WO2021032129A1 - 激酶抑制剂及其制备、药物组合物和用途 - Google Patents

激酶抑制剂及其制备、药物组合物和用途 Download PDF

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WO2021032129A1
WO2021032129A1 PCT/CN2020/110063 CN2020110063W WO2021032129A1 WO 2021032129 A1 WO2021032129 A1 WO 2021032129A1 CN 2020110063 W CN2020110063 W CN 2020110063W WO 2021032129 A1 WO2021032129 A1 WO 2021032129A1
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optionally substituted
compound
ester
pharmaceutically acceptable
disease
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PCT/CN2020/110063
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English (en)
French (fr)
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皮士卿
徐燕
杨代鸿
周志刚
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湖南华纳大药厂股份有限公司
湖南新医科技发展有限公司
湖南华纳大药厂科技开发有限公司
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Priority to CN202080030257.5A priority Critical patent/CN113727981B/zh
Publication of WO2021032129A1 publication Critical patent/WO2021032129A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This application belongs to the field of medicinal chemistry, and specifically relates to a compound that can be used as a kinase inhibitor (such as a tyrosine kinase inhibitor), a preparation method thereof, and a pharmaceutical composition containing the compound.
  • a kinase inhibitor such as a tyrosine kinase inhibitor
  • the application also relates to the therapeutic use of the compound or its pharmaceutical composition in diseases such as immune diseases, tumors and neurological diseases.
  • Protein kinases are a class of enzymes that catalyze the phosphorylation of proteins, thereby changing their substrate activity or the ability to bind to other proteins.
  • the kinase signaling pathway is the most common form of reversible post-translational modification and controls many aspects of cell function.
  • Abnormal activation of protein kinases is the main sign of malignant tumors, including changes in cell proliferation, survival, movement and metabolism, as well as diseases such as vascular proliferation and evasion of anti-tumor immune responses.
  • the resulting new blood vessels "supply" oxygen and nutrients for growing tumors.
  • Bcr-Abl tyrosine kinase in the pathogenesis of chronic myeloid leukemia (CML), and Bcr-Abl inhibitors have paved the way for the development of new targeted therapy small molecule drugs.
  • Imatinib, Bosutinib, Dasatinib, Nilotinib, Radotinib, and Ponatinib have been Approved for the treatment of chronic myelogenous leukemia eosinophilia syndrome, myelodysplastic/myeloproliferative tumor, chronic myelogenous leukemia, acute lymphocytic leukemia/lymphocytic lymphoma.
  • TKIs poorly selective tyrosinase inhibitors
  • BTK tyrosine kinase
  • Bcr-Abl inhibitors for tumor treatment, and can fundamentally improve the average survival rate of patients.
  • new gene mutations and drug resistance forms will also appear in clinical practice, so further development of new inhibitors is needed.
  • Large doses of drugs can cause mutations in the target protein, leading to loss of activity.
  • the application provides a compound of Formula I, or a pharmaceutically acceptable salt, ester, solvate, prodrug, active metabolite, crystal, stereoisomer, tautomer or geometric isomer thereof,
  • R 0 is selected 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 , and R 17 are each independently selected from H and D;
  • R 1 , R 4 and R 6 are each independently selected from optionally substituted alkyl, optionally substituted hydroxyalkyl, halogen, optionally substituted alkoxy, optionally substituted alkynyl, optionally substituted alkene Group, optionally substituted cycloalkyl, optionally substituted heterocyclic group, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carboxyalkyl, -NO 2 , -CN, -OH , -COOH, mercapto, optionally substituted amino, optionally substituted alkylthio, optionally substituted ester, optionally substituted acyl and optionally substituted sulfonyl;
  • R 8 is selected 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 heterocyclic group, optionally substituted aryl, optionally substituted heteroaryl, -NO 2 , -CN, -OH, -COOH, mercapto , Optionally substituted amino, optionally substituted alkylthio, optionally substituted ester, optionally substituted acyl and optionally substituted sulfonyl.
  • R 1 , R 4 and R 6 are each independently selected from optionally substituted C 1-6 alkyl, optionally substituted C 1-6 hydroxyalkyl, halogen, optionally substituted C 1 -6 alkoxy, optionally substituted C 2-6 alkynyl, optionally substituted C 2-6 alkenyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-10 membered heterocycle Group, optionally substituted 6-10 membered aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C 1-6 carboxyalkyl, -NO 2 , -CN, -OH, -COOH, Mercapto, optionally substituted amino, optionally substituted C 1-6 alkylthio, optionally substituted ester, optionally substituted acyl, and optionally substituted sulfonyl.
  • R 8 is selected from H, D, optionally substituted C 1-6 hydroxyalkyl, optionally substituted C 1-6 carboxyalkyl, optionally substituted C 1-6 alkyl, halogen , Optionally substituted C 1-6 alkoxy, optionally substituted C 2-6 alkynyl, optionally substituted C 2-6 alkenyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-10 membered heterocyclic group, optionally substituted 6-10 membered aryl group, optionally substituted 5-10 membered heteroaryl group, -NO 2 , -CN, -OH, -COOH, mercapto, optionally substituted , An optionally substituted C 1-6 alkylthio group, an optionally substituted ester group, an optionally substituted acyl group and an optionally substituted sulfonyl group.
  • one or more heteroatoms in the heterocyclic group and heteroaryl group are independently selected from O, S, and N; in some embodiments, the number of heteroatoms is independently selected from 1. , 2 and 3.
  • R 0 is selected from fluorine, chlorine, bromine and iodine. In some embodiments, R 0 is selected from fluorine.
  • R 2 , R 3 , R 5 , R 7 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 are each independently selected from H.
  • R 1 , R 4, and R 6 are each independently selected from optionally substituted C 1-6 alkyl, optionally substituted C 1-6 hydroxyalkyl, and halogen.
  • R 1 and R 4 are each independently selected from C 1-6 alkyl and halogen.
  • R 1 is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, and halogen.
  • R 1 is selected from -CH 3 , -CH 2 OH, and chlorine.
  • R 1 is selected from -CH 3 and chlorine.
  • R 4 is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 deuterated alkyl, and halogen.
  • R 4 is selected from -CH 3 , -CD 3 , fluorine, and chlorine.
  • R 4 is selected from -CH 3 , fluorine, and chlorine.
  • R 4 is selected from -CH 3 and chlorine.
  • R 6 is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 deuterated alkyl, C 1-4 hydroxyalkyl, and halogen.
  • R 6 is selected from C 1-4 alkyl.
  • R 6 is selected from -CH 3 , -CH 2 OH, and -CD 3 .
  • R 6 is selected from -CH 3 .
  • R 8 is selected from H, D, optionally substituted C 1-6 hydroxyalkyl, and optionally substituted C 1-6 carboxyalkyl.
  • R 8 is selected from H, D, C 1-4 hydroxyalkyl, and C 1-4 carboxyalkyl.
  • R 8 is selected from C 1-4 hydroxyalkyl.
  • R 8 is selected from H, D, -CH 2 CH 2 OH, and -CH 2 CO 2 H.
  • R 8 is selected from -CH 2 CH 2 OH.
  • the term "optionally substituted” means that the group is unsubstituted or substituted with one or more substituents, wherein the one or more substituents are independently selected from: deuterium, halogen, hydroxyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, 3-8 membered cycloalkyl, 3- 10-membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -NO 2 , -CN, -OH, -COOH, mercapto and amino.
  • this application provides the following compounds, or their pharmaceutically acceptable salts, esters, solvates, prodrugs, active metabolites, crystals, stereoisomers, tautomers or geometric isomers,
  • the application provides a pharmaceutical composition comprising at least any one of the compounds provided in the present disclosure or a pharmaceutically acceptable salt, ester, solvate, prodrug, active metabolite, crystal, stereoisomer, Tautomers or geometric isomers.
  • the composition provided herein further includes a pharmaceutically acceptable carrier, excipient or adjuvant.
  • the pharmaceutical composition of the present disclosure further includes another therapeutic agent for combination therapy.
  • the another therapeutic agent is selected from one or more of the following: cyclophosphamide, ifosfamide, vincristine, daunorubicin, doxorubicin, cytarabine, Mitoxantrone, dacarbazine, Idarubicin, Tretinoin, Prednisone, Dexamethasone, Mercaptopurine, Methotrexate, Paclitaxel, Melphalan, Long-acting Interferon, Venetog, Gram Zoltinib, Erlotinib, Ositinib, Ruxotinib, Afatinib, Erlotinib, Imatinib, Lapatinib, Bevacizumab, Trastuzumab, Li Tuximab, Cetuximab, Bonatumumab, Fludarabine, Gemcitabine, Decitabine, Capecitabine, Bendamustine, Everolimus, Tesirolimus
  • the application provides the compounds described in the present disclosure, or pharmaceutically acceptable salts, esters, solvates, prodrugs, active metabolites, crystals, stereoisomers, tautomers or geometric isomers thereof Or the use of the above-mentioned pharmaceutical composition in preparing a medicine for preventing or treating diseases related to tyrosine kinase.
  • the application provides the compound described in the present disclosure or a pharmaceutically acceptable salt, ester, solvate, prodrug, active metabolite, crystal, stereoisomer, tautomer or geometric isomer thereof Or the use of the above-mentioned pharmaceutical composition in preparing a medicine for inhibiting the activity of tyrosine kinase.
  • the present application provides a method for preventing or treating a disease or disorder related to tyrosine kinase, the method comprising administering to an individual in need a therapeutically effective amount of at least any one of the compounds provided in the present disclosure or a pharmaceutically acceptable compound thereof.
  • the present application provides a method for inhibiting the activity of tyrosine kinase, the method comprising administering to an individual or its tissues or cells at least any one of the compounds provided in the present disclosure or a pharmaceutically acceptable salt, ester, or solvent thereof Compounds, prodrugs, active metabolites, crystals, stereoisomers, tautomers or geometric isomers or the above-mentioned pharmaceutical compositions.
  • the method of inhibiting tyrosine kinase activity is performed in vitro or in vivo.
  • the method of inhibiting tyrosine kinase activity includes in vitro or in vivo tests.
  • the application provides the compounds described in the present disclosure, or pharmaceutically acceptable salts, esters, solvates, prodrugs, active metabolites, crystals, stereoisomers, tautomers or geometric isomers thereof Or the above-mentioned pharmaceutical composition for the purpose of inhibiting tyrosine kinase activity.
  • the present application provides the compound described in the present disclosure or a pharmaceutically acceptable salt, ester, solvate, prodrug, active metabolite, crystal, stereoisomer, tautomer or geometric isomer thereof Or the above-mentioned pharmaceutical composition for use in preventing or treating diseases related to tyrosine kinase.
  • the diseases associated with tyrosine kinases are diseases, disorders, and conditions that benefit from the inhibition or reduction of tyrosine kinase activity.
  • the tyrosine kinase includes Bcr-Abl tyrosine kinase and BTK tyrosine kinase.
  • the disease is selected from cancer.
  • the cancer is selected from the group consisting of: 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, malignant glioma, head and neck tumors, giant bulbs Proteinemia, follicular center lymphoma, prostate cancer, myelodysplastic syndrome, atherosclerotic myelodysplasia
  • CML
  • the cancer is selected from cancers that are resistant to the targets BCR-ABL and c-KIT by chemotherapeutic agents, and cancers that are resistant to imatinib.
  • the diseases, disorders, and conditions are selected from: bone metastases, hypercalcemia and/or osteoporosis; lung fibrosis; cardiovascular diseases or symptoms; mast cell-mediated inflammatory diseases; HTLV -1 related myelopathy/tropical spasmodic paralysis; complex regional pain syndrome (CRPS); weight loss or fat loss; arterial obstructive disease; ubiquitination; diseases or symptoms related to reduced sugar degradation; Fridreich co-help Disorders; Parkinson’s disease progression; Transplant rejection; Rheumatoid arthritis; Graft versus host disease; Autoimmune disease; Recurrent immune thrombocytopenic purpura, Pemphigus vulgaris, Systemic lupus erythematosus, Scleroderma Pulmonary fibrosis and spontaneous urticaria.
  • CRPS complex regional pain syndrome
  • weight loss or fat loss arterial obstructive disease
  • ubiquitination diseases or symptoms related to reduced sugar degradation
  • Fridreich co-help Disorders Parkinson’s disease progression
  • the cardiovascular disease or symptom is a cardiovascular disease caused by RASopathy, or a congenital heart disease related to Noonan or Noonan syndrome.
  • the mast cell-mediated inflammatory disease is selected from osteoarthritis, asthma, chronic obstructive pulmonary disease, uveitis, aspirin exacerbated respiratory disease (AERD), and Parkinson's disease.
  • C 1 -C 10 or “C 1-10” means that the group can have 1, 2, 3, 4 , 5, 6, 7, 8, 9, 10 carbon atoms.
  • member refers to the number of skeletal atoms constituting the ring.
  • 3-10 membered means that the number of skeleton atoms constituting the ring is 3, 4, 5, 6, 7, 8, 9, or 10.
  • alkyl refers to a linear or branched saturated hydrocarbon group, which can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
  • alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl) , T-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), etc.; for example, the term “C 1-6 alkyl” refers to containing 1 to 6 (e.g.
  • alkyl groups of carbon atoms e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1 -Methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.
  • hydroxyalkyl refers to -alkyl-OH, where "alkyl” is as defined above, and "optionally substituted hydroxyalkyl” means that the alkyl part of the group is substituted or unsubstituted.
  • halo or "halogen” by itself or as part of another substituent represents a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom.
  • alkoxy refers to -O-alkyl, where "alkyl” is defined as above.
  • alkoxy include but are not limited to methoxy, ethoxy, n-propoxy, and isopropoxy , N-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy.
  • Optionally substituted alkoxy means that the alkyl part of the group is substituted or unsubstituted.
  • C 2-6 alkynyl refers to having 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and having at least 1, preferably 1 to 2 sites of acetylenic (-C ⁇ C-) unsaturation
  • alkynyl groups include ethynyl (-C ⁇ CH) and propargyl (-CH 2 C ⁇ CH).
  • cycloalkyl refers to a saturated non-aromatic cyclic hydrocarbon group composed of carbon atoms and hydrogen atoms, preferably containing 1 or 2 rings.
  • the cycloalkyl group may be a monocyclic ring, a fused polycyclic ring, a bridged ring or a spiro ring structure.
  • Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl, spiro[3.3]heptyl, and the like.
  • heterocyclyl refers to a saturated or unsaturated, non-aromatic ring containing one or more heteroatoms (eg, O, N, S) as part of the ring structure and having 2-9 ring carbon atoms Group;
  • optionally substituted heterocyclic group refers to an unsubstituted heterocyclic group or a heterocyclic group substituted with one or more substituents as defined below.
  • aryl means that each atom in the aromatic ring is a carbon atom.
  • the aryl ring can be composed of five, six, seven, eight, nine, or more than nine atoms.
  • aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, anthracenyl, fluorenyl, and indenyl.
  • the aryl group may be a monovalent group or a divalent group, that is, an arylene group.
  • heteroaryl means a stable 5, 6, 7-membered monocyclic or bicyclic or 7, 8, 9 or 10-membered bicyclic heterocyclic aromatic ring, which contains carbon atoms and 1, 2, 3 or 4 Heteroatoms independently selected from N, O and S.
  • the nitrogen atom may be optionally substituted (ie, N or NR, where R is H or other substituents as defined below).
  • Nitrogen and sulfur atoms may optionally be oxidized (i.e., NO and S(O) p , p is 1 or 2).
  • Non-limiting examples of monocyclic heteroaryl groups include pyridyl; non-limiting examples of fused ring heteroaryl groups include benzimidazolyl, quinolinyl, acridinyl, non-fused Non-limiting examples of combined biheteroaryl groups include bipyridinyl.
  • heteroaryl groups include, but are not limited to: furanyl, thienyl, oxazolyl, acridinyl, phenazinyl, isoxazolyl ), isothiazolyl, pyrazolyl, purinyl, quinolinyl, triazolyl, thiazolyl, triazinyl and thiol Thiadiazolyl, etc., and oxides thereof, such as pyridyl-N-oxide.
  • carboxyalkyl refers to a group having the structure -alkyl-COOH, where the alkyl group is as defined above.
  • Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl (-CH 2 CO 2 H), 2-carboxyethyl, and the like.
  • Optionally substituted carboxyalkyl means that the alkyl part of the group is substituted or unsubstituted.
  • optionally substituted amino means -NH 2, mono - or di - substituted amino group, and a 5- to 7-membered cyclic amino group.
  • mercapto or "thiol” refers to the group -SH.
  • alkylthio refers to the group -S-alkyl, where alkyl is as defined herein. "Optionally substituted alkylthio" means that the alkyl part of the group is substituted or unsubstituted.
  • ester group refers to a group having the structure -C(O)OR', where R'is an optionally substituted alkyl group, an optionally substituted aryl group or an optionally substituted group as defined above Heteroaryl.
  • R' is alkyl, haloalkyl, aryl, heteroaryl, alkaryl, alkylheteroaryl.
  • R' is alkyl or haloalkyl.
  • R' is an alkyl group.
  • "Optionally substituted ester group” means that the R'part of the group is substituted or unsubstituted.
  • acyl refers to a group having the structure -C(O)R', where R'is as defined above. "Optionally substituted acyl” means that the R'part of the group is substituted or unsubstituted.
  • sulfonyl refers to a group having the structure -SO 2 R', where R'is as defined above. "Optionally substituted sulfonyl” means that the R'part of the group is substituted or unsubstituted.
  • optionally substituted means that the group is unsubstituted or substituted with one or more substituents, wherein the one or more substituents are independently selected from: deuterium, halogen, hydroxyl, C 1 -C 6 alkane Group, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, 3-8 membered cycloalkyl, 3-10 membered heterocyclic group, 6-10 membered aryl, 5-10 membered heteroaryl, -NO 2 , -CN, -OH, -COOH, mercapto and amino.
  • substituents When a group is substituted by more than one substituent, the substituents may be the same or different. Any substituted functional group herein can be substituted at 1 to 3 different positions, and those 1 to 3 substituents can be at 1 Up to 3 positions are each independently substituted.
  • pharmaceutically acceptable salt refers to a salt that retains the biological efficacy of the free acid and free base of the specified compound, and has no adverse biological or other effects.
  • the compounds described herein can have acidic or basic groups, and therefore can react with any of a variety of inorganic or organic bases, as well as inorganic and organic acids, to form pharmaceutically acceptable salts.
  • These salts can be prepared by the following methods: prepared in situ during the final isolation and purification of the compound of the present application, or by separately reacting the free base form of the compound of the present application with a suitable organic or inorganic acid and isolating the salt formed thereby.
  • Examples of pharmaceutically acceptable salts include salts prepared by the reaction between a compound described herein and an inorganic acid or organic acid or inorganic base or organic base. These salts include acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate , Butyne-1,4-diolate, camphorate, camphorsulfonate, caprylate, chlorobenzoate, chloride, citrate, cyclopentane propionate, caprate, Gluconate, dihydrogen phosphate, dinitrobenzoate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, Hemisulfate, heptanoate, hexyne-1,6-dioate, hydroxybenzoate, y-hydroxybutyrate
  • acids such as oxalic acid
  • acids can be used as intermediates in the preparation of salts to obtain the compounds of the application and their pharmaceutically acceptable acid addition salts (See the examples in Berge et al., J. Pharm. Sci. 1977, 66, 1-19).
  • the compounds described herein that may include free acid groups may be reacted with a suitable base (e.g., a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation), reacted with ammonia, or reacted with a pharmaceutical Acceptable organic primary, secondary or tertiary amine reactions.
  • a suitable base e.g., a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation
  • Representative alkali metal or alkaline earth metal salts include lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, and the like.
  • Illustrative examples of the base include sodium hydroxide, potassium hydroxide, hydroxyethyltrimethylamine hydroxide, sodium carbonate, IV'(C 1-4 alkyl) 4 and the like.
  • Representative organic amines used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include quaternary ammonium compounds of any basic nitrogen-containing groups that they may contain. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization reactions. See, for example, Berge et al. above.
  • solvate refers to a solvate formed by combining the compound of the present application and solvent molecules.
  • the solvate is a monohydrate, for example, the solvent is water, and the compound of the present application forms a monohydrate with water.
  • esters of the compounds of the present invention refer to those pharmaceutically acceptable esters that are suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic reactions, etc., within the scope of reasonable medical judgment. It should be understood that the esters of compounds of formula I containing carboxyl or hydroxyl groups include esters that are hydrolyzable in vivo, such as pharmaceutically acceptable esters that are hydrolyzed in humans or animals to form parent acids or alcohols.
  • Suitable pharmaceutically acceptable esters of the carboxyl group formed on the carboxyl group (if present) of the compound of the present invention include, for example, alkyl esters (such as C 1-6 or C 1-4 alkyl esters), cycloalkyl esters (such as C 3-12 , C 3-8 or C 3-6 cycloalkyl ester), aryl alkyl ester (such as C 6-12 or C 6-8 aryl alkyl ester) and heteroaryl alkyl ester (such as C 6-12 or C 6-8 heteroaryl alkyl ester) and the like.
  • alkyl esters such as C 1-6 or C 1-4 alkyl esters
  • cycloalkyl esters such as C 3-12 , C 3-8 or C 3-6 cycloalkyl ester
  • aryl alkyl ester such as C 6-12 or C 6-8 aryl alkyl ester
  • heteroaryl alkyl ester such as C 6-12 or C 6-8 heteroaryl alkyl este
  • the in vivo hydrolyzable esters of the compounds of the present invention containing a hydroxyl group include inorganic esters such as phosphoric acid esters, [ ⁇ ]-acyloxyalkyl ethers, and compounds related to the result of hydrolysis and decomposition of esters in vivo to obtain parent hydroxyl groups.
  • Further suitable in vivo hydrolyzable esters include those formed from amino acids. For example, an ester formed by reacting the hydroxyl group of a compound with the carboxylic acid of an amino acid.
  • Further in vivo hydrolyzable esters include phosphoramidates, and also include the compounds of the present invention in which any free hydroxyl groups independently form phosphoryl or phosphite esters.
  • the present invention includes all possible crystal forms or polymorphs of the compound of the present invention, including individual polymorphs or mixtures of multiple polymorphs in any ratio.
  • polymorph means that the compound of the present application exists in different crystal lattice forms.
  • prodrug includes acid derivatives or alcohol derivatives, etc., which are well-known to practitioners in the art.
  • acid derivatives are, for example, esters prepared by the reaction of a parent acid and a suitable alcohol, or amides, or acid anhydrides, or mixed acid anhydrides prepared by the reaction of a parent acid and a substituted or unsubstituted amine;
  • the alcohol derivatives are, for example, selected from Alcohol esters, alcohol alkoxylates, alcohol ethers, carboxylic acids, carboxylic acid esters, phosphates, and mixtures thereof.
  • Simple aliphatic or aromatic esters, amides and anhydrides, and phosphates on hydroxyl groups produced from acidic groups overhanging the compounds of the present invention are specific prodrugs.
  • active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
  • Certain compounds of this application may have asymmetric carbon atoms (stereocenters) or double bonds. Therefore, racemates, diastereomers, enantiomers, geometric isomers and individual isomers are all included within the scope of the present application.
  • the compounds of the present application may exist in specific geometric or stereoisomeric forms. This application contemplates all such compounds, including tautomers, cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers , Diastereomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, All these are within the scope of this application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of this application.
  • optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If you want to obtain an enantiomer of a compound of this application, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • the molecule when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with a suitable optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which employs a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
  • the present application also includes compounds of the present application that are the same as those described herein, but with one or more atoms replaced by an isotope-labeled atom having an atomic weight or mass number different from those generally found in nature.
  • isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
  • Certain isotope-labeled compounds of the application can be used in the analysis of compound and/or substrate tissue distribution. Tritiated (ie 3 H) and carbon-14 (ie 14 C) isotopes are especially preferred due to their ease of preparation and detectability.
  • Positron emission isotopes, such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • PET positron emission tomography
  • the isotope-labeled compounds of the present application can generally be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by replacing non-isotopically-labeled reagents with isotope-labeled reagents.
  • substitution with heavier isotopes can provide certain therapeutic advantages resulting from higher metabolic stability (for example, increased in vivo half-life or reduced dosage requirements), and therefore in certain situations
  • the following may be preferred, where the deuterium substitution may be partial or complete.
  • Partial deuterium substitution refers to the substitution of at least one hydrogen with at least one deuterium. All compounds in such forms are included within the scope of the present application.
  • subject refers to an individual suffering from a disease, disorder or condition, etc., including mammals and non-mammals.
  • mammals include, but are not limited to, any member of the class Mammals: humans, non-human primates (such as chimpanzees and other apes and monkeys); domestic animals such as cows, horses, sheep, goats, pigs; domestic animals , Such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs.
  • non-human mammals include, but are not limited to, birds and fish.
  • the mammal is a human.
  • treatment means administering the compound or formulation described in this application to ameliorate or eliminate a disease or one or more symptoms related to the disease, and includes:
  • prevention means administering the compound or formulation described in this application to prevent a disease or one or more symptoms related to the disease, and includes: preventing the occurrence of a disease or disease state in an individual, especially when the individual When susceptible to the disease state, but has not been diagnosed as having the disease state.
  • an effective amount refers to the amount of at least one agent or compound that is sufficient to relieve one or more symptoms of the disease or condition being treated after administration. The result can be a reduction and/or alleviation of signs, symptoms or causes, or any other desired changes in the biological system.
  • the "effective amount” for treatment is the amount of the composition containing the compound disclosed herein that is required to provide significant disease relief clinically. Techniques such as dose escalation tests can be used to determine the effective amount suitable for any individual case.
  • acceptable refers to no long-term harmful effects on the general health of the subject being treated.
  • pharmaceutically acceptable refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound of the present application, and is relatively non-toxic, that is, the substance can be administered to an individual without causing adverse biological reactions or Interacts with any components included in the composition in an undesirable manner.
  • composition refers to a biologically active compound optionally mixed with at least one pharmaceutically acceptable chemical ingredient, the pharmaceutically acceptable chemical ingredient including but not limited to a carrier, a stabilizer , Diluent, dispersant, suspending agent, thickener and/or excipient.
  • carrier refers to a relatively non-toxic chemical compound or reagent that helps to introduce the compound into cells or tissues.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious stimulating effect on the organism and will not damage the biological activity and performance of the active compound.
  • Suitable auxiliary materials are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
  • the pharmaceutical composition of the application can be prepared by combining the compound of the application with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , Granules, lozenges, ointments, syrups, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • suitable pharmaceutically acceptable excipients for example, can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , Granules, lozenges, ointments, syrups, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Drug routes or routes of administration include, but are not limited to, oral, rectal, transmucosal, topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous and intravenous administration .
  • the preferred route of administration is oral administration and injection administration.
  • the compound or composition of the present invention can be formulated and used as the following dosage forms: tablets, capsules or elixirs for oral administration; suppositories for rectal administration; sterile solutions and suspensions for injection administration; Transdermal patches and subcutaneous deposits.
  • Injections can be prepared in the following conventional forms: solutions or suspensions, solid dosage forms suitable for making solutions or suspensions before injection, or emulsions. Suitable excipients are, for example, water, saline, glucose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride and the like.
  • the pharmaceutical composition for injection may contain a relatively small amount of non-toxic auxiliary substances, such as wetting agents, pH buffering agents and the like. If necessary, absorption enhancers (for example, liposomes) may also be used.
  • Formulations for parenteral administration include aqueous solutions of the active compound in water-soluble form.
  • the suspension of the active compound can be prepared into a suitable oily injection suspension.
  • suitable lipophilic solvents or carriers include fatty oils such as sesame oil, or other organic oils such as soybean oil, grapefruit oil or almond oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes .
  • Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may contain a suitable stabilizer or agent that increases the solubility of the compound, so that a highly concentrated solution can be prepared.
  • the pharmaceutical composition of the present application can be prepared by methods known in the art, such as conventional mixing method, dissolution method, granulation method, sugar-coated pill method, grinding method, emulsification method and freeze-drying method.
  • the pharmaceutical composition of the application is in oral form.
  • the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients or excipients well known in the art. These adjuvants or excipients can make the compound of the present application be formulated into tablets, pills, lozenges, sugar coatings, capsules, powders, granules, liquids, syrups, emulsions, gels, slurries, suspensions Etc., for oral administration to patients.
  • the solid pharmaceutical composition suitable for oral administration can be prepared by conventional mixing, filling or tableting methods.
  • an oral composition in solid form can be obtained by the following method: mixing the active compound with solid excipients or excipients, optionally grinding the resulting mixture, adding other suitable excipients or excipients if necessary, and then The mixture is processed into granules to obtain tablets or dragee cores.
  • Suitable auxiliary materials or excipients include, but are not limited to: fillers, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • a pharmaceutical preparation for oral administration can be obtained by combining the active compound with a solid excipient, optionally grinding the resulting mixture, and processing the granular mixture, if necessary, adding suitable auxiliary agents The tablet or sugar-coated core is then obtained.
  • suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, Methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or alginates such as sodium alginate.
  • the sugar coating core is suitably coated.
  • a concentrated sugar solution may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, shellac paint solution and suitable organic solvents or Solvent mixture.
  • dyes or pigments can be added to the tablets or dragee coatings. These formulations can be manufactured using methods well known in the art.
  • the daily dose may be, for example, 0.001-300 mg/kg body weight, such as 0.01-300 mg/kg body weight, or 10-200 mg/kg body weight, in a single dose or divided Dosage form administration.
  • the pharmaceutical composition of the present application can also be suitable for parenteral administration, such as a sterile solution, suspension, emulsion or lyophilized product in a suitable unit dosage form.
  • Suitable excipients such as fillers, buffers or surfactants can be used.
  • This application takes Bcr-Abl and BTK as targets and develops a kinase inhibitor for the treatment of tumor neurological diseases, rheumatoid arthritis and other diseases.
  • the application provides a compound of Formula I, or a pharmaceutically acceptable salt, ester, solvate, prodrug, active metabolite, crystal, stereoisomer, tautomer or geometric isomer thereof,
  • R 0 is selected from halogen (eg fluorine, chlorine, bromine, iodine) and D;
  • R 2 , R 3 , R 5 , R 7 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 are each independently selected from H and D;
  • R 1 , R 4 and R 6 are each independently selected from optionally substituted alkyl, optionally substituted hydroxyalkyl, halogen, optionally substituted alkoxy, optionally substituted alkynyl, optionally substituted alkene Group, optionally substituted cycloalkyl, optionally substituted heterocyclic group, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carboxyalkyl, -NO 2 , -CN, -OH , -COOH, mercapto, optionally substituted amino, optionally substituted alkylthio, optionally substituted ester, optionally substituted acyl and optionally substituted sulfonyl;
  • R 8 is selected 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 heterocyclic group, optionally substituted aryl, optionally substituted heteroaryl, -NO 2 , -CN, -OH, -COOH, mercapto , Optionally substituted amino, optionally substituted alkylthio, optionally substituted ester, optionally substituted acyl and optionally substituted sulfonyl.
  • R 1 , R 4 and R 6 are each independently selected from optionally substituted C 1-6 alkyl, optionally substituted C 1-6 hydroxyalkyl, halogen, optionally substituted C 1 -6 alkoxy, optionally substituted C 2-6 alkynyl, optionally substituted C 2-6 alkenyl, optionally substituted 3-8 member (e.g. 3, 4, 5, 6, 7, 8 member ) Cycloalkyl, optionally substituted 3-10 membered (e.g. 3, 4, 5, 6, 7, 8, 9, 10-membered) heterocyclyl, optionally substituted 6-10 (e.g.
  • 6, 7, 8 , 9, 10-membered) membered aryl optionally substituted 5-10 membered (for example, 5, 6, 7, 8, 9, 10-membered) heteroaryl, optionally substituted C 1-6 carboxyalkyl,- NO 2 , -CN, -OH, -COOH, mercapto, optionally substituted amino, optionally substituted C 1-6 alkylthio, optionally substituted ester, optionally substituted acyl and optionally substituted sulfonate Acyl.
  • R 8 is selected from H, D, optionally substituted C 1-6 hydroxyalkyl, optionally substituted C 1-6 carboxyalkyl, optionally substituted C 1-6 alkyl, halogen , Optionally substituted C 1-6 alkoxy, optionally substituted C 2-6 alkynyl, optionally substituted C 2-6 alkenyl, optionally substituted 3-8 member (e.g. 3, 4, 5 , 6, 7, 8 membered) cycloalkyl, optionally substituted 3-10 membered (e.g. 3, 4, 5, 6, 7, 8, 9, 10 membered) heterocyclyl, optionally substituted 6-10 Member (e.g.
  • one or more heteroatoms in the heterocyclic group and heteroaryl group are independently selected from O, S, and N; in some embodiments, the number of heteroatoms is independently selected from 1. , 2 and 3.
  • R 0 is selected from fluorine, chlorine, bromine and iodine. In some embodiments, R 0 is selected from fluorine.
  • R 2 , R 3 , R 5 , R 7 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 are each independently selected from H.
  • R 1 , R 4 and R 6 are each independently selected from optionally substituted C 1-6 alkyl (e.g. C 1 , C 2 , C 3 , C 4 , C 5 , C 6 ), Optionally substituted C 1-6 hydroxyalkyl and halogen.
  • R 1 and R 4 are each independently selected from C 1-6 alkyl and halogen.
  • R 1 is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, and halogen (e.g., fluorine, chlorine, bromine, iodine).
  • halogen e.g., fluorine, chlorine, bromine, iodine
  • R 1 is selected from -CH 3 , -CH 2 OH, and chlorine.
  • R 1 is selected from -CH 3 and chlorine.
  • R 4 is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 deuterated alkyl, and halogen (eg, fluorine, chlorine, bromine, iodine).
  • halogen eg, fluorine, chlorine, bromine, iodine
  • R 4 is selected from -CH 3 , -CD 3 , fluorine, and chlorine.
  • R 4 is selected from -CH 3 , fluorine, and chlorine.
  • R 4 is selected from -CH 3 and chlorine.
  • R 6 is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 deuterated alkyl, C 1-4 hydroxyalkyl, and halogen.
  • R 6 is selected from C 1-4 alkyl.
  • R 6 is selected from -CH 3 , -CH 2 OH, and -CD 3 .
  • R 6 is selected from -CH 3 .
  • R 8 is selected from H, D, optionally substituted C 1-6 hydroxyalkyl, and optionally substituted C 1-6 carboxyalkyl.
  • R 8 is selected from H, D, C 1-4 hydroxyalkyl, and C 1-4 carboxyalkyl.
  • R 8 is selected from C 1-4 hydroxyalkyl.
  • R 8 is selected from H, D, -CH 2 CH 2 OH, and -CH 2 CO 2 H.
  • R 8 is selected from -CH 2 CH 2 OH.
  • this application provides the following compounds, or their pharmaceutically acceptable salts, esters, solvates, prodrugs, active metabolites, crystals, stereoisomers, tautomers or geometric isomers,
  • the application provides a pharmaceutical composition comprising at least any one of the compounds provided in the present disclosure or a pharmaceutically acceptable salt, ester, solvate, prodrug, active metabolite, crystal, stereoisomer, Tautomers or geometric isomers.
  • the composition provided herein further includes a pharmaceutically acceptable carrier, excipient or adjuvant.
  • the pharmaceutical composition of the present disclosure further includes another therapeutic agent for combination therapy.
  • the another therapeutic agent is selected from one or more of the following: cyclophosphamide, ifosfamide, vincristine, daunorubicin, doxorubicin, cytarabine, Mitoxantrone, dacarbazine, Idarubicin, Tretinoin, Prednisone, Dexamethasone, Mercaptopurine, Methotrexate, Paclitaxel, Melphalan, Long-acting Interferon, Venetog, Gram Zoltinib, Erlotinib, Ositinib, Ruxotinib, Afatinib, Erlotinib, Imatinib, Lapatinib, Bevacizumab, Trastuzumab, Li Tuximab, Cetuximab, Bonatumumab, Fludarabine, Gemcitabine, Decitabine, Capecitabine, Bendamustine, Everolimus, Tesirolimus
  • the application provides the compounds described in the present disclosure, or pharmaceutically acceptable salts, esters, solvates, prodrugs, active metabolites, crystals, stereoisomers, tautomers or geometric isomers thereof Or the use of the above-mentioned pharmaceutical composition in preparing a medicine for preventing or treating diseases related to tyrosine kinase.
  • the present application provides the compound described in the present disclosure or a pharmaceutically acceptable salt, ester, solvate, prodrug, active metabolite, crystal, stereoisomer, tautomer or geometric isomer thereof Or the use of the above-mentioned pharmaceutical composition in preventing or treating diseases related to tyrosine kinase.
  • the application provides the compounds described in the present disclosure, or pharmaceutically acceptable salts, esters, solvates, prodrugs, active metabolites, crystals, stereoisomers, tautomers or geometric isomers thereof Or the use of the above-mentioned pharmaceutical composition in preparing a medicine for inhibiting the activity of tyrosine kinase.
  • the present application provides a method for preventing or treating a disease or disorder related to tyrosine kinase, the method comprising administering to an individual in need a therapeutically effective amount of at least any one of the compounds provided in the present disclosure or a pharmaceutically acceptable compound thereof.
  • the present application provides a method for inhibiting the activity of tyrosine kinase, the method comprising administering to an individual or its tissues or cells at least any one of the compounds provided in the present disclosure or a pharmaceutically acceptable salt, ester, or solvent thereof Compounds, prodrugs, active metabolites, crystals, stereoisomers, tautomers or geometric isomers or the above-mentioned pharmaceutical compositions.
  • the method of inhibiting tyrosine kinase activity includes in vitro or in vivo tests.
  • the present application provides a compound of the present disclosure or a pharmaceutically acceptable salt, ester, solvate, prodrug, active metabolite, crystal, stereoisomer, mutual Mutants or geometric isomers or the aforementioned pharmaceutical compositions.
  • the present application provides compounds of the present disclosure or pharmaceutically acceptable salts, esters, solvates, prodrugs, active metabolites, crystals, etc., for preventing or treating diseases or disorders related to tyrosine kinases.
  • the diseases associated with tyrosine kinases are diseases, disorders, and conditions that benefit from the inhibition or reduction of tyrosine kinase activity.
  • the tyrosine kinase includes Bcr-Abl tyrosine kinase and BTK tyrosine kinase.
  • the disease is selected from cancer.
  • the cancer is selected from the group consisting of: 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, malignant glioma, head and neck tumors, giant bulbs Proteinemia, follicular center lymphoma, prostate cancer, myelodysplastic syndrome, atherosclerotic myelodysplasia
  • CML
  • the cancer is selected from cancers that are resistant to the targets BCR-ABL and c-KIT by chemotherapeutic agents, and cancers that are resistant to imatinib.
  • the diseases, disorders, and conditions are selected from: bone metastases, hypercalcemia and/or osteoporosis; lung fibrosis; cardiovascular diseases or symptoms; mast cell-mediated inflammatory diseases; HTLV -1 related myelopathy/tropical spasmodic paralysis; complex regional pain syndrome (CRPS); weight loss or fat loss; arterial obstructive disease; ubiquitination; diseases or symptoms related to reduced sugar degradation; Fridreich co-help Disorders; Parkinson’s disease progression; Transplant rejection; Rheumatoid arthritis; Graft versus host disease; Autoimmune disease; Recurrent immune thrombocytopenic purpura, Pemphigus vulgaris, Systemic lupus erythematosus, Scleroderma Pulmonary fibrosis and spontaneous urticaria.
  • CRPS complex regional pain syndrome
  • weight loss or fat loss arterial obstructive disease
  • ubiquitination diseases or symptoms related to reduced sugar degradation
  • Fridreich co-help Disorders Parkinson’s disease progression
  • the cardiovascular disease or symptom is a cardiovascular disease caused by RASopathy, or a congenital heart disease related to Noonan or Noonan syndrome.
  • the mast cell-mediated inflammatory disease is selected from osteoarthritis, asthma, chronic obstructive pulmonary disease, uveitis, aspirin exacerbated respiratory disease (AERD), and Parkinson's disease.
  • the compounds of the present disclosure have kinase inhibitory activity comparable to or better than existing drugs such as dasatinib.
  • the compound of formula I of the present disclosure has a longer half-life (>60h) and a lower clearance rate.
  • the current dose of dasatinib is 100 mg per day, 1-2 times a day, and the compound of formula I of the present disclosure can be used at a lower dose than existing drugs such as dasatinib with longer dosing intervals.
  • the inhibitor compounds of the present disclosure can inhibit the SRC kinase family ABL1, BTK and BTK (C481S) kinases. By inhibiting the effects of the above kinases, they can inhibit the proliferation of leukemia cells in CML and Ph+ALL bone marrow. However, normal red blood cells, white blood cells and platelets can continue to proliferate.
  • the inventions of the present application improve the efficacy of drugs, reduce the dosage, thereby reducing toxic and side effects, and better provide clinical treatment for diseases such as tumors and rheumatoid arthritis.
  • the novel low-dose inhibitor of the present disclosure will provide broad application prospects for disease treatment.
  • Triethylamine (2.70g, 27.0mmol) and acetic anhydride (1.84g, 18.0mmol) were added to the compound 2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2- Methylpyrimidin-4-yl)amino)thiazole-5-carboxylic acid methyl ester (3.3 g crude product, 9.00 mmol) in a dichloromethane solution (36 mL), and stirred at room temperature for 2 hours. Then add water (10ml) and extract in dichloromethane solution (10ml).
  • Triethylamine (303mg, 3.00mmol) and HATU (570mg, 1.50mmol) were added to the compound 2-((6-(4-(2-acetoxyethyl)piperazin-1-yl)-2-methyl Pyrimidine-4-yl)amino)thiazole-5-carboxylic acid (406mg, 1.00mmol) in DMF (4mL) was stirred at room temperature for 30 minutes, and 4-fluoro-2,6-dimethylaniline (209mg, 1.50mmol) and stirred for another 30 minutes. After the amide condensation reaction is complete (LCMS monitors the reaction), add saturated LiOH aqueous solution (2ml) and stir overnight at room temperature.
  • the compound of formula I of the present invention is used for in vitro kinase inhibitory activity studies and human liver microsomal metabolism studies.
  • Positive control group use staurosporine (supplier is Med Chem), matrix solution is DMSO.
  • the initial concentration of the positive control group 20 ⁇ M
  • the response dose (M) is shown in the following table:
  • Buffer conditions 20mM Hepes (pH 7.5), 10mM MgCl 2 , 1mM EGTA, 0.02% Brij35, 0.02mg/ml BSA, 0.1mM Na 3 VO 4 , 2mM DTT, 1% DMSO
  • Substrate Amount of substrate in RXN supplier ABLtide 20 ⁇ M GenScript pEY 0.2mg/ml Sigma pEY 0.2mg/ml Sigma
  • the kinase activity data is expressed as the percentage of the remaining kinase activity in the test sample that reacts with the carrier (dimethyl sulfoxide).
  • the carrier dimethyl sulfoxide.
  • the compounds of the present disclosure such as Compound 1, inhibit ABL1, BTK, and BTK (C481S) in inhibiting activity equal to or higher than dasatinib, which is significantly higher than the control group.
  • test compounds (compound 2 and compound 5) were dissolved in DMSO, and the final drug concentration was 10 mM.
  • Positive control group use staurosporine (the supplier is LC Laboratories), and the matrix solution is DMSO.
  • ATP concentration 20 ⁇ M (BTK), 12 ⁇ M (BTK-C481S), 14 ⁇ M (ABL1)
  • Reaction time 90min (BTK/BTK-C481S), 60min (ABL1)
  • the response dose (M) is shown in the following table:
  • Buffer conditions 50 mM Hepes (pH 7.5), 10 mM MgCl 2 , 1 mM EDTA, 0.01% Brij35.
  • Buffer conditions 50 mM Hepes (pH 7.5), 10 mM MgCl 2 , 1 mM EDTA, 0.01% Brij35, 1 mM DTT.
  • Substrate Amount of substrate in RXN supplier ABL1 substrate 2 ⁇ M Invitrogen BTK substrate 1 ⁇ M Cisbio BTK-C481S substrate 1 ⁇ M Cisbio
  • Time 60 minutes (BTK/BTK-C481S), 40 minutes (ABL1).
  • BTK/BTK-C481S Use Model205 in XLfit5 software to calculate data to obtain IC 50 value.
  • ABL1 First, the original signal is converted into the rate of phosphorylation, the phosphorylation rate and then converted to% inhibition, software reuse XLfit5 calculated IC 50.
  • Buffer 0.05M phosphate buffer (pH 7.4)
  • Test compound verapamil, dasatinib and compound 1
  • liver microsomal protein, buffer, and test compound Transfer the liver microsomal protein, buffer, and test compound to a 1.5 ml incubation tube according to the volume in the experimental design table, incubate at 37°C for 5 min, and keep constant shaking.
  • Mobile phase mobile phase A is water containing 0.1% formic acid
  • mobile phase B is acetonitrile containing 0.1% formic acid.
  • the gradient is a gradient of 5-95% B every 5.1 min.
  • the amount of parent compound at each time is determined based on the peak area ratio (compound area/warfarin area).
  • V( ⁇ L/mg) Incubation volume ( ⁇ L)/Incubation protein amount (mg)
  • the compound of formula I of the present disclosure is metabolically stable in vitro, has a longer half-life and a lower clearance rate compared with dasatinib, can prolong the administration interval and reduce the frequency of administration.

Abstract

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。

Description

激酶抑制剂及其制备、药物组合物和用途
相关申请的交叉引用
本申请要求于2019年8月20日向中国国家知识产权局提交的第201910771036.2号中国专利申请的优先权和权益，所述申请公开的内容通过引用整体并入本文中。
技术领域
本申请属于药物化学领域，具体涉及可作为激酶抑制剂(如酪氨酸激酶抑制剂)的化合物、其制备方法以及包含所述化合物的药物组合物。本申请还涉及所述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。
背景技术
蛋白激酶是一类催化蛋白质磷酸化，从而改变其底物活性或与其他蛋白结合能力的酶。激酶信号通路为最常见的可逆翻译后修饰形式，控制着细胞功能的许多方面。蛋白激酶异常活化是恶性肿瘤的主要标志，包括细胞增殖、存活、运动和代谢的改变，以及血管增生和逃避抗肿瘤免疫反应等疾病。所产生的新血管“供给”生长肿瘤的氧气和营养物质。
1.BCR-ABL
大量研究已经证实Bcr-Abl酪氨酸激酶在慢性粒细胞白血病(CML)发病机制中的作用，Bcr-Abl抑制剂为新的靶向治疗小分子药物的开发铺平了道路。伊马替尼(Imatinib)，博舒替尼(Bosutinib)，达沙替尼(Dasatinib)，尼洛替尼(Nilotinib)，拉多替尼(Radotinib)，和帕纳替尼(Ponatinib)已被批准用于治疗慢性粒细胞白血病嗜酸性粒细胞增多综合征、骨髓增生/骨髓增生性肿瘤、慢性粒细胞白血病、急性淋巴细胞白血病/淋巴细胞淋巴瘤。
尽管这些药物提高了肿瘤患者的生存率，同时这些药物也带来了严重不良反应，如严重的腹泻。这一问题尤其体现在胃和上消化道，因为口服后该部位的药物浓度较高。在该药物浓度下，选择性差的酪氨酸酶抑制剂(TKIs)能抑制胃肠道中大量表达的蛋白激酶，导致严重的常见剂量相关的毒性反应。
2.BTK
Bruton’s酪氨酸激酶(BTK)是一种非受体激酶，已经被证实为X-连锁无丙种球蛋白血症的遗传因素。BTK在致癌信号中起到了至关重要的作用，该信号对于许多B细胞恶性肿瘤的白血病细胞的增殖和生存有重要作用。因此，BTK是开发B细胞恶性肿瘤小分子抑制剂的关键靶点。
尽管目前已有批准用于肿瘤治疗的Bcr-Abl抑制剂，且能从根本上提高患者的平均生存率。但是新的基因突变和耐药形式也会出现在临床实践中，因此需要进一步开发新的抑制剂。大剂量药物可引起靶蛋白突变，导致活性丧失。仍需要寻找一种低剂量、能减少副作用和降低突变可能性的Bcr-Abl抑制剂和可逆的BTK抑制剂来满足医学需求。
发明内容
一方面，本申请提供式I的化合物，或者其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体，
Figure PCTCN2020110063-appb-000001
其中：
R 0选自卤素和D；
R 2、R 3、R 5、R 7、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17各自独立地选自H和D；
R 1、R 4和R 6各自独立地选自任选取代的烷基、任选取代的羟烷基、卤素、任选取代的烷氧基、任选取代的炔基、任选取代的烯基、任选取代的环烷基、任选取代的杂环基、任选取代的芳基、任选取代的杂芳基，任选取代的羧基烷基、-NO 2、-CN、-OH、-COOH、巯基、任选取代的氨基、任选取代的烷硫基、任选取代的酯基、任选取代的酰基和任选取代的磺酰基；
R 8选自H、D、任选取代的羟烷基、任选取代的羧基烷基、任选取代的烷基、卤素、任选取代的烷氧基、任选取代的炔基、任选取代的烯基、任选取代的环烷基、任选取代的杂环基、任选取代的芳基、任选取代的杂芳基，-NO 2、-CN、-OH、-COOH、巯基、任选取代的氨基、任选取代的烷硫基、任选取代的酯基、任选取代的酰基和任选取代的磺酰基。
在一些实施方案中，R 1、R 4和R 6各自独立地选自任选取代的C 1-6烷基、任选取代的C 1-6羟烷基、卤素、任选取代的C 1-6烷氧基、任选取代的C 2-6炔基、任选取代的C 2-6烯基、任选取代的3-8元环烷基、任选取代的3-10元杂环基、任选取代的6-10元芳基、任选取代的5-10元杂芳基，任选取代的C 1-6羧基烷基、-NO 2、-CN、-OH、-COOH、巯基、任选取代的氨基、任选取代的C 1-6烷硫基、任选取代的酯基、任选取代的酰基和任选取代的磺酰基。
在一些实施方案中，R 8选自H、D、任选取代的C 1-6羟烷基、任选取代的C 1-6羧基烷基、任选取代的C 1-6烷基、卤素、任选取代的C 1-6烷氧基、任选取代的C 2-6炔基、任选取代的C 2-6烯基、任选取代的3-8元环烷基、任选取代的3-10元杂环基、任选取代的6-10元芳基、任选取代的5-10元杂芳基，-NO 2、-CN、-OH、-COOH、巯基、任选取代的氨基、任选取代的C 1-6烷硫基、任选取代的酯基、任选取代的酰基和任选取代的磺酰基。
在一些实施方案中，所述杂环基和杂芳基中的一个或多个杂原子分别独立地选自O、S和N；在一些实施方案中，杂原子的数目分别独立地选自1、2和3。
在一些实施方案中，R 0选自氟、氯、溴和碘。在一些实施方案中，R 0选自氟。
在一些实施方案中，R 2、R 3、R 5、R 7、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17各自独立地选自H。
在一些实施方案中，R 1、R 4和R 6各自独立地选自任选取代的C 1-6烷基、任选取代的C 1-6羟烷基和卤素。
在一些实施方案中，R 1和R 4各自独立地选自C 1-6烷基和卤素。
在一些实施方案中，R 1选自C 1-4烷基、C 1-4卤代烷基、C 1-4羟烷基和卤素。
在一些实施方案中，R 1选自-CH 3、-CH 2OH和氯。
在一些实施方案中，R 1选自-CH 3和氯。
在一些实施方案中，R 4选自C 1-4烷基、C 1-4卤代烷基、C 1-4氘代烷基和卤素。
在一些实施方案中，R 4选自-CH 3、-CD 3、氟和氯。
在一些实施方案中，R 4选自-CH 3、氟和氯。
在一些实施方案中，R 4选自-CH 3和氯。
在一些实施方案中，R 6选自C 1-4烷基、C 1-4卤代烷基、C 1-4氘代烷基、C 1-4羟烷基和卤素。
在一些实施方案中，R 6选自C 1-4烷基。
在一些实施方案中，R 6选自-CH 3、-CH 2OH和-CD 3。
在一些实施方案中，R 6选自-CH 3。
在一些实施方案中，R 8选自H、D、任选取代的C 1-6羟烷基和任选取代的C 1-6羧基烷基。
在一些实施方案中，R 8选自H、D、C 1-4羟烷基和C 1-4羧基烷基。
在一些实施方案中，R 8选自C 1-4羟烷基。
在一些实施方案中，R 8选自H、D、-CH 2CH 2OH和-CH 2CO 2H。
在一些实施方案中，R 8选自-CH 2CH 2OH。
在一些实施方案中，术语“任选取代的”是指基团未被取代或者被一个或多个取代基取代，其中所述一个或多个取代基独立地选自：氘，卤素，羟基，C 1-C 6烷基，C 2-C 6烯基，C 2-C 6炔基，C 1-6羟烷基、C 1-6烷氧基、3-8元环烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基，-NO 2、-CN、-OH、-COOH、巯基和氨基。
另一方面，本申请提供以下化合物，或者其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体，
Figure PCTCN2020110063-appb-000002
Figure PCTCN2020110063-appb-000003
又一方面，本申请提供药物组合物，其包含至少任意一种本公开提供的化合物或其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体。在一些实施方案中，本文提供的组合物还包括药学上可接受的载体、赋形剂或辅料。在一些实施方案中，本公开的药物组合物进一步包含另一治疗剂用于联合治疗。在一些实施方案中，所述另一治疗剂选自以下中的一种或多种：环磷酰胺、异环磷酰胺、长春新碱、柔红霉素、阿霉素、阿糖胞苷、米托蒽醌、达卡巴嗪、伊达比星、维甲酸、强的松、***、巯嘌呤、甲氨蝶呤、紫杉醇、美法仑、长效干扰素、维奈托克、克唑替尼、埃罗替尼、奥西替尼、鲁索替尼、阿法替尼、厄洛替尼、伊马替尼、拉帕替尼、贝伐单抗、曲妥珠单抗、利妥昔单抗、西妥昔单抗、博纳吐单抗、氟达拉滨、吉西他滨、地西他滨、卡培他滨、苯达莫司汀、依维莫司、替西罗莫司、依托泊苷、粒细胞集落刺激因子、替莫唑胺、唑来膦酸、奥利沙铂、顺铂、卡铂和氟维司群。
还一方面，本申请提供本公开所述化合物或其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体或者上述药物组合物在制备预防或者治疗与酪氨酸激酶相关疾病的药物中的用途。
再一方面，本申请提供本公开所述化合物或其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体或者上述药物组合物在制备抑制酪氨酸激酶活性的药物中的用途。
另一方面，本申请提供预防或者治疗与酪氨酸激酶相关疾病或病症的方法，所述方 法包括向有需要的个体施用治疗有效量的本公开提供的至少任一种化合物或其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体或者上述药物组合物。
又一方面，本申请提供抑制酪氨酸激酶活性的方法，所述的方法包括向个体或者其组织或细胞施用本公开提供的至少任一种化合物或其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体或者上述药物组合物。在一些实施方案中，所述抑制酪氨酸激酶活性的方法在体外或者体内进行。在一些实施方案中，所述抑制酪氨酸激酶活性的方法包括体外或者体内试验。
还一方面，本申请提供本公开所述化合物或其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体或者上述药物组合物，其用于抑制酪氨酸激酶活性的用途。
另一方面，本申请提供本公开所述化合物或其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体或者上述药物组合物，其用于预防或者治疗与酪氨酸激酶相关的疾病的用途。
在一些实施方案中，所述与酪氨酸激酶相关的疾病为受益于酪氨酸激酶活性的抑制或减少的疾病、病症和病况。
在一些实施方案中，所述酪氨酸激酶包括Bcr-Abl酪氨酸激酶和BTK酪氨酸激酶。
在一些实施方案中，所述疾病选自癌症。
在一些实施方案中，所述癌症选自：慢性粒细胞白血病(CML)，胃肠间质瘤(GIST)，小细胞肺癌(SCLC)，非小细胞肺癌(NSCLC)，多发性骨髓瘤，实体瘤，B-细胞淋巴瘤，慢性淋巴细胞白血病(CLL)，急性淋巴细胞白血病(ALL)，非霍奇金淋巴瘤(NHL)，小淋巴细胞性淋巴瘤(SLL)，套细胞淋巴瘤(MCL)，黑色素瘤，肥大细胞增多症，生殖细胞肿瘤，急性髓细胞白血病(AML)，边缘区/弥漫性大B细胞淋巴瘤，肉瘤，胰腺癌，恶性胶质瘤，头颈部肿瘤，巨球蛋白血症，滤泡中心淋巴瘤，***癌，骨髓增生异常综合征，动脉粥样硬化性骨髓增生，骨髓纤维化，嗜酸性粒细胞增多症，真性红细胞增多症，肝癌，晚期肉瘤，多形性胶质母细胞瘤，胶质肉瘤，恶性间皮瘤，黑色素瘤，鳞状细胞癌皮肤癌，神经内分泌肿瘤，胃肿瘤，B细胞急性淋巴细胞白血病，毛细胞白血病，淋巴浆细胞淋巴瘤，卵泡中心淋巴瘤，肾细胞癌，移行细胞癌，类癌肿瘤，T细胞淋巴瘤，转移性非小细胞肺癌，***性肥大细胞增多症，转移性肾细胞癌，乳腺肿瘤，中枢神经***肿瘤，结直肠肿瘤，转移性膀胱癌，转移性胰腺癌，转移性头颈癌，卵巢肿瘤和其组合。
在一些实施方案中，所述癌症选自化学治疗剂对靶点BCR-ABL和c-KIT具有抗药性的癌症、以及对伊马替尼具有抗药性的癌症。
在一些实施方案中，所述疾病、病症和病况选自：骨转移，高钙血症和/或骨质疏松；肺纤维疾病；心血管疾病或症状；肥大细胞介导的炎性疾病；HTLV-1相关性脊髓病/热带痉挛性瘫痪；复杂区域疼痛综合征(CRPS)；体重减轻或脂肪减少；动脉阻塞性疾病；泛素化；与降解糖功能降低相关的疾病或症状；Fridreich共济失调；帕金森病进展移植 排斥反应；类风湿性关节炎；移植物抗宿主病；自身免疫性疾病；复发的免疫性血小板减少性紫癜，寻常型天疱疮，***性红斑狼疮，硬皮病肺间质纤维化和自发性荨麻疹。
在一些实施方案中，所述心血管疾病或症状为RASopathy引起的心血管类疾病，或与Noonan或Noonan综合征相关的先天性心脏病。
在一些实施方案中，所述肥大细胞介导的炎性疾病选自骨关节炎、哮喘、慢性阻塞性肺疾病、葡萄膜炎、阿司匹林加重呼吸道疾病(AERD)和帕金森氏病。
详细描述
定义
提供以下定义和方法用以更好地界定本申请以及在本申请实践中指导本领域普通技术人员。除非另作说明，术语按照相关领域普通技术人员的常规用法理解。本文所引用的所有专利文献、学术论文及其他公开出版物，其中的全部内容整体并入本文作为参考。
术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。
本文中表示碳原子数的数字范围，是指给定范围中的各个整数，例如，“C 1-C 10”或“C 1-10”是指该基团可具有1、2、3、4、5、6、7、8、9、10个碳原子。
术语“元”是表示构成环的骨架原子的个数。例如“3-10元”是表示构成环的骨架原子的个数为3、4、5、6、7、8、9或10。
术语“烷基”是指直链或支链的饱和烃基，其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的例子包括甲基(Me)，乙基(Et)，丙基(如，n-丙基和异丙基)，丁基(如，n-丁基，异丁基，s-丁基，t-丁基)，戊基(如，n-戊基，异戊基，新戊基)等；例如，术语“C 1-6烷基”指含有1至6(例如1、2、3、4、5、6)个碳原子的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等)。
术语“羟烷基”是指-烷基-OH，其中“烷基”定义如上，“任选取代的羟烷基”是指该基团中的烷基部分被取代或未取代。
术语“卤代”或“卤素”本身或作为另一取代基的一部分表示氟(F)、氯(Cl)、溴(Br)或碘(I)原子。
术语“烷氧基”是指-O-烷基，其中“烷基”定义如上，“烷氧基”的实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、异戊氧基。“任选取代的烷氧基”是指该基团中的烷基部分被取代或未取代。
术语“C 2-6烯基”是指具有2至6个碳原子且优选2至4个碳原子并且具有至少1个、优选1至2个不饱和位点(>C＝C<)的直链或支链烃基。这种基团例如例举为乙烯基，烯丙基和丁-3-烯-1-基。该术语包括顺式和反式异构体或这些异构体的混合物。
术语“C 2-6炔基”是指具有2至6个碳原子且优选2至3个碳原子并且具有至少1个、优选1至2个炔属(-C≡C-)不饱和位点的直链或支链单价烃基。这种炔基的实例包括乙炔基(-C≡CH)和炔丙基(-CH 2C≡CH)。
术语“环烷基”是指由碳原子和氢原子组成的饱和的非芳香性的环状烃基，优选包含1或2个环。所述环烷基可以是单环、稠合多环、桥环或螺环结构。环烷基的非限制性实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、双环[2.2.1]庚基和螺[3.3]庚基等。
术语“杂环基”是指含有一个或多个杂原子(如，O、N、S)作为环结构的一部分并具有2-9个环碳原子的饱和或不饱和、非芳香性的环状基团；“任选取代的杂环基”是指未取代的杂环基或被一个或多个如下文中所定义的取代基取代的杂环基。
术语“芳基”是指芳香基环中每一个构成环的原子都是碳原子。芳基环可以由五、六、七、八、九或多于九个原子构成。芳基的实例包括但不限于苯基、萘基、菲基、蒽基、芴基和茚基。根据结构，芳基可以是单价基团或双价基团，即亚芳基。
术语“杂芳基”意指稳定的5、6、7元单环或双环或7、8、9或10元双环杂环基的芳香环，它包含碳原子和1、2、3或4个独立地选自N、O和S的杂原子。氮原子可以是任选取代的(即N或NR，其中R是H或下文中定义的其他取代基)。氮原子和硫原子可任选被氧化(即NO和S(O) p，p是1或2)。单环杂芳基的非限定性实例包括吡啶基；稠合环杂芳基的非限定性实例包括苯并咪唑基(benzimidazolyl)、喹啉基(quinolinyl)、吖啶基(acridinyl)，非稠合的双杂芳基的非限定性实例包括联吡啶基(bipyridinyl)。杂芳基的其它实例包括但不限于：呋喃基(furanyl)、噻吩基(thienyl)、恶唑基(oxazolyl)、吖啶基(acridinyl)、吩嗪基(phenazinyl)、异噁唑基(isoxazolyl)、异噻唑基(isothiazolyl)、吡唑基(pyrazolyl)、嘌呤基(purinyl)、喹啉基(quinolinyl)、***基(triazolyl)、噻唑基(thiazolyl)、三嗪基(triazinyl)和噻二唑基(thiadiazolyl)等，及其氧化物，例如吡啶基-N-氧化物(pyridyl-N-oxide)。
术语“羧基烷基”是指具有-烷基-COOH结构的基团，其中烷基如上所定义。羧基烷基的代表性实例包括但不限于，羧甲基(-CH 2CO 2H)，2-羧乙基等。“任选取代的羧基烷基”是指该基团中的烷基部分被取代或未取代。
术语“任选取代的氨基”是指-NH 2，单-或二-取代氨基，以及5-至7-元环状氨基。
术语“巯基”或“硫醇”是指基团-SH。
术语“烷硫基”是指基团-S-烷基，其中烷基如本文所定义。“任选取代的烷硫基”是指该基团中的烷基部分被取代或未取代。
本文中所用的术语“酯基”是指具有-C(O)OR'结构的基团，其中R'为如上所定义的任选取代的烷基、任选取代的芳基或任选取代的杂芳基。在一些实施方案中，R'为烷基、卤代烷基、芳基、杂芳基、烷芳基、烷基杂芳基。在一些实施方案中，R'为烷基或卤代烷基。在一些实施方案中，R'为烷基。“任选取代的酯基”是指该基团中的R'部分被取代或未取代。
本文中所用的术语“酰基”是指具有-C(O)R'结构的基团，其中R'如上所定义。“任选取代的酰基”是指该基团中的R'部分被取代或未取代。
本文中所用的术语“磺酰基”是指具有-SO 2R'结构的基团，其中R'如上所定义。“任选取代的磺酰基”是指该基团中的R'部分被取代或未取代。
术语“任选取代的”是指基团未被取代或者被一个或多个取代基取代，其中所述一个或多个取代基独立地选自：氘，卤素，羟基，C 1-C 6烷基，C 2-C 6烯基，C 2-C 6炔基，C 1-6羟烷基、C 1-6烷氧基、3-8元环烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基，-NO 2、-CN、-OH、-COOH、巯基和氨基。当基团被多于一个的取代基取代时，取代基可以相同或不同，本文中任何取代的官能团可以在1至3个不同的位置被取代，并且那些1至3个取代基团能够在1至3个位置各自独立地被取代。
术语“药学上可接受的盐”是指保留了指定化合物的游离酸和游离碱的生物效力，并且在生物学或其它方面上没有不良作用的盐。本文所述的化合物可具有酸性或碱性基团，因此可与任意的多种无机碱或有机碱以及无机酸和有机酸反应，从而形成药学上可接受的盐。这些盐可以通过以下方法制备：在本申请化合物的最终分离和纯化过程中原位制备，或者通过本申请化合物的游离碱形式与适合的有机酸或无机酸单独反应，并分离由此形成的盐。药学上可接受的盐的实例包括通过本文所述化合物与无机酸或有机酸或无机碱或有机碱之间的反应而制备的盐。这些盐包括乙酸盐、丙烯酸盐、己二酸盐、海藻酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、重亚硫酸盐、溴化物、丁酸盐、丁炔-1，4-二酸盐、樟脑酸盐、樟脑磺酸盐、辛酸盐、氯代苯甲酸盐、氯化物、柠檬酸盐、环戊烷丙酸盐、癸酸盐、葡萄糖酸盐、磷酸二氢盐、二硝基苯甲酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、乙醇酸盐、半硫酸盐、庚酸盐、己炔-1，6-二酸盐(hexyne-1，6-dioate)、羟基苯甲酸盐、y-羟基丁酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟乙磺酸盐、碘化物、异丁酸盐、乳酸盐、马来酸盐、丙二酸盐、甲磺酸盐、扁桃酸盐、偏磷酸盐、甲氧基苯甲酸盐、甲基苯甲酸盐、磷酸一氢盐、1-萘磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、双羟萘酸盐、果冻酸盐(pectinate)、过硫酸盐、3-苯丙酸盐、磷酸盐、苦味酸盐、特戊酸盐、丙酸盐、焦硫酸盐、焦磷酸盐、丙炔酸、邻苯二甲酸盐、苯乙酸盐、苯丁酸盐、丙磺酸盐、水杨酸盐、琥珀酸盐、硫酸盐、亚硫酸盐、辛二酸盐、癸二酸盐、磺酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐(undeconate)和二甲苯磺酸盐。其它酸(如草酸)，尽管其本身在药学上是不可接受的，但可作为中间物在盐的制备过程中使用，以获得本申请的化合物及其在药学上可接受的酸加成盐(参见Berge et al.,J.Pharm.Sci.1977,66,1-19中的实施例)。此外，本文所述的可包括游离酸基团的化合物可与合适的碱反应(例如药学上可接受的金属阳离子的氢氧化物、碳酸盐或碳酸氢盐)，与氨反应，或与药学上可接受的有机伯胺、仲胺或叔胺反应。代表性的碱金属盐或碱土金属盐包括锂盐、钠盐、钾盐、钙盐、镁盐和铝盐等。碱的说明性实例包括氢氧化钠、氢氧化钾、氢氧化羟乙基三甲胺、碳酸钠和IV'(C 1-4烷基) 4等。用于形成碱加成盐的代表性有机胺包括乙胺、二乙胺、乙二胺、乙醇胺、二乙醇胺和哌嗪等。应理解，本文所述化合物还包括其可能包含的任意碱性含氮基团的季铵化物。可通过季铵化反应获得水溶性或油溶性或可分散的产物。参见，例如上文Berge等人的文献。
术语“溶剂化物”是指一个组合了本申请化合物与溶剂分子所形成的一种溶剂物。在一些实施方式中，这种溶剂化物是一水合物，例如溶剂是水，本申请化合物与水形成的 一水合物。
本发明化合物的酯是指那些在合理的医学判断范围内、适合用于与患者的组织接触而没有过多的毒性、刺激、过敏反应等的药学上可接受的酯。应当理解，含有羧基或羟基的式I化合物的酯包括体内可水解的酯，如在人体或动物体内被水解生成母体酸或醇的可药用酯。在本发明化合物的羧基基团(若存在)上形成的羧基的合适可药用酯包括如烷基酯(如C 1-6或C 1-4烷基酯)、环烷基酯(如C 3-12、C 3-8或C 3-6环烷基酯)、芳基烷基酯(如C 6-12或C 6-8芳基烷基酯)和杂芳基烷基酯(如C 6-12或C 6-8杂芳基烷基酯)等。
包含羟基基团的本发明化合物的体内可水解的酯包括无机酯，如磷酸酯、[α]-酰氧基烷基醚和与酯在体内水解分解得到母体羟基的结果相关的化合物。进一步合适的体内可水解的酯包括那些由氨基酸形成的酯。例如由化合物的羟基与氨基酸的羧酸反应形成的酯。进一步体内可水解酯包括磷酰胺酯，也包括其中任何游离羟基独立形成磷酰基或亚磷酸基酯的本发明化合物。
此外，本发明包括本发明化合物所有可能的晶形或多晶型物，包括其单独的多晶型物或任何比例的多种多晶型物的混合物。术语“多晶型物”是指本申请化合物存在于不同的晶格形式。
本文所用的术语“前药”包括为本领域的实践者所公知的酸衍生物或醇衍生物等。其中，酸衍生物例如通过母体酸与合适的醇的反应制备的酯、或通过母体酸与取代或未取代的胺的反应制备的酰胺、或酸酐、或混合酸酐等；醇衍生物例如选自醇酯、醇烷氧基化物、醇醚、羧酸、羧酸酯、磷酸化物以及它们的混合物等。由悬垂在本发明的化合物上酸性基团产生的简单的脂族或芳族酯、酰胺和酸酐以及羟基上的磷酸化物是具体的前药。
术语“活性代谢物”是指当化合物被代谢时形成的化合物的生物活性衍生物。
本申请的某些化合物可以具有不对称碳原子(立体中心)或双键。因此，外消旋体、非对映异构体、对映异构体、几何异构体和单个异构体都包括在本申请的范围之内。
当本申请的化合物含有烯属双键或其它几何不对称中心时，除非另有规定，它们包括E和Z几何异构体。同样地，所有的互变异构形式均包括在本申请的范围之内。
本申请的化合物可以存在特定的几何异构体或立体异构体形式。本申请设想所有的这类化合物，包括互变异构体、顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些都属于本申请的范围之内。烷基等取代基中可以存在另外的不对称碳原子。所有这些异构体以及它们的混合物均包括在本申请的范围之内。
可以通过手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本申请某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如 羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本申请还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本申请化合物。可结合到本申请化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。
某些同位素标记的本申请化合物(例如用 3H及 14C标记的那些)可用于化合物和/或底物组织分布分析中。氚化(即 3H)和碳-14(即 14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如 15O、 13N、 11C和 18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本申请化合物。
此外，用较重同位素(诸如氘(即 2H))取代可以提供某些由更高的代谢稳定性产生的治疗优点(例如增加的体内半衰期或降低的剂量需求)，并且因此在某些情形下可能是优选的，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被至少一个氘取代，所有这样的形式的化合物包含于本申请的范围内。
术语“受试者”、“患者”或“个体”是指患有疾病、病症或病况等的个体，包括哺乳动物和非哺乳动物。哺乳动物的实例包括但不限于哺乳动物纲的任何成员：人，非人的灵长类动物(例如黑猩猩和其它猿类和猴)；家畜，例如牛、马、绵羊、山羊、猪；家养动物，例如兔、狗和猫；实验室动物，包括啮齿类动物，例如大鼠、小鼠和豚鼠等。非人哺乳动物的实例包括但不限于鸟类和鱼类等。在本文提供的一个有关方法和组合物的实施方案中，所述哺乳动物为人。
术语“治疗”意为将本申请所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)抑制疾病或疾病状态，即遏制其发展；
(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“预防”意为将本申请所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，且包括：预防疾病或疾病状态在个体中出现，特别是当个体易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。
术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物***的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使 用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
术语“可接受的”是指对接受治疗的受试者的一般健康情况没有长期的有害影响。
术语“药学上可接受的”是指不影响本申请化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
术语“组合物”或“药物组合物”是指任选地混合有至少一种药学上可接受的化学成分的生物活性化合物，所述药学上可接受的化学成分包括但不限于载体、稳定剂、稀释剂、分散剂、悬浮剂、增稠剂和/或赋形剂。
术语“载体”是指相对无毒的化学化合物或试剂，其有助于将化合物引入到细胞或组织中。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
词语“包括/包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、锭剂、膏剂、糖浆剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
本申请化合物、其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体或者其药物组合物的典型的给药途径或施用途径包括但不限于口服、直肠、透黏膜、局部、经皮、吸入、肠胃外、舌下、***内、鼻内、眼内、腹膜内、肌内、皮下和静脉内给药。优选的给药途径是口服给药和注射给药。
本发明的化合物或组合物可按配方制造且作为以下剂型使用：供口服给药的片剂、胶囊或酏剂；供直肠给药的栓剂；供注射给药的无菌溶液，悬浮液；供透皮给药的贴片以及皮下沉积物等。注射剂可以下列常规形式制备：溶液或悬浮液、在注射前适合制成溶液或悬浮液的固体剂型、或乳剂。适合的赋形剂是，例如，水、盐水、葡萄糖、甘露醇、乳糖、卵磷脂、白蛋白、谷氨酸钠、半胱氨酸盐酸盐等。另外，如果需要，所述的注射用药物组合物可包含较少量的无毒性辅助物，例如湿润剂、pH缓冲剂等。如果需要，也可使用吸收增强剂(例如，脂质体)。
用于非肠道给药的制剂包括以水溶性形式存在的所述活性化合物的水溶液。另外，所述活性化合物的悬浮液可制备成合适的油状注射悬液。适合的亲脂性溶剂或载体包括诸如芝麻油的脂肪油，或其它诸如大豆油、柚油或杏仁油的有机油，或诸如油酸乙酯或甘油三酯的合成的脂肪酸酯，或脂质体。水性注射悬液可包含增加所述悬液粘度的物质，例如羧甲基纤维素钠、山梨糖醇或葡聚糖。任意地，所述的混悬液可包含适合的稳定剂 或提高所述化合物的溶解性的试剂，使得可制备高浓度的溶液。
本申请的药物组合物可以采用本领域已知的方法制备，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法和冷冻干燥法等。
在一些实施方案中，本申请的药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料或赋形剂混合来配制该药物组合物。这些辅料或赋形剂能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、粉剂、颗粒剂、液体、糖浆剂、乳剂、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备适于口服给药的固体药物组合物。例如，可通过下述方法获得固体形式的口服组合物：将活性化合物与固体辅料或赋形剂混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料或赋形剂，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。合适的辅料或赋形剂包括但不限于：填充剂、粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。例如用于口服的药物制剂可通过下述方法获得：将所述的活性化合物与固体赋形剂结合，任意地碾磨所得的混合物，以及加工该颗粒混合物，如果需要，在加入适合的辅助剂后得到了片剂或糖衣剂核。适合的赋形剂是，具体而言，诸如糖的填充剂，包括乳糖、蔗糖、甘露醇或山梨糖醇；纤维素制剂例如玉米淀粉、小麦淀粉、米淀粉、马铃薯淀粉、明胶、黄芪胶、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、和\或者聚乙烯吡咯酮(PVP)。如果需要，可加入崩解剂，例如交联聚乙烯吡咯烷酮、琼脂或藻酸或诸如藻酸钠的藻酸盐。对糖衣剂核进行适合的包被。为了这个目的，可使用浓缩的糖溶液，该溶液可任意地包含***胶、滑石、聚乙烯吡咯烷酮、聚羧乙烯凝胶、聚乙二醇和\或二氧化钛、紫胶漆溶液和适合的有机溶剂或溶剂混合物。为了识别或表示活性化合物剂量的不同组合的特征，可向片剂或糖衣剂包衣中加入染料或色素。使用本领域中公知的方法可制造这些制剂。
本文所述的化合物或组合物的所有施用方法中，每天给药的剂量可以例如为0.001-300mg/kg体重，如0.01-300mg/kg体重、或10-200mg/kg体重，以单独剂量或分开剂量的形式给药。
本申请的药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂、乳剂或冻干产品。能够使用适当的赋形剂，例如填充剂、缓冲剂或表面活性剂。
本申请以Bcr-Abl和BTK为靶点，研发了一种激酶抑制剂，用于***神经***疾病、风湿性关节炎等疾病。
一方面，本申请提供式I的化合物，或者其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体，
Figure PCTCN2020110063-appb-000004
其中：
R 0选自卤素(例如氟、氯、溴、碘)和D；
R 2、R 3、R 5、R 7、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17各自独立地选自H和D；
R 1、R 4和R 6各自独立地选自任选取代的烷基、任选取代的羟烷基、卤素、任选取代的烷氧基、任选取代的炔基、任选取代的烯基、任选取代的环烷基、任选取代的杂环基、任选取代的芳基、任选取代的杂芳基，任选取代的羧基烷基、-NO 2、-CN、-OH、-COOH、巯基、任选取代的氨基、任选取代的烷硫基、任选取代的酯基、任选取代的酰基和任选取代的磺酰基；
R 8选自H、D、任选取代的羟烷基、任选取代的羧基烷基、任选取代的烷基、卤素、任选取代的烷氧基、任选取代的炔基、任选取代的烯基、任选取代的环烷基、任选取代的杂环基、任选取代的芳基、任选取代的杂芳基，-NO 2、-CN、-OH、-COOH、巯基、任选取代的氨基、任选取代的烷硫基、任选取代的酯基、任选取代的酰基和任选取代的磺酰基。
在一些实施方案中，R 1、R 4和R 6各自独立地选自任选取代的C 1-6烷基、任选取代的C 1-6羟烷基、卤素、任选取代的C 1-6烷氧基、任选取代的C 2-6炔基、任选取代的C 2-6烯基、任选取代的3-8元(例如3、4、5、6、7、8元)环烷基、任选取代的3-10元(例如3、4、5、6、7、8、9、10元)杂环基、任选取代的6-10(例如6、7、8、9、10元)元芳基、任选取代的5-10元(例如5、6、7、8、9、10元)杂芳基，任选取代的C 1-6羧基烷基、-NO 2、-CN、-OH、-COOH、巯基、任选取代的氨基、任选取代的C 1-6烷硫基、任选取代的酯基、任选取代的酰基和任选取代的磺酰基。
在一些实施方案中，R 8选自H、D、任选取代的C 1-6羟烷基、任选取代的C 1-6羧基烷基、任选取代的C 1-6烷基、卤素、任选取代的C 1-6烷氧基、任选取代的C 2-6炔基、任选取代的C 2-6烯基、任选取代的3-8元(例如3、4、5、6、7、8元)环烷基、任选取代的3-10元(例如3、4、5、6、7、8、9、10元)杂环基、任选取代的6-10元(例如6、7、8、9、10元)芳基、任选取代的5-10元(例如5、6、7、8、9、10元)杂芳基，-NO 2、-CN、-OH、-COOH、巯基、任选取代的氨基、任选取代的C 1-6烷硫基、任选取代的酯基、任选取代的酰基和任选取代的磺酰基。
在一些实施方案中，所述杂环基和杂芳基中的一个或多个杂原子分别独立地选自O、S和N；在一些实施方案中，杂原子的数目分别独立地选自1、2和3。
在一些实施方案中，R 0选自氟、氯、溴和碘。在一些实施方案中，R 0选自氟。
在一些实施方案中，R 2、R 3、R 5、R 7、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17各自独立地选自H。
在一些实施方案中，R 1、R 4和R 6各自独立地选自任选取代的C 1-6烷基(例如C 1、C 2、C 3、C 4、C 5、C 6)、任选取代的C 1-6羟烷基和卤素。
在一些实施方案中，R 1和R 4各自独立地选自C 1-6烷基和卤素。
在一些实施方案中，R 1选自C 1-4烷基、C 1-4卤代烷基、C 1-4羟烷基和卤素(例如氟、氯、溴、碘)。
在一些实施方案中，R 1选自-CH 3、-CH 2OH和氯。
在一些实施方案中，R 1选自-CH 3和氯。
在一些实施方案中，R 4选自C 1-4烷基、C 1-4卤代烷基、C 1-4氘代烷基和卤素(例如氟、氯、溴、碘)。
在一些实施方案中，R 4选自-CH 3、-CD 3、氟和氯。
在一些实施方案中，R 4选自-CH 3、氟和氯。
在一些实施方案中，R 4选自-CH 3和氯。
在一些实施方案中，R 6选自C 1-4烷基、C 1-4卤代烷基、C 1-4氘代烷基、C 1-4羟烷基和卤素。
在一些实施方案中，R 6选自C 1-4烷基。
在一些实施方案中，R 6选自-CH 3、-CH 2OH和-CD 3。
在一些实施方案中，R 6选自-CH 3。
在一些实施方案中，R 8选自H、D、任选取代的C 1-6羟烷基和任选取代的C 1-6羧基烷基。
在一些实施方案中，R 8选自H、D、C 1-4羟烷基和C 1-4羧基烷基。
在一些实施方案中，R 8选自C 1-4羟烷基。
在一些实施方案中，R 8选自H、D、-CH 2CH 2OH和-CH 2CO 2H。
在一些实施方案中，R 8选自-CH 2CH 2OH。
另一方面，本申请提供以下化合物，或者其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体，
Figure PCTCN2020110063-appb-000005
Figure PCTCN2020110063-appb-000006
又一方面，本申请提供药物组合物，其包含至少任意一种本公开提供的化合物或其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体。在一些实施方案中，本文提供的组合物还包括药学上可接受的载体、赋形剂或辅料。在一些实施方案中，本公开的药物组合物进一步包含另一治疗剂用于联合治疗。在一些实施方案中，所述另一治疗剂选自以下中的一种或多种：环磷酰胺、异环磷酰胺、长春新碱、柔红霉素、阿霉素、阿糖胞苷、米托蒽醌、达卡巴嗪、伊达比星、维甲酸、强的松、***、巯嘌呤、甲氨蝶呤、紫杉醇、美法仑、长效干扰素、维奈托克、克唑替尼、埃罗替尼、奥西替尼、鲁索替尼、阿法替尼、厄洛替尼、伊马替尼、拉帕替尼、贝伐单抗、曲妥珠单抗、利妥昔单抗、西妥昔单抗、博纳吐单抗、氟达拉滨、吉西他滨、地西他滨、卡培他滨、苯达莫司汀、依维莫司、替西罗莫司、依托泊苷、粒细胞集落刺激因子、替莫唑胺、唑来膦酸、奥利沙铂、顺铂、卡铂和氟维司群。
还一方面，本申请提供本公开所述化合物或其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体或者上述药物组合物在制备预防或者治疗与酪氨酸激酶相关疾病的药物中的用途。
另一方面，本申请提供本公开所述化合物或其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体或者上述药物组合物在预防或者治疗与酪氨酸激酶相关疾病中的用途。
还一方面，本申请提供本公开所述化合物或其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体或者上述药物组合物在制备抑制酪氨酸激酶活性的药物中的用途。
另一方面，本申请提供预防或者治疗与酪氨酸激酶相关疾病或病症的方法，所述方法包括向有需要的个体施用治疗有效量的本公开提供的至少任一种化合物或其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何 异构体或者上述药物组合物。
又一方面，本申请提供抑制酪氨酸激酶活性的方法，所述的方法包括向个体或者其组织或细胞施用本公开提供的至少任一种化合物或其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体或者上述药物组合物。在一些实施方案中，所述抑制酪氨酸激酶活性的方法包括体外或者体内试验。
另一方面，本申请提供用于抑制酪氨酸激酶活性的本公开所述化合物或其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体或者上述药物组合物。
另一方面，本申请提供用于预防或者治疗与酪氨酸激酶相关疾病或病症的本公开所述化合物或其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体或者上述药物组合物。
在一些实施方案中，所述与酪氨酸激酶相关的疾病为受益于酪氨酸激酶活性的抑制或减少的疾病、病症和病况。
在一些实施方案中，所述酪氨酸激酶包括Bcr-Abl酪氨酸激酶和BTK酪氨酸激酶。
在一些实施方案中，所述疾病选自癌症。
在一些实施方案中，所述癌症选自：慢性粒细胞白血病(CML)，胃肠间质瘤(GIST)，小细胞肺癌(SCLC)，非小细胞肺癌(NSCLC)，多发性骨髓瘤，实体瘤，B-细胞淋巴瘤，慢性淋巴细胞白血病(CLL)，急性淋巴细胞白血病(ALL)，非霍奇金淋巴瘤(NHL)，小淋巴细胞性淋巴瘤(SLL)，套细胞淋巴瘤(MCL)，黑色素瘤，肥大细胞增多症，生殖细胞肿瘤，急性髓细胞白血病(AML)，边缘区/弥漫性大B细胞淋巴瘤，肉瘤，胰腺癌，恶性胶质瘤，头颈部肿瘤，巨球蛋白血症，滤泡中心淋巴瘤，***癌，骨髓增生异常综合征，动脉粥样硬化性骨髓增生，骨髓纤维化，嗜酸性粒细胞增多症，真性红细胞增多症，肝癌，晚期肉瘤，多形性胶质母细胞瘤，胶质肉瘤，恶性间皮瘤，黑色素瘤，鳞状细胞癌皮肤癌，神经内分泌肿瘤，胃肿瘤，B细胞急性淋巴细胞白血病，毛细胞白血病，淋巴浆细胞淋巴瘤，卵泡中心淋巴瘤，肾细胞癌，移行细胞癌，类癌肿瘤，T细胞淋巴瘤，转移性非小细胞肺癌，***性肥大细胞增多症，转移性肾细胞癌，乳腺肿瘤，中枢神经***肿瘤，结直肠肿瘤，转移性膀胱癌，转移性胰腺癌，转移性头颈癌，卵巢肿瘤和其组合。
在一些实施方案中，所述癌症选自化学治疗剂对靶点BCR-ABL和c-KIT具有抗药性的癌症、以及对伊马替尼具有抗药性的癌症。
在一些实施方案中，所述疾病、病症和病况选自：骨转移，高钙血症和/或骨质疏松；肺纤维疾病；心血管疾病或症状；肥大细胞介导的炎性疾病；HTLV-1相关性脊髓病/热带痉挛性瘫痪；复杂区域疼痛综合征(CRPS)；体重减轻或脂肪减少；动脉阻塞性疾病；泛素化；与降解糖功能降低相关的疾病或症状；Fridreich共济失调；帕金森病进展移植排斥反应；类风湿性关节炎；移植物抗宿主病；自身免疫性疾病；复发的免疫性血小板减少性紫癜，寻常型天疱疮，***性红斑狼疮，硬皮病肺间质纤维化和自发性荨麻疹。
在一些实施方案中，所述心血管疾病或症状为RASopathy引起的心血管类疾病，或与 Noonan或Noonan综合征相关的先天性心脏病。
在一些实施方案中，所述肥大细胞介导的炎性疾病选自骨关节炎、哮喘、慢性阻塞性肺疾病、葡萄膜炎、阿司匹林加重呼吸道疾病(AERD)和帕金森氏病。
本申请的各项发明提供下述一种或多种优势：
1.本公开的化合物具有与现有药物如达沙替尼相当或更好的激酶抑制活性。
2.体外肝微粒体试验显示：与现有药物如达沙替尼相比较，本公开的式I的化合物半衰期更长(＞60h)，清除率更低。目前达沙替尼剂量是每天100毫克，每日1-2次，而本公开的式I的化合物可比现有药物如达沙替尼的所用剂量低，给药间隔更长。
在纳摩尔浓度(nM)，本公开的抑制剂化合物能抑制SRC激酶家族ABL1，BTK和BTK(C481S)激酶，通过抑制上述激酶的作用，可抑制CML和Ph+ALL骨髓中白血病细胞的增殖，但正常红细胞、白细胞和血小板仍可继续增殖。
本申请的各项发明提高了药物疗效，降低了剂量从而降低了毒副作用，更好地为肿瘤和类风湿关节炎等疾病提供临床治疗。本公开的新型低剂量抑制剂将为疾病治疗提供广阔的应用前景。
具体实施方式
下面结合实施例，对本发明的具体实施方式作进一步详细描述。以下实施例仅用于说明的目的，而非用来限制本申请的范围。
制备例1
化合物1的合成:
Figure PCTCN2020110063-appb-000007
化合物1的合成路线如下：
[5-(2-氯-4-氟-6-甲基苯基氨甲酰基)噻唑-2-基]-氨甲酸叔丁酯的合成
Figure PCTCN2020110063-appb-000008
N 2气保护下，将2-叔丁氧羰基氨基噻唑-5-羧酸24.4g(0.1mol)和0.5ml DMF(N，N-二甲基甲酰胺)加入250ml二氯甲烷中，缓慢滴加13ml草酰氯溶液(0.15mol)，反应2h，旋蒸除去溶剂，得到白色固体，将该固体溶于100ml无水二氯甲烷中，冰浴条件下，缓慢滴加至2-氯-4-氟-6-甲基苯胺17.5g(0.11mol)和N，N-二异丙基乙基胺38.8g(0.3mol)的二氯甲烷溶液中，N 2气保护下室温反应10h，减压蒸馏除去溶剂，加入25ml乙酸乙酯和25ml正己烷的混合溶剂搅拌2小时，抽滤，用乙酸乙酯淋洗，得到类白色粉末状 固体35.2g，收率85％，纯度95％(ESI-MS(m/z)：[M+H] +，386。 1H NMR(DMSO-d 6)，δ：1.49(s，9H，-CH 3)，2.18(s，3H，-CH 3)，6.72(s，1H，芳香氢)，6.78(s，1H，芳香氢)，8.14(s，1H，噻唑氢)，9.51(s，1H，-NH)，11.81(s，1H，-NH)。
2-氨基-N-(2-氯-4-氟-6-甲基苯基)-5-噻唑甲酰胺的合成
Figure PCTCN2020110063-appb-000009
将[5-(2-氯-4-氟-6-甲基苯基氨甲酰基)噻唑-2-基]-氨甲酸叔丁酯33.6g(0.087mol)加入到200ml二氯甲烷中，加入100ml三氟乙酸，室温搅拌6h，TLC检测反应完全，减压浓缩，将得到的油状物加入冰水中，用NaOH溶液调pH到10，充分搅拌至无油状物，再将pH回调至7，析出大量固体，抽滤，淋洗，干燥，得到淡黄色固体23.0g，收率92.5％。ESI-MS(m/z)：[M+H] +，286。 1H NMR(DMSO-d 6)，δ：2.21(s，3H，-CH 3)，6.71(s，1H，芳香氢)，6.76(s，1H，芳香氢)，7.63(s，2H，-NH 2)，7.88(s，1H，噻唑氢)，9.66(s，1H，-NH)。
N-(2-氯-4-氟-6-甲基苯基)-2-[(2-甲基-6-氯-4-嘧啶基)氨基]-5-噻唑甲酰胺的合成
Figure PCTCN2020110063-appb-000010
将2-氨基-N-(2-氯-4-氟-6-甲基苯基)-5-噻唑甲酰胺21.3g(0.075mol)溶于100ml DMF中，加入2-甲基-4，6-二氯嘧啶17.93g(0.11mol)和48.9g碳酸铯(0.15mol)，40℃保温反应12h，抽滤，滤液加入300ml冰水中，用稀盐酸调pH至6，搅拌析晶，抽滤，滤饼用乙酸乙酯淋洗，干燥，得到浅黄色固体29.5g，收率95.3％。ESI-MS(m/z)：[M+H] +，412。 1H NMR(DMSO-d 6)，δ：2.25(s，3H，-CH 3)，2.59(s，3H，-CH 3)，6.98(s，1H，嘧啶氢)，6.73(s，1H，芳香氢)，6.77(s，1H，芳香氢)，8.32(s，1H，噻唑氢)，10.01(s，1H，-NH)，12.21(s，1H，-NH)。
N-(2-氯-4-氟-6-甲基苯基)-2-[[6-[4-(2-羟乙基)-1-哌嗪基]-2-甲基-4-嘧啶基]氨基]-5-噻唑甲酰胺的合成
Figure PCTCN2020110063-appb-000011
称取N-(2-氯-4-氟-6-甲基苯基)-2-[(2-甲基-6-氯-4-嘧啶基)氨基]-5-噻唑甲酰胺28.2g(0.068mol)、N-羟乙基哌嗪44.3g(0.34mol)、N，N-二异丙基乙胺26.4g(0.204mol)，溶于250ml异丙醇中，升温至83℃回流反应8h，减压浓缩掉部分溶剂，冷却至室温， 过滤，滤饼用乙醇和水1:1的混合溶液重结晶，得到白色粉末状固体31.36g，收率91.1％，纯度98％。ESI-MS(m/z)：[M+H] +，506。 1H NMR(DMSO-d 6)，δ：2.21(s，3H，-CH 3)，2.41(s，3H，-CH 3)，2.43(t，2H，-CH 2)，2.48(t，4H，-CH 2)，3.52-3.54(m，4H，-CH 2)，3.55-3.56(m，2H，-CH 2)，4.48(s，1H，-OH)，6.06(s，1H，嘧啶氢)，6.73(s，1H，芳香氢)，6.77(s，1H，芳香氢)，8.22(s，1H，噻唑氢)，9.87(s，1H，-NH)，11.45(s，1H，-NH)。
N-(2-氯-4-氟-6-甲基苯基)-2-[[6-[4-氧代-4-(2-羟乙基)-1-哌嗪基]-2-甲基-4-嘧啶基]氨基]-5-噻唑甲酰胺的合成
Figure PCTCN2020110063-appb-000012
称取N-(2-氯-4-氟-6-甲基苯基)-2-[[6-[4-(2-羟乙基)-1-哌嗪基]-2-甲基-4-嘧啶基]氨基]-5-噻唑甲酰胺30.4g(0.06mol)溶解于200mL二氯甲烷，常温下滴加30％的双氧水8.2g(0.072mol)，滴加完毕，继续反应24小时，分层，水洗，有机层减压浓缩，剩余物用85％乙醇重结晶，得到白色粉末状固体22.3g，收率71.0％，纯度98％。ESI-MS(m/z)：[M+H] +，522。 1H NMR(DMSO-d 6)，δ：2.16(m，3H，苯环-CH 3)，2.41(m，3H，嘧啶环-CH 3)，3.30(m，8H，CH 2)，3.61(m，2H，CH 2)，3.90(s，2H，CH 2)，4.08(m，2H，活泼氢)，6.10(s，1H，嘧啶氢)，7.21(d，J＝6.8，1H，芳香氢)，7.38(d，J＝5.6，1H，芳香氢)，8.20(s，1H，噻唑氢)，9.83(s，1H，活泼氢)。
制备例2
化合物2的合成:
Figure PCTCN2020110063-appb-000013
化合物2的合成路线如下：
2-(4-(6-氯-2-甲基嘧啶-4-基)哌嗪-1-基)乙醇的合成
Figure PCTCN2020110063-appb-000014
将2-(哌嗪-1-基)乙醇(13.0g，100mmol)和三乙胺(30.3g，300mmol)加到4，6-二氯-2-二甲基嘧啶(16.3g，100mmol)的400mL二氯甲烷溶液中，室温搅拌2小时 (LCMS监测反应)。反应完全后，分别用饱和食盐水(50ml×1)和水(50ml×1)洗涤反应液，无水硫酸钠干燥，过滤，取滤液真空浓缩得到黄色粉末状固体30.8g，收率82％，纯度68％。ESI-MS(m/z)：[M+H] +，257。
2-((6-(4-(2-羟乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-羧酸甲酯的合成
Figure PCTCN2020110063-appb-000015
化合物2-(4-(6-氯-2-甲基嘧啶-4-基)哌嗪-1-基)乙醇(30.8g粗品，100mol)，SM-2(20.5g，130mmol)，Pd 2(dba) 3(0.916g，1mmol)，Xantphos(1.418g，2mmol)，和Cs 2CO 3(97.8g，300mmol)加到甲苯中(400ml)，氩气保护下加热到120℃搅拌4小时。反应完全后，将反应液真空浓缩得到固体混合物，先后用水和石油醚打浆，烘干得到黄色粉末状固体40g，收率100％，纯度77％。ESI-MS(m/z)：[M+H] +，379。
2-((6-(4-(2-羟乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-羧酸的合成
Figure PCTCN2020110063-appb-000016
将LiOH(9.6g，400mol)加到化合物2-((6-(4-(2-羟乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-羧酸甲酯(40g粗品，100mol)的甲醇/水的混合液(200/200mL)中，60℃搅拌4小时。冷却后，加入1M盐酸调pH＝3。然后真空浓缩旋蒸去掉甲醇。然后加水(10ml)，过滤得到固体，烘干得到黄色粉末固体33g，收率100％，纯度90％。ESI-MS(m/z)：[M+H] +，365。
2-((6-(4-(2-乙酰氧基乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-羧酸的合成
Figure PCTCN2020110063-appb-000017
将三乙胺(2.70g，27.0mmol)和乙酸酐(1.84g，18.0mmol)加到化合物2-((6-(4-(2-羟乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-羧酸甲酯(3.3g粗品，9.00mmol)的二氯甲烷溶液中(36mL)，室温搅拌2小时。然后加水(10ml)，二氯甲烷溶液中(10mL)萃取。然后无水硫酸钠干燥，过滤浓缩得到固体混合物，旋干得到黄色粉末状固体3.65g，收率90％，纯度80％。ESI-MS(m/z)：[M+H] +，407。
化合物2-(4-(6-((5-((4-氟-2，6-二甲基苯基)氨基甲酰基)噻唑-2-基)氨基)-2-甲基嘧啶 -4-基)哌嗪-1-基)乙基醋酸盐和化合物N-(4-氟-2，6-二甲基苯基)-2-((6-(4-(2-羟乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺的制备
Figure PCTCN2020110063-appb-000018
三乙胺(303mg，3.00mmol)和HATU(570mg，1.50mmol)加入到化合物2-((6-(4-(2-乙酰氧基乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-羧酸(406mg，1.00mmol)的DMF(4mL)溶液中，室温搅拌30分钟后，加入4-氟-2，6-二甲基苯胺(209mg，1.50mmol)，再搅拌30分钟。酰胺缩合反应完全后(LCMS监测反应)，加入饱和LiOH水溶液(2ml)，室温搅拌过夜，反应完全后(LCMS监测反应)加入饱和氯化铵水溶液(10ml)，析出固体，过滤，水洗，然后干燥得到黄色粉末状固体300mg，两步收率62％，纯度97％。ESI-MS(m/z)：[M+H] +，486。
Figure PCTCN2020110063-appb-000019
将H 2O 2(30％浓度，2ml)加入到化合物N-(4-氟-2，6-二甲基苯基)-2-((6-(4-(2-羟乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(300mg，0.618mmol)的NMP(2ml)溶液中，室温搅拌24小时后，用高效液相色谱仪(洗脱体系0.1％氨水/乙腈)纯化，浓缩冻干得到化合物2的白色固体游离态80mg，收率26％，纯度97％。ESI-MS(m/z)：[M+H] +，502。 1H NMR(400MHz，DMSO-d 6)，δ：2.19(s，6H，苯环-CH 3)，2.44(s，3H，嘧啶环-CH 3)，3.28-3.39(m，8H，CH 2)，3.65(t，J＝10.7，2H，CH 2)，3.94(s，2H，CH 2)，4.12(br，2H，活泼氢)，6.16(s，1H，嘧啶氢)，6.99(d，J＝9.6，2H，芳香氢)，8.21(s，1H，噻唑氢)，9.64(s，1H，活泼氢)。
制备例3
化合物3的合成:
Figure PCTCN2020110063-appb-000020
化合物3的合成路线如下：
按化合物2合成步骤1～4制备2-((6-(4-(2-乙酰氧基乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-羧酸。
化合物4-氟-2-异丙烯基苯胺的合成
Figure PCTCN2020110063-appb-000021
在氩气保护下，将2-溴-4-氟苯胺(10.0g，52.6mmol)，异丙烯基硼酸频哪醇酯(9.7g，57.8mmol)，K 2CO 3(21.7g，157.8mmol)和Pd 2(dppf) 2Cl(3.8g，5.2mmol)加到250ml的1，4-二氧六环/水(10:1)溶液中，加热至80℃，反应25小时(TCL监测反应)。反应完全后，加入水(100ml)用乙酸乙酯提取(100ml×3)。合并有机相，干燥，浓缩得到粗品。采用乙酸乙酯/石油醚(50：1)过层析柱，最后得到黄色液体产品4.5g，收率：56.6％。ESI-MS(m/z)：[M+H] +，152。
化合物4-氟-2-异丙基苯胺的合成
Figure PCTCN2020110063-appb-000022
将化合物4-氟-2-异丙烯基苯胺(4.5g，29.7mmol)加入到100ml甲醇中，用氢气把反应瓶中的空气置换掉，再加入500mg 10％钯碳，室温反应过夜，通过LCMS检测。反应结束后，过滤出钯碳，将滤液浓缩得到蓝色液体产品4.0g，收率：87.7％。ESI-MS(m/z)：[M+H] +，154。
化合物2-氯-4-氟-6-异丙基苯胺的合成
Figure PCTCN2020110063-appb-000023
将化合物4-氟-2-异丙基苯胺(4g，26.1mmol)溶于100ml的乙腈中，再加入NCS(4.1g，31.3mmol)，反应加热至85℃，反应1h，通过LCMS检测。反应结束后，加入100ml水搅拌10min，再用乙酸乙酯提取(100ml×3)，合并有机相，干燥，浓缩得到粗品，采用乙酸乙酯/石油醚(50：1)过层析柱，最后得到棕色液体产品2.6g，收率：53.2％。ESI-MS(m/z)： [M+H] +，188。
化合物2-(4-(6-((5-((2-氯-4-氟-6-异丙基苯基)氨甲酰)噻唑-2-基)氨基)-2-甲基嘧啶-4-基)哌嗪-1-基)乙酸乙酯的合成
Figure PCTCN2020110063-appb-000024
将化合物2-((6-(4-(2-乙酰氧基乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酸(300mg，0.73mmol)和吡啶(50ml)加到100ml的单口瓶中，用氩气置换瓶里的空气，再把反应瓶放置在冰水浴中降温(10min)，再向反应瓶中加入0.9ml的POCl 3，搅拌10min，再向反应瓶中加入化合物4-氟-2-异丙基苯胺(205mg，1.09mmol)。反应1h后，通过LCMS检测，反应完全，加入50ml水搅拌，再用乙酸乙酯提取(50ml×3)，合并有机相，再用饱和食盐水洗涤(50ml×2)，再将有机相干燥，浓缩得到粗品，粗品用甲醇(15ml)溶解，过反相柱得到类白色固体产品150mg，收率：35.2％，纯度92％。ESI-MS(m/z)：[M+H] +，576。
化合物N-(2-氯-4-氟-6-异丙基苯基)-2-((6-(4-(2-羟乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺的合成
Figure PCTCN2020110063-appb-000025
将化合物2-(4-(6-((5-((2-氯-4-氟-6-异丙基苯基)氨甲酰)噻唑-2-基)氨基)-2-甲基嘧啶-4-基)哌嗪-1-基)乙酸乙酯(150mg，0.26mmol)溶于10ml甲醇中，将反应瓶放在冰水浴中，加入饱和LiOH溶液(LiOH:100mg)，反应0.5h后，通过LCMS检测，反应完全，浓缩干燥，得到粗品200mg，纯度85％。ESI-MS(m/z)：[M+H] +，534。
化合物4-(6-((5-((2-氯-4-氟-6-异丙基苯基)氨甲酰)噻唑-2-基)氨基)-2-甲基嘧啶-4-基)-1-(2-羟乙基)哌嗪1-氧化物的合成
Figure PCTCN2020110063-appb-000026
将H 2O 2(30％浓度，2ml)加入到化合物N-(2-氯-4-氟-6-异丙基苯基)-2-((6-(4-(2-羟乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(200mg，粗品)的NMP(10ml)溶液中，室温搅拌24小时后，用高效液相色谱仪(洗脱体系水/乙腈)纯化，浓缩冻干得到白色固体60mg，收率41.9％，纯度98.7％。ESI-MS(m/z)：[M+H] +，550。 1H NMR(400MHz，DMSO-d 6)，δ：1.15(d，J＝6.8Hz，6H，CH 3)，2.42(s，3H，-CH 3)，3.25(m，1H，-CH)，3.27(m，8H，-CH 2)，3.65(t，J＝22.4Hz，2H，-CH 2)，3.92(s，2H，-CH 2)，4.11(d，J＝11.2Hz，2H，活泼氢)，6.09(d，1H，嘧啶氢)，7.25-7.22(m，1H，芳香氢)，7.41-7.38(m，1H，芳香氢)，8.20(s，1H，噻唑氢)，9.77(s，1H，-OH).
制备例4
化合物4的合成:
Figure PCTCN2020110063-appb-000027
化合物4的合成路线如下：
按化合物2合成步骤1～4制备2-((6-(4-(2-乙酰氧基乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-羧酸。
化合物2-(4-(6-((5-((2-氯-4，6-二氟苯基)氨基甲酰基)噻唑-2-基)氨基)-2-甲基嘧啶-4-基)哌嗪-1-基)乙基醋酸盐的合成
Figure PCTCN2020110063-appb-000028
化合物2-((6-(4-(2-乙酰氧基乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-羧酸(550mg，1.354mmol)和化合物2-氯-4，6-二氟苯胺(243mg，1.489mmol)加入到吡啶(5mL)溶液中，在冰浴0℃滴加POCl 3(0.5mL)，室温搅拌60分钟，反应完全后(LCMS监测反应)，加入乙酸乙酯(15mL)和水(10mL)，饱和NaHCO 3水溶液调PH＝6～7，水相用乙酸乙酯(15mL×3)萃取，有机相分别用水(25mL×3)和饱和食盐水(25mL×1)洗涤，无水硫酸钠干燥，过滤，浓缩得到棕色油状粗品，用高效液相色谱仪(流动相乙腈/水)纯化，浓 缩冻干得白色固体150mg，收率：20.1％，纯度97.5％。ESI-MS(m/z)：[M+H] +，552。
化合物N-(2-氯-4，6-二氟苯基)-2-((6-(4-(2-羟乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺的合成
Figure PCTCN2020110063-appb-000029
将LiOH(150mg)加入到化合物2-(4-(6-((5-((2-氯-4，6-二氟苯基)氨基甲酰基)噻唑-2-基)氨基)-2-甲基嘧啶-4-基)哌嗪-1-基)乙基醋酸盐(150mg，0.272mmol)的甲醇/水的混合液(5/1mL)中，室温搅拌30分钟(LCMS监测反应)，真空浓缩得化合物N-(2-氯-4，6-二氟苯基)-2-((6-(4-(2-羟乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺，直接用于下一步反应。纯度99.4％。ESI-MS(m/z)：[M+H] +，510。
化合物4-(6-((5-((2-氯-4，6-二氟苯基)氨基甲酰基)噻唑-2-基)氨基)-2-甲基嘧啶-4-基)-1-(2-羟乙基)哌嗪1-氧化物的合成
Figure PCTCN2020110063-appb-000030
将H 2O 2(30％浓度，2ml)加入到化合物N-(2-氯-4，6-二氟苯基)-2-((6-(4-(2-羟乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(138mg，0.272mmol)的NMP(2ml)溶液中，室温搅拌24小时后，用高效液相色谱仪(洗脱体系水/乙腈)纯化，浓缩冻干得到白色固体游离态80mg，两步收率56％，纯度99％。ESI-MS(m/z)：[M+H] +，526。 1H NMR(400MHz，DMSO-d 6)，δ：2.43(s，3H，嘧啶环-CH 3)，3.25-3.33(m，8H，CH 2)，3.67-3.61(t，J＝12Hz，2H)，3.91(s，2H，CH 2)，4.12(2H，活泼氢)，6.16(s，1H，嘧啶氢)，7.52-7.47(m，2H，芳香氢)，8.22(s，1H，噻唑氢).
制备例5
化合物5的合成:
Figure PCTCN2020110063-appb-000031
化合物5的合成路线如下：
按化合物2反应步骤1～4制备2-((6-(4-(2-乙酰氧基乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-羧酸。
化合物2-(4-(6-((5-((2，6-二氯-4-氟苯基)氨基甲酰基)噻唑-2-基)氨基)-2-甲基嘧啶-4-基)哌嗪-1-基)乙基醋酸盐的合成
Figure PCTCN2020110063-appb-000032
化合物2-((6-(4-(2-乙酰氧基乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-羧酸(1.0g，2.462mmol)和化合物2，6-二氯-4-氟苯胺(485mg，2.708mmol)加入到吡啶(5mL)溶液中，在冰浴0℃滴加POCl 3(0.5mL)，室温搅拌60分钟，反应完全后(LCMS监测反应)，加入乙酸乙酯(15mL)和水(10mL)，饱和NaHCO 3水溶液调PH＝6～7，水相用乙酸乙酯(15mL×3)萃取，有机相分别用水(25mL×3)和饱和食盐水(25mL×1)洗涤，无水硫酸钠干燥，过滤，浓缩得到棕色油状粗品，用高效液相色谱仪(流动相乙腈/水)纯化，浓缩冻干得200mg黄色固体，收率14.1％，纯度96.3％。ESI-MS(m/z)：[M+H] +，568。
化合物N-(2，6-二氯-4-氟苯基)-2-((6-(4-(2-羟乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺的合成
Figure PCTCN2020110063-appb-000033
将LiOH(200mg)加入到化合物2-(4-(6-((5-((2，6-二氯-4-氟苯基)氨基甲酰基)噻唑-2-基)氨基)-2-甲基嘧啶-4-基)哌嗪-1-基)乙基醋酸盐(200mg，0.353mmol)的甲醇/水的混合液(5/1mL)中，室温搅拌30分钟(LCMS监测反应)，真空浓缩得化合物N-(2，6-二氯-4- 氟苯基)-2-((6-(4-(2-羟乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺，直接用于下一步反应。纯度92.1％。ESI-MS(m/z)：[M+H] +，526。
化合物4-(6-((5-((2，6-二氯-4-氟苯基)氨基甲酰基)噻唑-2-基)氨基)-2-甲基嘧啶-4-基)-1-(2-羟乙基)哌嗪1-氧化物的合成
Figure PCTCN2020110063-appb-000034
将H 2O 2(30％浓度，2ml)加入到上一步化合物N-(2，6-二氯-4-氟苯基)-2-((6-(4-(2-羟乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(165mg，0.353mmol)的NMP(2ml)溶液中，室温搅拌24小时后，用高效液相色谱仪(洗脱体系水/乙腈)纯化，浓缩冻干得到黄色固体80mg，两步收率42％，纯度98％。ESI-MS(m/z)：[M+H] +，542。 1H NMR(400MHz，DMSO-d 6)，δ：2.43(s，3H，嘧啶环-CH 3)，3.25-3.36(m，8H，CH 2)，3.61-3.67(t，J＝12Hz，2H)，3.91(s，2H，CH 2)，4.09-4.11(2H，活泼氢)，6.13(s，1H，嘧啶氢)，7.64-7.66(m，2H，芳香氢)，8.21(s，1H，噻唑氢)。
实施例1
采用本发明的式I化合物进行体外激酶抑制活性研究、人肝微粒体代谢研究。
1.化合物1的激酶抑制活性研究
1.1实验方法
1.1.1试验药物配制
实验组：分别用50μl DMSO溶解化合物1与达沙替尼，最终药物浓度为10mM。
阳性对照组：采用星形孢菌素(供应商为Med Chem)，基质溶液为DMSO。
1.1.2给药剂量
实验组药物起始浓度：1μM
阳性对照组起始浓度：20μM
化合物孵育时间：15min
ATP浓度：10μM
反应时间：2h
反应剂量(M)如下表所示：
Figure PCTCN2020110063-appb-000035
Figure PCTCN2020110063-appb-000036
1.1.3实验条件与过程
缓冲液条件：20mM Hepes(pH 7.5)，10mM MgCl 2，1mM EGTA，0.02％Brij35，0.02mg/ml BSA，0.1mM Na 3VO 4，2mM DTT，1％DMSO
备注：需要的辅酶因子单独加入到每个激酶反应中。
测定条件：
Figure PCTCN2020110063-appb-000037
底物 RXN中的底物量 供应商
ABLtide 20μM GenScript
pEY 0.2mg/ml Sigma
pEY 0.2mg/ml Sigma
反应过程：
a)在新制备的反应缓冲液中制备指示底物。
b)在上述底物溶液中添加任何必需的辅酶因子。
c)在底物溶液中加入指示激酶，轻轻混合。
d)采用Echo 550将试验药物加至激酶反应混合物中。
e)将 33P-ATP(放射性比度0.01μCi/μl)加入到反应混合物中并启动反应。
f)激酶反应在室温下孵育120分钟。
g)该反应在P81离子交换纸上显示斑点。
h)使用0.75％磷酸清洗过滤器。
i)测量滤纸上残留的放射性磷酸化底物。
1.2数据分析
激酶活性数据表示为测试样品中剩余激酶活性与载体(二甲基亚砜)反应的百分比。使用Prism4软件(GraphPad)获得IC 50值和曲线拟合。
1.3实验结果
Figure PCTCN2020110063-appb-000038
1.4实验结论
本公开的化合物例如化合物1抑制ABL1、BTK、BTK(C481S)活性与达沙替尼相当或更高，明显高于对照组。
2.化合物2和化合物5的激酶抑制活性研究
2.1实验方法
2.1.1试验药物配制
实验组：分别用DMSO溶解测试化合物(化合物2和化合物5)，最终药物浓度为10mM。
化合物 DMSO(uL)
化合物2 302.3
化合物5 47.3
阳性对照组：采用星形孢菌素(供应商为LC Laboratories)，基质溶液为DMSO。
2.1.2给药剂量
实验组药物起始浓度：1μM
阳性对照组起始浓度：1μM
化合物孵育时间：10min
ATP浓度：20μM(BTK)，12μM(BTK-C481S)，14μM(ABL1)
反应时间：90min(BTK/BTK-C481S)，60min(ABL1)
反应剂量(M)如下表所示：
Figure PCTCN2020110063-appb-000039
Figure PCTCN2020110063-appb-000040
2.1.3实验条件与过程
缓冲液条件(ABL1)：50mM Hepes(pH 7.5)，10mM MgCl 2，1mM EDTA，0.01％Brij35。
缓冲液条件(BTK/BTK-C481S)：50mM Hepes(pH 7.5)，10mM MgCl 2，1mM EDTA，0.01％Brij35，1mM DTT。
测定条件：
激酶种类 RXN中的激酶量 供应商
ABL1 0.2nM Invitrogen
BTK 1nM Carna
BTK-C481S 0.5nM Carna
底物 RXN中的底物量 供应商
ABL1底物 2μM Invitrogen
BTK底物 1μM Cisbio
BTK-C481S底物 1μM Cisbio
反应过程：
a)采用Echo 550将测试化合物和阳性化合物打入实验板中。
b)将酶与相应的底物混合，加入到实验板中。23℃孵育10分钟。
c)加入ATP启动反应。反应时间90分钟(BTK/BTK-C481S)，60分钟(ABL1)。
d)加入相关试剂进一步发展反应。时间60分钟(BTK/BTK-C481S)，40分钟(ABL1)。
e)在Envision上进行检测。
2.2数据分析
对于BTK/BTK-C481S：利用XLfit5软件中Model205进行数据计算，获得IC 50值。对于ABL1：首先将原始信号转化成磷酸化率，然后将磷酸化率转化为抑制率％，再 利用XLfit5软件计算IC 50。
2.3实验结果
Figure PCTCN2020110063-appb-000041
3.肝微粒体代谢实验
3.1实验方法
3.1.1孵育条件
底物浓度：1.0μM
缓冲液：0.05M磷酸盐缓冲液(pH 7.4)
人肝微粒体：
Figure PCTCN2020110063-appb-000042
UltraPool TM HLM 150，20mg/mL
微粒蛋白浓度：0.25mg/mL
NADPH浓度：1.0mM
总反应体积：850μL
孵育温度：37℃
预孵育时间：5min(未添加NADPH)
取样时间：0，5，10，15，20，30min(对照组为0，15，30min)
取样体积：每个时间点取样85μL
淬灭试剂：85μL乙腈含0.25μM华法林
测试化合物：维拉帕米、达沙替尼和化合物1
3.1.2实验设计
Figure PCTCN2020110063-appb-000043
3.1.3实验过程
a)采用乙腈：水(50：50)将10mM测试化合物的DMSO溶液稀释成100μM。
b)将微粒体蛋白用50mM磷酸盐缓冲盐稀释成0.5mg/mL并置于冰浴中(人肝微粒体浓度为20mg/ml)。
c)配制2.5mM NADPH溶液。
d)按实验设计表中的体积依次移取肝微粒体蛋白、缓冲液、测试化合物至1.5ml孵育管中，在37℃孵育5min，并保持恒定的振摇。
e)在250μL淬灭小瓶中加入85μL淬灭试剂，并置于冰浴上。
f)通过加入NADPH后开始启动反应，立即取样85μL，并在淬灭小瓶中控制孵育与淬灭，混合均匀，此为0min取样点。样品加盖，在4℃下涡旋并离心。
g)淬灭溶液置于4℃下10min用于沉淀蛋白。
h)其他取样点的操作类似0min取样操作。
i)将样品淬灭反应混溶液彻底混合均匀，并在室温下14000rpm离心10min。
j)移取(～100μl)上层清液用于LC-MS分析。
3.2 LC-MS分析方法
仪器：
Figure PCTCN2020110063-appb-000044
ACQUITY HPLC-Xevo G2-XS QTof
色谱柱：ACQUITY
Figure PCTCN2020110063-appb-000045
BEH C 18柱2.1×50mm，1.7μm
流动相：流动相A为含0.1％甲酸的水，流动相B为含0.1％甲酸的乙腈。梯度为每5.1min按5～95％B的梯度。
流速：100μl/min。
根据峰面积比(化合物面积/华法林面积)确定每个时间的母体化合物的量。
3.3计算公式
固有清除率(CL int)通过以下公式计算。
清除速率常数(k)＝-斜率(1/min)
半衰期(t 1/2)＝0.693/k
V(μL/mg)＝孵育体积(μL)/孵育蛋白量(mg)
固有清除率(CL int)(μL/min/mg)＝V×0.693/t 1/2
3.4实验结果
Figure PCTCN2020110063-appb-000046
3.5实验结论
本公开的式I化合物体外代谢稳定，与达沙替尼相比较半衰期较长，清除率较低，可延长给药间隔，减少用药次数。
上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。

Claims (16)

  1. 式I的化合物，或者其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体，
    Figure PCTCN2020110063-appb-100001
    其中：
    R 0选自卤素和D；
    R 2、R 3、R 5、R 7、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17各自独立地选自H和D；
    R 1、R 4和R 6各自独立地选自任选取代的烷基、任选取代的羟烷基、卤素、任选取代的烷氧基、任选取代的炔基、任选取代的烯基、任选取代的环烷基、任选取代的杂环基、任选取代的芳基、任选取代的杂芳基，任选取代的羧基烷基、-NO 2、-CN、-OH、-COOH、巯基、任选取代的氨基、任选取代的烷硫基、任选取代的酯基、任选取代的酰基和任选取代的磺酰基；
    R 8选自H、D、任选取代的羟烷基、任选取代的羧基烷基、任选取代的烷基、卤素、任选取代的烷氧基、任选取代的炔基、任选取代的烯基、任选取代的环烷基、任选取代的杂环基、任选取代的芳基、任选取代的杂芳基，-NO 2、-CN、-OH、-COOH、巯基、任选取代的氨基、任选取代的烷硫基、任选取代的酯基、任选取代的酰基和任选取代的磺酰基。
  2. 如权利要求1所述的式I的化合物，或者其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体，其中：
    R 1、R 4和R 6各自独立地选自任选取代的C 1-6烷基、任选取代的C 1-6羟烷基、卤素、任选取代的C 1-6烷氧基、任选取代的C 2-6炔基、任选取代的C 2-6烯基、任选取代的3-8元环烷基、任选取代的3-10元杂环基、任选取代的6-10元芳基、任选取代的5-10元杂芳基，任选取代的C 1-6羧基烷基、-NO 2、-CN、-OH、-COOH、巯基、任选取代的氨基、任选取代的C 1-6烷硫基、任选取代的酯基、任选取代的酰基和任选取代的磺酰基；
    R 8选自H、D、任选取代的C 1-6羟烷基、任选取代的C 1-6羧基烷基、任选取代的C 1-6烷基、卤素、任选取代的C 1-6烷氧基、任选取代的C 2-6炔基、任选取代的C 2-6烯基、任选取代的3-8元环烷基、任选取代的3-10元杂环基、任选取代的6-10元芳基和任选取代的5-10元杂芳基，-NO 2、-CN、-OH、-COOH、巯基、任选取代的氨基、任选取代的C 1-6烷硫基、任选取代的酯基、任选取代的酰基和任选取代的磺酰基。
  3. 如权利要求1或2所述的式I的化合物，或者其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体，其中：
    所述杂环基和杂芳基中的一个或多个杂原子分别独立地选自O、S和N；
    优选地，R 0选自氟、氯、溴和碘；
    优选地，R 2、R 3、R 5、R 7、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17各自独立地选自H；
    优选地，R 1、R 4和R 6各自独立地选自任选取代的C 1-6烷基、任选取代的C 1-6羟烷基和卤素；
    优选地，R 8选自H、D、任选取代的C 1-6羟烷基和任选取代的C 1-6羧基烷基。
  4. 如权利要求1至3中任一项所述的式I的化合物，或者其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体，其中：
    所述杂环基和杂芳基中的杂原子的数目分别独立地选自1、2和3；
    优选地，R 1选自C 1-4烷基、C 1-4卤代烷基、C 1-4羟烷基和卤素；
    优选地，R 4选自C 1-4烷基、C 1-4卤代烷基、C 1-4氘代烷基和卤素；
    优选地，R 1和R 4各自独立地选自C 1-6烷基和卤素；
    优选地，R 6选自C 1-4烷基、C 1-4卤代烷基、C 1-4氘代烷基、C 1-4羟烷基和卤素；
    优选地，R 8选自H、D、C 1-4羟烷基和C 1-4羧基烷基。
  5. 如权利要求1至4中任一项所述的式I的化合物，或者其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体，其中：
    R 0选自氟；
    优选地，R 1选自-CH 3、-CH 2OH和氯；
    优选地，R 1选自-CH 3和氯；
    优选地，R 4选自-CH 3、-CD 3、氟和氯；
    优选地，R 4选自-CH 3、氟和氯；
    优选地，R 4选自-CH 3和氯；
    优选地，R 6选自-CH 3、-CH 2OH和-CD 3；
    优选地，R 6选自-CH 3；
    优选地，R 8选自H、D、-CH 2CH 2OH和-CH 2CO 2H；
    优选地，R 8选自-CH 2CH 2OH。
  6. 如权利要求1至3中任一项所述的式I的化合物，或者其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体，其中：
    术语“任选取代的”是指基团未被取代或者被一个或多个取代基取代，其中所述一个 或多个取代基独立地选自：氘，卤素，羟基，C 1-C 6烷基，C 2-C 6烯基，C 2-C 6炔基，C 1-6羟烷基、C 1-6烷氧基、3-8元环烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基，-NO 2、-CN、-OH、-COOH、巯基和氨基。
  7. 以下化合物，或者其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体，
    Figure PCTCN2020110063-appb-100002
  8. 药物组合物，其包含如权利要求1-7中任一项所述的化合物或其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体；任选地，所述药物组合物还包含药学上可接受的载体、赋形剂或辅料。
  9. 如权利要求8所述的药物组合物，其进一步包含另一治疗剂用于联合治疗；
    任选地，所述另一治疗剂选自以下中的一种或多种：环磷酰胺、异环磷酰胺、长春新碱、柔红霉素、阿霉素、阿糖胞苷、米托蒽醌、达卡巴嗪、伊达比星、维甲酸、强的 松、***、巯嘌呤、甲氨蝶呤、紫杉醇、美法仑、长效干扰素、维奈托克、克唑替尼、埃罗替尼、奥西替尼、鲁索替尼、阿法替尼、厄洛替尼、伊马替尼、拉帕替尼、贝伐单抗、曲妥珠单抗、利妥昔单抗、西妥昔单抗、博纳吐单抗、氟达拉滨、吉西他滨、地西他滨、卡培他滨、苯达莫司汀、依维莫司、替西罗莫司、依托泊苷、粒细胞集落刺激因子、替莫唑胺、唑来膦酸、奥利沙铂、顺铂、卡铂和氟维司群。
  10. 权利要求1-7中任一项所述的化合物或其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体或者权利要求8或9所述的药物组合物在制备预防或者治疗与酪氨酸激酶相关的疾病的药物中的用途。
  11. 权利要求1-7中任一项所述的化合物或其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体或者权利要求8或9所述的药物组合物在制备抑制酪氨酸激酶活性的药物中的用途。
  12. 预防或者治疗与酪氨酸激酶相关的疾病的方法，所述方法包括向有需要的个体施用治疗有效量的权利要求1-7中任一项所述的化合物或其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体或者权利要求8或9所述的药物组合物。
  13. 抑制酪氨酸激酶活性的方法，所述方法包括向个体或者其组织或细胞施用权利要求1-7中任一项所述的化合物或其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体或者权利要求8或9所述的药物组合物，
    任选地，所述方法在体内或体外进行。
  14. 权利要求1-7中任一项所述的化合物或其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体或者权利要求8或9所述的药物组合物，其用于抑制酪氨酸激酶活性的用途。
  15. 权利要求1-7中任一项所述的化合物或其药学上可接受的盐、酯、溶剂化物、前药、活性代谢物、晶体、立体异构体、互变异构体或几何异构体或者权利要求8或9所述的药物组合物，其用于预防或者治疗与酪氨酸激酶相关的疾病的用途。
  16. 如权利要求10或11所述的用途，或者如权利要求12或13所述的方法，或者如权利要求14或15所述的用于所述用途的化合物或组合物，其中：
    所述与酪氨酸激酶相关的疾病为受益于酪氨酸激酶活性的抑制或减少的疾病、病症和病况；
    优选地，所述酪氨酸激酶包括Bcr-Abl酪氨酸激酶和BTK酪氨酸激酶；
    优选地，所述疾病选自癌症；
    优选地，所述癌症选自：慢性粒细胞白血病(CML)，胃肠间质瘤(GIST)，小细胞肺癌(SCLC)，非小细胞肺癌(NSCLC)，多发性骨髓瘤，实体瘤，B-细胞淋巴瘤，慢性淋巴细胞白血病(CLL)，急性淋巴细胞白血病(ALL)，非霍奇金淋巴瘤(NHL)，小淋巴细胞性淋巴瘤(SLL)，套细胞淋巴瘤(MCL)，黑色素瘤，肥大细胞增多症，生殖细胞肿瘤，急性髓细胞白血病(AML)，边缘区/弥漫性大B细胞淋巴瘤，肉瘤，胰腺癌，恶性胶质瘤，头颈部肿瘤，巨球蛋白血症，滤泡中心淋巴瘤，***癌，骨髓增生异常综合征，动脉粥样硬化性骨髓增生，骨髓纤维化，嗜酸性粒细胞增多症，真性红细胞增多症，肝癌，晚期肉瘤，多形性胶质母细胞瘤，胶质肉瘤，恶性间皮瘤，黑色素瘤，鳞状细胞癌皮肤癌，神经内分泌肿瘤，胃肿瘤，B细胞急性淋巴细胞白血病，毛细胞白血病，淋巴浆细胞淋巴瘤，卵泡中心淋巴瘤，肾细胞癌，移行细胞癌，类癌肿瘤，T细胞淋巴瘤，转移性非小细胞肺癌，***性肥大细胞增多症，转移性肾细胞癌，乳腺肿瘤，中枢神经***肿瘤，结直肠肿瘤，转移性膀胱癌，转移性胰腺癌，转移性头颈癌，卵巢肿瘤和其组合；
    优选地，所述癌症选自化学治疗剂对靶点BCR-ABL和c-KIT具有抗药性的癌症、以及对伊马替尼具有抗药性的癌症；
    优选地，所述疾病、病症和病况选自：骨转移，高钙血症和/或骨质疏松；肺纤维疾病；心血管疾病或症状；肥大细胞介导的炎性疾病；HTLV-1相关性脊髓病/热带痉挛性瘫痪；复杂区域疼痛综合征(CRPS)；体重减轻或脂肪减少；动脉阻塞性疾病；泛素化；与降解糖功能降低相关的疾病或症状；Fridreich共济失调；帕金森病进展移植排斥反应；类风湿性关节炎；移植物抗宿主病；自身免疫性疾病；复发的免疫性血小板减少性紫癜，寻常型天疱疮，***性红斑狼疮，硬皮病肺间质纤维化和自发性荨麻疹；
    优选地，所述心血管疾病或症状为RASopathy引起的心血管类疾病，或与Noonan或Noonan综合征相关的先天性心脏病；
    优选地，所述肥大细胞介导的炎性疾病选自骨关节炎、哮喘、慢性阻塞性肺疾病葡萄膜炎、阿司匹林加重呼吸道疾病(AERD)和帕金森氏病。
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