically, the present application relates to compositions based on piperazine compounds and PD-1 inhibitor antibodies or PD-L1 inhibitors, and their use in treating tumors.

[0002] [Background technology] Programmed cell death protein 1 (PD-1, Pdcd-1, or CD279) is a 55-kD receptor protein related to the CD28 / CTLA4 costimulatory / inhibitory receptor family. Cancer cells express the PD-1 ligand, PD-L1, which allows them to evade the host immune system. Commercially available PD-1 inhibitors can significantly extend overall patient survival by inhibiting tumor immunosuppressive mechanisms. However, this treatment elicits responses in only a subset of patients, or in some patients, the response may decline or disappear after a period of treatment despite a favorable initial response. Therefore, there is an urgent need to develop new therapies to enhance the therapeutic efficacy of existing therapies.

[0003] [Summary of the Invention] The applicant's PCT application, PCT / CN2022 / 094124, discloses the use of piperazine derivatives in the treatment of cancer, and the compounds described therein have high sensitivity and significant inhibitory activity against PARP7. Subsequent studies have unexpectedly found that a piperazine derivative in combination with a PD-1 inhibitor antibody can significantly enhance the anti-tumor effect of the PD-1 inhibitor antibody or PD-L1 inhibitor antibody.

[0004] Accordingly, the present disclosure aims to provide compositions of piperazine compounds and PD-1 inhibitor antibodies or PD-L1 inhibitor antibodies, and uses thereof in treating tumors.

[0005] One or more embodiments of the present disclosure provide a pharmaceutical combination of at least two components, including component A, which is a PD-1 inhibitor antibody or a PD-L1 inhibitor antibody, and component B, which is a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof: [ka] During the ceremony, X1 is NH, O, or a 4-6 membered heterocycle containing 1-3 heteroatoms selected from N and O; X2 is O or a single bond; X3 and X4 are each independently C or N; R 1a and R 1b are each independently H, D or C 1-6 alkyl; or R 1a and R 1b together with the carbon atom to which it is attached form a 3- to 5-membered cycloalkyl; R 2a and R 2b are each independently H, D or C 1-6 alkyl; or R 2a and R 2b together with the carbon atom to which it is attached form a 3- to 5-membered cycloalkyl; R3 is H, D, C 1-6 alkyl, halogen, or cyano, where C 1-6 The alkyl is optionally substituted with 1 to 3 halogens; R4 and R5 are each independently H, D, or C 1-6 alkyl; or R4 and R5 together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl; R6 and R7 are each independently H, D, or C 1-6 alkyl; or R6 and R7 together with the carbon atom to which they are attached form C=O; R8 and R9 are each independently H, D or C1-6 alkyl; or R8 and R9 together with the carbon atom connected thereto form C=O; or R8 and R9 together with the carbon atom connected thereto form a 3- to 5-membered cycloalkyl; Each R 10 independently, C 1-6 Alkyl, C 1-6 Alkoxy, CONR 10a R 10b , halogen, cyano, S(O)2R 10c , S.R. 10d or 3-5 membered cycloalkyl, where C 1-6 Alkyl and C 1-6 The alkoxy is optionally substituted with 1 to 3 halogens; R 10a , R 10b , R 10c and R 10d are each independently H, D or C 1-6 is alkyl; A is, [ka] and R a is C 1-6 Alkyl, C 3-5 cycloalkyl, halogen, or cyano, where C 1-6 The alkyl 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 5-6 membered heterocycle containing 1-3 N heteroatoms; m is 1, 2 or 3; n is 0, 1, 2, or 3; and p is 0, 1, 2 or 3.

[0006] One or more embodiments of the present disclosure provide a pharmaceutical combination of at least two components, including component A, which is a PD-1 inhibitor antibody, and component B, which is a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof, wherein: X1 is NH, O, or a 4-6 membered heterocycle containing 1-3 heteroatoms selected from N and O; X2 is O or a single bond; X3 and X4 are each independently C or N; R 1a and R 1b are each independently H, D or C 1-6 is alkyl; R 2a and R 2b are each independently H, D or C 1-6 alkyl; or R 2a and R 2b together with the carbon atom to which it is attached form a 3- to 5-membered cycloalkyl; R3 is H, D, C 1-6 alkyl, halogen, or cyano, where C 1-6 The alkyl is optionally substituted with 1 to 3 halogens; R4 and R5 are each independently H, D, or C 1-6 alkyl; or R4 and R5 together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl; R6 and R7 are each independently H, D, or C 1-6 is alkyl; R8 and R9 are each independently H, D or C 1-6 alkyl; or R8 and R9 together with the carbon atom to which they are attached form C=O; Each R 10 independently, C 1-6 Alkyl, C 1-6 Alkoxy, CONR 10a R 10b , halogen, cyano, S(O)2R 10c , S.R. 10dor 3-5 membered cycloalkyl, where C 1-6 Alkyl and C 1-6 The alkoxy is optionally substituted with 1 to 3 halogens; R 10a , R 10b , R 10c and R 10d are each independently H, D or C 1-6 is alkyl; A is, [ka] and R a is C 1-6 Alkyl, C 3-5 cycloalkyl, halogen, or cyano, where C 1-6 The alkyl is optionally substituted with 1 to 3 halogens; B is a 5-6 membered carbocyclic or heterocyclic ring, wherein the heterocyclic ring contains 1-3 heteroatoms selected from N, O and S; C is a 5-6 membered heterocycle containing 1-3 N heteroatoms; m is 1, 2 or 3; n is 0, 1, 2, or 3; and p is 0, 1, 2 or 3.

[0007] One or more embodiments of the present disclosure provide a pharmaceutical combination of at least two components, including component A, which is a PD-1 inhibitor antibody, and component B, which is a compound of formula (I-1), or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof: [ka] During the ceremony, X1 is NH or a 4-6 membered heterocycle containing 1-3 heteroatoms selected from N and O; X2 is O; X3 and X4 are each independently C or N; R 1a and R1b are each independently H, D or C 1-6 is alkyl; R 2a and R 2b are each independently H, D or C 1-6 is alkyl; R3 is H, D, C 1-6 alkyl or halogen, where C 1-6 The alkyl is optionally substituted with 1 to 3 halogens; R4 and R5 are each independently H, D, or C 1-6 is alkyl; R6 and R7 are each independently H, D, or C 1-6 is alkyl; R8 and R9 are each independently H, D or C 1-6 alkyl; or R8 and R9 together with the carbon atom to which they are attached form C=O; R 10 is C 1-6 Alkyl, C 1-6 Alkoxy, cyano or SR 10d where C 1-6 Alkyl and C 1-6 The alkoxy is optionally substituted with 1 to 3 halogens; R 10d is H, D or C 1-6 is alkyl; A is, [ka] and; B is a 5-6 membered carbocyclic or heterocyclic ring, wherein the heterocyclic ring contains 1-3 heteroatoms selected from N, O and S; C is a 5-6 membered heterocycle containing 1-3 N heteroatoms; m is 1, 2, or 3; and n is 0, 1, 2, or 3.

[0008] One or more embodiments of the present disclosure provide a pharmaceutical combination of at least two components, including component A, which is a PD-1 inhibitor antibody, and component B, which is a compound of formula (I-2), or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof: [ka] During the ceremony, X1 is NH; X2 is O; R 1a and R 1b are each independently H, D or C 1-6 is alkyl; R 2a and R 2b are each independently H, D or C 1-6 is alkyl; R3 is H, D, C 1-6 alkyl or halogen, where C 1-6 The alkyl is optionally substituted with 1 to 3 halogens; R4 and R5 are each independently H, D, or C 1-6 is alkyl; R6 and R7 are each independently H, D, or C 1-6 is alkyl; R8 and R9 are each independently H, D or C 1-6 alkyl; or R8 and R9 together with the carbon atom to which they are attached form C=O; R 10 is C 1-6 Alkyl, C 1-6 Alkoxy, cyano or SR 10d where C 1-6 Alkyl and C 1-6 The alkoxy is optionally substituted with 1 to 3 halogens; R 10d is H, D or C 1-6 is alkyl; A is, [ka] and B is a 5-6 membered carbocyclic or heterocyclic ring, wherein the heterocyclic ring contains 1-3 heteroatoms selected from N, O and S; m is 1, 2, or 3, and n is 0, 1, 2, or 3.

[0009] One or more embodiments of the present disclosure provide a pharmaceutical combination of at least two components, including component A which is a PD-1 inhibitor antibody, and component B which is a compound of formula (I-2), or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof, wherein: X1 is NH; X2 is O; R 1a and R 1b are each independently H, D or C 1-6 is alkyl; R 2a and R 2b are each independently H, D or C 1-6 is alkyl; R3 is H, D, C 1-6 alkyl or halogen, where C 1-6 The alkyl is optionally substituted with 1 to 3 halogens; R4 and R5 are each independently H, D, or C 1-6 is alkyl; R6 and R7 are each independently H, D, or C 1-6 is alkyl; R8 and R9 are each independently H, D or C 1-6 alkyl; or R8 and R9 together with the carbon atom to which they are attached form C=O; R 10 is C 1-6 Alkyl, cyano or SR 10d where C 1-6 The alkyl is optionally substituted with 1 to 3 halogens; R 10d is H, D or C1-6 is alkyl; A is, [ka] and; B is a 5-6 membered carbocyclic or heterocyclic ring, wherein the heterocyclic ring contains 1-3 heteroatoms selected from N, O and S; m is 1, 2, or 3, and n is 0, 1, 2, or 3.

[0010] One or more embodiments of the present disclosure provide a pharmaceutical combination of at least two components, including component A, which is a PD-1 inhibitor antibody, and component B, which is a compound of formula (I-2), or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof, wherein: X1 is selected from NH; X2 is selected from O; R 1a and R 1b are each independently H, D or C 1-6 alkyl; R 2a and R 2b are each independently H, D or C 1-6 alkyl; R3 is H, D, C 1-6 alkyl or halogen, where C 1-6 The alkyl 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 and; R 10d is H, D or C 1-6 is alkyl; A is, [ka] and; B is [ka] and; m is 1, 2, or 3; and n is 0, 1, 2, or 3.

[0011] One or more embodiments of the present disclosure provide a pharmaceutical combination of at least two components, including component A, which is a PD-1 inhibitor antibody, and component B, which is a compound of formula (I-2), or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof, wherein: X1 is selected from NH; X2 is selected from O; R 1a and R 1b are each independently H, D or C 1-3 alkyl; R 2a and R 2b are each independently 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 CF 3で can be; A is, [ka] and; B is [ka] and; m is 1, 2, or 3; and n is 0, 1, or 2.

[0012] One or more embodiments of the present disclosure provide a pharmaceutical combination of at least two components, including component A, which is a PD-1 inhibitor antibody, and component B, which is a compound of formula (I-3), or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof: [ka] During the ceremony, X1 is NH or a 4-6 membered heterocycle containing 1-3 heteroatoms selected from N and O; X2 is O; R 1a and R 1b are each independently H, D or C 1-6 is alkyl; R 2a and R 2b are each independently H, D or C 1-6 is alkyl; R4 and R5 are each independently H, D, or C 1-6 is alkyl; R6 and R7 are each independently H, D, or C 1-6 is alkyl; R8 and R9 are each independently H, D or C 1-6 alkyl; or R8 and R9 together with the carbon atom to which they are attached form C=O; R 10 is C 1-6 Alkyl, C 1-6 Alkoxy, cyano or SR 10d where C 1-6 Alkyl and C 1-6 The alkoxy is optionally substituted with 1 to 3 halogens; R 10d is H, D or C 1-6 is alkyl; A is, [ka] and; B is a 5-6 membered carbocyclic or heterocyclic ring, wherein the heterocyclic ring contains 1-3 heteroatoms selected from N, O and S; m is 1, 2, or 3; and n is 0, 1, 2, or 3.

[0013] One or more embodiments of the present disclosure provide a pharmaceutical combination of at least two components, including component A, which is a PD-1 inhibitor antibody, and component B, which is a compound of formula (I-3), or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof, wherein: X1 is NH or a 4-6 membered heterocycle containing 1-3 heteroatoms selected from N and O; X2 is O; R 1a and R 1b are each independently H, D or C 1-3 is alkyl; R 2a and R 2b are each independently H, D or C 1-3 is alkyl; R4 and R5 are each independently H, D, or C 1-3 is alkyl; R6 and R7 are each independently H, D, or C 1-3 is alkyl; R8 and R9 are each independently H, D or C 1-3 alkyl; or R8 and R9 together with the carbon atom to which they are attached form C=O; R 10 is C 1-6 Alkyl, cyano or SR 10d where C 1-6 The alkyl is optionally substituted with 1 to 3 halogens; R 10d is H, D or C 1-6 is alkyl; A is, [ka] and; B is [ka] and; m is 1, 2, or 3, and n is 0, 1, or 2.

[0014] One or more embodiments of the present disclosure provide a pharmaceutical combination of at least two components, including component A, which is a PD-1 inhibitor antibody, and component B, which is a compound of formula (I-3), or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof, wherein: X1 is NH; X2 is O; R 1a and R 1b are each independently H, D or C 1-3 is alkyl; R 2a and R 2b are each independently 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 CF 3で can be; A is, [ka] and; B is [ka] and; m is 1, 2, or 3; and n is 0, 1, or 2.

[0015] One or more embodiments of the present disclosure provide a pharmaceutical combination of at least two components, including component A, which is a PD-1 inhibitor antibody, and component B, which is selected from the compounds shown below, or pharmaceutically acceptable salts, stereoisomers, or deuterated compounds thereof: [ka] JPEG2025526003000021.jpg1169 JPEG2025526003000022.jpg223169 JPEG2025526003000023.jpg224169 JPEG2025526003000024.jpg220169 JPEG2025526003000025.jpg184169.

[0016] One or more embodiments of the present disclosure provide a pharmaceutical combination of at least two components, wherein said component A is pembrolizumab, nivolumab, serpulimab, pidilizumab, lambrolizumab, atezolizumab, toripalimab, sintilimab, tislelizumab, camrelizumab, penprimab, zimberelimab, emvafolimab, sugemalimab, dostallimab, kadnilimab, cemiplimab, retifanlimab, BMS-986213, HX-008, geptanolimab, prorugolimab, socazolimab, avelumab, adeburelimab, or durvalumab.

[0017] In one or more embodiments of the present disclosure, the pharmaceutical combination comprises component A described above and component B described above, and one or more pharmaceutically acceptable excipients, diluents, or carriers.

[0018] In one or more embodiments of the present disclosure, the total daily dose of Component B is selected from 50 to 1500 mg, preferably 100 to 1000 mg, and more preferably 400 to 800 mg, measured in terms of the amount of free base.

[0019] In one or more embodiments of the present disclosure, the disclosure relates to the use of the pharmaceutical combination in the treatment or prevention of solid tumors.

[0020] In one or more embodiments of the present disclosure, 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, advanced solid tumor with PARP7 amplification, colon cancer or lung cancer, preferably colon cancer or lung cancer, more preferably colon cancer.

[0021] In one or more embodiments of the present disclosure, component A described above and component B described above are provided simultaneously.

[0022] In one or more embodiments of the present disclosure, component A and component B are administered sequentially. For example, component A is administered first, followed by component B, or component B is administered first, followed by component A. The interval between administrations may be several hours, days, weeks, or months.

[0023] In one or more embodiments of the present disclosure, component A is intravenously administered twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every three to six months, preferably twice a week, once a week, once every two weeks, or once every three weeks.

[0024] In one or more embodiments of the present disclosure, component B is orally 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, and is preferably administered twice a day or once a day.

[0025] Benefits of this disclosure The combination of the compound of the present disclosure with a PD-1 inhibitor or a PD-L1 inhibitor has superior in vivo antitumor effects and exhibits good safety and tolerability compared to monotherapy with a PD-1 inhibitor or a PD-L1 inhibitor, demonstrating that the pharmaceutical combination of the present disclosure has a significant synergistic effect.

[0026] [Brief description of the drawing] FIG. 1 shows the structural formula of compound [1].

[0027] FIG. 2 shows the growth curve of tumor volume in tumor-bearing mice.

[0028] FIG. 3 shows the weight change rate of tumor-bearing mice.

[0029] Detailed Description of the Embodiments The implementation process and advantageous effects of the present disclosure will be described in detail below through specific examples. These examples are intended to help better understand the essence and features of the present disclosure, and are not intended to limit the implementation scope of the present disclosure.

[0030] The present disclosure will now be described in more detail with reference to the accompanying drawings.

[0031] The compound [1] in the examples is compound 1 of PCT application PCT / CN2022 / 094124, and is prepared according to the preparation method thereof. Efficacy test in CT26 mouse tumor model 1. Experimental Steps 1.1 Cell culture

[0032] Colon cancer cells CT26 were purchased from ATCC and cultured in DMEM medium supplemented with 10% fetal bovine serum, 1% penicillin, and 1% streptomycin at 37°C in a cell incubator containing 5% CO. Exponentially growing cells were digested with trypsin, harvested, counted, and then inoculated. 1.2. Grouping and Medication

[0033] BALB / c mice were allowed to acclimate to the laboratory environment and then injected with 1 × 10 CT26 cell suspension into the right flank. 6 Cells were inoculated subcutaneously at an inoculum volume of 0.1 mL per mouse. Tumors were approximately 30–80 mm 3 At the time of tumor growth, 32 animals were screened for group assignment. The animals were randomly divided into four groups based on tumor volume, with eight mice per group. The day of group assignment was designated day 0 (PG-D0) of the experiment, and dosing began on day 1. The group assignments and dosing regimens are shown in Table 1. Table 1. Medication Regimen [Table 1] 2. Assay Method 2.1 Tumor volume

[0034] To calculate tumor volume, tumor diameters were measured twice weekly using a vernier caliper and tumor growth curves were plotted. The formula for calculating tumor volume (V) is as follows: V=1 / 2×a×b 2 , where a and b represent the long and short diameters of the tumor, respectively. 2.2 Mouse weight

[0035] Mice were weighed at least twice a week during the drug treatment cycle. 3. Experimental Results

[0036] As shown in Figures 2 and 3, the combination of compound [1] and an anti-PD-1 antibody has superior in vivo antitumor efficacy compared to the anti-PD-1 antibody alone, and exhibits favorable safety and tolerability profiles. The pharmaceutical combination of the present disclosure demonstrates significant synergistic effects.

[0037] Specific embodiments are described in detail in the specification of the present disclosure. Those skilled in the art should recognize that the above-described embodiments are illustrative and cannot be construed as limiting the present disclosure. Furthermore, those skilled in the art can make some improvements and modifications to the present disclosure without departing from the principles of the present disclosure, and the technical solutions obtained based on these improvements and modifications also fall within the scope of protection of the claims of the present disclosure. [Brief explanation of the drawings]

[0038] [Figure 1] FIG. 1 shows the structural formula of compound [1]. [Figure 2] FIG. 2 shows the growth curve of tumor volume in tumor-bearing mice. [Figure 3] FIG. 3 shows the weight change rate of tumor-bearing mice.

Claims

1. A pharmaceutical combination of at least two components, comprising component A which is a PD-1 inhibitor antibody or a PD-L1 inhibitor antibody, and component B which is a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof: 【Chemical 1】 During the ceremony, X １ is NH, O, or a 4-6 membered heterocycle containing 1-3 heteroatoms selected from N and O; X ２ is O or a single bond; X ３ and X ４ are each independently C or N; R １ａ and R １ｂ are each independently H, D or C １－６ alkyl; or R １ａ and R １ｂ together with the carbon atom to which it is attached form a 3- to 5-membered cycloalkyl; R ２ａ and R ２ｂ are each independently H, D or C １－６ alkyl; or R ２ａ and R ２ｂ together with the carbon atom to which it is attached form a 3- to 5-membered cycloalkyl; R ３ H, D, C １－６ alkyl, halogen or cyano, where C １－６ The alkyl is optionally substituted with 1 to 3 halogens; R ４ and R ５ are each independently H, D or C １－６ alkyl; or R ４ and R ５ together with the carbon atom to which it is attached form a 3- to 5-membered cycloalkyl; R ６ and R ７ are each independently H, D or C １－６ alkyl; or R ６ and R ７ together with the carbon atom attached thereto forms C=O; R ８ and R ９ are each independently H, D or C １－６ alkyl; or R ８ and R ９ together with the carbon atom attached thereto form C=O; or R ８ and R ９ together with the carbon atom to which it is attached form a 3- to 5-membered cycloalkyl; Each R １０ are independently １－６ Alkyl, C １－６ Alkoxy, CONR １０ａ R １０ｂ , halogen, cyano, S(O) ２ R １０ｃ , S.R. １０ｄ or 3-5 membered cycloalkyl, where C １－６ Alkyl and C １－６ The alkoxy is optionally substituted with 1 to 3 halogens; R １０ａ , R １０ｂ , R １０ｃ and R １０ｄ are each independently H, D or C １－６ is alkyl; A is 【Chemistry 2】 and R ａ is C １－６ Alkyl, C ３－５ cycloalkyl, halogen, or cyano, where C １－６ The alkyl is optionally substituted with 1 to 3 halogens; B is a 5-10 membered carbocyclic or heterocyclic ring, wherein the heterocyclic ring contains 1-3 heteroatoms selected from N, O and S; C is a 5- to 6-membered heterocycle containing 1 to 3 N heteroatoms; m is 1, 2 or 3; n is 0, 1, 2 or 3; and p is 0, 1, 2 or 3;

2. 2. The pharmaceutical combination according to claim 1, wherein said component B is a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof, wherein: X １ is NH, O, or a 4-6 membered heterocycle containing 1-3 heteroatoms selected from N and O; X ２ is O or a single bond; X ３ and X ４ are each independently C or N; R １ａ and R １ｂ are each independently H, D or C １－６ is alkyl; R ２ａ and R ２ｂ are each independently H, D or C １－６ alkyl; or R ２ａ and R ２ｂ together with the carbon atom to which it is attached form a 3- to 5-membered cycloalkyl; R ３ H, D, C １－６ alkyl, halogen or cyano, where C １－６ The alkyl is optionally substituted with 1 to 3 halogens; R ４ and R ５ are each independently H, D or C １－６ alkyl; or R ４ and R ５ together with the carbon atom to which it is attached form a 3- to 5-membered cycloalkyl; R ６ and R ７ are each independently H, D or C １－６ is alkyl; R ８ and R ９ are each independently H, D or C １－６ alkyl; or R ８ and R ９ together with the carbon atom attached thereto forms C=O; Each R １０ are independently １－６ Alkyl, C １－６ Alkoxy, CONR １０ａ R １０ｂ , halogen, cyano, S(O) ２ R １０ｃ , S.R. １０ｄ or 3-5 membered cycloalkyl, where C １－６ Alkyl and C １－６ The alkoxy is optionally substituted with 1 to 3 halogens; R １０ａ , R １０ｂ , R １０ｃ and R １０ｄ are each independently H, D or C １－６ is alkyl; A is, 【Chemistry 3】 and R ａ is C １－６ Alkyl, C ３－５ cycloalkyl, halogen, or cyano, where C １－６ The alkyl is optionally substituted with 1 to 3 halogens; B is a 5-6 membered carbocyclic or heterocyclic ring, wherein the heterocyclic ring contains 1-3 heteroatoms selected from N, O and S; C is a 5-6 membered heterocycle containing 1-3 N heteroatoms; m is 1, 2 or 3; n is 0, 1, 2 or 3; and A pharmaceutical combination wherein p is 0, 1, 2 or 3.

3. The pharmaceutical combination according to claim 2, wherein said component B is a compound of formula (I-1), or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof; 【Chemistry 4】 During the ceremony, X １ is NH or a 4-6 membered heterocycle containing 1-3 heteroatoms selected from N and O; X ２ is O; X ３ and X ４ are each independently C or N; R １ａ and R １ｂ are each independently H, D or C １－６ is alkyl; R ２ａ and R ２ｂ are each independently H, D or C １－６ is alkyl; R ３ H, D, C １－６ alkyl or halogen, where C １－６ The alkyl is optionally substituted with 1 to 3 halogens; R ４ and R ５ are each independently H, D or C １－６ is alkyl; R ６ and R ７ are each independently H, D or C １－６ is alkyl; R ８ and R ９ are each independently H, D or C １－６ alkyl; or R ８ and R ９ together with the carbon atom attached thereto forms C=O; R １０ is C １－６ Alkyl, C １－６ Alkoxy, cyano or SR １０ｄ where C １－６ Alkyl and C １－６ The alkoxy is optionally substituted with 1 to 3 halogens; R １０ｄ is H, D or C １－６ is alkyl; A is, 【Chemistry 5】 and B is a 5-6 membered carbocyclic or heterocyclic ring, wherein the heterocyclic ring contains 1-3 heteroatoms selected from N, O and S; C is a 5-6 membered heterocycle containing 1-3 N heteroatoms; m is 1, 2 or 3; and A pharmaceutical combination wherein n is 0, 1, 2 or 3.

4. The pharmaceutical combination according to claim 3, wherein component B is a compound of formula (I-2), or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof, 【Chemistry 6】 During the ceremony, X １ is NH; X ２ is O; R １ａ and R １ｂ are each independently H, D or C １－６ is alkyl; R ２ａ and R ２ｂ are each independently H, D or C １－６ is alkyl; R ３ H, D, C １－６ alkyl or halogen, where C １－６ The alkyl is optionally substituted with 1 to 3 halogens; R ４ and R ５ are each independently H, D or C １－６ is alkyl; R ６ and R ７ are each independently H, D or C １－６ is alkyl; R ８ and R ９ are each independently H, D or C １－６ alkyl; or R ８ and R ９ together with the carbon atom attached thereto forms C=O; R １０ is C １－６ Alkyl, C １－６ Alkoxy, cyano or SR １０ｄ where C １－６ Alkyl and C １－６ The alkoxy is optionally substituted with 1 to 3 halogens; R １０ｄ is H, D or C １－６ is alkyl; A is, 【Chemistry 7】 and B is a 5-6 membered carbocyclic or heterocyclic ring, wherein the heterocyclic ring contains 1-3 heteroatoms selected from N, O and S; m is 1, 2 or 3, and A pharmaceutical combination wherein n is 0, 1, 2 or 3.

5. 5. The pharmaceutical combination according to claim 4, wherein said component B is a compound of formula (I-2), or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof, wherein X １ is NH; X ２ is O; R １ａ and R １ｂ are each independently H, D or C １－６ is alkyl; R ２ａ and R ２ｂ are each independently H, D or C １－６ is alkyl; R ３ H, D, C １－６ alkyl or halogen, where C １－６ The alkyl is optionally substituted with 1 to 3 halogens; R ４ and R ５ are each independently H, D or C １－６ is alkyl; R ６ and R ７ are each independently H, D or C １－６ is alkyl; R ８ and R ９ are each independently H, D or C １－６ alkyl; or R ８ and R ９ together with the carbon atom attached thereto forms C=O; R １０ is C １－６ alkyl, cyano or SR １０ｄ where C １－６ The alkyl is optionally substituted with 1 to 3 halogens; R １０ｄ is H, D or C １－６ is alkyl; A is, 【Chemistry 8】 and B is a 5-6 membered carbocyclic or heterocyclic ring, wherein the heterocyclic ring contains 1-3 heteroatoms selected from N, O and S; m is 1, 2 or 3 A pharmaceutical combination wherein n is 0, 1, 2 or 3.

6. 6. The pharmaceutical combination according to claim 5, wherein said component B is a compound of formula (I-2), or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof, wherein X １ is selected from NH; X ２ is selected from O; R １ａ and R １ｂ are each independently H, D or C １－６ alkyl; R ２ａ and R ２ｂ are each independently H, D or C １－６ alkyl; R ３ H, D, C １－６ alkyl or halogen, where C １－６ The alkyl is optionally substituted with 1 to 3 halogens; R ４ and R ５ are each independently H or D; R ６ and R ７ are each independently H or D; R ８ and R ９ are each independently H or D; R １０ is CF ３ or SR １０ｄ and R １０ｄ is H, D or C １－６ is alkyl; A is, 【Chemistry 9】 and B is, 【Chemistry 10】 and m is 1, 2 or 3; and A pharmaceutical combination wherein n is 0, 1, 2 or 3.

7. 7. The pharmaceutical combination according to claim 6, wherein said component B is a compound of formula (I-2), or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof, wherein: X １ is selected from NH; X ２ is selected from O; R １ａ and R １ｂ are each independently H, D or C １－３ alkyl; R ２ａ and R ２ｂ are each independently H, D or C １－３ alkyl; R ３ is H, D or CF ３ Selected from: R ４ and R ５ are each independently selected from H or D; R ６ and R ７ are each independently selected from H or D; R ８ and R ９ are each independently selected from H or D; R １０ is CF ３ and A is, 【Chemistry 11】 and B is, 【Chemistry 12】 and m is 1, 2 or 3; and A pharmaceutical combination wherein n is 0, 1 or 2.

8. The pharmaceutical combination according to claim 1, wherein component B is a compound of formula (I-3), or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof: 【Chemistry 13】 During the ceremony, X １ is NH or a 4-6 membered heterocycle containing 1-3 heteroatoms selected from N and O; X ２ is O; R １ａ and R １ｂ are each independently H, D or C １－６ is alkyl; R ２ａ and R ２ｂ are each independently H, D or C １－６ is alkyl; R ４ and R ５ are each independently H, D or C １－６ is alkyl; R ６ and R ７ are each independently H, D or C １－６ is alkyl; R ８ and R ９ are each independently H, D or C １－６ alkyl; or R ８ and R ９ together with the carbon atom attached thereto forms C=O; R １０ is C １－６ Alkyl, C １－６ Alkoxy, cyano or SR １０ｄ where C １－６ Alkyl and C １－６ The alkoxy is optionally substituted with 1 to 3 halogens; R １０ｄ is H, D or C １－６ is alkyl; A is, 【Chemistry 14】 and B is a 5-6 membered carbocyclic or heterocyclic ring, wherein the heterocyclic ring contains 1-3 heteroatoms selected from N, O and S; m is 1, 2 or 3; and A pharmaceutical combination wherein n is 0, 1, 2 or 3.

9. 9. The pharmaceutical combination according to claim 8, wherein said component B is a compound of formula (I-3), or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof, wherein X １ is NH or a 4-6 membered heterocycle containing 1-3 heteroatoms selected from N and O; X ２ is O; R １ａ and R １ｂ are each independently H, D or C １－３ is alkyl; R ２ａ and R ２ｂ are each independently H, D or C １－３ is alkyl; R ４ and R ５ are each independently H, D or C １－３ is alkyl; R ６ and R ７ are each independently H, D or C １－３ is alkyl; R ８ and R ９ are each independently H, D or C １－３ alkyl; or R ８ and R ９ together with the carbon atom attached thereto forms C=O; R １０ is C １－６ alkyl, cyano or SR １０ｄ where C １－６ The alkyl is optionally substituted with 1 to 3 halogens; R １０ｄ is H, D or C １－６ is alkyl; A is, 【Chemistry 15】 and B is, 【Chemistry 16】 and m is 1, 2 or 3; and A pharmaceutical combination wherein n is 0, 1 or 2.

10. 10. The pharmaceutical combination according to claim 9, wherein said component B is a compound of formula (I-3), or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof, wherein X １ is NH; X ２ is O; R １ａ and R １ｂ are each independently H, D or C １－３ is alkyl; R ２ａ and R ２ｂ are each independently H or D; R ４ and R ５ are each independently H or D; R ６ and R ７ are each independently H or D; R ８ and R ９ are each independently H or D; R １０ is CF ３ and A is, 【Chemistry 17】 and B is, 【Chemistry 18】 and m is 1, 2 or 3; and A pharmaceutical combination wherein n is 0, 1 or 2.

11. 11. The pharmaceutical combination according to any one of claims 1 to 10, wherein component B is selected from the following compounds, or pharmaceutically acceptable salts, stereoisomers, or deuterated compounds thereof: 【Chemistry 19】 【change】 【change】 【change】 【change】 【change】 。

12. The pharmaceutical combination according to claim 1, wherein component A is pembrolizumab, nivolumab, serprimab, pidilizumab, lambrolizumab, atezolizumab, toripalimab, sintilimab, tizulizumab, camrelizumab, penprimab, zimberelimab, embafolimab, sugemalimab, dostallimab, kadonilimab, cemiplimab, retifanlimab, BMS-986213, HX-008, geptanolimab, prorugolimab, socazolimab, avelumab, adebrelimab, or durvalumab.

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

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

16. 16. Use according to claim 15, in which component A according to claim 12 and component B according to any one of claims 1 to 11 are provided simultaneously.

17. 16. Use according to claim 15, in which component A according to claim 12 and component B according to any one of claims 1 to 11 are applied sequentially.

18. 18. The use according to any one of claims 15 to 17, wherein component A according to claim 12 is administered intravenously at a frequency of twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every 3 to 6 months, preferably twice a week, once a week, once every two weeks, or once every three weeks.

19. 18. Use according to any one of claims 15 to 17, wherein component B according to any one of claims 1 to 11 is orally administered twice a day or once a day.

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