Use of imidazolidinone derivative in preparation of drug for treating tumors in combination with radiotherapy, and treatment method

Abstract

A use of a compound represented by general formula (I), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, as an active ingredient in the preparation of a drug for treating tumors in combination with radiotherapy.

Description

Application of imidazolinone derivatives in the preparation of drugs for combined radiotherapy for treating tumors and treatment methods Technical Field

[0001] The present invention relates to the application of an imidazolidinone derivative in preparing a medicine for treating tumors in combination with radiotherapy. Background Art

[0002] Radiotherapy is an important modality in the comprehensive treatment of malignant tumors. Neoadjuvant therapy based on conventional long-term radiotherapy has become the standard treatment for a variety of malignant tumors. However, long-term clinical studies have found that the response of patients with malignant tumors to radiotherapy varies greatly. Although some patients can achieve complete pathological remission at the end of the treatment cycle, some patients do not benefit from long-term treatment, and a small number of patients even experience worsening of the disease. Studies have found that the enhancement of DNA damage repair mechanisms caused by radiotherapy is an important factor in tumor tolerance to radiotherapy.

[0003] DNA double-strand breaks (DSBs) are a highly detrimental form of DNA damage within cells. Unrepaired DSBs are closely associated with cell carcinogenesis. Non-homologous end-joining (NHEJ) is one of the major mechanisms for repairing DSBs within cells. In NHEJ, the DSB ends are first recognized and bound by Ku70 / 80, which then associates with DNA-dependent protein kinase (DNA-PKcs) to form a DNA-dependent protein kinase (DNAPK), the NHEJ initiation complex (DNAPK). Subsequently, the two DNAPKs bind to the broken DNA ends and simultaneously recruit subsequent NHEJ repair factors (XRCC4 and XLF) and DNA ligase IV (LigIV) to repair the broken DNA.

[0004] WO2021209055 describes the use of an imidazolidinone derivative in the preparation of a drug for treating cancer, wherein the compound described in the specification has high selectivity and significant inhibitory activity against DNA-PK.

[0005] Summary of the Invention

[0006] In this article, the present inventors combine the existing technology with radiotherapy to improve the sensitivity of tumors to radiotherapy, so as to overcome the shortcomings of the existing technology.

[0007] The purpose of the present invention is to provide an application of an imidazolinone derivative combined with radiotherapy in tumor treatment, so as to overcome the shortcomings of the prior art.

[0008] One or more embodiments of the present application provide a compound of formula (I), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof as an active ingredient in the preparation of a drug for combined radiotherapy for treating tumors, wherein the tumor is selected from esophageal cancer, lung cancer, head and neck cancer, gastric cancer, pleural mesothelioma, thymic cancer, renal cancer, bladder cancer, hepatocellular carcinoma, colorectal cancer, lymphoma, ovarian cancer, breast cancer, fibrosarcoma, myosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovialoma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, pancreatic cancer, prostate cancer, Carcinoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, small cell lung cancer, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, chronic leukemia, polycythemia vera, lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, or heavy chain disease, or any combination thereof:

[0009] in:

[0010] for

[0011] is a single bond or a double bond;

[0012] A, B, C, and D are each independently C or N, and at least one of A, B, C, and D is N;

[0013] R0 is H, C 1-6 Alkyl or cyclopropyl, the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from halogen and deuterium;

[0014] R1 is or pyridyl, and R1 is optionally further substituted by 1 or 2 groups selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups;

[0015] R 1a H or C 1-6 alkyl;

[0016] R1b C substituted with H, OH, cyano or hydroxyl 1-6 alkyl;

[0017] R2 is H, cyano, =O, carboxyl, -C(=O)NR 2a R 2b 、C 1-6 Alkoxy, C 1-6 Alkyl, halogen, -S(=O)2R 2a or -C(=O)OC 1-6 Alkyl; the C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with one or more substituents selected from halogen and deuterium;

[0018] R 2a and R 2b Each independently is H, C 1-6 alkyl or 3 to 5 membered cycloalkyl, wherein the C 1-6 The alkyl group is optionally further substituted by one or more groups selected from OH, D, halogen, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups;

[0019] Or, R 2a and R 2b Together with the atoms to which it is attached, it forms a 5- to 6-membered heterocyclic group, wherein the 5- to 6-membered heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, O and S, and the 5- to 6-membered heterocyclic group is optionally further substituted by 1 or more heteroatoms selected from C 1-6 Substitution of alkyl, OH and halogen substituents;

[0020] R3 is halogen or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with 1 to 3 substituents selected from D and halogen;

[0021] m is 0 or 1;

[0022] n is 0, 1, or 2;

[0023] x and y are each independently 1, 2, or 3;

[0024] The condition is,

[0025] when When R0, R2, and R3 meet the following conditions at the same time, R1 is not

[0026] for n is 1, R0 is H or methyl, R2 is methoxy or -S(=O)2Me, and R3 is methyl.

[0027] In one or more embodiments of the present application, R1 is

[0028] R 1a H or C 1-6 alkyl;

[0029] R2 is H, cyano, -C(=O)NR 2a R 2b 、C 1-6 Alkoxy, halogen, -S(=O)2R 2a or -C(=O)OC 1-6 Alkyl; said -C(=O)OC 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with one or more substituents selected from halogen and deuterium;

[0030] R 2a and R 2b Each independently is H, C 1-6 alkyl or 3 to 5 membered cycloalkyl, wherein the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from OH, D or halogen;

[0031] Or, R 2a and R 2b Together with the atoms to which it is attached, it forms a 5- to 6-membered heterocyclic group, wherein the 5- to 6-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O and S, and the heterocyclic group is optionally further substituted with one or more substituents selected from OH and halogen;

[0032] R3 is halogen or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with 1 to 3 substituents selected from D and halogen;

[0033] m is 0 or 1;

[0034] n is 0, 1, or 2;

[0035] The condition is,

[0036] when When R0, R2, and R3 meet the following conditions at the same time, R1 is not

[0037] for n is 1, R0 is H or methyl, R2 is methoxy or -S(=O)2Me, and R3 is methyl.

[0038] In one or more embodiments of the present application, wherein:

[0039] for

[0040] R0 is H, C 1-4 Alkyl or cyclopropyl, the C 1-4 The alkyl group is optionally further substituted with one or more substituents selected from halogen and D;

[0041] R1 is

[0042] R 1a H, C 1-6 Alkyl or -C(=O)C 1-6 alkyl;

[0043] R2 is H, cyano, -C(=O)NR 2a R 2b 、C 1-6 Alkoxy, halogen, -S(=O)2R 2a or -C(=O)OC 1-6 Alkyl; the -C(=O)O alkyl or C 1-6 The alkoxy group is optionally substituted with one or more substituents selected from halogen and deuterium;

[0044] R 2a and R 2b Each independently is H, C 1-6 alkyl or 3 to 5 membered cycloalkyl, wherein the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from OH, D and halogen;

[0045] Or, R 2a and R 2b Together with the atoms to which it is attached, it forms a 5- to 6-membered heterocyclic group, wherein the 5- to 6-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O and S, and the 5- to 6-membered heterocyclic group is optionally further substituted with one or more substituents selected from OH and halogen;

[0046] R3 is halogen or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with 1 to 3 substituents selected from D and halogen;

[0047] m is 0 or 1;

[0048] n is 0, 1, or 2;

[0049] The condition is,

[0050] when When R0, R2, and R3 meet the following conditions at the same time, R1 is not

[0051] when for n is 1, R0 is H or methyl, R2 is methoxy or -S(=O)2Me, and R3 is methyl.

[0052] One or more embodiments of the present application provide the use of a compound of formula (II), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof as an active ingredient in the preparation of a medicament for combined radiotherapy for treating tumors:

[0053] in:

[0054] R0 is H, C 1-6 Alkyl or cyclopropyl, the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from halogen and deuterium;

[0055] R1 is or pyridyl, and R1 is optionally further substituted by 1 to 2 groups selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups;

[0056] R 1a H or C 1-6 alkyl;

[0057] R 1b C substituted with H, OH, cyano or hydroxyl 1-6 alkyl;

[0058] R 2c is H, cyano, halogen or C 1-6 alkoxy;

[0059] R 2d H, cyano, carboxyl, -C(=O)NR 2a R 2b 、C 1-6 Alkyl, halogen, -S(=O)2R 2a or -C(=O)OC 1- 6 alkyl; the C 1-6 Alkyl, -C(=O)OC 1-6The alkyl group is optionally substituted with one or more substituents selected from halogen and deuterium;

[0060] R 2a 、R 2b H, C 1-6 alkyl or 3 to 5 membered cycloalkyl, wherein the C 1-6 The alkyl group is optionally further substituted by one or more groups selected from OH, D, halogen, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups;

[0061] Or, R 2a and R 2b Together with the atoms to which it is attached, it forms a 5- to 6-membered heterocyclic group, wherein the 5- to 6-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O and S, and the 5- to 6-membered heterocyclic group is optionally further substituted by one or more heteroatoms selected from C 1-6 Substitution of alkyl, OH and halogen substituents;

[0062] R3 is halogen or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with 1 to 3 substituents selected from D and halogen;

[0063] m is 0 or 1;

[0064] n is 0, 1, or 2;

[0065] x and y are each independently 1, 2, or 3;

[0066] The condition is,

[0067] when When R0, R2, and R3 meet the following conditions at the same time, R1 is not

[0068] Selected from n is 1, R0 is H or methyl, R2 is methoxy or -S(=O)2Me, and R3 is methyl.

[0069] One or more embodiments of the present application provide the use of a compound of formula (III), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof as an active ingredient in the preparation of a medicament for combined radiotherapy for treating tumors:

[0070] in,

[0071] R0 is H, C 1-6 Alkyl or cyclopropyl, the C 1-6The alkyl group is optionally further substituted with one or more substituents selected from halogen and deuterium;

[0072] R1 is or pyridyl, and R1 is optionally further substituted by 1 to 2 groups selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups;

[0073] R 1b C substituted with H, OH, cyano or hydroxyl 1-6 alkyl;

[0074] R 2a and R 2b Each independently is H, C 1-6 alkyl or 3 to 5 membered cycloalkyl, wherein the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from D or halogen;

[0075] Or, R 2a and R 2b Together with the atoms to which it is attached, it forms a 5- to 6-membered heterocyclic group, wherein the 5- to 6-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O and S, and the 5- to 6-membered heterocyclic group is optionally further substituted by one or more heteroatoms selected from C 1-6 Substitution of alkyl, OH and halogen substituents;

[0076] R 2c is H, cyano, halogen or C 1-6 Alkoxy, the C 1-6 The alkoxy group is optionally substituted with one or more deuterium groups;

[0077] R3 is halogen or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with 1 to 3 substituents selected from D and halogen;

[0078] m is 0 or 1;

[0079] n is 0, 1, or 2;

[0080] x and y are each independently 1, 2 or 3.

[0081] One or more embodiments of the present application provide a compound of formula (IV), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, as an active ingredient in the preparation of a drug for combined radiotherapy for treating tumors:

[0082] in:

[0083] R0 is H, C 1-6 Alkyl or cyclopropyl, the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from halogen and deuterium;

[0084] R1 is -(CH) m -4 to 7 membered carbocyclic group, -(CH) m -4 to 7 membered heterocyclic group, -(CH) m -8 to 12-membered bridged ring, -(CH) m -7 to 12 membered spiro ring, said -(CH) m -4 to 7 membered carbocyclic group, -(CH) m -4 to 7 membered heterocyclic group, -(CH) m -8 to 12-membered bridged ring or -(CH) m -7 to 12 membered spiro ring is optionally further substituted by one or more groups selected from hydroxy, cyano, halogen, =O, C 1-6 Alkyl, C 1-6 Alkoxy and hydroxy substituted C 1-6 The alkyl group is substituted with a substituent.

[0085] In one or more embodiments of the present application, wherein:

[0086] R0 is H, C 1-6 Alkyl or cyclopropyl, the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from halogen and deuterium;

[0087] R1 is or pyridyl, and R1 is optionally further substituted by 1 to 2 groups selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups;

[0088] R 1a H or C 1-6 alkyl;

[0089] R 1b C substituted with H, OH, cyano or hydroxyl 1-6 alkyl;

[0090] m is 0 or 1;

[0091] x and y are each independently 1, 2 or 3.

[0092] In one or more embodiments of the present application, wherein:

[0093] R0 is C 1-4 Alkyl, the C1-4 The alkyl group is optionally further substituted with one or more substituents selected from halogen and deuterium;

[0094] R1 is

[0095] In one or more embodiments of the present application, the active ingredient is selected from:

[0096] In other embodiments of the present application, in the aforementioned tumors, the leukemia is selected from acute lymphocytic leukemia or acute myeloblastic leukemia, and the acute myeloblastic leukemia includes myeloblasts, promyeloblasts, myelomonocytic cells, monocytic cells and / or erythrocyte leukemia; the chronic leukemia includes chronic myeloid / granulocytic leukemia and / or chronic lymphocytic leukemia; the lymphoma includes Hodgkin's disease and / or non-Hodgkin's disease; the gastric cancer includes gastric adenocarcinoma; the head and neck cancer includes tongue adenoid cystic carcinoma and / or adenoid cystic carcinoma; the lung cancer includes large cell neuroendocrine carcinoma of the lung, lung adenocarcinoma, sarcomatoid carcinoma of the lung and / or squamous cell carcinoma of the lung; the cervical cancer includes cervical squamous cell carcinoma; the breast cancer includes invasive ductal carcinoma of the breast and ductal carcinoma of the breast; the ovarian cancer includes ovarian clear cell carcinoma or ovarian serous carcinoma.

[0097] The present application also provides a method for treating esophageal cancer, lung cancer, head and neck cancer, gastric cancer, pleural mesothelioma, thymic cancer, kidney cancer, bladder cancer, hepatocellular carcinoma, colorectal cancer, lymphoma, ovarian cancer, breast cancer, fibrosarcoma, myosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovial tumor, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, pancreatic cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland cancer, sebaceous gland cancer, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, hepatoma, bile duct cancer, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, small cell lung cancer, A method for treating epithelial cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, chronic leukemia, polycythemia vera, lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia or heavy chain disease or any combination thereof, comprising: oral administration in combination with radiotherapy, oral administration of a therapeutically effective amount of a DNA-PK inhibitor, continuous daily administration or cyclical administration until disease progression or unacceptable toxicity, oral administration of the DNA-PK inhibitor before or after radiotherapy, wherein the DNA-PK inhibitor has the structure of the active ingredient as described above.

[0098] In one or more embodiments of the present application, the DNA-PK inhibitor is orally administered before or after radiotherapy on the day of radiotherapy.

[0099] In one or more embodiments of the present application, the DNA-PK inhibitor is taken orally once a day on an empty stomach 1 to 2 hours before radiotherapy on each radiotherapy day, and is administered concomitantly with radiotherapy. The drug is taken on radiotherapy days and not on non-radiotherapy days.

[0100] In one or more embodiments of the present application, the cyclical administration method includes: 7 days as a cycle, administration for 5 consecutive days in a cycle, followed by a 2-day drug suspension, and then entering the next administration cycle.

[0101] In one or more embodiments of the present application, the daily dose of the active ingredient is 25-600 mg, preferably 50-400 mg, more preferably 100-300 mg.

[0102] In one or more embodiments of the present application, the daily dose of the active ingredient is 25 mg, 50 mg, or 75 mg. BRIEF DESCRIPTION OF THE DRAWINGS

[0103] Figure 1 shows compound A.

[0104] Figure 2 is a graph showing the tumor volume trend in the CT26 BALB / c mouse xenograft tumor model.

[0105] Figure 3 is a graph showing the body weight change trend in the CT26 BALB / c mouse transplanted tumor model. DETAILED DESCRIPTION

[0106] 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.

[0107] The present invention is described in further detail below with reference to the accompanying drawings:

[0108] Compound A in the embodiment is compound 62 of WO2021209055, and compound A was prepared according to its preparation method.

[0109] Inhibitory experiment on CT26 BALB / c mouse transplanted tumor model

[0110] 1. Experimental steps

[0111] Female BALB / c mice were selected and tumor cells were injected subcutaneously to establish a CT26 subcutaneous xenograft tumor model. 3 The mice were divided into three experimental groups, namely Vehicle, IR, and (Compound A (20 mpk) + IR), with 8 animals in each group, and a total of 24 animals were enrolled for group experiments. Each irradiation group was given a 2 Gy irradiation dose for 5 consecutive days, and the drug-treated group was given the corresponding drug once a day for 39 consecutive days. Vehicle was given the solvent.

[0112] 2. Determination method

[0113] 2.1 Tumor volume: During the drug treatment cycle, the long diameter (a) and short diameter (b) of the tumor tissue were measured with an electronic vernier caliper, and the tumor volume was calculated (tumor volume = 0.5 × a × b2).

[0114] 2.2 Mouse body weight: During the drug treatment period, the mice were weighed at least twice a week.

[0115] 3. Experimental results

[0116] 3.1 Tumor volume results

[0117] Table 1. Tumor volume statistics (Mean ± SEM, mm 3 ) Note: The day of grouping was designated as D0; * indicates P ≤ 0.05 compared with the animals in the Vehicle group; ** indicates P ≤ 0.01 compared with the animals in the Vehicle group; *** indicates P ≤ 0.001 compared with the animals in the Vehicle group; # indicates P ≤ 0.05 compared with the animals in the IR group; mpk is mg / kg; on D18, due to the large tumor size of some mice in the Vehicle group, this group of mice was euthanized for animal ethical reasons.

[0118] As shown in Table 1 and Figure 2, the tumor volume of the compound A and IR combination group was significantly smaller than that of the Vehicle group and the IR group. After four days of treatment, the volume difference between the compound A and IR combination group and the IR group gradually increased, indicating that compound A can significantly enhance the anti-tumor efficacy of radiotherapy.

[0119] 3.2 Weight results

[0120] Table 2. Weight statistics Note: mpk is mg / kg. On D18, due to the large tumor size of some mice in the vehicle, this group of mice was euthanized for animal ethical reasons.

[0121] As shown in Table 2 and Figure 3, the body weight of mice in the Vehicle group remained stable during the experiment; the body weight of the IR group decreased slightly during irradiation and began to recover after the end of irradiation; at the end of the D39 experiment, there was no significant difference in the average body weight of the IR group, Compound A, and the IR combination group, indicating that Compound A combined with radiotherapy had no effect on the weight gain of the animals and was well tolerated by the animals.

[0122] Clinical evaluation

[0123] Purpose of the study: To evaluate the safety, tolerability and preliminary efficacy of compound A combined with radiotherapy in patients with malignant solid tumors.

[0124] Clinical subjects: Age ranged from 18 years (minimum age) to no upper limit (maximum age);

[0125] Gender: male or female;

[0126] Solid tumors confirmed by histology or cytology and evaluated by an oncologist as suitable for radiotherapy. Radiotherapy techniques can include IMRT, IGRT, VMAT, TOMO, SBRT, or SRS.

[0127] Test plan:

[0128] Dosage: 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg. Administer the study drug (Compound A) orally once daily on an empty stomach 1-2 hours before radiotherapy on each day of radiotherapy, concurrently with radiotherapy (take the drug on radiotherapy days and not on non-radiation days). Dosage duration: Until the end of radiotherapy or until the subject cannot tolerate the study drug and / or radiotherapy.

[0129] End point indicators:

[0130] Table 3 Endpoint indicators

[0131] Clinical efficacy evaluation results

[0132] Table 4 Evaluation of efficacy of subjects

[0133] Clinical research results show that during the clinical trial period, the tumor growth in the radiotherapy field of patients with large cell neuroendocrine carcinoma of the lung was well suppressed, and the treatment was safe. In other indications, including prostate cancer and pleural mesothelioma, the tumor growth in the radiotherapy field of patients was significantly suppressed, and the safety and tolerability of the treatment process were excellent.

[0134] 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 compound represented by formula (I), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof as an active ingredient in the preparation of a drug for combined radiotherapy for treating a tumor, wherein the tumor is selected from esophageal cancer, lung cancer, head and neck cancer, gastric cancer, pleural mesothelioma, thymic cancer, kidney cancer, bladder cancer, hepatocellular carcinoma, colorectal cancer, lymphoma, ovarian cancer, breast cancer, fibrosarcoma, myosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovialoma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, pancreatic cancer, prostate cancer, squamous cell carcinoma , basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, small cell lung cancer, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, chronic leukemia, polycythemia vera, lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia or heavy chain disease or any combination thereof: in: for or is a single bond or a double bond; A, B, C, and D are each independently C or N, and at least one of A, B, C, and D is N; R0 is H, C 1-6 Alkyl or cyclopropyl, the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from halogen and deuterium; R1 is or pyridyl, and R1 is optionally further substituted by 1 or 2 selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups; R 1a H or C 1-6 alkyl; R 1b C substituted with H, OH, cyano or hydroxyl 1-6 alkyl; R2 is H, cyano, =O, carboxyl, -C(=O)NR 2a R 2b , C 1-6 Alkoxy, C 1-6 Alkyl, halogen, -S(=O)2R 2a or -C(=O)OC 1-6 Alkyl; the C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with one or more substituents selected from halogen and deuterium; R 2a and R 2b Each independently is H, C 1-6 alkyl or 3 to 5 membered cycloalkyl, wherein the C 1-6 The alkyl group is optionally further substituted with one or more groups selected from OH, D, halogen, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups; Or, R 2a and R 2b The atoms to which it is attached together form a 5- to 6-membered heterocyclic group, wherein the 5- to 6-membered heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, O and S, and the 5- to 6-membered heterocyclic group is optionally further substituted by 1 or more heteroatoms selected from C 1-6 Substitution of alkyl, OH and halogen substituents; R3 is halogen or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1; n is 0, 1 or 2; x and y are independently 1, 2, or 3; The condition is, when When R0, R2, and R3 meet the following conditions at the same time, R1 is not or for n is 1, R0 is H or methyl, R2 is methoxy or -S(=O)2Me, and R3 is methyl.

2. The use according to claim 1, characterized in that: The active ingredient is a compound of formula (I), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: or R 1a H or C 1-6 alkyl; R2 is H, cyano, -C(=O)NR 2a R 2b , C 1-6 Alkoxy, halogen, -S(=O)2R 2a or -C(=O)OC 1-6 Alkyl; the -C(=O)OC 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with one or more substituents selected from halogen and deuterium; R 2a and R 2b Each independently is H, C 1-6 alkyl or 3 to 5 membered cycloalkyl, wherein the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from OH, D or halogen; Or, R 2a and R 2b Together with the atoms to which it is attached, it forms a 5- to 6-membered heterocyclic group, wherein the 5- to 6-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O and S, and the heterocyclic group is optionally further substituted with 1 or more substituents selected from OH and halogen; R3 is halogen or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1; n is 0, 1 or 2; The condition is, when When R0, R2, and R3 meet the following conditions at the same time, R1 is not or for n is 1, R0 is H or methyl, R2 is methoxy or -S(=O)2Me, and R3 is methyl.

3. The use according to claim 1, characterized in that: The active ingredient is a compound of formula (I), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: for or R0 is H, C 1-4 Alkyl or cyclopropyl, the C 1-4 The alkyl group is optionally further substituted with one or more substituents selected from halogen and D; R1 is or R 1a H, C 1-6 Alkyl or -C(=O)C 1-6 alkyl; R2 is H, cyano, -C(=O)NR 2a R 2b , C 1-6 Alkoxy, halogen, -S(=O)2R 2a or -C(=O)OC 1-6 Alkyl; the -C(=O)O alkyl or C 1-6 The alkoxy group is optionally substituted with one or more substituents selected from halogen and deuterium; R 2a and R 2b Each independently is H, C 1-6 alkyl or 3 to 5 membered cycloalkyl, wherein the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from OH, D and halogen; Or, R 2a and R 2b Together with the atoms to which it is attached, it forms a 5- to 6-membered heterocyclic group, wherein the 5- to 6-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O and S, and the 5- to 6-membered heterocyclic group is optionally further substituted by 1 or more substituents selected from OH and halogen; R3 is halogen or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1; n is 0, 1 or 2; The condition is, when When R0, R2, and R3 meet the following conditions at the same time, R1 is not or when for n is 1, R0 is H or methyl, R2 is methoxy or -S(=O)2Me, and R3 is methyl.

4. The use according to claim 1, characterized in that: The active ingredient is selected from the compound of formula (II), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: in: R0 is H, C 1-6 Alkyl or cyclopropyl, the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from halogen and deuterium; R1 is or pyridyl, and R1 is optionally further substituted by 1 to 2 groups selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups; R 1a H or C 1-6 alkyl; R 1b C substituted with H, OH, cyano or hydroxyl 1-6 alkyl; R 2c is H, cyano, halogen or C 1-6 Alkoxy; R 2d H, cyano, carboxyl, -C(=O)NR 2a R 2b , C 1-6 Alkyl, halogen, -S(=O)2R 2a or -C(=O)OC 1- 6 alkyl; said C 1-6 Alkyl, -C(=O)OC 1-6 The alkyl group is optionally substituted with one or more substituents selected from halogen and deuterium; R 2a , R 2b H, C 1-6 alkyl or 3 to 5 membered cycloalkyl, wherein the C 1-6 The alkyl group is optionally further substituted with one or more groups selected from OH, D, halogen, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups; Or, R 2a and R 2b The atoms to which it is attached together form a 5- to 6-membered heterocyclic group, wherein the 5- to 6-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O and S, and the 5- to 6-membered heterocyclic group is optionally further substituted by 1 or more heteroatoms selected from C 1-6 Substitution of alkyl, OH and halogen substituents; R3 is halogen or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1; n is 0, 1 or 2; x and y are independently 1, 2, or 3; The condition is, when When R0, R2, and R3 meet the following conditions at the same time, R1 is not or Selected from n is 1, R0 is H or methyl, R2 is methoxy or -S(=O)2Me, and R3 is methyl.

5. The use according to claim 4, characterized in that: The active ingredient is selected from a compound of formula (III), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: in, R0 is H, C 1-6 Alkyl or cyclopropyl, the C 1-6 The alkyl group is optionally further substituted with one or more halogen groups. and deuterium substitution; R1 is or pyridyl, and R1 is optionally further substituted by 1 to 2 groups selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups; R 1b C substituted with H, OH, cyano or hydroxyl 1-6 alkyl; R 2a and R 2b Each independently is H, C 1-6 alkyl or 3 to 5 membered cycloalkyl, wherein the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from D or halogen; Or, R 2a and R 2b The atoms to which it is attached together form a 5- to 6-membered heterocyclic group, wherein the 5- to 6-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O and S, and the 5- to 6-membered heterocyclic group is optionally further substituted by 1 or more heteroatoms selected from C 1-6 Substitution of alkyl, OH and halogen substituents; R 2c is H, cyano, halogen or C 1-6 Alkoxy, the C 1-6 The alkoxy group is optionally substituted with one or more deuteriums; R3 is halogen or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1; n is 0, 1 or 2; x and y are each independently 1, 2 or 3.

6. The use according to claim 1, characterized in that: The active ingredient is selected from a compound of formula (IV), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: in: R0 is H, C 1-6 Alkyl or cyclopropyl, the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from halogen and deuterium; R1 is -(CH) m -4 to 7 membered carbocyclic group, -(CH) m -4 to 7 membered heterocyclic group, -(CH) m -8 to 12-membered bridge ring, -(CH) m -7 to 12 membered spiro ring, said -(CH) m -4 to 7 membered carbocyclic group, -(CH) m -4 to 7 membered heterocyclic group, -(CH) m -8 to 12 membered bridged ring or -(CH) m -7 to 12 membered spiro ring is optionally further substituted by one or more selected from hydroxyl, cyano, halogen, =O, C 1-6 Alkyl, C 1-6 Alkoxy and hydroxy substituted C 1-6 The alkyl group is substituted with a substituent.

7. The use according to claim 6, characterized in that: The active ingredient is selected from a compound of formula (IV), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: R0 is H, C 1-6 Alkyl or cyclopropyl, the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from halogen and deuterium; R1 is or pyridyl, and R1 is optionally further substituted by 1 to 2 groups selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups; R 1a H or C 1-6 alkyl; R 1b C substituted with H, OH, cyano or hydroxyl 1-6 alkyl; m is 0 or 1; x and y are each independently 1, 2 or 3.

8. The use according to claim 7, characterized in that: The active ingredient is a compound of formula (IV), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: R0 is C 1-4 Alkyl, the C 1-4 The alkyl group is optionally further substituted with one or more substituents selected from halogen and deuterium; R1 is or 9. The use according to claims 1-8, characterized in that: The active ingredient is selected from: or 10. The use according to any one of claims 1 to 9, characterized in that: The leukemia is selected from acute lymphocytic leukemia or acute myeloblastic leukemia, and the acute myeloblastic leukemia includes myeloblasts, promyeloblasts, myelomonocytic cells, monocytic cells and / or erythroblastic leukemia; the chronic leukemia includes chronic myeloid / granulocytic leukemia and / or chronic lymphocytic leukemia; the lymphoma includes Hodgkin's disease and / or non-Hodgkin's disease; the gastric cancer includes gastric adenocarcinoma; the head and neck cancer includes tongue adenoid cystic carcinoma and / or adenoid cystic carcinoma; the lung cancer includes large cell neuroendocrine carcinoma of the lung, adenocarcinoma of the lung, sarcomatoid carcinoma of the lung and / or squamous cell carcinoma of the lung; the cervical cancer includes cervical squamous cell carcinoma; the breast cancer includes breast invasive ductal carcinoma and breast ductal carcinoma; the ovarian cancer includes ovarian clear cell carcinoma or ovarian serous carcinoma.

11. A method for treating esophageal cancer, lung cancer, head and neck cancer, gastric cancer, pleural mesothelioma, thymic cancer, kidney cancer, bladder cancer, hepatocellular carcinoma, colorectal cancer, lymphoma, ovarian cancer, breast cancer, fibrosarcoma, myosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovial tumor, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, pancreatic cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchial cancer The method for treating a tumor selected from the group consisting of leukemia, chronic leukemia, polycythemia vera, lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia or heavy chain disease or any combination thereof, wherein: include: Oral administration and radiotherapy in combination, oral administration of a therapeutically effective amount of a DNA-PK inhibitor, continuous daily administration or periodic administration until disease progression or unacceptable toxicity, oral administration of a DNA-PK inhibitor before or after radiotherapy, wherein the DNA-PK inhibitor has the structure of an active ingredient as described in any one of claims 1 to 9.

12. The method according to claim 11, characterized in that DNA-PK inhibitors were taken orally before or after radiotherapy on the day of radiotherapy.

13. The method according to claim 11 or 12, characterized in that: On each day of radiotherapy, take DNA-PK inhibitor orally once a day on an empty stomach 1 to 2 hours before radiotherapy. Administer it along with radiotherapy. Take the medicine on the radiotherapy day and do not take the medicine on the non-radiotherapy day.

14. The method according to claim 13, characterized in that The cyclical administration method includes: 7 days as a cycle, within one cycle, the drug is administered for 5 consecutive days, then stopped for 2 days, and then the next administration cycle begins.

15. The use according to any one of claims 1 to 10 or the method according to any one of claims 11 to 14, characterized in that The daily dose of the active ingredient is 25-600 mg, preferably 50-400 mg, more preferably 100-300 mg.

16. The use according to any one of claims 1 to 10 or the method according to any one of claims 11 to 14, characterized in that The daily dose of the active ingredient is 25 mg, 50 mg or 75 mg.

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