阅读说明：本技术 激酶抑制剂及其制备、药物组合物和用途 (Kinase inhibitor, preparation, pharmaceutical composition and application thereof ) 是由 皮士卿 徐燕 杨代鸿 周志刚 于 2020-08-19 设计创作，主要内容包括：本申请涉及可作为激酶抑制剂(如酪氨酸激酶抑制剂)的式I化合物、其制备方法以及包含所述式I化合物的药物组合物。本申请还涉及所述式I化合物或其药物组合物在免疫疾病、肿瘤和神经疾病等疾病中的治疗用途。(The present application relates to compounds of formula I that are useful as kinase inhibitors (e.g., tyrosine kinase inhibitors), methods for their preparation, and pharmaceutical compositions comprising the compounds of formula I. The application also relates to the therapeutic application of the compound of the formula I or the pharmaceutical composition thereof in immune diseases, tumors, neurological diseases and other diseases.)

A compound of formula I, or a pharmaceutically acceptable salt, ester, solvate, prodrug, active metabolite, crystal, stereoisomer, tautomer, or geometric isomer thereof,

wherein:

R ₀selected from halogen and D;

R ₂、R ₃、R ₅、R ₇、R ₁₀、R ₁₁、R ₁₂、R ₁₃、R ₁₄、R ₁₅、R ₁₆、R ₁₇each independently selected from H and D;

R ₁、R ₄and R₆Each independently selected from optionally substituted alkyl, optionally substituted hydroxyalkyl, halogen, optionally substituted alkoxy, optionally substituted alkynyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carboxyalkyl, -NO₂-CN, -OH, -COOH, mercapto, or a salt thereof,Optionally substituted amino, optionally substituted alkylthio, optionally substituted ester, optionally substituted acyl, and optionally substituted sulfonyl;

R ₈selected from H, D, optionally substituted hydroxyalkyl, optionally substituted carboxyalkyl, optionally substituted alkyl, halogen, optionally substituted alkoxy, optionally substituted alkynyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -NO₂-CN, -OH, -COOH, thiol, optionally substituted amino, optionally substituted alkylthio, optionally substituted ester, optionally substituted acyl, and optionally substituted sulfonyl.

A compound of formula I according to claim 1, or a pharmaceutically acceptable salt, ester, solvate, prodrug, active metabolite, crystal, stereoisomer, tautomer, or geometric isomer thereof, wherein:

R ₁、R ₄and R₆Each independently selected from optionally substituted C_1-6Alkyl, optionally substituted C_1-6Hydroxyalkyl, halogen, optionally substituted C_1-6Alkoxy, optionally substituted C_2-6Alkynyl, optionally substituted C_2-6Alkenyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 6-10 membered aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C_1-6Carboxyalkyl, -NO₂-CN, -OH, -COOH, mercapto, optionally substituted amino, optionally substituted C_1-6An alkylthio group, an optionally substituted ester group, an optionally substituted acyl group and an optionally substituted sulfonyl group;

R ₈selected from H, D, optionally substituted C_1-6Hydroxyalkyl, optionally substituted C_1-6Carboxyalkyl, optionally substituted C_1-6Alkyl, halogen, optionally substituted C_1-6Alkoxy, optionally substituted C_2-6Alkynyl, optionally substitutedC of (A)_2-6Alkenyl, optionally substituted 3-to 8-membered cycloalkyl, optionally substituted 3-to 10-membered heterocyclyl, optionally substituted 6-to 10-membered aryl and optionally substituted 5-to 10-membered heteroaryl, -NO₂-CN, -OH, -COOH, mercapto, optionally substituted amino, optionally substituted C_1-6Alkylthio, optionally substituted ester, optionally substituted acyl and optionally substituted sulfonyl.

A compound of formula I according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, solvate, prodrug, active metabolite, crystal, stereoisomer, tautomer, or geometric isomer thereof, wherein:

one or more heteroatoms in said heterocyclyl and heteroaryl groups are each independently selected from O, S and N;

preferably, R₀Selected from fluorine, chlorine, bromine and iodine;

preferably, R₂、R ₃、R ₅、R ₇、R ₁₀、R ₁₁、R ₁₂、R ₁₃、R ₁₄、R ₁₅、R ₁₆、R ₁₇Each independently selected from H;

preferably, R₁、R ₄And R₆Each independently selected from optionally substituted C_1-6Alkyl, optionally substituted C_1-6Hydroxyalkyl and halogen;

preferably, R₈Selected from H, D, optionally substituted C_1-6Hydroxyalkyl and optionally substituted C_1-6A carboxyalkyl group.

A compound of formula I according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, solvate, prodrug, active metabolite, crystal, stereoisomer, tautomer, or geometric isomer thereof, wherein:

the number of heteroatoms in the heterocyclyl and heteroaryl groups are each independently selected from 1, 2 and 3;

preferably, R₁Is selected from C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Hydroxyalkyl and halogen;

preferably, R₄Is selected from C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Deuterated alkyl and halogen;

preferably, R₁And R₄Each independently selected from C_1-6Alkyl and halogen;

preferably, R₆Is selected from C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Deuterated alkyl, C_1-4Hydroxyalkyl and halogen;

preferably, R₈Selected from H, D, C_1-4Hydroxyalkyl and C_1-4A carboxyalkyl group.

A compound of formula I according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, ester, solvate, prodrug, active metabolite, crystal, stereoisomer, tautomer, or geometric isomer thereof, wherein:

R ₀selected from fluorine;

preferably, R₁Is selected from-CH₃、-CH ₂OH and chlorine;

preferably, R₁Is selected from-CH₃And chlorine;

preferably, R₄Is selected from-CH₃、-CD ₃Fluorine and chlorine;

preferably, R₄Is selected from-CH₃Fluorine and chlorine;

preferably, R₄Is selected from-CH₃And chlorine;

preferably，R ₆Is selected from-CH₃、-CH ₂OH and-CD₃；

Preferably, R₆Is selected from-CH₃；

Preferably, R₈Selected from H, D, -CH₂CH ₂OH and-CH₂CO ₂H；

Preferably, R₈Is selected from-CH₂CH ₂OH。

A compound of formula I according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, solvate, prodrug, active metabolite, crystal, stereoisomer, tautomer, or geometric isomer thereof, wherein:

the term "optionally substituted" means that the group is unsubstituted or substituted with one or more substituents independently selected from: deuterium, halogen, hydroxy, C₁-C ₆Alkyl radical, C₂-C ₆Alkenyl radical, C₂-C ₆Alkynyl, C_1-6Hydroxyalkyl radical, C_1-6Alkoxy, 3-to 8-membered cycloalkyl, 3-to 10-membered heterocyclyl, 6-to 10-membered aryl, 5-to 10-membered heteroaryl, -NO₂-CN, -OH, -COOH, mercapto and amino.

A compound, or a pharmaceutically acceptable salt, ester, solvate, prodrug, active metabolite, crystal, stereoisomer, tautomer, or geometric isomer thereof,

a pharmaceutical composition comprising a compound of any one of claims 1-7, or a pharmaceutically acceptable salt, ester, solvate, prodrug, active metabolite, crystal, stereoisomer, tautomer, or geometric isomer thereof; optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient or adjuvant.

The pharmaceutical composition of claim 8, further comprising another therapeutic agent for combination therapy;

optionally, the further therapeutic agent is selected from one or more of: cyclophosphamide, ifosfamide, vincristine, daunorubicin, doxorubicin, cytarabine, mitoxantrone, dacarbazine, idarubicin, tretinoin, prednisone, dexamethasone, mercaptopurine, methotrexate, paclitaxel, melphalan, long-acting interferon, venetock, crizotinib, erlotinib, ocitinib, ruxotinib, afatinib, erlotinib, imatinib, lapatinib, bevacizumab, trastuzumab, rituximab, cetuximab, bornauzumab, fludarabine, gemcitabine, decitabine, capecitabine, bendamustine, everolimus, temsirolimus, etoposide, granulocyte colony stimulating factor, temozolomide, zoledram, olixaplatin, cisplatin, carboplatin, and fulvestrant.

Use of a compound of any one of claims 1-7, or a pharmaceutically acceptable salt, ester, solvate, prodrug, active metabolite, crystal, stereoisomer, tautomer, or geometric isomer thereof, or a pharmaceutical composition of claim 8 or 9, for the manufacture of a medicament for the prevention or treatment of a tyrosine kinase-associated disease.

Use of a compound of any one of claims 1-7, or a pharmaceutically acceptable salt, ester, solvate, prodrug, active metabolite, crystal, stereoisomer, tautomer, or geometric isomer thereof, or a pharmaceutical composition of claim 8 or 9, for the manufacture of a medicament for inhibiting tyrosine kinase activity.

A method of preventing or treating a tyrosine kinase-associated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-7, or a pharmaceutically acceptable salt, ester, solvate, prodrug, active metabolite, crystal, stereoisomer, tautomer, or geometric isomer thereof, or a pharmaceutical composition of claim 8 or 9.

A method of inhibiting tyrosine kinase activity, comprising administering to a subject or a tissue or cell thereof a compound of any one of claims 1-7, or a pharmaceutically acceptable salt, ester, solvate, prodrug, active metabolite, crystal, stereoisomer, tautomer, or geometric isomer thereof, or a pharmaceutical composition of claim 8 or 9,

optionally, the method is performed in vivo or in vitro.

A compound of any one of claims 1-7, or a pharmaceutically acceptable salt, ester, solvate, prodrug, active metabolite, crystal, stereoisomer, tautomer, or geometric isomer thereof, or a pharmaceutical composition of claim 8 or 9, for use in inhibiting tyrosine kinase activity.

A compound of any one of claims 1-7, or a pharmaceutically acceptable salt, ester, solvate, prodrug, active metabolite, crystal, stereoisomer, tautomer, or geometric isomer thereof, or a pharmaceutical composition of claim 8 or 9, for use in the prevention or treatment of a tyrosine kinase-associated disease.

The use according to claim 10 or 11, or the method according to claim 12 or 13, or the compound or composition for use according to claim 14 or 15, wherein:

the tyrosine kinase-associated diseases are diseases, disorders, and conditions that benefit from inhibition or reduction of tyrosine kinase activity;

preferably, the tyrosine kinases include Bcr-Abl tyrosine kinase and BTK tyrosine kinase;

preferably, the disease is selected from cancer;

preferably, the cancer is selected from: chronic Myelogenous Leukemia (CML), gastrointestinal stromal tumor (GIST), Small Cell Lung Cancer (SCLC), non-small cell lung cancer (NSCLC), multiple myeloma, solid tumor, B-cell lymphoma, Chronic Lymphocytic Leukemia (CLL), Acute Lymphocytic Leukemia (ALL), non-Hodgkin's lymphoma (NHL), Small Lymphocytic Lymphoma (SLL), Mantle Cell Lymphoma (MCL), melanoma, mastocytosis, germ cell tumors, Acute Myeloid Leukemia (AML), marginal zone/diffuse large B-cell lymphoma, sarcoma, pancreatic cancer, glioblastoma, head and neck tumors, macroglobulinemia, follicular central lymphoma, prostate cancer, myelodysplastic syndrome, atherosclerotic myelohyperplasia, myelofibrosis, eosinophilia, polycythemia vera, liver cancer, advanced sarcoma, glioblastoma multiforme, gliosarcoma, malignant mesothelioma, melanoma, squamous cell carcinoma skin cancer, neuroendocrine tumor, gastric tumor, B-cell acute lymphocytic leukemia, hairy cell leukemia, lymphoplasmacytic lymphoma, follicular central lymphoma, renal cell carcinoma, transitional cell carcinoma, carcinoid tumor, T-cell lymphoma, metastatic non-small cell lung cancer, systemic mastocytosis, metastatic renal cell carcinoma, breast tumor, central nervous system tumor, colorectal tumor, metastatic bladder cancer, metastatic pancreatic cancer, metastatic head and neck cancer, ovarian tumor and combinations thereof;

preferably, the cancer is selected from the group consisting of cancers with chemotherapeutic agents resistant to target BCR-ABL and c-KIT, and cancers with resistance to imatinib;

preferably, the diseases, disorders and conditions are selected from: bone metastasis, hypercalcemia and/or osteoporosis; pulmonary fiber disease; cardiovascular disease or condition; mast cell mediated inflammatory diseases; HTLV-1 associated myelopathy/tropical spastic paralysis; complex Regional Pain Syndrome (CRPS); weight loss or fat loss; arterial occlusive disease; ubiquitination; diseases or conditions associated with reduced function of degrading sugars; fridriich ataxia; graft rejection in parkinson's disease progression; rheumatoid arthritis; graft versus host disease; (ii) an autoimmune disease; recurrent immune thrombocytopenic purpura, pemphigus vulgaris, systemic lupus erythematosus, scleroderma interstitial pulmonary fibrosis and idiopathic urticaria;

preferably, the cardiovascular disease or condition is a cardiovascular disease caused by RASopathy, or a congenital heart disease associated with nosan or nosan syndrome;

preferably, the mast cell mediated inflammatory disease is selected from osteoarthritis, asthma, chronic obstructive pulmonary disease uveitis, aspirin-aggravated respiratory disease (AERD), and parkinson's disease.