Purinone derivatives, processes for their preparation and their use in medicine

Abstract

Purine ketone derivatives of general formula (IG), processes for their preparation, pharmaceutical compositions containing them 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. In the general formula (IG) the various radicals are as defined in the specification.

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a purine ketone derivative, its preparation method, and its pharmaceutical applications. In particular, this disclosure relates to a purine ketone derivative represented by general formula (IG), its preparation method, pharmaceutical compositions containing the derivative, and its use as a DNA-PK inhibitor in the preparation of medicaments for treating and / or preventing 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 resistance to chemotherapy drugs 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 (IG) or a pharmaceutically acceptable salt thereof:

[0008]

[0009] in:

[0010] G 1 G 2 and G 3Whether they are the same or different, and each is an independent CR 2 Or nitrogen atoms;

[0011] Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0012] Ring B is a cycloalkyl or heterocyclic group;

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

[0015] R 3 The group is selected from hydrogen atoms, alkyl, haloalkyl, cycloalkyl and heterocyclic groups, wherein each of the alkyl, haloalkyl, cycloalkyl and heterocyclic groups is independently and optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0016] R 4 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;

[0017] p is 0, 1, 2, 3, 4, or 5; and

[0018] q can be 0, 1, 2, 3, 4 or 5.

[0019] In some preferred embodiments of this disclosure, the compound represented by the general formula (IG) or a pharmaceutically acceptable salt thereof, wherein G 1 For CR 2 Or nitrogen atom; G 2 and G 3 Whether they are the same or different, and each is an independent CR 2 ;R 2 As defined in general formula (IG).

[0020] In some preferred embodiments of this disclosure, the compound represented by the general formula (IG) or a pharmaceutically acceptable salt thereof, wherein G 1 For nitrogen atoms; G 2 and G 3 Whether they are the same or different, and each is an independent CR 2 ;R2 As defined in general formula (IG).

[0021] In some preferred embodiments of this disclosure, a compound of general formula (I) or a pharmaceutically acceptable salt thereof is provided:

[0022]

[0023] in:

[0024] Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0025] Ring B is a cycloalkyl or heterocyclic group;

[0026] 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;

[0027] R 2 They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl and hydroxyalkyl;

[0028] R 3 The group is selected from hydrogen atoms, alkyl, haloalkyl, cycloalkyl and heterocyclic groups, wherein each of the alkyl, haloalkyl, cycloalkyl and heterocyclic groups is independently and optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0029] R 4 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;

[0030] n is 0, 1, 2, or 3;

[0031] p is 0, 1, 2, 3, 4, or 5; and

[0032] q can be 0, 1, 2, 3, 4 or 5.

[0033] In some preferred embodiments of this disclosure, a compound of general formula (II) or a pharmaceutically acceptable salt thereof is provided:

[0034]

[0035] in:

[0036] Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0037] Ring B is a cycloalkyl or heterocyclic group;

[0038] 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;

[0039] R 2 They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl and hydroxyalkyl;

[0040] R 3 The group is selected from hydrogen atoms, alkyl, haloalkyl, cycloalkyl and heterocyclic groups, wherein each of the alkyl, haloalkyl, cycloalkyl and heterocyclic groups is independently and optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0041] R 4 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;

[0042] n is 0, 1, or 2;

[0043] p is 0, 1, 2, 3, 4, or 5; and

[0044] q can be 0, 1, 2, 3, 4 or 5.

[0045] In some preferred embodiments of this disclosure, the compound represented by general formula (IG), general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein ring A is a 5- to 6-membered heteroaryl or a 3- to 6-membered heterocyclic group; preferably a 5-membered heteroaryl or a 5- to 6-membered heterocyclic group; more preferably selected from imidazolyl, pyrazolyl, triazolyl, 1,2,4-oxadiazol-5(2H)-one, thiazolyl, pyrrolel, thiophene, and furanyl.

[0046] In some preferred embodiments of this disclosure, the compound represented by general formula (IG), general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heteroaryl group, preferably selected from imidazolyl, pyrazolyl, triazolyl, thiazolyl, pyrroleyl, thiophene, and furanyl.

[0047] In some preferred embodiments of this disclosure, the compound represented by general formula (IG), general formula (I), or general formula (II), or a pharmaceutically acceptable salt thereof, wherein ring B is a 3- to 14-membered heterocyclic group; preferably a 3- to 6-membered heterocyclic group; more preferably a 6-membered heterocyclic group; even more preferably a tetrahydropyranyl group; most preferably...

[0048] In some preferred embodiments of this disclosure, the compound represented by general formula (IG), general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heteroaryl or a 5- to 6-membered heterocyclic group; and ring B is a 3- to 6-membered heterocyclic group.

[0049] In some preferred embodiments of this disclosure, the compound represented by general formula (IG), general formula (I), or general formula (II), or a pharmaceutically acceptable salt thereof, wherein R 3 C 1-6 Alkyl or 3- to 6-membered cycloalkyl; preferably, R 3 It is methyl or cyclopropyl; more preferably, R 3 It is a methyl group.

[0050] In some preferred embodiments of this disclosure, the compound represented by general formula (IG), general formula (I), or general formula (II), or a pharmaceutically acceptable salt thereof, wherein R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and oxo; preferably, R 1 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and oxo; more preferably, R 1 They may be the same or different, and each is independently selected from hydrogen atoms, methyl groups, and oxo groups; more preferably, R 1 They may be the same or different, and each is independently a hydrogen atom or an oxygen atom.

[0051] In some preferred embodiments of this disclosure, the compound represented by general formula (IG), general formula (I), or general formula (II), or a pharmaceutically acceptable salt thereof, wherein R 1 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and oxo; preferably, R 1 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; more preferably, R 1 C 1-6 Alkyl; most preferably, R 1 It is a methyl group.

[0052] In some preferred embodiments of this disclosure, the compound represented by general formula (IG), general formula (I), or general formula (II), or a pharmaceutically acceptable salt thereof, wherein R 2They 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 2 They may be the same or different, and each is independently selected from hydrogen, cyano, and C atoms. 1-6 Alkyl; more preferably, R 2 They may be the same or different, and each is independently a hydrogen atom or a cyano group; more preferably, R 2 It is a hydrogen atom.

[0053] In some preferred embodiments of this disclosure, the compound represented by general formula (IG), general formula (I), or general formula (II), or a pharmaceutically acceptable salt thereof, wherein R 4 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; preferably, R 4 It is a hydrogen atom.

[0054] In some preferred embodiments of this disclosure, the compound represented by general formula (IG), general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3, preferably 0 or 1.

[0055] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or general formula (II) or its pharmaceutically acceptable salt, wherein n is 0 or 1.

[0056] In some preferred embodiments of this disclosure, the compound represented by general formula (IG), general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein q is 0 or 1.

[0057] In some preferred embodiments of this disclosure, the compound represented by the general formula (IG) or a pharmaceutically acceptable salt thereof, wherein G 1 For CR 2 Or nitrogen atom; G 2 and G 3 Whether they are the same or different, and each is an independent CR 2 Ring A is a 5-membered heteroaryl or a 5- to 6-membered heterocyclic group; Ring B is... R 3 It is methyl or cyclopropyl; R 1 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and oxo; R 2 They may be the same or different, and each is independently selected from hydrogen, cyano, and C atoms. 1-6 Alkyl; R 4 It is a hydrogen atom; p is 0, 1, 2 or 3; and q is 0 or 1.

[0058] In some preferred embodiments of this disclosure, the compound represented by the general formula (IG) or a pharmaceutically acceptable salt thereof, wherein G1 For nitrogen atoms; G 2 and G 3 Whether they are the same or different, and each is an independent CR 2 Ring A is a 5-membered heteroaryl group; Ring B is... R 3 Methyl; R 1 C 1-6 Alkyl; p is 0 or 1; R 2 For hydrogen atoms; R 4 It is a hydrogen atom; and q is 0 or 1.

[0059] 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 5-membered heteroaryl or a 5- to 6-membered heterocyclic group; ring B is R 3 It is methyl or cyclopropyl; R 1 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and oxo; R 2 They may be the same or different, and each is independently selected from hydrogen, cyano, and C atoms. 1-6 Alkyl; R 4 It is a hydrogen atom; n is 0 or 1; p is 0, 1, 2 or 3; and q is 0 or 1.

[0060] In some preferred embodiments of this disclosure, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heteroaryl or a 5- to 6-membered heterocyclic group; ring B is R 3 It is methyl or cyclopropyl; R 1 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and oxo; p is 0, 1, 2 or 3; R 2 They may be the same or different, and each is independently selected from hydrogen, cyano, and C atoms. 1-6 Alkyl; n is 0 or 1; R 4 It is a hydrogen atom; and q is 0 or 1.

[0061] In some preferred embodiments of this disclosure, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heteroaryl group; ring B is... R 3 Methyl; R 1 C 1-6 Alkyl; p is 0 or 1; R 2 For hydrogen atoms; n is 0 or 1; R 4 It is a hydrogen atom; and q is 0 or 1.

[0062] Table A lists typical compounds disclosed herein, including but not limited to:

[0063]

[0064]

[0065]

[0066] 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:

[0067]

[0068] A compound of general formula (IA) or a salt thereof undergoes a coupling reaction with a compound of general formula (IGB) or a salt thereof to yield a compound of general formula (IG) or a pharmaceutically usable salt thereof.

[0069] in:

[0070] X is a halogen; preferably a chlorine atom.

[0071] Ring A, Ring B, G 1 G 2 G 3 R 1 R 3 R 4 p and q are as defined in general formula (IG).

[0072] Another aspect of this disclosure relates to a method for preparing a compound of general formula (I), or a pharmaceutically usable salt thereof, the method comprising:

[0073]

[0074] 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.

[0075] in:

[0076] X is a halogen; preferably a chlorine atom.

[0077] Ring A, Ring B, R 1 To R 4 , n, p and q are as defined in general formula (I).

[0078] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II), or a pharmaceutically usable salt thereof, the method comprising:

[0079]

[0080] A compound of general formula (IA) or a salt thereof undergoes a coupling reaction with a compound of general formula (IIB) or a salt thereof to give a compound of general formula (II) or a pharmaceutically usable salt thereof.

[0081] in:

[0082] X is a halogen; preferably a chlorine atom.

[0083] Ring A, Ring B, R 1 To R 4 n, p and q are as defined in general formula (II).

[0084] Another aspect of this disclosure relates to a pharmaceutical composition comprising a compound of formula (IG), formula (I), formula (II) and Table A of this disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0085] This disclosure further relates to the use of compounds of general formula (IG), general formula (I), general formula (II) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of a medicament for inhibiting DNA-PK.

[0086] This disclosure further relates to the use of compounds of general formula (IG), general formula (I), general formula (II) 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, preferably in the preparation of medicaments for the treatment and / or prevention of DNA-PK-mediated cancers. The cancers mentioned therein are preferably 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. The lymphoma is selected from Hodgkin's disease and non-Hodgkin's lymphoma (including mantle cell lymphoma); the lung cancer is non-small cell lung cancer (NSCLC) (including squamous cell carcinoma, adenocarcinoma and large cell carcinoma, etc.) or small cell lung cancer (SCLC), more preferably non-small cell lung cancer (NSCLC); the renal cell carcinoma is preferably selected from renal cell carcinoma, clear cell and renal eosinophilic tumor; the sarcoma is preferably selected from chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, Ewing's sarcoma and Kaposi's sarcoma.

[0087] 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 (IG), formula (I), formula (II) and shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof.

[0088] This disclosure further relates to a method for treating and / or preventing cancer, preferably a method for treating and / or preventing DNA-PK-mediated cancer, comprising administering a therapeutically effective amount of a compound of formula (IG), formula (I), formula (II) and shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, to a desired patient. The cancers mentioned therein are preferably 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. The lymphoma is selected from Hodgkin's disease and non-Hodgkin's lymphoma (including mantle cell lymphoma); the lung cancer is non-small cell lung cancer (NSCLC) (including squamous cell carcinoma, adenocarcinoma and large cell carcinoma, etc.) or small cell lung cancer (SCLC), more preferably non-small cell lung cancer (NSCLC); the renal cell carcinoma is preferably selected from renal cell carcinoma, clear cell and renal eosinophilic tumor; the sarcoma is preferably selected from chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, Ewing's sarcoma and Kaposi's sarcoma.

[0089] This disclosure further relates to a compound of general formula (IG), general formula (I), general formula (II) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, which is used as a medicine.

[0090] This disclosure further relates to a compound of general formula (IG), general formula (I), general formula (II) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, which is used as a drug to inhibit DNA-PK.

[0091] This disclosure further relates to a compound of general formula (IG), general formula (I), general formula (II) 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, preferably as a medicament for treating and / or preventing DNA-PK-mediated cancer. The cancers mentioned therein are preferably 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. The lymphoma is selected from Hodgkin's disease and non-Hodgkin's lymphoma (including mantle cell lymphoma); the lung cancer is non-small cell lung cancer (NSCLC) (including squamous cell carcinoma, adenocarcinoma and large cell carcinoma, etc.) or small cell lung cancer (SCLC), preferably non-small cell lung cancer (NSCLC); the renal cell carcinoma is preferably selected from renal cell carcinoma, clear cell and renal eosinophilic tumor; the sarcoma is preferably selected from chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, Ewing's sarcoma and Kaposi's sarcoma.

[0092] The tumors mentioned in the above cancer definition are malignant tumors.

[0093] 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 blow-through administration. The compounds of this disclosure can also be formulated into sustained-release dosage forms, such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions, used 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.

[0099] Oil suspensions are prepared 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.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] 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 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, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment mode, such as the treatment pattern, the daily dosage of the compound, or the type of medicinal salt can be validated based on conventional treatment protocols.

[0106] Terminology Explanation

[0107] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0108] 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, and 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. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. 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, etc. Alkyl groups can be substituted or unsubstituted, and 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, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclicoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0109] The term "alkylene" refers to a saturated straight-chain or branched aliphatic hydrocarbon group, which is a residue derived from the same carbon atom or two different carbon atoms of a parent alkane by removing two hydrogen atoms. It is a straight-chain or branched group containing 1 to 20 carbon atoms (i.e., C164-C2 ... 1-20 Alkylene, preferably containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e., C 1-12Alkylenes, more preferably alkylenes containing 1 to 6 carbon atoms (i.e., C16-64 ... 1-6 Alkylenes. Non-limiting examples of alkylenes include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), etc. Alkylenes can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker. Substituents are preferably selected from one or more of alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclic alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, and oxo.

[0110] The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in its molecule, wherein the definition of alkyl is as described above. Preferably, it is an alkenyl compound containing 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C14-C14-C14). 2-12 Alkenyl), more preferably alkenyl containing 2 to 6 carbon atoms (i.e., C14-C ... 2-6 Alkenyl). The alkenyl 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, heterocyclicoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0111] The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in its molecule, wherein the definition of alkyl is as described above. Preferably, the alkynyl group (i.e., C14) contains 2 to 12 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12). 2-12 Alkyne group), more preferably an alkyne group containing 2 to 6 carbon atoms (i.e., C12-C6 ... 2-6 (Alkyne). 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, heterocyclicoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0112] 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 14 carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14) (i.e., 3 to 14-membered cycloalkyl), more preferably 3 to 8 carbon atoms (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.

[0113] The term "spirocycloalkyl" refers to a 5- to 20-membered (i.e., 5- to 20-membered spirocycloalkyl) polycyclic group that shares a single carbon atom (called a spiro atom) between the rings and may contain one or more double bonds. 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). Spirocycloalkyls are classified into monospirocycloalkyls, bispirocycloalkyls, or polyspirocycloalkyls according to the number of shared spiro atoms between the rings, with monospirocycloalkyls and bispirocycloalkyls 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, 5 / 6-membered, or 6 / 6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyls include:

[0114]

[0115] The term "fused cycloalkyl" refers to a 5- to 20-membered (i.e., 5- to 20-membered fused cycloalkyl) all-carbon 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. 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, and 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 fused cycloalkyl. Non-limiting examples of fused cycloalkyl include:

[0116]

[0117] The term "bridged cycloalkyl" refers to a 5- to 20-membered (i.e., 5- to 20-membered bridged cycloalkyl) all-carbon polycyclic group in which any two rings share two non-directly bonded carbon atoms, and may contain one or more double bonds. 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, and polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

[0118]

[0119] The cycloalkyl ring comprises a cycloalkyl group (including monocyclic, spirocyclic, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocyclic alkyl ring as described above, wherein the ring attached to the parent structure is a cycloalkyl group. Non-limiting examples include... Preferred

[0120] 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.

[0121] 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.

[0122] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent comprising 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 a sulfoxide or sulfone), but excluding the ring moiety of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Preferably, it comprises 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14) ring atoms (i.e., a 3 to 14-membered heterocyclic group), wherein 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, it comprises 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, and 14) ring atoms (i.e., a 6 to 14-membered heterocyclic group), wherein 1 to 3 are heteroatoms (e.g., 1, 2, and 3). More preferably, it comprises 3 to 8 ring atoms (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 (e.g., 1, 2, and 3) are heteroatoms; most preferably, it comprises 5 or 6 ring atoms (i.e., 5 to 6-membered heterocyclic groups), wherein 1 to 3 are heteroatoms; and most preferably, it comprises 6 ring atoms (i.e., 6-membered heterocyclic groups), wherein 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, 1,2,4-oxadiazol-5(2H)-one, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include spiroheterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0123] The term "spiroheterocyclic group" refers to a 5- to 20-membered (i.e., 5- to 20-membered spiroheterocyclic group) polycyclic heterocyclic group in which the monocyclic rings share a single atom (called a spiro atom), 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), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably, it is 6- to 14-membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13, and 14-membered) (i.e., 6- to 14-membered spiroheterocyclic groups), more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered) (i.e., 7- to 10-membered spiroheterocyclic groups). 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, 5 / 6, or 6 / 6 monospirocyclic heterocyclic group. Non-limiting examples of spirocyclic groups include:

[0124]

[0125] 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, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is a 6- to 14-membered group (e.g., 6, 7, 8, 9, 10, 11, 12, 13, and 14-membered group) (i.e., a 6- to 14-membered fused heterocyclic group), more preferably a 7- to 10-membered group (e.g., 7, 8, 9, or 10-membered group) (i.e., a 7- to 10-membered fused heterocyclic group). Based on the number of constituent rings, fused heterocyclic groups can be classified into bicyclic, tricyclic, tetracyclic, and polycyclic 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, and pentacyclic / pentacyclic bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0126]

[0127] The term "bridged heterocyclic group" refers to a 5- to 20-membered (i.e., 5- to 20-membered bridged heterocyclic group) polycyclic heterocyclic group in which any two rings share two non-directly connected atoms, and 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), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13, and 14-membered) (i.e., 6- to 14-membered bridged heterocyclic groups), more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered) (i.e., 7- to 10-membered bridged heterocyclic groups). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, and polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0128]

[0129] The heterocyclic ring comprises a heterocyclic group (including monocyclic, spirocyclic, fused heterocyclic, and bridged heterocyclic rings) 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:

[0130] wait.

[0131] 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.

[0132] 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 (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:

[0133]

[0134] 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.

[0135] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms (e.g., 1, 2, 3, and 4) and 5 to 14 ring atoms (i.e., 5 to 14-membered heteroaryl), 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 heteroaryl), more preferably 5 or 6-membered (i.e., 5 to 6-membered heteroaryl), and most preferably 5-membered (i.e., 5-membered heteroaryl), such as furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, and tetrazolyl. 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:

[0136]

[0137] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0138] 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 ring atom or two different ring atoms of the parent, namely "divalent cycloalkyl", "divalent heterocyclic", "aryl", and "heteroaryl".

[0139] The term "amino protecting group" is used to protect the amino group by means of an easily removable group, so that the amino group remains unchanged when other parts of the molecule react. Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl, acetyl, benzyl, allyl, and p-methoxybenzyl, etc. These groups may optionally be replaced by 1-3 substituents selected from halogens, alkoxy groups, or nitro groups.

[0140] The term "hydroxyl protecting group" refers to a hydroxyl derivative that is typically used to block or protect the hydroxyl group in a reaction on other functional groups of a compound. As an example, preferably, the hydroxyl protecting group can be (C... 1-10 Alkyl or aryl) 3-silyl, such as: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, etc.; can be C 1-10 Alkyl or substituted alkyl, preferably alkoxy or aryl-substituted alkyl, more preferably C 1-6 alkoxy-substituted C 1-6 alkyl or phenyl substituted C 1-6 Alkyl group, C is the most preferred. 1-4 alkoxy-substituted C 1-4 Alkyl groups, such as methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), etc.; can be (C 1-10 Alkyl or aromatic acyl group, such as formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.; can be (C 1-6 alkyl or 6 to 10 aryl) sulfonyl; or (C 1-6 Alkyl or 6 to 10 aryloxy) carbonyl group.

[0141] The term “cycloalkyloxy” refers to cycloalkyl-O-, where the cycloalkyl group is as defined above.

[0142] The term “heterocyclic oxy group” refers to the heterocyclic group -O-, where the heterocyclic group is as defined above.

[0143] The term "aryloxy group" refers to aryl-O-, where the aryl group is as defined above.

[0144] The term “heteroaryloxy” refers to heteroaryl-O-, where the heteroaryl group is as defined above.

[0145] The term "alkylthio" refers to alkyl-S-, where the alkyl group is as defined above.

[0146] 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.

[0147] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0148] 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.

[0149] The term "hydroxyalkyl" refers to an alkyl group that is replaced by one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0150] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0151] The term "hydroxyl group" refers to -OH.

[0152] The term "thiol" refers to -SH.

[0153] The term "amino" refers to -NH2.

[0154] The term "cyano" refers to -CN.

[0155] The term "nitro" refers to -NO2.

[0156] The term "oxo" or "oxo group" refers to "=O".

[0157] The term "carbonyl" refers to C=O.

[0158] The term "carboxyl group" refers to -C(O)OH.

[0159] The term "carboxylic acid ester group" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are as defined above.

[0160] 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 Or simultaneously include and Two configurations.

[0161] 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.

[0162] The compounds disclosed herein include 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 14 Compounds 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. In the deuterated form of the compound, each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the deuterated form of the compound of formula (I) with reference to relevant literature. Commercially available deuterated starting materials can be used in the preparation of the deuterated form of the compound, or they can be synthesized using conventional techniques with deuterating 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.

[0163] "Optional" or "optional" means that the event or situation subsequently described may, but is not necessarily, occur; the description includes the possibility or possibility that the event or situation may or may not occur. For example, "optionally halogenated or cyano-substituted C..." 1-6 "Alkyl" means that halogens or cyano groups may or may not be present. This description includes cases where alkyl groups are substituted by halogens or cyano groups and cases where alkyl groups are not substituted by halogens or cyano groups.

[0164] "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).

[0165] "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.

[0166] "Pharmacologically acceptable salt" refers to the salt of the compounds disclosed herein, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and possess the expected biological activity. They can be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid. 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.

[0167] For the purposes of pharmaceuticals or pharmacologically active agents, the term "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. The determination of the 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 effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0168] 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.

[0169] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0170] 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, not as limitations.

[0171] The method for synthesizing the compounds disclosed herein

[0172] In order to achieve the purpose of this disclosure, the following technical solution is adopted:

[0173] Option 1

[0174] A method for preparing a compound of formula (IG) or a pharmaceutically acceptable salt thereof, comprising:

[0175]

[0176] A compound of general formula (IA) or a salt thereof undergoes a coupling reaction with a compound of general formula (IGB) or a salt thereof under basic conditions in the presence of a catalyst to give a compound of general formula (IG) or a pharmaceutically usable salt thereof.

[0177] in:

[0178] X is a halogen; preferably a chlorine atom.

[0179] Ring A, Ring B, G 1 G 2 G 3 R 1 R 3 R 4 p and q are as defined in general formula (IG).

[0180] Option 2

[0181] A method for preparing the compound represented by general formula (I) of this disclosure, or a pharmaceutically acceptable salt thereof, comprising:

[0182]

[0183] 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 in the presence of a catalyst to give a compound of general formula (I) or a pharmaceutically usable salt thereof.

[0184] in:

[0185] X is a halogen; preferably a chlorine atom.

[0186] Ring A, Ring B, R 1 To R 4 , n, p and q are as defined in general formula (I).

[0187] Option 3

[0188] A method for preparing the compound of formula (II) or a pharmaceutically acceptable salt thereof, comprising:

[0189]

[0190] A compound of general formula (IA) or a salt thereof undergoes a coupling reaction with a compound of general formula (IIB) or a salt thereof under basic conditions in the presence of a catalyst to give a compound of general formula (II) or a pharmaceutically usable salt thereof.

[0191] in:

[0192] X is a halogen; preferably a chlorine atom.

[0193] Ring A, Ring B, R 1 To R 4 n, p and q are as defined in general formula (II).

[0194] 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, cesium carbonate.

[0195] 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).

[0196] 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

[0197] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0198] Example

[0199] 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. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0200] 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), and a THERMO Ultimate 3000-Q Exactive system (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0201] 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.

[0202] Chiral HPLC analysis was performed using an Agilent 1260DAD high-performance liquid chromatograph.

[0203] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0204] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0205] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0206] 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.

[0207] Silica gel column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200 to 300 as the carrier.

[0208] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0209] 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.

[0210] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0211] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0212] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0213] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0214] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0215] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0216] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0217] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0218] 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. The volume ratio of the solvent was adjusted according to the polarity of the compounds. Small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0219] Example 1

[0220] 4-Methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2-(1H-pyrazol-1-yl)benzonitrile

[0221]

[0222] first step

[0223] 4-Methyl-5-nitro-2-(1H-pyrazol-1-yl)benzonitrile 1b

[0224] 2-Fluoro-4-methyl-5-nitrobenzenenitrile 1a (1.00 g, 5.55 mmol, prepared by the method disclosed in patent application "WO2017125530A1, P256"), pyrazole (908 mg, 13.34 mmol, from Bismuth Substrate), and potassium carbonate (921 mg, 6.66 mmol, from Shanghai Experimental Plant) were mixed and suspended in 25 mL of N,N-dimethylformamide and stirred for 2 hours. 50 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The resulting organic phase was concentrated under reduced pressure, and the residue was purified using a CombiFlash rapid reagent system with eluent system A to give title product 1b (522 mg), yield: 41.2%.

[0225] MS m / z(ESI):228.9[M+1].

[0226] Step 2

[0227] 5-Amino-4-methyl-2-(1H-pyrazol-1-yl)benzonitrile 1c

[0228] Compound 1b (522 mg, 2.29 mmol) and palladium on carbon (wet) (49 mg, 0.46 mmol, Inocai) were mixed and suspended in 50 mL of ethanol, purged with hydrogen six times, and stirred for 17 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title product 1c (450 mg), yield: 99.2%.

[0229] MS m / z(ESI):198.9[M+1].

[0230] Step 3

[0231] 4-Methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2-(1H-pyrazol-1-yl)benzonitrile

[0232] Compound 1c (74 mg, 0.37 mmol), 2-chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-one 1d (100 mg, 0.37 mmol, prepared by the method disclosed in patent application "CN110177791A, P43"), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (34 mg, 0.037 mmol, Acon), and cesium carbonate (243 mg, 0.75 mmol, Shaoyuan) were dissolved in 20 mL of 1,4-dioxane under an argon atmosphere, heated to 100 °C, and stirred for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified using a CombiFlash rapid reagent system with eluent system A to obtain title product 1 (70 mg), yield: 43.7%.

[0233] MS m / z(ESI):431.1[M+1].

[0234] 1 H NMR (500MHz, DMSO-d6): δ8.81(s,1H),8.35-8.29(m,2H),8.18(s,1H),7.85-7.80(m,1H),7.66(s,1H),6.65-6.55( m,1H),4.45-4.40(m,1H),4.00-3.97(m,2H),3.50-3.40(m,5H),2.56-2.53(m,2H),2.43(s,3H),1.71-1.69(m,2H).

[0235] Example 2

[0236] 7-Methyl-2-((2-methyl-4-(1H-1,2,3-triazol-1-yl)phenyl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-one)

[0237]

[0238] first step

[0239] 1-(3-methyl-4-nitrophenyl)-1H-1,2,3-triazole 2c

[0240] 4-Fluoro-2-methyl-1-nitrobenzene 2a (3.0 g, 19.34 mmol, prepared by the method disclosed in patent application “US20100324043A1, P26”) was dissolved in 20 mL of N,N-dimethylformamide, and 1,2,3-triazole (1.74 g, 25.2 mmol) and potassium carbonate (4.01 g, 29.05 mmol) were added sequentially. The mixture was stirred at 80 °C for 3 hours. Water was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified using a CombiFlash rapid preparative apparatus with eluent system A to give compound 2b (1.5 g, yield: 38.0%) and compound 2c (1.8 g, yield: 45.4%).

[0241] MS m / z(ESI):205.1[M+1].

[0242] Step 2

[0243] 2-Methyl-4-(1H-1,2,3-triazol-1-yl)aniline 2d

[0244] Under a hydrogen atmosphere, compound 2c (100 mg, 0.49 mmol) was dissolved in 15 mL of methanol, and 10% Pd / C (80 mg) was added. The mixture was stirred at room temperature for 1 hour. The solution was filtered through diatomaceous earth, washed once with methanol, and the filtrate was evaporated to dryness to give compound 2d (80 mg), yield: 93.8%.

[0245] MS m / z(ESI):175.0[M+1].

[0246] Step 3

[0247] 7-Methyl-2-((2-methyl-4-(1H-1,2,3-triazol-1-yl)phenyl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-one)

[0248] Compound 2d (80 mg, 0.46 mmol) and compound 1d (120 mg, 0.45 mmol) were suspended separately in 1,4-dioxane (10 mL), and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (30 mg, 0.033 mmol) and cesium carbonate (292 mg, 0.90 mmol) were added sequentially. The mixture was heated to 100 °C and stirred for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified using a CombiFlash rapid reagent system with eluent system A to give title product 2 (108 mg), yield: 59.5%.

[0249] MS m / z(ESI):407.1[M+1].

[0250] 1 H NMR (500MHz, DMSO-d6): δ8.75(s,1H),8.60(s,1H),8.10(s,1H),7.96(s,1H),7.86(d,1H),7.75(s,1H),7. 67(d,1H),4.45(brs,1H),4.02(d,2H),3.43(t,2H),3.25(s,3H),2.56(brs,2H),2.36(s,3H),1.64(d,2H).

[0251] Example 3

[0252] 7-Methyl-2-((2-methyl-4-(2H-1,2,3-triazol-2-yl)phenyl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-one)

[0253]

[0254] first step

[0255] 2-Methyl-4-(2H-1,2,3-triazol-2-yl)aniline 3a

[0256] Compound 2b (120 mg, 0.60 mmol) was dissolved in 15 mL of methanol, and 10% Pd / C (80 mg) was added. The mixture was purged with hydrogen three times and stirred at room temperature for 1 hour. The solution was filtered through diatomaceous earth, washed once with methanol, and the filtrate was evaporated to dryness to give compound 3a (100 mg), yield: 94.8%.

[0257] MS m / z(ESI):175.0[M+1].

[0258] Step 2

[0259] 7-Methyl-2-((2-methyl-4-(2H-1,2,3-triazol-2-yl)phenyl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-one)

[0260] Compound 3a (100 mg, 0.57 mmol) and compound 1d (139 mg, 0.52 mmol) were suspended in 1,4-dioxane (10 mL), and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (30 mg, 0.033 mmol) and cesium carbonate (375 mg, 1.15 mmol) were added sequentially. The mixture was heated to 100 °C and stirred for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified using a CombiFlash rapid reagent system with eluent A to give title product 3 (110 mg), yield: 48.5%.

[0261] MS m / z(ESI):407.1[M+1].

[0262] 1 H NMR (500MHz, DMSO-d6): δ8.56(s,1H),8.10(s,1H),8.09(s,1H),7.90(s,1H),7.82(d,1H),7.80(s,1H),7.78(d ,1H),4.39-4.45(m,1H),3.4.00(d,2H),3.42(t,2H),3.31(s,3H),2.54-2.57(m,2H),2.36(s,3H),1.67(d,2H).

[0263] Example 4

[0264] 7-Methyl-2-((2-methyl-4-(1H-pyrazol-1-yl)phenyl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-one 4

[0265]

[0266] Compound 1d (100 mg, 0.37 mmol), 2-methyl-4-(1H-pyrazol-1-yl)aniline 4a (65 mg, 0.37 mmol, prepared by the method disclosed in patent application "WO2004062665A1, P39"), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (34 mg, 0.037 mmol, Acon), and cesium carbonate (243 mg, 0.75 mmol, Shaoyuan) were dissolved in 10 mL of 1,4-dioxane under an argon atmosphere, heated to 100 °C, and stirred for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified using a CombiFlash rapid reagent system with eluent A to give title product 4 (64.2 mg), yield: 42.5%.

[0267] MS m / z(ESI):406.1[M+1].

[0268] 1 H NMR (500MHz, DMSO-d6): δ8.49(s,1H),8.42-8.41(m,1H),8.05(s,1H), 7.71-7.68(m,3H),7.60-7.58(m,1H),6.52-6.51(m,1H),4.44-4.37(m,1H),3.99-3.95(m ,2H),3.44-3.39(m,2H),3.30(s,3H),2.57-2.52(m,2H),2.32(s,3H),1.68-1.64(m,2H).

[0269] Example 5

[0270] 3-(3-methyl-4-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine-2-yl)amino)phenyl)-1,2,4-oxadiazol-5(2H)-one5

[0271]

[0272] first step

[0273] 3-Methyl-4-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl-8,9-dihydro-7H-purin-2-yl)amino)benzonitrile 5b

[0274] Under an argon atmosphere, compound 1d (280 mg, 1.04 mmol), 4-amino-3-methylbenzonitrile 5a (160 mg, 1.21 mmol, prepared by the method disclosed in patent application "WO2011086377A1, P26-27"), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (60 mg, 0.066 mmol), and cesium carbonate (790 mg, 2.42 mmol) were dissolved in 20 mL of 1,4-dioxane. The mixture was heated to 100 °C and stirred for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified using a CombiFlash rapid reagent system with eluent system A to give compound 5b (320 mg), yield: 72.5%.

[0275] MS m / z(ESI): 365.1 [M+1].

[0276] Step 2

[0277] N'-hydroxy-3-methyl-4-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)benzamide 5c

[0278] Compound 5b (320 mg, 0.88 mmol) was dissolved in 15 mL of ethanol, and sodium bicarbonate (222 mg, 2.64 mmol) and hydroxylamine chloride (184 mg, 2.64 mmol) were added sequentially. The mixture was stirred at 70 °C for 17 hours. After concentration, water was added, and the mixture was filtered and washed with water to give compound 5c (220 mg), yield: 63.0%.

[0279] MS m / z(ESI):398.1[M+1].

[0280] Step 3

[0281] 3-(3-methyl-4-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine-2-yl)amino)phenyl)-1,2,4-oxadiazol-5(2H)-one5

[0282] Compound 5c (220 mg, 0.55 mmol) was suspended in 10 mL of 1,4-dioxane, and 1,8-diazabicyclo[5.4.0]undec-7-ene (93 mg, 0.61 mmol) and diimidazole methyl ketone (99 mg, 0.61 mmol) were added sequentially. The mixture was stirred at 90 °C for 3 hours. The solution was concentrated, neutralized with water and dilute hydrochloric acid, filtered, washed with water, recrystallized from methanol, and filtered to give title product 5 (95 mg), yield: 40.5%.

[0283] MS m / z(ESI):424.1[M+1].

[0284] 1 H NMR (500MHz, DMSO-d6): δ12.7(s,1H),8.62(s,1H),8.15(s,1H),8.03(d,1H),7.65(s,1H),7.60(d,1H), 4.40-4.45(m,1H),3.99(d,2H),3.43(t,2H),3.30(s,3H),2.54-2.57(m,2H),2.35(s,3H),1.69(d,2H).

[0285] Example 6

[0286] 4-Methyl-2-(1-Methyl-1H-pyrazol-4-yl)-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine-2-yl)amino)benzonitrile 6

[0287]

[0288] Compound 1d (100 mg, 0.37 mmol), 5-amino-4-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzonitrile 6a (90 mg, 0.42 mmol, prepared by the method disclosed in patent application "WO2017125530A1, P317-318"), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (34 mg, 0.037 mmol, Aikon), and cesium carbonate (364 mg, 1.12 mmol, Shaoyuan) were dissolved in 15 mL of 1,4-dioxane under an argon atmosphere, heated to 100 °C, and stirred for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified using a CombiFlash rapid reagent system with eluent system A to give title product 6 (57.2 mg), yield: 34.6%.

[0289] MS m / z(ESI):445.0[M+1].

[0290] 1H NMR (500MHz, DMSO-d6): δ8.65(s,1H),8.19(s,1H),8.16(s,1H),8.13(s,1H),7.91(s,1H),7.56(s,1H),4.44-4.38(m,1 H),4.00-3.96(m,2H),3.92(s,3H),3.47-3.44(m,2H),3.31(s,3H),2.52-2.49(m,2H),2.36(s,3H),1.70-1.67(m,2H).

[0291] Example 7

[0292] 4-Methyl-2-(1-Methyl-1H-pyrazol-5-yl)-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine-2-yl)amino)benzonitrile 7

[0293]

[0294] first step

[0295] 4-Methyl-2-(1-methyl-1H-pyrazol-5-yl)-5-nitrobenzenenitrile 7b

[0296] Under an argon atmosphere, 2-bromo-4-methyl-5-nitrobenzene 7a (300 mg, 1.24 mmol, prepared by the method disclosed in patent application "WO2017125530A1, P311"), (1-methyl-1H-pyrazol-5-yl)boronic acid (220 mg, 1.75 mmol, Shaoyuan), [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride (92 mg, 0.13 mmol, Aikon), and potassium carbonate (517 mg, 3.74 mmol, Hushi) were mixed and suspended in 18 mL of a mixed solvent of 1,4-dioxane and water (V / V = 5:1). The mixture was heated to 100 °C and stirred for 7 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified using a CombiFlash rapid reagent system with eluent system A to obtain the title product 7b (94 mg), yield: 31.2%.

[0297] MS m / z(ESI):242.9[M+1].

[0298] Step 2

[0299] 5-Amino-4-methyl-2-(1-methyl-1H-pyrazole-5-yl)benzonitrile 7c

[0300] Compound 7b (94 mg, 0.39 mmol) and palladium on carbon (wet) (42 mg, 0.39 mmol, Inokai) were mixed and suspended in 20 mL of ethanol, purged with hydrogen six times, and stirred for 17 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title product 7c (75 mg), yield: 91.1%.

[0301] MS m / z(ESI):213.0[M+1].

[0302] Step 3

[0303] 4-Methyl-2-(1-Methyl-1H-pyrazol-5-yl)-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine-2-yl)amino)benzonitrile 7

[0304] Compound 7c (75 mg, 0.35 mmol), compound 1d (100 mg, 0.37 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (33 mg, 0.036 mmol, Acon), and cesium carbonate (346 mg, 1.06 mmol, Shaoyuan) were dissolved in 15 mL of 1,4-dioxane under an argon atmosphere. The mixture was heated to 100 °C and stirred for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified using a CombiFlash rapid reagent system with eluent system A to give title product 7 (75.4 mg), yield: 48.0%.

[0305] MS m / z(ESI):445.1[M+1].

[0306] 1 H NMR (500MHz, DMSO-d6): δ8.82(s,1H),8.39(s,1H),8.19(s,1H),7.55-7.54(m,1H),7.51(s,1H),6.48-6.47(m,1H),4.47-4.4 0(m,1H),4.00-3.96(m,2H),3.79(s,3H),3.45-3.40(m,2H),3.33(s,3H),2.56-2.47(m,2H),2.42(s,3H),1.72-1.68(m,2H).

[0307] Example 8

[0308] 4-Methyl-2-(1-Methyl-1H-pyrazol-3-yl)-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine-2-yl)amino)benzonitrile 8

[0309]

[0310] first step

[0311] 4-Methyl-2-(1-methyl-1H-pyrazol-3-yl)-5-nitrobenzenenitrile 8a

[0312] Under an argon atmosphere, compound 7a (300 mg, 1.24 mmol), (1-methyl-1H-pyrazole-3-yl)boronic acid (187 mg, 1.49 mmol, prepared by the method disclosed in patent application "US20190106427A1, P446-447"), [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride (92 mg, 0.13 mmol, Acon), and potassium carbonate (517 mg, 3.74 mmol, Shanghai Experimental) were mixed and suspended in 25 mL of a mixed solvent of 1,4-dioxane and water (V / V = 5:1). The mixture was heated to 100 °C and stirred for 7 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified using a CombiFlash rapid reagent system with eluent system A to give title product 8a (96 mg), yield: 31.8%.

[0313] MS m / z(ESI):242.9[M+1].

[0314] Step 2

[0315] 5-Amino-4-methyl-2-(1-methyl-1H-pyrazol-3-yl)benzonitrile 8b

[0316] Compound 8a (96 mg, 0.40 mmol) and palladium on carbon (wet) (43 mg, 0.40 mmol, Inocai) were mixed and suspended in 20 mL of ethanol, purged with hydrogen six times, and stirred for 17 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title product 8b (71 mg), yield: 84.4%.

[0317] MS m / z(ESI):213.0[M+1].

[0318] Step 3

[0319] 4-Methyl-2-(1-Methyl-1H-pyrazol-3-yl)-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine-2-yl)amino)benzonitrile 8

[0320] Compound 8b (71 mg, 0.334 mmol), compound 1d (100 mg, 0.37 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (31 mg, 0.034 mmol, Acon), and cesium carbonate (327 mg, 1.00 mmol, Shaoyuan) were dissolved in 15 mL of 1,4-dioxane under an argon atmosphere. The mixture was heated to 100 °C and stirred for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified using a CombiFlash rapid reagent system with eluent A to give title compound 8 (81.1 mg), yield: 54.5%.

[0321] MS m / z(ESI):445.0[M+1].

[0322] 1 H NMR (500MHz, DMSO-d6): δ8.69(s,1H),8.24(s,1H),8.16(s,1H),7.83-7.82(m,1H),7.76(s,1H),6.80-6.79(m,1H),4.46-4.3 9(m,1H),4.00-3.97(m,2H),3.93(s,3H),3.45-3.40(m,2H),3.32(s,3H),2.56-2.47(m,2H),2.40(s,3H),1.71-1.68(m,2H).

[0323] Example 9

[0324] 7-Methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-one)

[0325]

[0326]

[0327] first step

[0328] 4-Methyl-2-(1-methyl-1H-pyrazol-4-yl)-5-nitropyridine 9b

[0329] Under an argon atmosphere, 2-bromo-4-methyl-5-nitropyridine 9a (300 mg, 1.38 mmol, Bio-Tech Pharmaceuticals), (1-methyl-1H-pyrazole-4-yl)boronic acid (192 mg, 1.52 mmol, Shaoyuan), [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride (102 mg, 0.139 mmol, Aikon), and potassium carbonate (574 mg, 4.15 mmol, Shanghai Experimental) were mixed and suspended in 18 mL of a mixed solvent of 1,4-dioxane and water (V / V = 5:1). The mixture was heated to 100 °C and stirred for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified using a CombiFlash rapid reagent system with eluent system A to give the title product 9b (200 mg), yield: 66.3%.

[0330] MS m / z(ESI):218.9[M+1].

[0331] Step 2

[0332] 4-Methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridine-3-amine 9c

[0333] Compound 9b (200 mg, 0.916 mmol) and palladium on carbon (wet) (98 mg, 0.39 mmol, Inocai) were mixed and suspended in 25 mL of ethanol, purged with hydrogen six times, and stirred for 17 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title product 9c (172 mg), yield: 99.7%.

[0334] MS m / z(ESI):188.9[M+1].

[0335] Step 3

[0336] 7-Methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-one)

[0337] Under an argon atmosphere, compound 9c (183 mg, 0.972 mmol), compound 1d (200 mg, 0.744 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (68 mg, 0.075 mmol, Acon), and cesium carbonate (728 mg, 2.23 mmol, Shaoyuan) were added to 30 mL of 1,4-dioxane. The mixture was heated to 100 °C and stirred for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified using a CombiFlash rapid reagent system with eluent A to give title product 9 (145.7 mg), yield: 46.5%.

[0338] MS m / z(ESI):421.0[M+1].

[0339] 1 H NMR (500MHz, DMSO-d6): δ8.64(s,1H),8.54(s,1H),8.19(s,1H),8.02(s,1H),7.93(s,1H),7.51(s,1H),4.43-4.37(m,1 H),3.98-3.95(m,2H),3.89(s,3H),3.44-3.39(m,2H),3.34(s,3H),2.56-2.48(m,2H),2.25(s,3H),1.68-1.65(m,2H).

[0340] Biological evaluation

[0341] The following test examples further describe and explain this disclosure, but these test examples are not intended to limit the scope of this disclosure.

[0342] Test Example 1

[0343] DNA-PK Enzymatic Experimental Methods

[0344] 1. Experimental Objective

[0345] 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.

[0346] 2. Experimental Methods

[0347] Dilute substrate P53 (Eurofins, catalog number: 14-952-M) to 500 nM with reaction buffer [25 mM HEPES (Gibco, catalog number: 15630-080), pH 8.0, 0.01% Brij-35 (Thermo, catalog number: 20150), 1% glycerol (Sangon Biotech, catalog number: A100854-0100)]. Dilute with dilution buffer [25 mM HEPES, pH 8.0, 0.01% Brij-35, 1% glycerol, 5 mM DTT (Sangon Biotech, catalog number: B645939), 1 mg / mL]. [BSA (Beyotime, catalog number: ST023)] Dilute DNA-PK enzyme (Eurofins, catalog number: 14-950M) to 0.16 nM; dilute magnesium acetate (Sigma, catalog number: 63052) to 40 mM with dilution buffer, and then dilute ATP (Thermo, catalog number: PV3227) to 29.2 μM. Using a liquid workstation (PV3227, catalog number: 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, catalog number: 267462). Mix well and incubate at 25°C for 1 hour.

[0348] Using a liquid workstation, stop solution [12.5 mM HEPES pH 8.0, 0.005% Brij-35, 0.5% glycerol, 250 mM EDTA (Thermo, catalog number: AM9260G)] and assay mixture [50 mM HEPES pH 7.0, 150 mM NaCl (Sanko, catalog number: B548121), 267 mM EDTA] were sequentially added to a 384-well plate. KF (China National Pharmaceutical Group Co., Ltd., 7789-23-3), 0.1% sodium cholate (Sigma, catalog number: C6445), 0.01% Tween 20 (Sigma, catalog number: P7949), 0.0125% sodium azide (Sigma, catalog number: S8032), 0.42 ng / well of antiphosphorylation-p53Eu (Cisbio, catalog number: 61P08KAE) and 25 ng / well of anti-GST-d2 (Cisbio, 61GSTDLF) were incubated overnight at 25°C. The absorbance at 665 nm and 620 nm was read using a microplate reader (BMG, PHERAstar FS). Data were analyzed using Graphpad Prism 6 and are shown in Table 1.

[0349] Table 1 IC50 values ​​of the inhibitory activity of the disclosed compounds against DNA-PK enzyme 50 value

[0350] Example number <![CDATA[IC 50 (nM)]]> 1 0.13 2 1.85

[0351] 3 0.46 4 0.36 5 0.36 6 0.26 8 0.17 9 0.37

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

[0353] Test Example 2

[0354] DNA-PK cell proliferation inhibition assay

[0355] 1. Experimental Objective

[0356] 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.

[0357] 2. Experimental Methods

[0358] 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 (ThermoFisher 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).

[0359] Compounds were prepared using a Bravo liquid workstation (Agilent Technologies, SGS120TH34702) and diluted with complete culture medium. The cell culture plate was removed, 10 μL of culture medium was aspirated, and 5 μL of the diluted compound was added. The plate was then returned to a CO2 incubator for 1 hour. Bleomycin (Selleck, S1214) was diluted to 20 μM with complete culture medium, and 5 μL was added to each well of the plate (final concentration 500 nM). The plate was returned to the CO2 incubator for further incubation. After 6 days, the 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. The luminescence values ​​were detected using a PerkinElmer (Vector3) microplate reader, and the data were analyzed using a Graphpad Prism 6. The results are shown in Table 2.

[0360] Table 2 IC50 values ​​of the disclosed compounds against DNA-PK cell proliferation 50 value

[0361] Example number <![CDATA[IC 50 (nM)]]> 1 105 3 143 4 122 6 51 8 70 9 37

[0362] Conclusion: The compound disclosed herein has a good inhibitory effect on DNA-PK cell proliferation.

[0363] Test Example 3

[0364] TTK Enzyme Experiment

[0365] 1. Experimental Objective

[0366] The Lantha Screen method was used to detect changes in ATP levels, and the inhibitory effect of reaction compounds on TTK enzyme activity was determined based on the IC50 of the inhibitory effect. 50 Evaluate the selectivity of compounds.

[0367] 2. Experimental Methods

[0368] Dilute TTK enzyme (Invitrogen, #PR7264B), substrate fluorescein-polygat (Invitrogen, #PV3611), and ATP (ADP-GloKinase Assay Kit, Promega, #V9102) with reaction buffer [50mM HEPES (Gibco, #11344-041) pH 7.5, 10mM MgCl2 (Sigma, #M2670), 2mM DTT (Sigma, #D0632), 0.01% Triton X-100 (Sigma, #T9284)]. Add 100nL of the prepared compound and 5μL each of TTK enzyme, substrate, and ATP to each well of a 96-well plate (Corning, #3365). Mix well and incubate at 28°C for 30 minutes. Add 10μL of detection buffer to each well. The Tb-PY20 antibody kit (Invitrogen, #PV3552) was mixed and incubated at 28°C for 1 hour. The luminescence values ​​were read using Envision (PE). The data were analyzed using Graphpad Prism, and the results are shown in Table 3.

[0369] Table 3 IC50 of the disclosed compounds against TTK enzymes 50 value

[0370] Example number <![CDATA[IC 50 (nM)]]> 1 7584 6 2776 9 1852

[0371] Conclusion: The compound disclosed herein has a weak inhibitory effect on TTK enzymes, but a good selective inhibitory effect on DNA-PK enzymes.

[0372] Test Example 4

[0373] Pharmacokinetic evaluation

[0374] I. C57 Mouse Experiment

[0375] 1. Abstract

[0376] Using C57 mice as test animals, the plasma drug concentrations at different time points after administration of the compound of Example 9 by gavage (ig) / intravenous injection (iv) and the positive control Example 1 to C57 mice were determined by LC / MS / MS. The pharmacokinetic behavior of the disclosed compound in C57 mice was investigated to evaluate its pharmacokinetic characteristics.

[0377] 2. Test Plan

[0378] 2.1 Test Drugs

[0379] Compound of Example 9 and Positive Control Example 1. Positive Control Example 1 (see Compound of Example 3 in WO2018114999A1) has the following structure:

[0380]

[0381] 2.2 Experimental Animals

[0382] Thirty-six female C57 mice were purchased from Vital River Laboratory Animal Co., Ltd., and divided into four groups on average.

[0383] 2.3 Drug Preparation

[0384] Weigh a certain amount of the compound from Example 9 and the positive control from Example 1, add 5% volume DMSO + 5% volume Tween 80 + 90% volume physiological saline to dissolve them, and prepare a clear solution of 0.1 mg / mL.

[0385] 2.4 Administration

[0386] Gavage administration group: The dosage was 2.0 mg / kg, and the administration volume was 0.2 mL / 10 g.

[0387] Intravenous administration group: The dosage was 1.0 mg / kg, and the administration volume was 0.1 mL / 10 g.

[0388] 3. Operation

[0389] In the gavage administration group: 0.1 mL of blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration, placed in EDTA-K2 anticoagulant tubes, centrifuged at 10,000 rpm for 5 minutes (4℃), and plasma was separated within 1 hour and stored at -80℃ for later analysis. The entire process from blood collection to centrifugation was performed under ice bath conditions.

[0390] Intravenous injection group: 0.1 mL of blood was collected 5 minutes, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 11.0 and 24 hours after administration, and the treatment was the same as that of the gavage group.

[0391] To determine the content of the target compound in mouse plasma after administration of different drug concentrations: 25 μL of mouse plasma samples were taken at each time point after administration, and 200 μL of acetonitrile and 50 μL of internal standard solution camptothecin (100 ng / mL) were added. The mixture was vortexed for 5 minutes and centrifuged for 10 minutes (4000 rpm). 0.1 μL of the supernatant of the plasma sample was taken for LC / MS / MS analysis.

[0392] 4. Pharmacokinetic Parameter Results

[0393] Table 4 shows the pharmacokinetic parameters of the compounds disclosed in this paper:

[0394]

[0395] Conclusion: The compound disclosed herein exhibits excellent pharmacokinetic absorption activity in C57 mice, high oral bioavailability, and pharmacokinetic advantages.

[0396] II. Beagle Dog Test

[0397] 1. Abstract

[0398] Using beagle dogs as test animals, the plasma drug concentrations at different time points after gavage (ig) / intravenous injection (iv) of the compound of Example 9 and the positive control Example 1 were determined by LC / MS / MS. The pharmacokinetic behavior of the disclosed compound in beagle dogs was investigated to evaluate its pharmacokinetic characteristics.

[0399] 2. Test Plan

[0400] 2.1 Test Drugs

[0401] Example 9: Compound and Positive Control Example 1.

[0402] 2.2 Experimental Animals

[0403] Sixteen beagles, half male and half female, were divided into four groups. After fasting overnight, they were administered medication by gavage and intravenous injection.

[0404] 2.3 Drug Preparation

[0405] Weigh a certain amount of the compound from Example 9 and the positive control from Example 1, add 5% volume DMSO + 20% volume PG + 20% volume PEG400 + 55% volume physiological saline to prepare a 0.4 mg / mL clear solution (gavage administration group) and a 0.25 mg / mL clear solution (intravenous injection group).

[0406] 2.4 Administration

[0407] Gavage administration group: The dosage was 2.0 mg / kg, and the administration volume was 5.0 mL / kg.

[0408] Intravenous administration group: The dosage was 0.5 mg / kg, and the administration volume was 2.0 mL / kg.

[0409] 3. Operation

[0410] In the gavage administration group: 1.0 mL of blood was collected from the jugular vein or forelimb vein before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, and 24.0 hours after administration. The blood was placed in an EDTA-K2 anticoagulant tube, centrifuged at 10,000 rpm for 5 minutes (4℃), and the plasma was separated within 1 hour and stored at -80℃ for analysis. The blood collection and centrifugation process was performed under ice bath conditions. Patients ate 3 hours after administration.

[0411] Intravenous injection group: Blood samples were collected before administration and 5 minutes after administration, and at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0 and 24 hours after administration. The treatment was the same as that of the gavage group.

[0412] Determination of the content of the target compound in beagle plasma after administration of different concentrations of the drug: 20 μL of beagle plasma sample was taken at each time point after drug administration, and 400 μL of methanol (containing 100 ng / mL internal standard solution) was added for protein precipitation. The mixture was vortexed for 1 minute and centrifuged at 18000g for 7 minutes. 1 μL of the supernatant of the plasma sample was taken for LC / MS / MS analysis.

[0413] 4. Pharmacokinetic Parameter Results

[0414] Table 5 shows the pharmacokinetic parameters of the compounds disclosed in this study:

[0415]

[0416]

[0417] Conclusion: The compound disclosed herein exhibits excellent pharmacokinetic absorption activity in beagle dogs, high oral bioavailability, and pharmacokinetic advantages.

Claims

1. A compound of general formula (IG) or a pharmaceutically acceptable salt thereof: ###0001### (IG) wherein: ring A is selected from the group consisting of 3- to 14-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 14-membered heteroaryl; ring B is 3- to 14-membered cycloalkyl or 3- to 14-membered heterocyclyl; p is 0, 1, 2, 3, 4, or 5; and q is 0, 1, 2, 3, 4, or 5.

3. The compound of general formula (IG) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of general formula (I) or a pharmaceutically acceptable salt thereof: ###0002### (I) wherein: n is 0, 1, 2, or 3. G 1 CR 2 or nitrogen atom; G 2 and G 3 are the same or different and each independently CR 2 ; 4. The compound of general formula (IG) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein ring A is 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl.

5. The compound of general formula (IG) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein ring A is 5-membered heteroaryl. R 1 the same or different and each independently selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 haloalkyl group, a C 1-6 haloalkoxy group, an oxo group, a cyano group, a hydroxy group and a C 1-6 hydroxyalkyl group; R 2 the same or different and each independently selected from the group consisting of a hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, hydroxy and C 1-6 hydroxyalkyl; R 3 selected from the group consisting of a hydrogen atom, C 1-6 alkyl group, C 1-6 haloalkyl group and a 3- to 14-membered cycloalkyl group; R 4 the same or different, and each independently selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 haloalkyl group, a C 1-6 haloalkoxy group, an oxo group, a cyano group, a hydroxyl group, and a C 1-6 hydroxyalkyl group; 6. The compound of general formula (IG) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein ring B is 3- to 14-membered heterocyclyl.

7. The compound of general formula (IG) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein ring B is 3- to 6-membered heterocyclyl.

2. The compound according to claim 1 represented by the general formula (IG) or a pharmaceutically acceptable salt thereof, wherein G 1 is a nitrogen atom.​ 8. The compound of general formula (IG) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein ring B is 6-membered heterocyclyl.

9. The compound of general formula (IG) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein ring B is tetrahydropyranyl and ring A is pyrazolyl.

17. The compound of general formula (IG) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein p is 0, 1, 2, or 3. ring A, ring B, R 1 to R 4 p and q are as defined in claim 1.

18. The compound of general formula (IG) or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from the group consisting of: ###0003### ###0004### ###0005### ###0006### ###0007### ###0008### ###0009### ###0010### ###0011### ###0012### ###0013### ###0014### ###0015### ###0016### ###0017### ###0018### ###0019### ###0020### ###0021### ###0022### ###0023### ###0024### ###0025### ###0026### ###0027### ###0028### ###0029### ###0030### ###0031### ###0032### ###0033### ###0034### ###0035### ###0036### ###0037### ###0038### ###0039### ###0040### ###0041### ###0042### ###0043### ###0044### ###0045### ###0046### ###0047### ###0048### ###0049### ###0050### ###0051### ###0052### ###0053### ###0054### ###0055### ###0056### ###0057### ###0058### ###0059### ###0060### ###0061### ###0062### ###0063### ###0064### ###0065### ###0066### ###0067### ###0068### ###0069### ###0070### ###0071### ###0072### ###0073### ###0074### ###0075### ###0076### ###0077### ###0078### ###0079### ###0080### ###0081### ###0082### ###0083### ###0084### ###0085### ###0086### ###0087### ###0088### ###0089### ###0090### ###0091### ###0092### ###0093### ###0094### ###0095### ###0096### ###0097### ###0098### ###0099### ###0100### ###0101### ###0102### ###0103### ###0104### ###0105### ###0106### ###0107### ###0108### ###0109### ###0110### ###0111### ###0112### ###0113### ###0114### ###0115### ###0116### ###0117### ###0118### ###0119### ###0120### ###0121### ###0122### ###0123### ###0124### ###0125### ###0126### ###0127### ###0128### ###0129### ###0130### ###0131### ###0132### ###0133### ###0134### ###0135### ###0136### ###0137### ###0138### ###0139### ###0140### ###0141### ###0142### ###0143### ###0144### ###0145### ###0146### ###0147### ###0148### ###0149### ###0150### ###0151### ###0152### ###0153### ###0154### ###0155### ###0156### ###0157### ###0158### ###0159### ###0160### ###0161### ###0162### ###0163### ###0164### ###0165### ###0166### ###0167### ###0168### ###0169### ###0170### ###0171### ###0172### ###0173### ###0174### ###0175### ###0176### ###0177### ###0178### ###0179### ###0180### ###0181### ###0182### ###0183### ###0184### ###0185### ###0186### ###0187### ###0188### ###0189### ###0190### ###0191### ###0192### ###0193### ###0194### ###0195### ###0196### ###0197### ###0198### ###0199### ###0200### ###0201### ###0202### ###0203### ###0204### ###0205### ###0206### ###0207### ###0208### ###0209### ###0210### ###0211### ###0212### ###0213### ###0214### ###0215### ###0216### ###0217### ###0218### ###0219### ###0220### ###0221### ###0222### ###0223### ###0224### ###0225### ###0226### ###0227### ###0228### ###0229### ###0230### ###0231### ###0232### ###0233### ###0234### ###0235### ###0236### ###0237### ###0238### ###0239### ###0240### ###0241### ###0242### ###0243### ###0244### ###0245### ###0246### ###0247### ###0248### ###0249### ###0250### ###0251### ###0252### ###0253### ###0254### ###0255### ###0256### ###0257### ###0258### ###0259### ###0260### ###0261### ###0262### ###0263### ###0264### ###0265### ###0266### ###0267### ###0268### ###0269### ###0270### ###0271### ###0272### ###0273### ###0274### ###0275### ###0276### ###0277### ###0278### ###0279### ###0280### ###0281### ###0282### ###0283### ###0284### ###0285### ###0286### ###0287### ###0288### ###0289### ###0290### ###0291### ###0292### ###0293### ###0294### ###0295### ###0296### ###0297### ###0298### ###0299### ###0300### ###0301### ###0302### ###0303### ###0304### ###0305### ###0306### ###0307### ###0308### ###0309### ###0310### ###0311### ###0312### ###0313### ###0314### ###0315### ###0316### ###0317### ###0318### ###0319### ###0320### ###0321### ###0322### ###0323### ###0324### ###0325### ###0326### ###0327### ###0328### ###0329### ###0330### ###0331### ###0332### ###0333### ###0334### ###0335### ###0336### ###0337### ###0338### ###0339### ###0340### ###0341### ###0342### ###0343### ###0344### ###0345### ###0346### ###0347### ###0348### ###0349### ###0350### ###0351### ###0352### ###0353### ###0354### ###0355### ###0356### ###0357### ###0358### ###0359### ###0360### ###0361### ###0362### ###0363### ###0364### ###0365### ###0366### ###0367### ###0368 ​ ​ ​ ​ ​ 10. The compound according to any one of claims 1 to 3 represented by General Formula (IG) : ###00010### or a pharmaceutically acceptable salt thereof, wherein R 3 is C 1-6 alkyl or 3- to 6-membered cycloalkyl.

11. The compound according to any one of claims 1 to 3 represented by General Formula (IG) : ###00013### or a pharmaceutically acceptable salt thereof, wherein R is a methyl group or a cyclopropyl group. 3 is a methyl group or a cyclopropyl group.

12. The compound according to any one of claims 1 to 3 represented by General Formula (IG) : ###0000079### or a pharmaceutically acceptable salt thereof, wherein R 3 is C 1-6 alkyl.

13. The compound according to any one of claims 1 to 3 represented by General Formula (IG) : ###00010### or a pharmaceutically acceptable salt thereof, wherein R 1 the same or different, and each independently selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group, and an oxo group.

14. The compound according to any one of claims 1 to 3 represented by General Formula (IG) : ###00010### or a pharmaceutically acceptable salt thereof, wherein R 2 the same or different, and each independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, and a C 1-6 alkyl group.

15. The compound of general formula (IG) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 2 It is a hydrogen atom.

16. The compound according to any one of claims 1 to 3 represented by General Formula (IG) : ###0009### or a pharmaceutically acceptable salt thereof, wherein R 4 the same or different, and each independently is a hydrogen atom or a C 1-6 alkyl group. ​ ​ ​ ​ ​ ​ ring A, ring B, G 1 , G 2 , G 3 , R 1 , R 3 , R 4 , p and q are as defined in claim 1. ​ ​ ​ ​ ​ ring A, ring B, R 1 to R 4 n, p and q are as defined in claim 3. ​ ​ 24. Use of a compound of Formula (IG) according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23, for the manufacture of a medicament for the inhibition of DNA-PK.

25. Use of a compound of Formula (IG) according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23, for the manufacture of a medicament for the treatment and / or prevention of cancer.

26. Use according to claim 25, wherein the cancer is selected from the group consisting of leukemia, multiple myeloma, lymphoma, myelodysplastic syndrome, breast cancer, lung cancer, endometrial cancer, central nervous system tumor, dysembryoplastic neuroepithelial tumor, glioblastoma multiforme, mixed glioma, medulloblastoma, retinoblastoma, neuroblastoma, germinoma, teratoma, gastric cancer, esophageal cancer, liver cancer, cholangiocellular carcinoma, colorectal cancer, small intestinal 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, renal cancer, squamous cell carcinoma, sarcoma, gastrointestinal stromal tumor and pediatric cancer.

27. Use according to claim 26, wherein the sarcoma is selected from the group consisting of chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, Ewing's sarcoma and Kaposi's sarcoma; and the lung cancer is non-small cell lung cancer.

Images