Use of piperazine compounds in combination with radiation therapy for tumor treatment

Abstract

The present application relates to the use of piperazine compounds in combination with radiation therapy for the treatment of tumors. [Formula 1] JPEG2025528115000048.jpg38169

Description

Detailed Description of the Invention

[0001] [Technical field] This application relates to the use of piperazine compounds in combination with radiation therapy for the treatment of tumors. [Background technology]

[0002] Radiation therapy is one of the important methods for the comprehensive treatment of malignant tumors, and conventional neoadjuvant therapy based on long-term radiation therapy has become the standard regimen for the treatment of various malignant tumors. However, long-term clinical studies have shown that the response of patients with malignant tumors to radiation therapy varies greatly. While some patients can achieve complete pathological remission at the end of a treatment cycle, some patients still do not benefit from long-term treatment, and a small number even experience worsening disease progression. Therefore, improving tumor treatment efficacy by combining small molecule antitumor compounds with radiation therapy is clinically important.

[0003] [Summary of the Invention] The applicant's PCT application PCT / CN2022 / 094124 describes the use of piperazine derivatives in the preparation of medicaments for the treatment of cancer, and the compounds described therein have high sensitivity and significant inhibitory activity against PARP7. Subsequent studies have unexpectedly found that piperazine derivatives can significantly improve the antitumor effect of radiation therapy.

[0004] Accordingly, the present invention aims to provide the use of piperazine compounds in combination with radiation therapy for the treatment of tumors.

[0005] One or more embodiments of the present invention provide for the use of a compound of general formula (I), or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof, as an active ingredient in combination with radiation therapy for the treatment of tumors: [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 C 1-6 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 invention provide the use of a compound of general formula (I), or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof, as an active ingredient in combination with radiation therapy for tumor treatment, 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 1-6is 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. 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 C1-6 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 invention provide for the use of a compound of general formula (I-1), or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof, as an active ingredient in combination with radiation therapy for tumor treatment: [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 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 C1-6 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 invention provide for the use of a compound of general formula (I-2), or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof, as an active ingredient in combination with radiation therapy for tumor treatment: [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 2bare 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 invention provide the use of a compound of general formula (I-2), or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof, as an active ingredient in combination with radiation therapy for tumor treatment, wherein: X1 is NH; X2 is O; R1a 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 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.

[0010] One or more embodiments of the present invention provide the use of a compound of general formula (I-2), or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof, as an active ingredient in combination with radiation therapy for tumor treatment, 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 for the use of a compound of general formula (I-2), or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof, as an active ingredient in combination with radiation therapy for tumor treatment, 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 for the use of a compound of general formula (I-3), or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof, as an active ingredient in combination with radiation therapy for tumor treatment: [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 for the use of a compound of general formula (I-3), or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof, as an active ingredient in combination with radiation therapy for tumor treatment, 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 for the use of a compound of general formula (I-3), or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof, as an active ingredient in combination with radiation therapy for tumor treatment, 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] In one or more embodiments of the invention, the active ingredient is selected from the compounds shown below, or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof: [ka] JPEG2025528115000021.jpg240169 JPEG2025528115000022.jpg250169 JPEG2025528115000023.jpg240169 JPEG2025528115000024.jpg158169.

[0016] In one or more embodiments of the present application, the active ingredients have a synergistic effect when applied in combination with radiation therapy.

[0017] In one or more embodiments of the present application, the active ingredient is contained in a pharmaceutical composition that further comprises one or more pharmaceutically acceptable excipients, diluents, or carriers.

[0018] In one or more embodiments of the present application, the total daily dose of the active ingredient 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 application, the active ingredient and radiation therapy are administered simultaneously.

[0020] In one or more embodiments of the present application, the active ingredient and the radiation therapy are administered sequentially, for example, the active ingredient is administered first, followed by the radiation therapy, or the radiation therapy is administered first, followed by the active ingredient, with the interval between administrations being hours, days, weeks, or months.

[0021] In one or more embodiments of the present application, the active ingredient 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, preferably twice a day or once a day.

[0022] In one or more embodiments of the present application, the tumor is selected from a solid tumor.

[0023] In one or more embodiments of the present application, 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. Benefits of this disclosure

[0024] The compound [1] in combination with radiotherapy has a significantly better antitumor effect than radiotherapy alone, and is also excellent in tolerability and safety. It has been found that when the active ingredient of the present invention is applied in combination with radiotherapy, a significant synergistic effect can be obtained.

[0025] [Brief description of the drawing] FIG. 1 shows the structural formula of compound [1].

[0026] FIG. 2 shows the growth curve of tumor volume in tumor-bearing mice.

[0027] FIG. 3 shows the rate of weight change in tumor-bearing mice.

[0028] Detailed Description of the Embodiments The implementation process and advantageous effects of the present invention will be described in detail below with reference to specific examples. These examples are intended to help better understand the essence and characteristics of the present invention, but are not intended to limit the scope of the present invention.

[0029] The present invention will now be described in more detail with reference to the accompanying drawings.

[0030] 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

[0031] 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 Construction of subcutaneously implanted tumors

[0032] Female BALB / c mice were selected to construct the CT26 subcutaneous tumor model by subcutaneous injection of tumor cells. The average tumor volume was 120–130 mm. 3 At the time of tumor volume, 32 mice were screened for enrollment. Based on tumor volume, the mice were randomly divided into four groups: a blank group, a compound [1] group, an irradiation group, and a compound [1] and irradiation combination group, with eight mice per group. The day of grouping was designated study day 0 (PG-D0). Each irradiation group received 2 Gy of irradiation for five consecutive days starting on day 1 (D1), and compound [1] (125 mpk, BID) was administered starting on day 1 (D1). 2. Assay Method 2.1 Tumor volume

[0033] 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

[0034] Mice were weighed at least twice a week during the drug treatment cycle. 3. Experimental Results

[0035] As shown in Figures 2 and 3, the antitumor effect of compound [1] in combination with radiation therapy is significantly superior to that of radiation therapy alone, and is also highly tolerable and safe. It has been found that the active ingredient of the present invention has a significant synergistic effect when used in combination with radiation therapy.

[0036] Specific embodiments are described in detail in the specification of the present invention. Those skilled in the art should realize that the above-mentioned embodiments are illustrative and cannot be construed as limiting the present invention. Furthermore, those skilled in the art can make some improvements and modifications to the present invention without departing from the principles of the present invention, and the technical solutions obtained based on these improvements and modifications also fall within the scope of protection of the claims of the present invention. [Brief explanation of the drawings]

[0037] [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 rate of weight change in tumor-bearing mice.

Claims

1. Use of a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer or deuterated compound thereof, as an active ingredient in combination with radiation therapy for tumor treatment: 【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 use according to claim 1, wherein the active ingredient is a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof: 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 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 p is 0, 1, 2 or 3, use.

3. The use according to claim 2, wherein the active ingredient 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 n is 0, 1, 2 or 3, use.

4. The use according to claim 3, wherein the active ingredient 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 n is 0, 1, 2 or 3, use.

5. The use according to claim 4, wherein the active ingredient 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 n is 0, 1, 2 or 3, use.

6. The use according to claim 5, wherein the active ingredient 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 n is 0, 1, 2 or 3, use.

7. 7. The use according to claim 6, wherein the active ingredient 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 n is 0, 1 or 2, use.

8. 2. The use according to claim 1, wherein the active ingredient 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 n is 0, 1, 2 or 3, use.

9. 9. The use according to claim 8, wherein the active ingredient 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 n is 0, 1 or 2, use.

10. 10. The use according to claim 9, wherein the active ingredient 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 n is 0, 1 or 2, use.

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

12. 12. The use according to any one of claims 1 to 11, wherein the active ingredient is comprised in a pharmaceutical composition further comprising one or more pharmaceutically acceptable excipients, diluents or carriers.

13. 13. Use according to any one of claims 1 to 12, wherein the total daily dosage of the active ingredient is selected from 50 to 1500 mg, preferably 100 to 1000 mg, more preferably 400 to 800 mg, measured as the free base.

14. 14. The use according to any one of claims 1 to 13, wherein the active ingredient and the radiotherapy are administered simultaneously.

15. 14. The use according to any one of claims 1 to 13, wherein the active ingredient and the radiotherapy are administered sequentially.

16. 16. The use according to any one of claims 1 to 15, wherein the active ingredient is orally administered twice a day or once a day.

17. The use according to any one of claims 1 to 16, wherein the tumor is selected from solid tumors.

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