Pyrrolone pyrimidines, processes for their preparation and their use in medicine

Abstract

The present disclosure relates to pyrrolone pyrimidine compounds, methods for preparing the same and their use in medicine. In particular, the present disclosure relates to a pyrrolone pyrimidine compound of general formula (I), methods for preparing the same, pharmaceutical compositions containing the same and their use as therapeutic agents, in particular as DNA-PK inhibitors and in the manufacture of a medicament for the treatment and / or prevention of cancer. Wherein the groups in general formula (I) are as defined in the specification.

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a pyrrolidone-pyrimidine compound, its preparation method, and its pharmaceutical application. In particular, this disclosure relates to a pyrrolidone-pyrimidine compound of general formula (I), its preparation method, pharmaceutical compositions containing such compounds, and its use as a DNA-PK inhibitor in the preparation of medicaments for the treatment and / or prevention of cancer. Background Technology

[0002] DNA-dependent protein kinases (DNA-PKs) are serine / hydroxybutyrine protein kinase complexes composed of the catalytic subunit DNA-PKcs and the heterodimer of Ku protein (Ku70 / Ku80). They are an important protein in the process of DNA damage repair (Cancer Discovery, 2014, 4, 1126-1139). They also play an important role in maintaining telomerase stability, participating in innate immunity and V(D)J recombination, and in transcriptional regulation (Curr Opin Allergy Clin Immunol, 2009, 9, 503–509).

[0003] There are four main types of DNA repair in eukaryotes: nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR), and double-strand break repair (DSBR). NER can excise large segments of DNA damage, BER can repair individual base damage, MMR is used to repair base mismatches, and DSBR includes two mechanisms: non-homologous end joining (NHEJ) and homologous recombination (HR). NHEJ directly joins the broken ends without a template, while HR requires intact sister chromatids as a template. NHEJ is the most important repair pathway and can occur in all phases of the cell cycle. HR mainly occurs in the G2 / M phase of the cell cycle (ChemMedChem, 2017, 12, 895–900). Three PI3K-associated kinase (PIKK) families of kinases play a dominant role in DNA damage repair: DNA-dependent protein kinase (DNA-PK), ataxia-associated kinase (ATM), and ATM and Rad3-associated kinase (ATR). DNA-PK is mainly involved in the NHEJ pathway, ATM is mainly involved in the HR pathway, and ATR is mainly involved in the repair of single-strand DNA damage (Nat Rev Clin Oncol., 2019, 81-104).

[0004] When DNA double-strand breaks occur, the circular Ku70 / Ku80 heterodimer recognizes and binds to the broken DNA ends, recruiting DNA-PKcs. The recruitment of DNA-PKcs promotes the movement of Ku heterodimers into the DNA double strand, allowing DNA-PKcs to act as a tie-in for the broken DNA ends and prevent degradation by exonucleases. Simultaneously, binding to DNA promotes the activation of DNA-PKcs catalytic activity, with the main autophosphorylation sites being Ser2056 and Thr2609. DNA-PKcs also lead to the phosphorylation of a series of downstream proteins, including Artemis, DNA ligase 4, and histone H2A variants (H2AX), collectively contributing to DNA double-strand repair (NatRev Clin Oncol., 2019, 81-104).

[0005] DNA-PK is highly expressed in various types of tumor tissues and can lead to tumor metastasis by stimulating angiogenesis and tumor cell migration (Clin Cancer Res, 2019, 25, 5623-5637). Furthermore, increased DNA-PK activity is closely associated with chemotherapy resistance and poor prognosis. Studies have shown that DNA-PK inhibitors can significantly increase the sensitivity of tumor cells to X-ray irradiation (IR) and chemotherapy drugs, and enhance the antitumor effect of the PAPR inhibitor olaparib (Nat Commun., 2019, 10, 5065-5079; Mol Cancer Res., 2019, 17, 2457-2468).

[0006] Currently, companies such as AstraZeneca and Merck have published several patents for DNA-PK inhibitors (WO2019238929A1, WO2018114999A1, and WO2014183850A1, etc.). These compounds, with their respective structures, still have room for improvement in both in vitro activity and selectivity. AstraZeneca's small-molecule DNA-PK inhibitor entered Phase I clinical trials in October 2019. Currently, no DNA-PK inhibitor drugs have been approved for marketing, indicating a significant unmet medical need among relevant patient populations. Summary of the Invention

[0007] The purpose of this disclosure is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof:

[0008]

[0009] in:

[0010] Ring A is a 3- to 14-membered cycloalkyl group or a 3- to 14-membered heterocyclic group;

[0011] Rm and R n They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, and heterocyclic groups;

[0012] Or R m and R n Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, each of which is optionally independently formed by one or more R atoms. 4 replace;

[0013] Each R 1 They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, amino, nitro, hydroxyl and hydroxyalkyl;

[0014] R 2 Selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups, and hydroxyalkyl groups;

[0015] Each R 3 They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxyl and hydroxyalkyl;

[0016] Each R 4 They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkoxy, haloalkoxy, oxo, cyano, amino, nitro, hydroxyl and hydroxyalkyl;

[0017] n is 0, 1, or 2; and

[0018] p can be 0, 1, 2, 3, or 4.

[0019] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein R m and R n They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 alkyl.

[0020] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein R m and R n Together with the connected carbon atom, it forms a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclic group, each of which is independently and optionally converted by one or more R... 4 Replace; R 4As defined in general formula (I). In some preferred embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof:

[0021]

[0022] in:

[0023] t is 0, 1, or 2;

[0024] m can be 0, 1, 2, 3, or 4;

[0025] Rings A and R 1 To R 4 , n and p are as defined in general formula (I).

[0026] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof:

[0027]

[0028] in:

[0029] m can be 0, 1, 2, 3, or 4;

[0030] Rings A and R 1 To R 4 , n, and p are as defined in general formula (I). In some preferred embodiments of this disclosure, the compound represented by general formula (I), general formula (II), or general formula (III) or a pharmaceutically acceptable salt thereof, wherein ring A is a 3- to 14-membered heterocyclic group; preferably, ring A is selected from 3- to 6-membered heterocyclic groups, 6- to 14-membered spirocyclic groups, 6- to 14-membered bridged heterocyclic groups, and 6- to 14-membered fused heterocyclic groups; more preferably, ring A is a 3- to 6-membered heterocyclic group; most preferably, ring A is

[0031] In some preferred embodiments of this disclosure, the compounds represented by general formula (I), general formula (II) or general formula (III) or their pharmaceutically acceptable salts, wherein each R 1 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; preferably, R 1 It is a hydrogen atom.

[0032] In some preferred embodiments of this disclosure, the compounds represented by general formula (I), general formula (II) or general formula (III) or their pharmaceutically acceptable salts, wherein each R 1 The same or different, and each independently is C. 1-6 alkyl.

[0033] In some preferred embodiments of this disclosure, the compound represented by general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, R 2 It is a hydrogen atom.

[0034] In some preferred embodiments of this disclosure, the compounds represented by general formula (I), general formula (II) or general formula (III) or their pharmaceutically acceptable salts, wherein each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, and C atoms. 1-6 Alkyl; preferably, R 3 It is a hydrogen atom.

[0035] In some preferred embodiments of this disclosure, the compounds represented by general formula (I), general formula (II) or general formula (III) or their pharmaceutically acceptable salts, wherein each R 3 They may be the same or different, and each is independently selected from halogens, cyano groups, and C. 1-6 alkyl.

[0036] In some preferred embodiments of this disclosure, the compounds represented by general formula (I), general formula (II) or general formula (III) or their pharmaceutically acceptable salts, wherein each R 4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; preferably, R 4 It is a hydrogen atom.

[0037] In some preferred embodiments of this disclosure, the compounds represented by general formula (I), general formula (II) or general formula (III) or their pharmaceutically acceptable salts, wherein each R 4 They may be the same or different, and each is independently a halogen or a carbon. 1-6 alkyl.

[0038] In some preferred embodiments of this disclosure, the compound represented by general formula (I), general formula (II) or general formula (III) or its pharmaceutically usable salt, wherein n is 0 or 1; preferably, n is 0.

[0039] In some preferred embodiments of this disclosure, the compound represented by general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein p is 0 or 1; preferably, p is 0.

[0040] In some preferred embodiments of this disclosure, the compound represented by general formula (II) or general formula (III) or its pharmaceutically usable salt is used, wherein m is 0 or 1; preferably, m is 0.

[0041] The purpose of this disclosure is to provide a compound of general formula (IG) or a pharmaceutically acceptable salt thereof:

[0042]

[0043] in:

[0044] Ring A is a 3- to 6-membered heterocyclic group;

[0045] Ring B is a 5-membered heteroaryl group;

[0046] G 1 G 2 and G 3 Whether they are the same or different, and each is an independent CR 6 Or nitrogen atoms;

[0047] Each R 1 The same or different, and each independently is C. 1-6 alkyl.

[0048] Each R 4 They may be the same or different, and each is independently a halogen or a carbon. 1-6 alkyl;

[0049] Each R 5 The same or different, and each independently is C. 1-6 alkyl;

[0050] R 6 Selected from hydrogen atom, halogen, cyano group and C 1-6 alkyl;

[0051] m is 0 or 1;

[0052] p is 0 or 1; and

[0053] q is 0 or 1.

[0054] In some preferred embodiments of this disclosure, the compound represented by the general formula (IG) or a pharmaceutically acceptable salt thereof, wherein ring A is

[0055] In some preferred embodiments of this disclosure, the compound represented by the general formula (IG) or a pharmaceutically acceptable salt thereof, wherein ring B is selected from imidazolyl, pyrazolyl, triazolyl, thiazolyl, pyrroleyl, thiophenyl, and furanyl, preferably pyrazolyl.

[0056] In some preferred embodiments of this disclosure, the compound represented by the general formula (IG) or a pharmaceutically acceptable salt thereof, wherein R 5 It is a methyl group.

[0057] In some preferred embodiments of this disclosure, the compound represented by the general formula (IG) or a pharmaceutically acceptable salt thereof, wherein R 6 It can be a hydrogen atom or a cyano group.

[0058] In some preferred embodiments of this disclosure, the compound represented by the general formula (IG) or a pharmaceutically acceptable salt thereof, wherein m is 0.

[0059] In some preferred embodiments of this disclosure, the compound represented by the general formula (IG) or a pharmaceutically acceptable salt thereof, wherein p is 0.

[0060] In some preferred embodiments of this disclosure, the compound represented by the general formula (IG) or a pharmaceutically acceptable salt thereof, wherein q is 1.

[0061] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a 3- to 6-membered heterocyclic group; R m and R n They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; or, R m and R n Together with the connected carbon atom, it forms a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclic group, each of which is independently and optionally converted by one or more R... 4 Replace; each R 1 The same or different, and each independently is C. 1-6 Alkyl; R 2 For hydrogen atoms; each R 3 They may be the same or different, and each is independently selected from halogens, cyano groups, and C. 1-6 Alkyl groups; each R 4 They may be the same or different, and each is independently a halogen or a carbon. 1-6 Alkyl; n is 0 or 1; and p is 0 or 1.

[0062] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a 3- to 6-membered heterocyclic group; R m and R n Together with the connected carbon atom, it forms a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclic group, each of which is independently and optionally converted by one or more R... 4 Replace; R 1 For hydrogen atoms; R 2 For hydrogen atoms; R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, and C atoms. 1-6 Alkyl; R 4They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; n is 0 or 1; and p is 1. In some preferred embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a 3- to 6-membered heterocyclic group; R m and R n They may be the same or different, and each is independently selected from hydrogen atoms or C atoms. 1-6 Alkyl; R 1 For hydrogen atoms; R 2 For hydrogen atoms; R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, and C atoms. 1-6 Alkyl group; n is 0 or 1; and p is 1.

[0063] In some preferred embodiments of this disclosure, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein ring A is R 1 For hydrogen atoms; R 2 For hydrogen atoms; R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, and C atoms. 1-6 Alkyl; R 4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; t is 0, 1 or 2; n is 0 or 1; p is 1; and m is 0 or 1.

[0064] In some preferred embodiments of this disclosure, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein ring A is R 2 For hydrogen atoms; each R 3 They may be the same or different, and each is independently selected from halogens, cyano groups, and C. 1-6 Alkyl groups; each R 4 They may be the same or different, and each is independently a halogen or a carbon. 1-6 Alkyl; t is 0, 1 or 2; n is 0 or 1; p is 0; and m is 0 or 1.

[0065] In some preferred embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein ring A is R 1 For hydrogen atoms; R 2 For hydrogen atoms; R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, and C atoms. 1-6 Alkyl; R 4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; n is 0 or 1; p is 1; and m is 0 or 1.

[0066] In some preferred embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein ring A is R 2 For hydrogen atoms; each R 3 They may be the same or different, and each is independently selected from halogens, cyano groups, and C. 1-6 Alkyl groups; each R 4 They may be the same or different, and each is independently a halogen or a carbon. 1-6 Alkyl; n is 0 or 1; p is 0; and m is 0 or 1. Table A lists typical compounds disclosed herein, including but not limited to:

[0067]

[0068]

[0069] Another aspect of this disclosure relates to compounds of general formula (IA) or salts thereof:

[0070]

[0071] in:

[0072] X is a halogen; preferably a chlorine atom.

[0073] Ring A is a 3- to 14-membered heterocyclic group;

[0074] R m R n R 1 p is as defined in general formula (I).

[0075] Another aspect of this disclosure relates to compounds of general formula (IIA) or salts thereof:

[0076]

[0077] in:

[0078] X is a halogen; preferably a chlorine atom.

[0079] Ring A is a 3- to 14-membered heterocyclic group;

[0080] R 1 R 4 , t, m and p are as defined in general formula (II).

[0081] Another aspect of this disclosure relates to compounds of general formula (IIIA) or salts thereof:

[0082]

[0083] in:

[0084] X is a halogen; preferably a chlorine atom.

[0085] Ring A is a 3- to 14-membered heterocyclic group;

[0086] R 1 R 4 m and p are as defined in general formula (III).

[0087] Table B lists typical intermediate compounds disclosed herein, including but not limited to:

[0088]

[0089]

[0090] Another aspect of this disclosure relates to a method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0091]

[0092] A compound of general formula (IA) or a salt thereof undergoes a coupling reaction with a compound of general formula (IB) or a salt thereof to yield a compound of general formula (I) or a pharmaceutically usable salt thereof.

[0093] in:

[0094] X is a halogen; preferably, X is a chlorine atom;

[0095] Rings A and R m R n R 1 To R 3 , n and p are as defined in general formula (I).

[0096] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0097]

[0098] A compound of general formula (IIA) or a salt thereof undergoes a coupling reaction with a compound of general formula (IB) or a salt thereof to give a compound of general formula (II) or a pharmaceutically usable salt thereof.

[0099] in:

[0100] X is a halogen; preferably, X is a chlorine atom;

[0101] Rings A and R 1 To R 4 , t, n, m and p are as defined in general formula (II).

[0102] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0103]

[0104] A compound of general formula (IIIA) or a salt thereof undergoes a coupling reaction with a compound of general formula (IB) or a salt thereof to give a compound of general formula (III) or a pharmaceutically usable salt thereof.

[0105] in:

[0106] X is a halogen; preferably, X is a chlorine atom;

[0107] Rings A and R 1 To R 4 , n, m and p are as defined in general formula (III).

[0108] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IG) or a pharmaceutically acceptable salt thereof, the method comprising:

[0109]

[0110] A compound of general formula (IIIA) or a salt thereof undergoes a coupling reaction with a compound of general formula (IGB) or a salt thereof to give a compound of general formula (IG) or a pharmaceutically usable salt thereof.

[0111] in:

[0112] X is a halogen; preferably, X is a chlorine atom;

[0113] Ring A, Ring B, G 1 G 2 G 3 R 1 R 4 R 5 m, p and q are as defined in general formula (IG).

[0114] Another aspect of this disclosure relates to a pharmaceutical composition comprising a compound of formula (I), formula (II), formula (III), formula (IG) and Table A thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0115] This disclosure further relates to the use of compounds of general formula (I), general formula (II), general formula (III), general formula (IG) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of a medicament for inhibiting DNA-PK.

[0116] This disclosure further relates to the use of compounds of general formula (I), general formula (II), general formula (III), general formula (IG) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the treatment and / or prevention of cancer.

[0117] This disclosure further relates to the use of compounds of formulas (I), (II), (III), (IG) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of medicaments for treating and / or preventing diseases or conditions, wherein said diseases or conditions are selected from leukemia, multiple myeloma, lymphoma, myelodysplastic syndrome, breast cancer, lung cancer, endometrial cancer, central nervous system tumors, dysplastic neuroepithelial tumors, glioblastoma multiforme, mixed glioma, medulloblastoma, retinoblastoma, neuroblastoma, germ cell tumor, teratoma, gastric cancer, esophageal cancer, liver cancer, cholangiocarcinoma, colorectal cancer, small bowel cancer, pancreatic cancer, skin cancer, melanoma, thyroid cancer, head and neck cancer, salivary gland cancer, prostate cancer, testicular cancer, ovarian cancer, cervical cancer, vulvar cancer, bladder cancer, kidney cancer, squamous cell carcinoma, sarcoma, gastrointestinal stromal tumor (GIST), and pediatric cancers. Preferably, the sarcoma is selected from chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, Ewing's sarcoma, and Kaposi's sarcoma; preferably, the colorectal cancer is colon cancer or rectal cancer; preferably, the lymphoma is selected from Hodgkin's disease and non-Hodgkin's lymphoma (e.g., mantle cell lymphoma, diffuse large B-cell lymphoma, follicular center lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma, and peripheral T-cell lymphoma); the lung cancer is selected from non-small cell lung cancer (NSCLC) (e.g., squamous cell carcinoma of the lung) and small cell lung cancer (SCLC); the renal cancer is preferably selected from renal cell carcinoma, clear cell renal cell carcinoma, and renal eosinophilic tumor; the leukemia is selected from chronic leukemia (e.g., chronic lymphocytic leukemia) and acute leukemia (e.g., acute myeloid leukemia).

[0118] This disclosure further relates to a method for inhibiting DNA-PK, comprising administering to a patient a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), formula (IG) and shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof.

[0119] This disclosure further relates to a method of treating and / or preventing cancer, comprising administering to a desired patient a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), formula (IG) and shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof.

[0120] This disclosure further relates to a method of treating and / or preventing a disease or condition, comprising administering to a desired patient a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), formula (IG), and the compound shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. The disease or condition is selected from leukemia, multiple myeloma, lymphoma, myelodysplastic syndrome, breast cancer, lung cancer, endometrial cancer, central nervous system tumors, dysplastic neuroepithelial tumors, glioblastoma multiforme, mixed glioma, medulloblastoma, retinoblastoma, neuroblastoma, germ cell tumor, teratoma, gastric cancer, esophageal cancer, liver cancer, cholangiocarcinoma, colorectal cancer, small bowel cancer, pancreatic cancer, skin cancer, melanoma, thyroid cancer, head and neck cancer, salivary gland cancer, prostate cancer, testicular cancer, ovarian cancer, cervical cancer, vulvar cancer, bladder cancer, kidney cancer, squamous cell carcinoma, sarcoma, gastrointestinal stromal tumor (GIST), and pediatric cancers. Preferably, the sarcoma is selected from chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, Ewing's sarcoma, and Kaposi's sarcoma; preferably, the colorectal cancer is colon cancer or rectal cancer; preferably, the lymphoma is selected from Hodgkin's disease and non-Hodgkin's lymphoma (e.g., mantle cell lymphoma, diffuse large B-cell lymphoma, follicular center lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma, and peripheral T-cell lymphoma); the lung cancer is selected from non-small cell lung cancer (NSCLC) (e.g., squamous cell carcinoma of the lung) and small cell lung cancer (SCLC); the renal cancer is preferably selected from renal cell carcinoma, clear cell renal cell carcinoma, and renal eosinophilic tumor; the leukemia is selected from chronic leukemia (e.g., chronic lymphocytic leukemia) and acute leukemia (e.g., acute myeloid leukemia).

[0121] This disclosure further relates to a compound of general formula (I), general formula (II), general formula (III), general formula (IG) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, which is used as a medicine.

[0122] This disclosure further relates to a compound of general formula (I), general formula (II), general formula (III), general formula (IG) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, which is used as a drug for inhibiting DNA-PK.

[0123] This disclosure further relates to a compound of general formula (I), general formula (II), general formula (III), general formula (IG) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, which is used as a medicament for treating and / or preventing cancer.

[0124] This disclosure further relates to a compound of formula (I), formula (II), formula (III), formula (IG) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof, used as a medicine for treating and / or preventing diseases or conditions, wherein said diseases or conditions are selected from leukemia, multiple myeloma, lymphoma, myelodysplastic syndrome, breast cancer, lung cancer, endometrial cancer, central nervous system tumors, dysplastic neuroepithelial tumors, glioblastoma multiforme, mixed glioma, medulloblastoma, retinoblastoma, neuroblastoma, germ cell tumor, teratoma, gastric cancer, esophageal cancer, liver cancer, cholangiocarcinoma, colorectal cancer, small bowel cancer, pancreatic cancer, skin cancer, melanoma, thyroid cancer, head and neck cancer, salivary gland cancer, prostate cancer, testicular cancer, ovarian cancer, cervical cancer, vulvar cancer, bladder cancer, kidney cancer, squamous cell carcinoma, sarcoma, gastrointestinal stromal tumor (GIST), and pediatric cancers. Preferably, the sarcoma is selected from chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, Ewing's sarcoma, and Kaposi's sarcoma; preferably, the colorectal cancer is colon cancer or rectal cancer; preferably, the lymphoma is selected from Hodgkin's disease and non-Hodgkin's lymphoma (e.g., mantle cell lymphoma, diffuse large B-cell lymphoma, follicular center lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma, and peripheral T-cell lymphoma); the lung cancer is selected from non-small cell lung cancer (NSCLC) (e.g., squamous cell carcinoma of the lung) and small cell lung cancer (SCLC); the renal cancer is preferably selected from renal cell carcinoma, clear cell renal cell carcinoma, and renal eosinophilic tumor; the leukemia is selected from chronic leukemia (e.g., chronic lymphocytic leukemia) and acute leukemia (e.g., acute myeloid leukemia).

[0125] The cancers, diseases, or conditions mentioned above are preferably DNA-PK mediated cancers, diseases, or conditions.

[0126] The active compounds can be formulated into forms suitable for administration via any appropriate route, using one or more pharmaceutically acceptable carriers through conventional methods. Therefore, the active compounds of this disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or insufflation. The compounds of this disclosure can also be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.

[0127] As a general guideline, the active compound is preferably expressed in a unit dose manner, or in a manner that allows the patient to self-administer a single dose. The unit dose of the disclosed compound or composition may be expressed as a tablet, capsule, sachet, bottled liquid, powder, granule, lozenge, suppository, regenerated powder, or liquid formulation. Suitable unit doses may range from 0.1 to 1000 mg.

[0128] In addition to the active compound, the pharmaceutical compositions disclosed herein may contain one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, or excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0129] Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation, used for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period.

[0130] Oral formulations can also be provided using soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble carrier or an oil solvent.

[0131] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions for mixing. These excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweeteners.

[0132] Oil suspensions are formulated by suspending the active ingredient in vegetable or mineral oil. Oil suspensions may contain thickeners. Sweeteners and flavoring agents mentioned above may be added to provide palatable formulations. These compositions may be preserved by adding antioxidants.

[0133] The pharmaceutical compositions disclosed herein may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain modifiers, preservatives, colorants, and antioxidants.

[0134] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable solvents or media that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, which can be injected into the patient's bloodstream via local large-volume injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compounds disclosed herein. To maintain such a constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous infusion pump.

[0135] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents as described above, according to known techniques. The sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral-acceptable, non-toxic diluents or solvents. Furthermore, sterile fixative oils may be conveniently used as solvents or suspension media. For this purpose, any blended fixative oil may be used. Additionally, fatty acids may also be used to prepare injectable formulations.

[0136] The disclosed compounds can be administered in suppository form for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at normal temperatures but liquid in the rectum, and thus dissolves in the rectum to release the drug.

[0137] The compounds disclosed herein can be administered by adding water to prepare water-soluble dispersible powders and granules. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersant or wetting agent, a suspending agent, or one or more preservatives.

[0138] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to: the activity of the specific compound used, the severity of the disease, the patient's age, the patient's weight, the patient's health status, the patient's behavior, the patient's diet, the timing of administration, the route of administration, the rate of excretion, and the combination of drugs; in addition, the optimal treatment mode, such as the treatment regimen, the daily dosage of the compound, or the type of pharmaceutically acceptable salt, can be validated based on conventional treatment protocols.

[0139] Terminology Explanation

[0140] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0141] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C12). 1-12 Alkyl groups, more preferably alkyl groups containing 1 to 6 carbon atoms (i.e., C1646-C ... 1-6Alkyl groups). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. Alkyl groups can be substituted or unsubstituted. When substituted, they can be substituted at any usable connection point. The substituents are preferably selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0142] The term "alkenyl" refers to an alkyl compound containing a carbon-carbon double bond in its molecule, wherein the definition of alkyl is as described above. Alkenyl groups can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0143] The term "alkynyl" refers to an alkyl compound containing a carbon-carbon triple bond in its molecule, wherein the definition of alkyl is as described above. The alkynyl group can be substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl groups.

[0144] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring comprises 3 to 20 carbon atoms (i.e., 3 to 20-membered cycloalkyl), preferably 3 to 12 carbon atoms (i.e., 3 to 12-membered cycloalkyl), more preferably 3 to 8 carbon atoms (e.g., 3, 4, 5, 6, 7, and 8) (i.e., 3 to 8-membered cycloalkyl), and more preferably 3 to 6 carbon atoms (i.e., 3 to 6-membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl includes spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0145] The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group that shares a single carbon atom (called a spiro atom) between its rings, and may contain one or more double bonds (i.e., 5- to 20-membered spirocycloalkyl). Preferably, it is 6- to 14-membered (i.e., 6- to 14-membered spirocycloalkyl), more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered) (i.e., 7- to 10-membered spirocycloalkyl). Spirocycloalkyl groups are classified as monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between the rings, with monospirocycloalkyl and bispirocycloalkyl being preferred. More preferably, it is a 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 5-membered, or 5 / 6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

[0146]

[0147] The term "fused cycloalkyl" refers to a 5- to 20-membered polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds (i.e., 5- to 20-membered fused cycloalkyl). Preferably, it is 6- to 14-membered (i.e., 6- to 14-membered fused cycloalkyl), more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered) (i.e., 7- to 10-membered fused cycloalkyl). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 3 / 4-membered, 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 4-membered, 5 / 5-membered, 5 / 6-membered, 6 / 3-membered, 6 / 4-membered, 6 / 5-membered, and 6 / 6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include:

[0148]

[0149] The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms, and may contain one or more double bonds (i.e., 5- to 20-membered bridged cycloalkyl). Preferably, it is 6- to 14-membered (i.e., 6- to 14-membered bridged cycloalkyl), more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered) (i.e., 7- to 10-membered bridged cycloalkyl). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

[0150]

[0151] The cycloalkyl ring comprises a cycloalkyl group (including monocycloalkyl, spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl) fused to an aryl, heteroaryl, or heterocycloalkyl ring as described above, wherein the ring attached to the parent structure is a cycloalkyl group, and non-limiting examples include indenyl. Tetrahydronaphthyl Benzocycloheptyl etc.; preferred indene and tetrahydronaphthyl

[0152] The cycloalkyl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0153] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclic oxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups.

[0154] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms (i.e., a 3 to 20-membered heterocyclic group), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), but does not include the ring moiety of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Preferably, it comprises 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms (i.e., 3 to 12-membered heterocyclic groups), wherein 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, it comprises 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8) (i.e., 3 to 8-membered heterocyclic groups), wherein 1 to 3 (e.g., 1, 2, and 3) are heteroatoms; even more preferably, it comprises 3 to 6 ring atoms (i.e., 3 to 6-membered heterocyclic groups), wherein 1 to 3 are heteroatoms; most preferably, it comprises 5 or 6 ring atoms (i.e., 5 or 6-membered heterocyclic groups), wherein 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0155] The term "spiroheterocyclic group" refers to a 5- to 20-membered (i.e., 5- to 20-membered spiroheterocyclic group) polycyclic heterocyclic group in which one or more ring atoms share a single atom (called a spiro atom), wherein the one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, and the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), but does not include the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably, it is 6- to 14-membered (i.e., 6- to 14-membered spiroheterocyclic group), more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered) (i.e., 7- to 10-membered spiroheterocyclic group). Spiroheterocyclic groups are classified into monospirocyclic, bispirocyclic, or polyspirocyclic groups according to the number of shared spiro atoms between the rings, with monospirocyclic and bispirocyclic groups being preferred. More preferably, it is a 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocyclic heterocyclic group. Non-limiting examples of spirocyclic groups include:

[0156]

[0157] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group (i.e., a 5- to 20-membered fused heterocyclic group), in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur. The sulfur may optionally be oxidized (i.e., forming sulfoxides or sulfones), but does not include the -OO-, -OS-, or -SS- ring moieties, and the remaining ring atoms are carbon. Preferably, it is a 6- to 14-membered fused heterocyclic group (i.e., a 6- to 14-membered fused heterocyclic group), more preferably a 7- to 10-membered fused heterocyclic group (e.g., 7, 8, 9, or 10-membered fused heterocyclic group). Based on the number of constituent rings, fused heterocyclic groups can be classified into bicyclic, tricyclic, tetracyclic, or multicyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably ternary / quadricyclic, ternary / pentacyclic, ternary / hexacyclic, quadricyclic / quadricyclic, quadricyclic / pentacyclic, quadricyclic / hexacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / hexacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, and pentacyclic / pentacyclic bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0158]

[0159] The term "bridged heterocyclic group" refers to a 5- to 14-membered (i.e., 5- to 14-membered bridged heterocyclic group) polycyclic heterocyclic group in which any two rings share two non-directly connected atoms. It may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), but does not include the -OO-, -OS-, or -SS- ring moiety, and the remaining ring atoms are carbon. Preferably, it is a 6- to 14-membered (i.e., 6- to 14-membered bridged heterocyclic group), more preferably a 7- to 10-membered (e.g., 7, 8, 9, or 10-membered) (i.e., 7- to 10-membered bridged heterocyclic group). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0160]

[0161] The heterocyclic ring comprises a heterocyclic group (including monocyclic heterocyclic groups, spirocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups) fused to an aryl, heteroaryl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0162] wait.

[0163] The heterocyclic group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0164] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system (i.e., 6- to 14-membered aryl), preferably 6- to 10-membered (e.g., 6, 7, 8, 9, or 10-membered) (i.e., 6- to 10-membered aryl), such as phenyl and naphthyl. The aryl ring comprises an aryl ring fused to a heteroaryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples include:

[0165]

[0166] The aryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0167] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms (i.e., 5 to 14-membered heteroaryls), wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered) (i.e., 5 to 10-membered heteroaryls), more preferably 5 or 6-membered (i.e., 5 or 6-membered heteroaryls), such as furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring comprises a heteroaryl ring fused to an aryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0168]

[0169] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0170] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups include residues derived from removing one hydrogen atom from a parent ring atom, or residues derived from removing two hydrogen atoms from the same or two different ring atoms of the parent, namely "divalent cycloalkyl", "divalent heterocyclic", "aryl", and "heteroaryl".

[0171] The term “cycloalkyloxy” refers to cycloalkyl-O-, where the cycloalkyl group is as defined above.

[0172] The term “heterocyclic oxy group” refers to the heterocyclic group -O-, where the heterocyclic group is as defined above.

[0173] The term "alkylthio" refers to alkyl-S-, where the alkyl group is as defined above.

[0174] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0175] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0176] The term “deuterated alkyl” refers to an alkyl group that is replaced by one or more deuterium atoms, wherein the alkyl group is as defined above.

[0177] The term "hydroxyalkyl" refers to an alkyl group that is substituted with one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0178] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0179] The term "hydroxyl group" refers to -OH.

[0180] The term "thiol" refers to -SH.

[0181] The term "amino" refers to -NH2.

[0182] The term "cyano" refers to -CN.

[0183] The term "nitro" refers to -NO2.

[0184] The term "oxo" or "oxo" refers to "=O".

[0185] The term "carbonyl" refers to C=O.

[0186] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations. In the chemical structure of the compounds described in this disclosure, the bonds... No configuration is specified, meaning it can be Z configuration, E configuration, or both configurations.

[0187] The compounds disclosed herein can exist in various tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to a structural isomer that exists in equilibrium and readily transforms from one isomer to another. This includes all possible tautomers, i.e., existing as a single isomer or as a mixture of said tautomers in any proportion. Non-limiting examples include, for example, keto-enol tautomers, imine-enamine tautomers, lactam-lactamimide tautomers, etc. An example of a lactam-lactamimide equilibrium is between A and B as shown below:

[0188]

[0189] When referring to the pyrazolyl group, it should be understood to include any one or a mixture of two tautomers of the following two structures:

[0190]

[0191] All tautomers are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

[0192] The compounds disclosed herein contain their isotopic derivatives. The term "isotopic derivative" refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure disclosed herein, using "deuterium" or "tritium" instead of hydrogen, or using... 18 F-fluorine labeling ( 18 F isotopes) can be used instead of fluorine, or... 11 C-, 13 C-, or 14 C-enriched carbon ( 11 C-, 13 C-, or 14 C-carbon labeling; 11 C-, 13 C-, or 14Compounds in which carbon atoms are replaced by C-isotopes are within the scope of this disclosure. Such compounds can be used as analytical tools or probes in, for example, biological assays, or as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamic, pharmacokinetic, or receptor studies. The various deuterated forms of compounds disclosed herein refer to compounds in which each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of compounds by referring to relevant literature. Commercially available deuteration starting materials can be used in the preparation of deuterated forms of compounds, or they can be synthesized using conventional techniques with deuteration reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane. Deuterated compounds generally retain activity comparable to undeuterated compounds, and better metabolic stability can be achieved when deuterated at certain specific sites, resulting in certain therapeutic advantages.

[0193] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of the event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0194] "Substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, which are independently substituted by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without much effort (through experimentation or theory). For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0195] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0196] "Pharmacologically acceptable salts" refer to salts of the compounds disclosed herein that are safe and effective in mammalian use and possess the intended biological activity. Salts can be prepared separately during the final isolation and purification of the compounds, or by reacting suitable groups with suitable bases or acids. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include both inorganic and organic acids.

[0197] For the purposes of pharmaceuticals or pharmacologically active agents, the term "therapeutic effective amount" refers to the amount of a drug or agent sufficient to achieve or at least partially achieve the intended effect. The determination of the therapeutic effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate therapeutic effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0198] As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0199] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0200] When the term "about" is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are usually given for illustrative purposes only and not as limitations.

[0201] The method for synthesizing the compounds disclosed herein

[0202] In order to achieve the purpose of this disclosure, the following technical solution is adopted:

[0203] Option 1

[0204] A method for preparing the compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising:

[0205]

[0206] A compound of general formula (IA) or a salt thereof undergoes a coupling reaction with a compound of general formula (IB) or a salt thereof under basic conditions and in the presence of a catalyst to give a compound of general formula (I) or a pharmaceutically acceptable salt thereof.

[0207] in:

[0208] X is a halogen; preferably, X is a chlorine atom;

[0209] Rings A and R m R n R 1 To R 3 , n and p are as defined in general formula (I).

[0210] Option 2

[0211] A method for preparing the compound of formula (II) or a pharmaceutically acceptable salt thereof, comprising:

[0212] A compound of general formula (IIA) or a salt thereof, under basic conditions and in the presence of a catalyst, undergoes a coupling reaction with a compound of general formula (IB) or a salt thereof to give a compound of general formula (II) or a pharmaceutically acceptable salt thereof.

[0213] in:

[0214] X is a halogen; preferably, X is a chlorine atom;

[0215] Rings A and R 1 To R 4 , t, n, m and p are as defined in general formula (II).

[0216] Option 3

[0217] A method for preparing the compound of formula (III) or a pharmaceutically acceptable salt thereof, comprising:

[0218]

[0219] A compound of general formula (IIIA) or a salt thereof, under basic conditions and in the presence of a catalyst, undergoes a coupling reaction with a compound of general formula (IB) or a salt thereof to give a compound of general formula (III) or a pharmaceutically acceptable salt thereof.

[0220] in:

[0221] X is a halogen; preferably, X is a chlorine atom;

[0222] Rings A and R 1 To R 4 , n, m and p are as defined in general formula (III).

[0223] Option 4

[0224] A method for preparing the compound of formula (IG) or a pharmaceutically acceptable salt thereof, comprising:

[0225]

[0226] A compound of general formula (IIIA) or a salt thereof undergoes a coupling reaction with a compound of general formula (IGB) or a salt thereof under basic conditions and in the presence of a catalyst to give a compound of general formula (IG) or a pharmaceutically acceptable salt thereof.

[0227] in:

[0228] X is a halogen; preferably, X is a chlorine atom;

[0229] Ring A, Ring B, G 1 G 2 G 3 R 1 R 4 R 5 m, p and q are as defined in general formula (IG).

[0230] The reagents providing alkaline conditions in the above synthesis scheme include organic and inorganic bases. The organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylaminolithium, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, or 1,8-diazabicycloundec-7-ene. The inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, and potassium hydroxide. Preferably, the reagent providing alkaline conditions is cesium carbonate.

[0231] The catalysts used in the above synthesis schemes include, but are not limited to, tetra-triphenylphosphine palladium, palladium dichloride, palladium acetate, (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), 1,1'-bis(dibenzylphosphine)dichlorodipentadienylferrocene, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex, tris(dibenzylacetone)dipalladium, etc., preferably (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II).

[0232] The reactions described above are preferably carried out in a solvent, which may include, but is not limited to, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane, and mixtures thereof. Detailed Implementation

[0233] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0234] Example

[0235] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6The unit (ppm) is given. NMR determination was performed using a Bruker AVANCE NEO 500M or Bruker AVANCE-400M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0236] MS measurements were performed using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS LC-MS system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a waters ACQuity UPLC-QD / SQD system (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector), a THERMO Ultimate 3000-Q Exactive system (manufacturer: THERMO, MS model: THERMO Q Exactive), and an Agilent 1290-6125 single quadrupole (ESI) mass spectrometer.

[0237] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 HPLC system.

[0238] Chiral HPLC analysis was performed using an Agilent 1260 DAD high-performance liquid chromatograph and an Agilent 1290 DAD high-performance liquid chromatograph.

[0239] High-performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, Gilson GX-281 preparative chromatographs, and Hanbang NP7010C and Hanbang NP7100C preparative HPLC systems.

[0240] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph and a SepaBean machine T.

[0241] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0242] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0243] Silica gel column chromatography generally uses Yantai Huanghai silica gel of 100-200 mesh or 200-300 mesh as the carrier.

[0244] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0245] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, and Darui Chemicals.

[0246] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0247] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0248] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0249] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0250] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0251] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0252] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0253] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0254] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0255] Example 1

[0256] 2'-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7'-((tetrahydro-2H-pyran-4-yl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidine]-6'(7'H)-one

[0257]

[0258] first step

[0259] (1-(methoxycarbonyl)cyclopropyl)zinc bromide 1b

[0260] Activated zinc powder (2.9 g, 44.96 mmol, Sinopharm) was added to N,N-dimethylacetamide (45 mL, Anegatech) and purged with nitrogen three times. Trimethylchlorosilane (0.35 g, 3.22 mmol, Anegatech) was added dropwise, and the mixture was stirred for 10 min. The temperature was maintained below 30 °C, and 1,2-dibromoethane (1.1 g, 6.07 mmol, Anegatech) was added dropwise, and the mixture was stirred for 30 min after the addition was complete. The temperature was maintained below 30 °C, and methyl 1-bromocyclopropaneformate 1a (5.3 g, 30 mmol, Anegatech) was added dropwise, and the mixture was stirred for 1.5 h after the addition was complete. Unreacted zinc powder was filtered off, yielding a solution of product 1b in N,N-dimethylacetamide, which was used directly in the next step.

[0261] Step 2

[0262] 2'-Chloro-7'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidine]-6'(7'H)-one1d

[0263] 5-Bromo-2-chloro-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine 1c (4.40 g, 15.04 mmol, prepared by the method disclosed in the example on page 51 of patent application "WO2009085185A1"), tris(dibenzylideneacetone)palladium (686 mg, 0.75 mmol, Shanghai Hanhong), and 1,2,3,4,5-pentanphenyl-1'-(di-tert-butylphospho)ferrocene (533 mg, 0.75 mmol, Jiangsu Aikang) were added to N,N-dimethylacetamide solution 1b, purged with nitrogen three times, and reacted at room temperature for 12 h. Add 150 mL of water and 150 mL of ethyl acetate to the reaction solution and stir thoroughly. Filter through diatomaceous earth, separate the phases, extract the aqueous phase with ethyl acetate (100 mL × 2), combine the organic phases, wash with saturated sodium chloride solution (150 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue using a rapid filtration apparatus with eluent system B (n-hexane: ethyl acetate = 1:0-1:1) to obtain the title product 1d (1.91 g, yield: 45.5%).

[0264] MS m / z(ESI):280.1[M+1].

[0265] 1 H NMR (400MHz, DMSO-d6): δ8.20(s,1H),4.49-4.41(m,1H),3.99-3.95(m,2H),3.43( t,2H),2.51-2.42(m,2H),1.91-1.88(m,2H),1.70-1.67(m,2H),1.65-1.61(m,2H).

[0266] Step 3

[0267] 2'-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7'-((tetrahydro-2H-pyran-4-yl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidine]-6'(7'H)-one

[0268] Compound 1d (1.6 g, 5.65 mmol), 7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine 1e (0.84 g, 5.65 mmol, prepared by the method disclosed in intermediate 4 on page 53 of the specification “WO2018114999A1”), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.77 g, 0.85 mmol, Shaoyuan), and cesium carbonate (3.7 g, 11.32 mmol, Sinopharm) were dissolved in 1,4-dioxane (50 mL) and stirred at 95 °C for 16 hours under a nitrogen atmosphere. Add 100 mL of water, extract with ethyl acetate (100 mL × 2), combine the organic phases, wash successively with water (100 mL) and saturated sodium chloride solution (100 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue using a CombiFlash rapid preparation instrument with eluent system A (dichloromethane:methanol = 1:0-10:1) to give title product 1 (0.24 g, yield: 10.85%).

[0269] MS m / z(ESI):392.0[M+1].

[0270] 1 H NMR (500MHz, CDCl3): δ9.71(s,1H),8.26(s,1H),7.72(s,1H),7.58(s,1H),6.74(s,1H),4.59-4.53(m,1H),4.15-4.1 2(m,2H),3.56-3.48(m,2H),2.83-2.75(m,2H),2.53(s,3H),1.79-1.77(m,2H),1.69-1.65(m,2H),1.59-1.56(m,2H).

[0271] Example 2

[0272] 2'-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-7'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidine]-6'(7'H)-one 2

[0273]

[0274]

[0275] first step

[0276] 4-Methyl-2-(1-methyl-1H-pyrazol-4-yl)-5-nitropyridine 2b

[0277] Under an argon atmosphere, 2-bromo-4-methyl-5-nitropyridine 2a (500 mg, 2.30 mmol, Bio-Tech Pharmaceuticals), 1-methylpyrazole-4-boronic acid (321 mg, 2.54 mmol, Shaoyuan Chemicals), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (169 mg, 230.9 μmol), and potassium carbonate (957 mg, 6.92 mmol) were added to 50 mL of a mixed solvent of 1,4-dioxane and water (V:V = 4:1), and the mixture was heated to 100 °C and reacted for 17 hours. After cooling the reaction solution to room temperature, the solution was concentrated under reduced pressure. The residue was purified using a CombiFlash rapid reagent system with eluent system A to give title product 2b (441 mg, yield: 87.7%).

[0278] Step 2

[0279] 4-Methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridine-3-amine 2c

[0280] Compound 2b (441 mg, 2.02 mmol) was added to 50 mL of ethanol, followed by the addition of 10% palladium on carbon hydrogenation catalyst (216 mg, 2.02 mmol). The mixture was purged with hydrogen three times and stirred at room temperature for 17 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the title product 2c (339 mg, yield: 89.1%).

[0281] Step 3

[0282] 2'-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-7'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidine]-6'(7'H)-one 2

[0283] Under a nitrogen atmosphere, compound 1d (154 mg, 550.5 μmol), compound 2c (104 mg, 552.5 μmol), cesium carbonate (540 mg, 1.65 mmol), and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2,4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (50 mg, 55.09 μmol) were added to 15 mL of 1,4-dioxane and the mixture was heated to 100 °C for 16 hours. After cooling the reaction solution to room temperature, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography using solvent system A to give title product 2 (35 mg, yield: 14.6%).

[0284] MS m / z(ESI):432.1[M+1].

[0285] 1 H NMR (500MHz, DMSO-d6): δ8.90(s,1H),8.47(d,1H),8.20(s,1H),7.94(s,1H),7.83(s,1H),7.53(s,1H),4.46-4.39(m,1H),3.97-3. 94(m,2H),3.89(s,3H),3.40-3.33(m,2H),2.57-3.51(m,2H),2.25(s,3H),1.66-1.64(m,2H),1.62-1.59(m,2H),1.52-1.50(m,2H).

[0286] Example 3

[0287] 4-Methyl-2-(1-Methyl-1H-pyrazol-4-yl)-5-((6'-oxo-7'-(tetrahydro-2H-pyran-4-yl)-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-2'-yl)amino)benzonitrile 3

[0288]

[0289] Using the synthetic route of compound 1 in Example 1, the starting compound 1e was replaced with the starting compound 5-amino-4-methyl-2-(1-methyl-1H-pyrazole-4-yl)benzyl 3a (prepared by the method disclosed on page 317 of the specification in "WO2017125530 A1") to obtain title product 3 (12 mg).

[0290] MS m / z(ESI):456.1[M+1].

[0291] 1 H NMR (500MHz, DMSO-d6): δ8.93(s,1H),8.21(s,1H),8.10(d,1H),7.94(d,1H),7.92(s,1H),7.58(s,1H),4.47-4.41(m,1H),3.99-3. 95(m,2H),3.93(s,3H),3.42-3.36(m,2H),2.56-2.53(m,2H),2.37(s,3H),1.70-1.67(m,2H),1.64-1.60(m,2H),1.55-1.53(m,2H).

[0292] Example 4

[0293] 2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one

[0294]

[0295]

[0296] first step

[0297] (2-(tert-butoxy)-2-oxoethyl)zinc bromide 4b

[0298] Activated zinc powder (2.3 g, 35.38 mmol, Sinopharm) was added to N,N-dimethylacetamide (45 mL, Anegatech), purged with nitrogen three times, and trimethylchlorosilane (0.33 g, 3.03 mmol, Anegatech) was added dropwise, stirring for 10 minutes. Maintaining the temperature below 30°C, 1,2-dibromoethane (1.13 g, 6.07 mmol, Anegatech) was added dropwise, stirring for 30 minutes after the addition was complete. Maintaining the temperature below 30°C, tert-butyl bromoacetate 4a (5.8 g, 29.7 mmol, Anegatech) was added dropwise, stirring at 60°C for 20 minutes after the addition was complete. The mixture was cooled to room temperature, and unreacted zinc powder was filtered off to obtain an N,N-dimethylacetamide solution of the title product 4b, which was used directly in the next step.

[0299] Step 2

[0300] 2-(2-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-5-yl)tert-butyl acetate 4c

[0301] 5-Bromo-2-chloro-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine 1c (4.40 g, 15.04 mmol, prepared by the method disclosed in the example on page 51 of patent application "WO2009085185A1"), tris(dibenzylideneacetone)palladium (686 mg, 0.75 mmol, Shanghai Hanhong), and 1,2,3,4,5-pentanphenyl-1'-(di-tert-butylphospho)ferrocene (533 mg, 0.75 mmol, Jiangsu Aikang) were dissolved in N,N-dimethylacetamide solution 4b, purged with nitrogen three times, and reacted at room temperature for 12 hours. Add 150 mL of water and 150 mL of ethyl acetate to the reaction solution, stir thoroughly, filter through diatomaceous earth, separate the phases, extract the aqueous phase with ethyl acetate (100 mL × 2), combine the organic phases, wash with saturated sodium chloride solution (150 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue obtained by using a rapid preparation instrument from Sante Technology with eluent system B to obtain the title product 4c (2.0 g, yield: 45.5%).

[0302] Step 3

[0303] 2-Chloro-7-(tetrahydro-2H-pyran-4-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one4d

[0304] Compound 4c (2.0 g, 7.9 mmol) and tetrahydrofuran (50 mL, Adamas) were added to a 100 mL three-necked flask. Sodium hydride (412 mg, 17.16 mmol) was added at 15 °C, and the mixture was stirred for 1 hour. After the starting material reacted completely, the reaction was quenched with 1 M dilute hydrochloric acid (10 mL). 50 mL of water and 50 mL of ethyl acetate were added, and the mixture was extracted. The aqueous phase was then extracted again with 30 mL of ethyl acetate. The combined organic phases were washed with 50 mL of 10% brine and 50 mL of saturated brine, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the residue was slurried for 30 minutes with a mixture of 20 mL of petroleum ether and ethyl acetate (V:V = 4:1). The mixture was filtered and dried to give the title product 4d (1.0 g, 77%).

[0305] Step 4

[0306] 2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one

[0307] Compound 4d (0.3 g, 1.18 mmol), compound 1e (175 mg, 1.18 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2,4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (161 mg, 0.18 mmol, Shaoyuan), and cesium carbonate (768.6 mg, 2.36 mmol, Sinopharm) were dissolved in 1,4-dioxane (50 mL) and stirred at 95 °C for 16 hours under a nitrogen atmosphere. Add 100 mL of water and extract with ethyl acetate (100 mL × 2). Combine the organic phases and wash successively with water (100 mL) and saturated sodium chloride solution (100 mL). Dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue using a CombiFlash rapid preparation instrument with eluent system A to give title product 4 (12 mg, yield: 2.77%).

[0308] MS m / z(ESI): 366.0 [M+1].

[0309] 1H NMR (500MHz, CD3Cl3): δ9.68(s,1H),8.27(s,1H),8.07(s,1H),7.59(s,1H),6.75(s,1H),4.53-4.4 8(m,1H),4.14-4.11(m,2H),3.55-3.50(m,3H),2.81-2.73(m,3H),2.53(s,3H),1.65-1.61(m,2H).

[0310] Example 5

[0311] 5-Methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one

[0312]

[0313] first step

[0314] 2-Chloro-5-methyl-7-(tetrahydro-2H-pyran-4-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 5a

[0315] Add 4d (1.7 g, 6.72 mmol) and tetrahydrofuran (60 mL) to a 100 mL three-necked flask, cool to -30 °C under nitrogen protection, and add LiHMDS (10 mL, 1 M in THF, Adamas) dropwise. After the addition is complete, maintain the temperature at -30 ± 5 °C and stir for 1 hour. Then, add iodomethane (951 mg, 6.69 mmol, Adamas) dropwise at -30 ± 5 °C. After the addition is complete, raise the temperature to 10-20 °C and react for 1 hour, then stop the reaction. Add 40 mL of saturated ammonium chloride solution, 10 mL of 2 M hydrochloric acid solution and 50 mL of ethyl acetate to the system, extract, separate the phases, extract the aqueous phase with 100 mL of ethyl acetate, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify using a rapid elution system with eluent B to obtain the title product 5a (180 mg, yield: 10%).

[0316] Step 2

[0317] 5-Methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one

[0318] Compound 5a (70 mg, 261.47 μmol), compound 1e (39 mg, 261.53 μmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2,4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (35.6 mg, 39.21 μmol, Shaoyuan), and cesium carbonate (170 mg, 522.95 μmol, Sinopharm) were dissolved in 1,4-dioxane (50 mL) and stirred at 95 °C for 16 hours under a nitrogen atmosphere. Add 100 mL of water and extract with ethyl acetate (100 mL × 2). Combine the organic phases and wash successively with water (100 mL) and saturated sodium chloride solution (100 mL). Dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue using a CombiFlash rapid reagent system with eluent system A to give title product 5 (8 mg, yield: 8.1%).

[0319] MS m / z(ESI):380.0[M+1].

[0320] 1 H NMR (500MHz, CD3Cl3): δ9.68(s,1H),8.27(s,1H),8.04(s,1H),7.59(s,1H),6.76(s,1H),4.49-4.47(m,1 H),4.14-4.11(m,2H),3.54-3.46(m,3H),2.77-2.74(m,2H),2.53(s,3H),1.49(d,3H),1.29-1.25(t,2H).

[0321] Example 6

[0322] 5,5-Dimethyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one

[0323]

[0324] first step

[0325] 2-Chloro-5,5-dimethyl-7-(tetrahydro-2H-pyran-4-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 6a

[0326] Compound 4d (1.7 g, 6.72 mmol) and tetrahydrofuran (60 mL) were added to a 100 mL three-necked flask. Under nitrogen protection, the temperature was lowered to -30 °C, and LiHMDS (10 mL, 1 M in THF, Adamas) was added dropwise. After the addition was complete, the mixture was stirred at -30 ± 5 °C for 1 hour. Then, iodomethane (951 mg, 6.69 mmol, Adamas) was added dropwise at -30 ± 5 °C. After the addition was complete, the temperature was raised to 10-20 °C and the reaction was stopped after 1 hour. 40 mL of saturated ammonium chloride solution, 10 mL of 2 M hydrochloric acid solution, and 50 mL of ethyl acetate were added to the system. The mixture was extracted, separated, and the aqueous phase was extracted again with ethyl acetate (100 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified using a rapid preparative system with eluent B to obtain the title product 6a (270 mg, yield: 14.3%).

[0327] Step 2

[0328] 5,5-Dimethyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one

[0329] Compound 6a (247.7 mg, 879.18 μmol), compound 1e (130.3 mg, 879.22 μmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2,4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (119.7 mg, 131.88 μmol, Shaoyuan), and cesium carbonate (571.5 mg, 1.76 mmol, Sinopharm) were dissolved in 1,4-dioxane (50 mL) and stirred at 95 °C for 16 hours under a nitrogen atmosphere. Add 100 mL of water and extract with ethyl acetate (100 mL × 2). Combine the organic phases and wash successively with water (100 mL) and saturated sodium chloride solution (100 mL). Dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue using a CombiFlash rapid preparation instrument with eluent system A to give title product 6 (32 mg, yield: 9.25%).

[0330] MS m / z(ESI):394.0[M+1].

[0331] 1H NMR (500MHz, CD3Cl3): δ9.69(s,1H),8.27(s,1H),8.02(s,1H),7.59(s,1H),6.75(s,1H),4.50-4.45(m,1 H),4.14-4.11(m,2H),3.55-3.50(m,2H),2.80-2.72(m,2H),2.53(s,3H),1.63(s,6H),1.41-1.26(m,2H).

[0332] Biological evaluation

[0333] The following test examples further describe and explain this disclosure, but these test examples are not intended to limit the scope of this disclosure.

[0334] Test Example 1

[0335] DNA-PK Enzymatic Experimental Methods

[0336] 1. Experimental Objective

[0337] The level of phosphorylated p53 was detected using the HTRF method, and the inhibitory effect of the reaction compound on DNA-PK enzyme activity was determined based on the IC50 of the inhibitory effect. 50 Evaluate the in vitro activity of the compound.

[0338] 2. Experimental Methods

[0339] Dilute substrate P53 (Eurofins, 14-952-M) to 500 nM with reaction buffer [25 mM HEPES (Gibco, 15630-080) pH 8.0, 0.01% Brij-35 (Thermo, 20150), 1% glycerol (Sangon Biotech, A100854-0100)]. Dilute DNA-PK enzyme (Eurofins, 14-950M) to 0.16 nM with dilution buffer [25 mM HEPES pH 8.0, 0.01% Brij-35, 1% glycerol, 5 mM DTT (Sangon Biotech, B645939), 1 mg / mL BSA (Beyotime, ST023)]. Dilute magnesium acetate (Sigma, 63052) to 40 mM with dilution buffer, then dilute ATP (Thermo, PV3227) to 29.2 μM. Using a liquid chromatography-mass spectrometry system (PV3227, #SP2-096-0125-03), add 10 μL of the prepared compound, 2.5 μL of DNA-PK enzyme, 2.5 μL of 500 nM P53 substrate, and 5 μL of ATP sequentially to a 384-well plate (Thermo, 267462). After mixing, incubate at 25°C for 1 hour.

[0340] Using a liquid workstation, add 5 μL each of the stop solution [12.5 mM HEPES pH 8.0, 0.005% Brij-35, 0.5% glycerol, 250 mM EDTA (Thermo, AM9260G)] and the assay mixture [50 mM HEPES pH 7.0, 150 mM NaCl (Sangon Biotech, B548121), 267 mM KF (Sinopharm, 7789-23-3), 0.1% sodium cholate (Sigma, C6445), 0.01% Tween 20 (Sigma, P7949), 0.0125% sodium azide (Sigma, S8032), 0.42 ng / well of antiphosphorylation-p53 Eu (Cisbio, 61P08KAE), and 25 ng / well of anti-GST-d2 (Cisbio, 61GSTDLF)] to a 384-well plate and incubate overnight at 25°C. The absorbance values ​​at 665 nm and 620 nm were read using a microplate reader (BMG, PHERAstar FS). The data were analyzed using a Graphpad Prism 6 and are shown in Table 1.

[0341] Table 1 IC50 values ​​of the inhibitory activity of the disclosed compounds against DNA-PK enzyme 50 value.

[0342] Example number <![CDATA[IC 50 (nM)]]> 1 0.2 2 0.8 3 0.5 4 0.9 5 6.8 6 17.4

[0343] Conclusion: The compound disclosed herein has a good inhibitory effect on DNA-PK enzyme.

[0344] Test Example 2

[0345] DNA-PK cell proliferation inhibition assay

[0346] 1. Experimental Objective

[0347] The killing effect of compounds on the non-small cell lung cancer cell line A549 was studied by detecting the response of intracellular ATP levels to cell activity. The IC50 of the killing effect was then used to determine the cytotoxic effect. 50 Size is used to evaluate the in vitro activity of compounds.

[0348] 2. Experimental Methods

[0349] A549 cells (ATCC, CCL-185) were digested with trypsin (Gibico, 25200-072) at 37°C for 3 minutes, resuspended in complete medium [F-12K medium (Gibico, 21127030), 10% FBS (Thermo Fisher Scientific, 10099-141)] for counting, and 1000 cells were added to each well of a 96-well plate (Corning, 3903) and incubated overnight at 37°C in a CO2 incubator (Thermo Fisher, HERAcell 240i). Compounds were prepared using a Bravo liquid workstation (Agilent Technologies, SGS120TH34702), and the prepared compounds were diluted with complete medium for later use. Remove the cell culture plate, aspirate 10 μL of culture medium, add 5 μL of the diluted compound, and return to the CO2 incubator for 1 hour. Bleomycin (Selleck, S1214) was diluted to 20 μM using complete culture medium, and 5 μL was added to each well of the culture plate (final concentration 500 nM). The culture plate was returned to the CO2 incubator for further incubation. After 6 days, the culture plate was removed, and 50 μL of CellTiter-Glo (Promega, G7573) was added to each well. The plate was incubated at 25°C in the dark for 5 minutes. Luminescence values ​​were detected using a microplate reader (PerkinElmer, Vector3), and the data were analyzed using Graphpad Prism 6. The results are shown in Table 2.

[0350] Table 2 IC50 values ​​of the disclosed compounds against DNA-PK cell proliferation 50 value

[0351] Example number <![CDATA[IC 50 (nM)]]> 1 42 2 52 3 70

[0352] Conclusion: The compound disclosed herein has a good inhibitory effect on DNA-PK cell proliferation.

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof: in: Ring A is a 3- to 6-membered heterocyclic group; R m and R n They may be the same or different, and each is independently selected from hydrogen atoms and C atoms. 1-6 alkyl; Or R m and R n Together with the connected carbon atoms, a 3- to 6-membered cycloalkyl group is formed, wherein the 3- to 6-membered cycloalkyl group is optionally bonded by one or more R atoms. 4 replace; Each R 1 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 alkyl; R 2 Selected from hydrogen atoms, halogens and C 1-6 alkyl; Each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and cyano groups; Each R 4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 alkyl; n is 0, 1, or 2; p is 0, 1, 2, 3, or 4; and The compound represented by general formula (I) is not .

2. The compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, is a compound of general formula (II) or a pharmaceutically acceptable salt thereof: in: t is 0, 1, or 2; m can be 0, 1, 2, 3, or 4; Rings A and R 1 To R 4 n and p are as defined in claim 1.

3. The compound of general formula (I) or a pharmaceutically acceptable salt thereof as described in claim 1 or 2, wherein the compound is of general formula (III) or a pharmaceutically acceptable salt thereof: in: m can be 0, 1, 2, 3, or 4; Rings A and R 1 To R 4 n and p are as defined in claim 1.

4. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, R m and R n They may be the same or different, and each is independently selected from hydrogen atoms and C atoms. 1-6 alkyl; Or R m and R n Together with the carbon atoms connected to it, it forms 3 to 6-membered cycloalkyl groups.

5. The compound of formula (I) according to claim 4, or a pharmaceutically acceptable salt thereof, wherein, R m and R n They may be the same or different, and each is independently selected from hydrogen atoms and methyl groups; Or R m and R n Together with the carbon atoms they are attached to, they form cyclopropane.

6. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each R 1 They may be the same or different, and each is an independent hydrogen atom.

7. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 It is a hydrogen atom.

8. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 3 It is a hydrogen atom.

9. A compound or a pharmaceutically acceptable salt thereof, said compound being selected from the following structures: , , , and .

10. A method for preparing a compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, the method comprising: A compound of general formula (IA) or a salt thereof undergoes a coupling reaction with a compound of general formula (IB) or a salt thereof to give a compound of general formula (I) or a pharmaceutically usable salt thereof. in: X is a halogen; Rings A and R m R n R 1 To R 3 n and p are as defined in claim 1.

11. The method of claim 10, wherein X is a chlorine atom.

12. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, and one or more pharmaceutically acceptable carriers, diluents or excipients.

13. Use of the compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 12 in the preparation of a medicament for inhibiting DNA-PK.

14. Use of the compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 12 in the preparation of a medicament for treating and / or preventing a disease or condition; wherein the disease or condition is selected from leukemia, multiple myeloma, lymphoma, myelodysplastic syndrome, breast cancer, lung cancer, endometrial cancer, central nervous system tumors, retinoblastoma, neuroblastoma, germ cell tumor, teratoma, gastric cancer, esophageal cancer, liver cancer, cholangiocarcinoma, colorectal cancer, small bowel cancer, pancreatic cancer, skin cancer, melanoma, thyroid cancer, head and neck cancer, prostate cancer, testicular cancer, ovarian cancer, cervical cancer, vulvar cancer, bladder cancer, kidney cancer, squamous cell carcinoma, sarcoma, and pediatric cancers.

15. The use according to claim 14, wherein the sarcoma is selected from chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, Ewing's sarcoma and Kaposi's sarcoma.

16. The use according to claim 14, wherein the colorectal cancer is colon cancer or rectal cancer.

17. Use of the compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 12 in the preparation of a medicament for treating and / or preventing a disease or condition; wherein the disease or condition is selected from dysplastic neuroepithelial tumors, glioblastoma multiforme, mixed glioma, medulloblastoma, salivary gland carcinoma, and gastrointestinal stromal tumors.

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