WO2021063207A1 - Jnk抑制剂、其药物组合物和用途 - Google Patents

Jnk抑制剂、其药物组合物和用途 Download PDF

Info

Publication number
WO2021063207A1
WO2021063207A1 PCT/CN2020/116617 CN2020116617W WO2021063207A1 WO 2021063207 A1 WO2021063207 A1 WO 2021063207A1 CN 2020116617 W CN2020116617 W CN 2020116617W WO 2021063207 A1 WO2021063207 A1 WO 2021063207A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
unsubstituted
alkoxy
optionally substituted
group
Prior art date
Application number
PCT/CN2020/116617
Other languages
English (en)
French (fr)
Inventor
李金平
娄军
陈永凯
郭晓丹
张轶涵
曾弦
钱丽娜
王朝东
Original Assignee
武汉朗来科技发展有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 武汉朗来科技发展有限公司 filed Critical 武汉朗来科技发展有限公司
Priority to EP20872098.7A priority Critical patent/EP4023642A4/en
Priority to US17/754,333 priority patent/US20230104283A1/en
Publication of WO2021063207A1 publication Critical patent/WO2021063207A1/zh

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • 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
    • 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • A61P17/06—Antipsoriatics
    • 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
    • A61P17/08—Antiseborrheics
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • 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
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/38—One sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/50—Three nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to the field of medicine, in particular to a compound capable of inhibiting the activity of JNK, its pharmaceutical composition and application.
  • MAPK Mitogen-activated protein kinases
  • the MAPK chain is composed of three types of protein kinases MAP3K-MAP2K-MAPK, which transmit upstream signals to downstream response molecules through sequential phosphorylation.
  • MAPK signal transduction pathways ERK (extracellular signal regulated kinase) 1/2, JNK (c-Jun N-terminal kinase) and p38 signal pathways, of which ERK1/2 signal transduction pathway Regulating cell growth and differentiation, JNK and p38MAPK signal transduction pathways play an important role in stress responses such as inflammation and apoptosis.
  • JNK is an important member of the MAPK family, which can be activated by stress signals, so it is also called stress-activated protein kinase (SAPK). JNK participates in a wide range of biological processes including embryonic development, cell apoptosis/survival, transformation angiogenesis of oncogene-expressing cells, T cell activation, B cell proliferation, cytokine production and inflammation.
  • SAPK stress-activated protein kinase
  • JNK1, JNK2, and JNK3 are distinct genes, which encode 10 splice variants.
  • JNK1 and JNK2 are expressed in a wide variety of tissues, while JNK3 is mainly expressed in neurons and to a lesser extent in the heart and testis.
  • JNK3 is mainly expressed in neurons and to a lesser extent in the heart and testis.
  • pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) and environmental stress.
  • TNF-alpha tumor necrosis factor alpha
  • IL-1 beta interleukin-1 beta
  • the activation of JNK is mediated by its upstream kinases, MKK4 and MKK7, through the dual phosphorylation of Thr-183 and Tyr-185.
  • MKK4 and MMK7 can be activated by different upstream kinases including MEKK1 and MEKK4, depending on external stimuli and cellular environment.
  • the specificity of JNK signaling is achieved by using a scaffold protein called JNK-interacting protein to form a JNK-specific signaling complex, which contains multiple components of the kinase cascade.
  • JNK has been shown to play an important role in inflammation, T cell function, apoptosis and survival.
  • the substrates include transcription factors such as c-Jun, activin-1 (AP1) family members and ATF2, and non-transcription factors such as IRS-1 and Bcl-2.
  • JNK JNK signal transduction pathway
  • Idiopathic interstitial pulmonary fibrosis is a chronic and diffuse pulmonary interstitial disease characterized by pathological changes of ordinary interstitial pneumonia of unknown cause. Its histopathology and imaging Most studies show the performance of ordinary interstitial pneumonia. Due to its complex pathogenesis, irreversible progression of the disease, early diagnosis is difficult; after diagnosis, the survival rate of patients has decreased significantly over time, with a 3-year survival rate of 50% and a 5-year survival rate of only 20%, which is higher than most cancers (such as : Leukemia, breast cancer, colon cancer, uterine tumor, kidney cancer, etc.) have low survival rates and are called "cancers that are not cancer.”
  • cancers such as : Leukemia, breast cancer, colon cancer, uterine tumor, kidney cancer, etc.
  • Liver fibrosis is a common link in the progression of chronic liver disease to cirrhosis. Previous related researches were limited to avoiding the occurrence of fibrosis, delaying or even blocking the progress of fibrosis. However, many experiments in recent years have shown that whether it is to eliminate pathogenic factors or apply effective anti-fibrosis drugs, it is possible to partially or completely reverse liver fibrosis in patients and model animals, that is, liver fibrosis is reversible to a certain extent. of. However, the reversal process of liver fibrosis is very complicated.
  • Y 1 and Y 2 are independently CR 4 or N;
  • X and W are independently selected from CR 5 R 6 , O or NR 7 ;
  • R 2 is selected from H, or unsubstituted or optionally substituted by one, two or more of the following groups of R b : C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl , C 1-40 alkoxy, C 3-20 cycloalkyl, 3-20 membered heterocyclic group, C 6-20 aryl, C 6-20 aryl-C 1-40 alkyl, 5-20 member Heteroaryl or 5-20 membered heteroaryl-C 1-40 alkyl; or
  • R 2 together with X form the following groups which are unsubstituted or optionally substituted with one, two or more R b : NHC(O)NR 11 R 12 , C 3-20 cycloalkyl, 3-20 member Heterocyclic group, C 6-20 aryl group or 5-20 membered heteroaryl group;
  • R 3 is selected from H, or unsubstituted or optionally substituted with one, two or more R c groups as follows: NR 11 R 12 , C(O)NR 11 R 12 , C(O)R 14 , C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 1-40 alkoxy, C 3-20 cycloalkyl, 3-20 membered heterocyclic group, C 6-20 Aryl or 5-20 membered heteroaryl; or
  • R 3 together with W form the following groups that are unsubstituted or optionally substituted with one, two or more R c : NHC(O)NR 11 R 12 , C 3-20 cycloalkyl, 3-20 member Heterocyclic group, C 6-20 aryl group or 5-20 membered heteroaryl group;
  • R 4 is selected from H, hydroxyl, halogen, cyano, nitro, amino, or unsubstituted or optionally substituted with one, two or more R d as follows: C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl or C 1-40 alkoxy;
  • R 7 is selected from H, or unsubstituted or optionally substituted by one, two or more R e groups are as follows: C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, , C 1-40 alkoxy, C 3-20 cycloalkyl, 3-20 membered heterocyclic group, C 6-20 aryl or 5-20 membered heteroaryl;
  • R 11, R 12 are each independently selected from H, or unsubstituted or optionally substituted with one, two or more R e substituents of the following groups: C (O) R 14, C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 1-40 alkoxy, C 3-20 cycloalkyl, 3-20 membered heterocyclic group, C 6-20 aryl or 5-20 membered hetero Aryl; or
  • R 11 and R 12 together with the nitrogen atom to which they are attached form an unsubstituted or optionally substituted with one, two or more R e substituted 3-20 membered heterocyclyl or 5-20 membered heteroaryl;
  • R 13 is selected from H, hydroxyl, cyano, or C 1-40 alkyl or C 1-40 alkoxy which is unsubstituted or optionally substituted with one, two or more R e;
  • R 14 is selected from H, hydroxyl, halogen, or unsubstituted or optionally substituted with one, two or more R f as follows: C 1-40 alkyl, C 2-40 alkenyl, C 2 -40 alkynyl, C 1-40 alkoxy, C 3-20 cycloalkyl, 3-20 membered heterocyclic group, C 6-20 aryl or 5-20 membered heteroaryl;
  • R 15 is selected from H, or unsubstituted or optionally substituted with one, two or more R f as follows: C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl , C 3-20 cycloalkyl, 3-20 membered heterocyclic group, C 6-20 aryl group or 5-20 membered heteroaryl group;
  • Each Ra is independently selected from CN, halogen, OH, NH 2 , oxo, or unsubstituted or optionally substituted with one, two or more R f as follows: C 1-40 alkyl Or C 1-40 alkoxy;
  • Each R b is independently selected from CN, halogen, OH, NH 2 , COOH, NO 2 , oxo, S (O) 2 CH 3 , C (O) NHCH 2 CH 3 , or unsubstituted or optionally One, two or more of the following groups substituted by R f : C 1-40 alkyl, C 1-40 alkoxy, C 3-20 cycloalkyl, 3-20 membered heterocyclic group, C 6- 20 aryl or 5-20 membered heteroaryl;
  • Each R c is independently selected from CN, halogen, OH, NH 2 , COOH, NO 2 , C (O) NH 2 , C (O) NHOH, C (O) N (OH) CH 3 , oxo, C (O)CH 2 COOH, C(O)CH 2 CN, C(O)CH 2 Cl, C(O)CH 2 F or C(O)CH 2 Br, or unsubstituted or optionally one or two One or more of the following groups substituted by R f : C 1-40 alkyl group, C 1-40 alkoxy group, C 3-20 cycloalkyl group, 3-20 membered heterocyclic group, C 6-20 aryl group Or 5-20 membered heteroaryl group;
  • R d, R e, R f identical or different are each independently selected from CN, halogen, OH, NH 2, oxo, S (O) 2 CH 3 , C 1-40 alkyl, halogeno C 1 -40 alkyl, C 1-40 alkoxy or halogenated C 1-40 alkoxy.
  • Y 1 and Y 2 are independently CR 4 or N;
  • X and W are independently selected from CR 5 R 6 , O or NR 7 ;
  • R 2 is selected from H, or unsubstituted or optionally substituted by one, two or more of the following groups of R b : C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl , C 1-10 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 6-14 aryl, C 6-14 aryl-C 1-10 alkyl, 5-14 member Heteroaryl or 5-14 membered heteroaryl-C 1-10 alkyl; or
  • R 2 together with X form the following groups which are unsubstituted or optionally substituted with one, two or more R b : NHC(O)NR 11 R 12 , C 3-10 cycloalkyl, 3-10 member Heterocyclic group, C 6-14 aryl group or 5-14 membered heteroaryl group;
  • R 3 is selected from H, or unsubstituted or optionally substituted with one, two or more R c groups as follows: NR 11 R 12 , C(O)NR 11 R 12 , C(O)R 14 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; or
  • R 3 together with W form the following group which is unsubstituted or optionally substituted with one, two or more R c : NHC(O)NR 11 R 12 , C 3-10 cycloalkyl, 3-10 member Heterocyclic group, C 6-14 aryl group or 5-14 membered heteroaryl group;
  • R 4 is selected from H, hydroxyl, halogen, cyano, nitro, amino, or unsubstituted or optionally substituted with one, two or more R d as follows: C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy;
  • R 7 is selected from H, or unsubstituted or optionally substituted by one, two or more R e groups are as follows: C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, , C 1-10 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl;
  • R 11 and R 12 are each independently selected from H, or unsubstituted or optionally substituted with one, two or more of the following groups of R e : C(O)R 14 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 6-14 aryl or 5-14 membered hetero Aryl; or
  • R 11 and R 12 together with the nitrogen atom to which they are attached form an unsubstituted or optionally substituted with one, two or more R e substituted 3-10 membered heterocyclyl or 5-14 membered heteroaryl group;
  • R 13 is selected from H, hydroxyl, cyano, or C 1-10 alkyl or C 1-10 alkoxy which is unsubstituted or optionally substituted with one, two or more R e;
  • R 14 is selected from H, hydroxyl, halogen, or unsubstituted or optionally substituted with one, two or more R f as follows: C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl;
  • R 15 is selected from H, or unsubstituted or optionally substituted with one, two or more R f as follows: C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl , C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl;
  • Each Ra is independently selected from CN, halogen, OH, NH 2 , oxo, or unsubstituted or optionally substituted with one, two or more R f as follows: C 1-10 alkyl Or C 1-10 alkoxy;
  • Each R b is independently selected from CN, halogen, OH, NH 2 , COOH, NO 2 , oxo, S (O) 2 CH 3 , C (O) NHCH 2 CH 3 , or unsubstituted or optionally One, two or more of the following groups substituted by R f : C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6- 14 aryl or 5-14 membered heteroaryl;
  • Each R c is independently selected from CN, halogen, OH, NH 2 , COOH, NO 2 , C (O) NH 2 , C (O) NHOH, C (O) N (OH) CH 3 , oxo, C (O)CH 2 COOH, C(O)CH 2 CN, C(O)CH 2 Cl, C(O)CH 2 F, C(O)CH 2 Br, or unsubstituted or optionally one or two One or more of the following groups substituted by R f : C 1-10 alkyl group, C 1-10 alkoxy group, C 3-10 cycloalkyl group, 3-10 membered heterocyclic group, C 6-14 aryl group Or 5-14 membered heteroaryl;
  • R d, R e, R f identical or different are each independently selected from CN, halogen, OH, NH 2, oxo, S (O) 2 CH 3 , C 1-10 alkyl, halogeno C 1 -10 alkyl, C 1-10 alkoxy or halogenated C 1-10 alkoxy.
  • Y 1 and Y 2 are independently CR 4 or N;
  • X and W are independently selected from CR 5 R 6 , O or NR 7 ;
  • R 2 is selected from H, or unsubstituted or optionally substituted with one, two or more R b as follows: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 1-6 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 6-14 aryl, C 6-14 aryl-C 1-6 alkyl, 5-14 membered Heteroaryl or 5-14 membered heteroaryl-C 1-6 alkyl; or
  • R 2 together with X form the following groups which are unsubstituted or optionally substituted with one, two or more R b : NHC(O)NR 11 R 12 , C 3-10 cycloalkyl, 3-10 member Heterocyclic group, C 6-14 aryl group or 5-14 membered heteroaryl group;
  • R 3 is selected from H, or unsubstituted or optionally substituted with one, two or more R c groups as follows: NR 11 R 12 , C(O)NR 11 R 12 , C(O)R 14 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; or
  • R 3 together with W form the following group which is unsubstituted or optionally substituted with one, two or more R c : NHC(O)NR 11 R 12 , C 3-10 cycloalkyl, 3-10 member Heterocyclic group, C 6-14 aryl group or 5-14 membered heteroaryl group;
  • R 4 is selected from H, hydroxyl, halogen, cyano, nitro, amino, or unsubstituted or optionally substituted with one, two or more R d as follows: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 alkoxy;
  • R 7 is selected from H, or unsubstituted or optionally substituted by one, two or more R e groups are as follows: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 1-6 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl;
  • R 11, R 12 are each independently selected from H, or unsubstituted or optionally substituted with one, two or more R e substituents of the following groups: C (O) R 14, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-14 aryl or 5-14 membered hetero Aryl; or
  • R 11 and R 12 together with the nitrogen atom to which they are attached form an unsubstituted or optionally substituted with one, two or more R e substituted 3-10 membered heterocyclyl or 5-14 membered heteroaryl group;
  • R 13 is selected from H, hydroxyl, cyano, or C 1-6 alkyl or C 1-6 alkoxy which is unsubstituted or optionally substituted with one, two or more R e;
  • R 14 is selected from H, hydroxyl, halogen, or unsubstituted or optionally substituted with one, two or more R f as follows: C 1-6 alkyl, C 2-6 alkenyl, C 2 -6 alkynyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl;
  • R 15 is selected from H, or unsubstituted or optionally substituted by one, two or more of the following groups of R f : C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl;
  • Each Ra is independently selected from CN, halogen, OH, NH 2 , oxo, or unsubstituted or optionally substituted with one, two or more R f as follows: C 1-6 alkyl Or C 1-6 alkoxy;
  • Each R b is independently selected from CN, halogen, OH, NH 2 , COOH, NO 2 , oxo, S (O) 2 CH 3 , C (O) NHCH 2 CH 3 , or unsubstituted or optionally One, two or more of the following groups substituted by R f : C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 6- 14 aryl or 5-14 membered heteroaryl;
  • Each R c is independently selected from CN, halogen, OH, NH 2 , COOH, NO 2 , C (O) NH 2 , C (O) NHOH, C (O) N (OH) CH 3 , oxo, C (O)CH 2 COOH, C(O)CH 2 CN, C(O)CH 2 Cl, C(O)CH 2 F, C(O)CH 2 Br, or unsubstituted or optionally one or two One or more of the following groups substituted by R f : C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-14 aryl Or 5-14 membered heteroaryl;
  • R d, R e, R f identical or different are each independently selected from CN, halogen, OH, NH 2, oxo, S (O) 2 CH 3 , C 1-6 alkyl, halogeno C 1 -6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkoxy.
  • Y 1 and Y 2 are independently CR 4 or N;
  • X and W are independently O or NR 7 ;
  • R 2 is selected from H, or unsubstituted or optionally substituted with one, two or more R b as follows: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 1-6 alkoxy, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, phenyl, benzyl, 5-6 membered heteroaryl or 5-6 membered heteroaryl -C 1- 6 alkyl; or
  • R 2 together with X form an unsubstituted or optionally substituted with one, two or more R b NHC(O)NR 11 R 12 , a 3-7 membered heterocyclic group or a 5-6 membered heteroaryl group;
  • R 3 is selected from H, or unsubstituted or optionally substituted with one, two or more R c groups as follows: NR 11 R 12 , C(O)NR 11 R 12 , C(O)R 14 , C 1-6 alkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; or
  • R 3 together with W form an unsubstituted or optionally substituted with one, two or more R c NHC(O)NR 11 R 12 , a 3-7 membered heterocyclic group or a 5-6 membered heteroaryl group;
  • R 4 is selected from H, hydroxyl or halogen
  • R 7 is H
  • R 11 and R 12 are each independently selected from H, or unsubstituted or optionally substituted with one, two or more of R e as follows: C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; or
  • R 11 and R 12 together with the nitrogen atom to which they are attached form an unsubstituted or optionally substituted with one, two or more R e substituted 3-7 membered heterocyclyl or 5-6 membered heteroaryl;
  • R 13 is selected from H, cyano, methyl or hydroxyl
  • R 14 is selected from H, hydroxyl, halogen, or unsubstituted or optionally substituted with one, two or more R f as follows: C 1-6 alkyl, C 2-6 alkenyl, C 2 -6alkynyl , C 1-6 alkoxy or C 3-6 cycloalkyl;
  • R 15 is selected from H, or unsubstituted or optionally substituted C 1-6 alkyl with one, two or more R f;
  • Each Ra is independently selected from CN, halogen, OH, NH 2 , oxo, or unsubstituted or optionally substituted with one, two or more R f as follows: C 1-6 alkyl Or C 1-6 alkoxy;
  • Each R b is independently selected from CN, halogen, OH, NH 2 , COOH, NO 2 , oxo, S (O) 2 CH 3 , C (O) NHCH 2 CH 3 , or unsubstituted or optionally One, two or more of the following groups substituted by R f : C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
  • Each R c is independently selected from CN, halogen, OH, NH 2 , COOH, NO 2 , C (O) NH 2 , C (O) NHOH, C (O) N (OH) CH 3 , oxo, C (O)CH 2 COOH, C(O)CH 2 CN, C(O)CH 2 Cl, C(O)CH 2 F or C(O)CH 2 Br, or unsubstituted or optionally one or two One or more of the following groups substituted by R f : C 1-6 alkyl, C 1-6 alkoxy, 3-7 membered heterocyclyl or 5-6 membered heteroaryl;
  • Each R e and R f are the same or different, and are independently selected from CN, halogen, OH, NH 2 , oxo, S(O) 2 CH 3 , C 1-6 alkyl, and halogenated C 1-6 alkane Group, C 1-6 alkoxy or halogenated C 1-6 alkoxy.
  • Y 1 and Y 2 are independently CR 4 or N;
  • X and W are independently O or NR 7 ;
  • R 2 is selected from H, or unsubstituted or optionally substituted with one, two or more R b as follows: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 1-6 alkoxy, C 3-6 cycloalkyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, phenyl, benzyl, imidazolyl, pyrazole Group, triazolyl, oxadiazolyl, isoxadiazolyl, thiadiazolyl, isothiadiazolyl, tetrazolyl, pyrrolyl, furyl, thiazolyl, isothiazolyl, oxazolyl, Isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyranyl, thienyl or or or
  • R 2 together with X form the following groups that are unsubstituted or optionally substituted with one, two or more R b : NHC(O)NR 11 R 12 , azetidinyl, oxetanyl, Piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, imidazolidinyl, pyrrolinyl, pyranyl, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, isoxadiazolyl, Thiadiazolyl, isothiadiazolyl, tetrazolyl, pyrrolyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazine base;
  • R 3 is selected from H, or unsubstituted or optionally substituted by one, two or more of the following groups of R c : C(O)NR 11 R 12 , C(O)R 14 , C 1-6 Alkyl, cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, phenyl, imidazolyl, pyrazolyl, triazolyl, pyrrolyl, furyl, piperazinyl, morpholinyl, pyranyl, Oxadiazole, isoxadiazole, thiadiazolyl, isothiadiazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl, Pyrazinyl, thiazolyl or thienyl; or
  • R 3 together with W form the following groups that are unsubstituted or optionally substituted with one, two or more R c : NHC(O)NR 11 R 12 , piperidinyl, piperazinyl, morpholinyl, Pyrrolidinyl, imidazolidinyl, pyrrolinyl, azetidinyl, oxetanyl, pyranyl, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, isoxadiazolyl, Thiadiazolyl, isothiadiazolyl, tetrazolyl, pyrrolyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazine base;
  • R 4 is selected from H, hydroxyl or halogen
  • R 7 is H
  • R 11 and R 12 are each independently selected from H, or C 1-6 alkyl that is unsubstituted or optionally substituted with one, two or more R e; or
  • R 11 and R 12 together with the nitrogen atom to which they are attached form an unsubstituted or optionally substituted with one, two or more R e substituted 3-7 membered azacycloalkyl;
  • R 13 is selected from H, cyano, methyl or hydroxyl
  • R 14 is selected from H, hydroxyl, halogen, or unsubstituted or optionally substituted with one, two or more R f as follows: C 1-6 alkyl, C 2-6 alkenyl, C 2 -6alkynyl , C 1-6 alkoxy or C 3-6 cycloalkyl;
  • R 15 is selected from H, or unsubstituted or optionally substituted C 1-6 alkyl with one, two or more R f;
  • Each Ra is independently selected from CN, halogen, OH, NH 2 , oxo, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 Alkoxy or CH 2 CH 2 S(O) 2 CH 3 ;
  • Each R b is independently selected from CN, halogen, OH, NH 2 , COOH, NO 2 , oxo, S (O) 2 CH 3 , C (O) NHCH 2 CH 3 , or unsubstituted or optionally One, two or more of the following groups substituted by R f : C 1-6 alkyl, C 1-6 alkoxy, phenyl or piperidinyl;
  • Each R c is independently selected from CN, halogen, OH, NH 2 , COOH, NO 2 , C (O) NH 2 , C (O) NHOH, C (O) N (OH) CH 3 , oxo, C (O)CH 2 COOH, C(O)CH 2 CN, C(O)CH 2 Cl, C(O)CH 2 F or C(O)CH 2 Br, or unsubstituted or optionally one or two One or more of the following groups substituted by R f : C 1-6 alkyl, C 1-6 alkoxy, 5-membered heterocyclyl or 5-membered heteroaryl;
  • Each R e and R f are the same or different, and are each independently selected from CN, halogen, OH, NH 2 , oxo, S(O) 2 CH 3 , C 1-6 alkyl, halo C 1-6 alkane Group, halogenated C 1-6 alkoxy or C 1-6 alkoxy.
  • Y 1 and Y 2 are both N, or Y 1 is N and Y 2 is CH;
  • X and W are both NH, or X is O and W is NH;
  • R 2 is selected from H, tert-butyl, (1-ethylaminoacyl)-piperidinyl, hydroxyethyl, isopropyl, fluoropropyl, C(CH 3 ) 2 CF 3 , cyclopropyl, hydroxy ring Propyl, cyclobutyl, hydroxycyclobutyl, cyclopentyl, hydroxycyclopentyl, cyclohexyl, hydroxycyclohexyl, methoxyphenyl, methoxybenzyl, methylsulfonylphenyl, (4- Methylpiperazinyl)-phenyl, triazolyl, R 2 is preferably selected from methoxyphenyl, methoxybenzyl, methylsulfonylphenyl, (4-methylpiperazinyl)-phenyl, triazolyl, or
  • R 2 together with X form unsubstituted or substituted by one or two oxo, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy substituted ureido, pyrazolyl, pyrrolidinyl, imidazolidinyl, Pyrrolinyl, piperidinyl, morpholinyl or piperazinyl; preferably, R 2 together with X form morpholinyl, tert-butylureido, pyrazolyl or (3-oxo)-piperazinyl;
  • R 3 is selected from H, (3-hydroxy-4-methyl)-cyclohexyl, formyl, dimethylcyclohexyl, vinylcarbonyl, (1-chloromethylcarbonyl)-piperidinyl, (1-carboxy (Methylcarbonyl)-piperidinyl, carboxyphenyl, (1-cyanomethylcarbonyl)-piperidinyl, (1-amido)-piperidinyl, piperidinone, hydroxyethylpiperidinone , Piperidinyl, hydroxypiperidinyl, hydroxymethylphenyl, 1-(2-methylsulfonylethyl)-pyrazolyl, or or
  • R 3 together with W form ureido, hydroxypiperidinyl, hydroxymethylpiperidinyl, hydroxymethylpyrrolidinyl, Or (2-hydroxy-2-propyl)-azetidinyl.
  • Y 1 and Y 2 are both N, or Y 1 is N and Y 2 is CH;
  • X and W are both NH, or X is O and W is NH;
  • R 2 and R 3 have the definitions given above in any of the embodiments.
  • Y 1 and Y 2 are both N, or Y 1 is N and Y 2 is CH;
  • X and W are both NH, or X is O and W is NH;
  • R 2 is selected from H, tert-butyl, (1-ethylaminoacyl)-piperidinyl, hydroxyethyl, isopropyl, fluoropropyl, C(CH 3 ) 2 CF 3 , cyclopropyl, hydroxy ring Propyl, cyclobutyl, hydroxycyclobutyl, cyclopentyl, hydroxycyclopentyl, cyclohexyl, hydroxycyclohexyl, methoxyphenyl, methoxybenzyl, methylsulfonylphenyl, (4- Methylpiperazinyl)-phenyl, triazolyl, or
  • R 2 together with X form morpholinyl, tert-butylureido, pyrazolyl or (3-oxo)-piperazinyl;
  • R 3 is selected from H, (3-hydroxy-4-methyl)-cyclohexyl, formyl, dimethylcyclohexyl, vinylcarbonyl, (1-chloromethylcarbonyl)-piperidinyl, (1-carboxy (Methylcarbonyl)-piperidinyl, carboxyphenyl, (1-cyanomethylcarbonyl)-piperidinyl, (1-amido)-piperidinyl, piperidinone, hydroxyethylpiperidinone , Piperidinyl, hydroxypiperidinyl, hydroxymethylphenyl, 1-(2-methylsulfonylethyl)-pyrazolyl, or or
  • R 3 together with W form ureido, hydroxypiperidinyl, hydroxymethylpiperidinyl, hydroxymethylpyrrolidinyl, Or (2hydroxy-2-propyl)-azetidinyl.
  • Y 1 and Y 2 are both N, or Y 1 is N and Y 2 is CH;
  • X is O and W is NH;
  • R 1 , R 2 and R 3 have the definitions given above in any of the embodiments.
  • Y 1 and Y 2 are both N, or Y 1 is N and Y 2 is CH;
  • X is O and W is NH;
  • R 2 is selected from H, tert-butyl, (1-ethylaminoacyl)-piperidinyl, hydroxyethyl, isopropyl, fluoropropyl, C(CH 3 ) 2 CF 3 , cyclopropyl, hydroxy ring Propyl, cyclobutyl, hydroxycyclobutyl, cyclopentyl, hydroxycyclopentyl, cyclohexyl, hydroxycyclohexyl, methoxyphenyl, methoxybenzyl, methylsulfonylphenyl, (4- Methylpiperazinyl)-phenyl, triazolyl, or
  • R 2 together with X form morpholinyl, tert-butylureido, pyrazolyl or (3-oxo)-piperazinyl;
  • R 3 is selected from H, (3-hydroxy-4-methyl)-cyclohexyl, formyl, dimethylcyclohexyl, vinylcarbonyl, (1-chloromethylcarbonyl)-piperidinyl, (1-carboxy (Methylcarbonyl)-piperidinyl, carboxyphenyl, (1-cyanomethylcarbonyl)-piperidinyl, (1-amido)-piperidinyl, piperidinone, hydroxyethylpiperidinone , Piperidinyl, hydroxypiperidinyl, hydroxymethylphenyl, 1-(2-methylsulfonylethyl)-pyrazolyl, or or
  • R 3 together with W form ureido, hydroxypiperidinyl, hydroxymethylpiperidinyl, hydroxymethylpyrrolidinyl, Or (2-hydroxy-2-propyl)-azetidinyl.
  • Y 1 and Y 2 are both N, or Y 1 is N and Y 2 is CH;
  • X and W are both NH, or X is O and W is NH;
  • R 2 together with X form unsubstituted or substituted by one, two or more oxo, hydroxy, C 1-6 alkyl, C 1-6 alkoxy substituted ureido, 5-6 membered heterocyclic group or 5-6 membered heteroaryl;
  • R 2 together with X form the following groups that are unsubstituted or optionally substituted with one, two or more R b : NHC(O)NR 11 R 12 , azetidinyl, piperidinyl , Piperazinyl, morpholinyl, pyrrolidinyl, imidazolidinyl, pyrrolinyl, pyranyl, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, isoxadiazolyl, thiadiazole Group, isothiadiazolyl, tetrazolyl, pyrrolyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl;
  • R 1 , R 3 , R 11 , R 12 and R b have the definitions given above in any of the embodiments.
  • Y 1 and Y 2 are both N, or Y 1 is N and Y 2 is CH;
  • X and W are both NH, or X is O and W is NH;
  • R 2 together with X form ureido, pyrrolidinyl, imidazolidinyl, pyrrolinyl, pyrazolyl substituted by one or two oxo, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy groups , Imidazolyl, piperidinyl, morpholinyl or piperazinyl;
  • R 3 is selected from H, (3-hydroxy-4-methyl)-cyclohexyl, formyl, dimethylcyclohexyl, vinylcarbonyl, (1-chloromethylcarbonyl)-piperidinyl, (1-carboxy (Methylcarbonyl)-piperidinyl, carboxyphenyl, (1-cyanomethylcarbonyl)-piperidinyl, (1-amido)-piperidinyl, piperidinone, hydroxyethylpiperidinone , Piperidinyl, hydroxypiperidinyl, hydroxymethylphenyl, 1-(2-methylsulfonylethyl)-pyrazolyl, or or
  • R 3 together with W form ureido, hydroxypiperidinyl, hydroxymethylpiperidinyl, hydroxymethylpyrrolidinyl, Or (2-hydroxy-2-propyl)-azetidinyl.
  • Y 1 and Y 2 are both N, or Y 1 is N and Y 2 is CH;
  • X and W are both NH, or X is O and W is NH;
  • R 3 together with W forms unsubstituted or is substituted by one, two or more C (O) NHOH, C (O) N (OH) CH 3 , oxo, hydroxyl, C 1-6 alkyl, hydroxyl-
  • R 1 and R 2 have the definitions given above in any of the embodiments.
  • Y 1 and Y 2 are both N, or Y 1 is N and Y 2 is CH;
  • X and W are both NH, or X is O and W is NH;
  • R 3 together with W forms unsubstituted or is substituted by one, two or more C (O) NHOH, C (O) N (OH) CH 3 , oxo, hydroxyl, C 1-6 alkyl, hydroxyl-
  • R 1 and R 2 have the definitions given above in any of the embodiments.
  • Y 1 and Y 2 are both N, or Y 1 is N and Y 2 is CH;
  • X and W are both NH, or X is O and W is NH;
  • R 2 is selected from H, tert-butyl, (1-ethylaminoacyl)-piperidinyl, hydroxyethyl, isopropyl, fluoropropyl, C(CH 3 ) 2 CF 3 , cyclopropyl, hydroxy ring Propyl, cyclobutyl, hydroxycyclobutyl, cyclopentyl, hydroxycyclopentyl, cyclohexyl, hydroxycyclohexyl, methoxyphenyl, methoxybenzyl, methylsulfonylphenyl, (4- Methylpiperazinyl)-phenyl, triazolyl, or
  • R 2 together with X form morpholinyl, tert-butylureido, pyrazolyl or (3-oxo)-piperazinyl;
  • R 3 together with W form hydroxypiperidinyl, hydroxymethylpiperidinyl, hydroxymethylpyrrolidinyl, Or (2-hydroxy-2-propyl)-azetidinyl.
  • the compound represented by formula (I) is a compound of formula (II) below:
  • Y 2 , X, R 1 and R 2 have the definitions given above in any of the embodiments of formula (I);
  • Y 3 is CR 8 R 9 or NR 10 ;
  • R 10 is selected from H, C(O)NH 2 , C(O)CH 2 CN, C(O)CH 2 COOH or C which is unsubstituted or optionally substituted by one, two or more hydroxyl groups or halogens 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkenyl or C 1-6 alkynyl;
  • R 3a and R 3b are the same or different and are independently selected from H, hydroxy, halo, cyano, oxo, or unsubstituted or optionally substituted with one, two or more hydroxyl groups substituted with halogen or a C 1 -6 alkyl, C 1-6 alkoxy, C 1-6 alkenyl or C 1-6 alkynyl.
  • Y 2 , X, R 1 and R 2 have the definitions given above in any of the embodiments of formula (I);
  • Y 3 is CR 8 R 9 or NR 10 ;
  • R 10 is selected from H, C(O)NH 2 , C(O)CH 2 CN, C(O)CH 2 COOH, or unsubstituted or optionally substituted by one, two or more hydroxyl groups or halogens C 1-6 alkyl;
  • R 3a and R 3b are the same or different, each independently selected from H, hydroxy, halo, cyano, oxo, or unsubstituted or optionally substituted by one, two or more hydroxy or halo C 1- 6 Alkyl, C 1-6 alkoxy, C 1-6 alkenyl or C 1-6 alkynyl.
  • Y 2 , X, R 1 and R 2 have the definitions given above in any of the embodiments of formula (I);
  • Y 3 is CR 8 R 9 ;
  • R 8 is H, and R 9 is selected from hydroxyl, or C 1-6 alkoxy which is unsubstituted or optionally substituted with one, two or more hydroxyl groups or halogen;
  • R 3a is located at the 4-position of the cyclohexyl ring and is selected from H, hydroxy, halogen, cyano, oxo, or unsubstituted or optionally substituted with one, two or more hydroxy groups or halogen C 1-6 Alkyl, C 1-6 alkoxy, C 1-6 alkenyl or C 1-6 alkynyl; and
  • R 3b is selected from H, hydroxy, halogen, cyano, oxo, or unsubstituted or optionally substituted by one, two or more hydroxy or halogen C 1-6 alkyl or C 1-6 alkoxy base.
  • the compound represented by formula (I) is a compound of the following formula (II-1):
  • Y 2 is N or CH
  • X is NH or O
  • R 2 is selected from H, or unsubstituted or optionally substituted with one, two or more R b as follows: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 1-6 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 6-14 aryl, C 6-14 aryl C 1-10 alkyl, 5-14 membered hetero Aryl or 5-14 membered heteroaryl C 1-10 alkyl; or
  • R 2 together with X form the following groups that are unsubstituted or optionally substituted with one, two or more R b : NHC(O)NR 11 R 12 , 3-10 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl;
  • R 11 , R 12 , R 13 , R 14 and R 15 have the definitions given above in any embodiment of the compound of formula (I);
  • Each Ra is independently selected from CN, halogen, OH, NH 2 , oxo, or unsubstituted or optionally substituted with one, two or more R f as follows: C 1-6 alkyl Or C 1-6 alkoxy; and
  • Each R b is independently selected from CN, halogen, OH, NH 2 , COOH, NO 2 , oxo, S (O) 2 CH 3 , C (O) NHCH 2 CH 3 , or unsubstituted or optionally One, two or more of the following groups substituted by R f : C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 6- 14 aryl or 5-14 membered heteroaryl;
  • R f has the definition given above in any of the embodiments of the compound of formula (I).
  • Y 2 is N or CH
  • X is NH or O
  • R 2 is selected from H, or unsubstituted or optionally substituted with one, two or more R b as follows: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 1-6 alkoxy, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, phenyl, benzyl, 5-6 membered heteroaryl or 5-6 membered heteroaryl -C 1- 6 alkyl; or
  • R 2 together with X form an unsubstituted or optionally substituted with one, two or more R b NHC(O)NR 11 R 12 , a 3-7 membered heterocyclic group or a 5-6 membered heteroaryl group;
  • R 11 , R 12 , R 13 , R 14 and R 15 have the definitions given above in any embodiment of the compound of formula (I);
  • Each Ra is independently selected from CN, halogen, OH, NH 2 , oxo, or unsubstituted or optionally substituted with one, two or more R f as follows: C 1-6 alkyl Or C 1-6 alkoxy; and
  • Each R b is independently selected from CN, halogen, OH, NH 2 , COOH, NO 2 , oxo, S (O) 2 CH 3 , C (O) NHCH 2 CH 3 , or unsubstituted or optionally One, two or more of the following groups substituted by R f : C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
  • Each R c is independently selected from CN, halogen, OH, NH 2 , COOH, NO 2 , C (O) NH 2 , C (O) NHOH, C (O) N (OH) CH 3 , oxo, C (O)CH 2 COOH, C(O)CH 2 CN, C(O)CH 2 Cl, C(O)CH 2 F or C(O)CH 2 Br, or unsubstituted or optionally one or two One or more of the following groups substituted by R f : C 1-6 alkyl, C 1-6 alkoxy, 3-7 membered heterocyclyl or 5-6 membered heteroaryl;
  • Each R f is the same or different, and is independently selected from CN, halogen, OH, NH 2 , oxo, S(O) 2 CH 3 , C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkoxy.
  • Y 2 is N or CH
  • X is NH or O
  • R 2 is selected from H, or unsubstituted or optionally substituted with one, two or more R b as follows: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 1-6 alkoxy, C 3-6 cycloalkyl, phenyl, benzyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl , Isoxadiazolyl, thiadiazolyl, isothiadiazolyl, tetrazolyl, pyrrolidinyl, oxetanyl, pyrrolyl, furyl, thiazolyl, isothiazolyl, oxazolyl, Isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyranyl, thienyl or or
  • R 2 together with X form the following groups which are unsubstituted or optionally substituted with one, two or more R b : NHC(O)NR 11 R 12 , azetidinyl, piperidinyl, piperazine Group, morpholinyl, pyrrolidinyl, imidazolidinyl, pyrrolinyl, pyranyl, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, isoxadiazolyl, thiadiazolyl, iso Thiadiazolyl, tetrazolyl, pyrrolyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl;
  • R 11 and R 12 are independently selected from H, or unsubstituted or optionally substituted C 1-6 alkyl with one, two or more R e; or
  • R 11 and R 12 together with the nitrogen atom to which they are attached form an unsubstituted or optionally substituted with one, two or more R e substituted 3-7 membered azacycloalkyl;
  • R 13 is selected from H, cyano, methyl or hydroxyl
  • R 14 is selected from H, hydroxyl, halogen, or unsubstituted or optionally substituted with one, two or more R f as follows: C 1-6 alkyl, C 2-6 alkenyl, C 2 -6alkynyl , C 1-6 alkoxy or C 3-6 cycloalkyl;
  • R 15 is selected from H, or unsubstituted or optionally substituted C 1-6 alkyl with one, two or more R f;
  • Each Ra is independently selected from CN, halogen, OH, NH 2 , oxo, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 Alkoxy or CH 2 CH 2 S(O) 2 CH 3 ; and
  • Each R b is independently selected from CN, halogen, OH, NH 2 , COOH, NO 2 , oxo, S (O) 2 CH 3 , C (O) NHCH 2 CH 3 , or unsubstituted or optionally One, two or more of the following groups substituted by R f : C 1-6 alkyl, C 1-6 alkoxy, phenyl or piperidinyl;
  • Each R e and R f is independently selected from CN, halogen, OH, NH 2 , oxo, S(O) 2 CH 3 , C 1-6 alkyl, halo C 1-6 alkyl, C 1- 6 alkoxy or halo C 1-6 alkoxy group.
  • Y 2 is N or CH
  • X is NH or O
  • R 2 is selected from H, tert-butyl, (1-ethylaminoacyl)-piperidinyl, hydroxyethyl, isopropyl, fluoropropyl, C(CH 3 ) 2 CF 3 , cyclopropyl, hydroxy ring Propyl, cyclobutyl, hydroxycyclobutyl, hydroxycyclopentyl, cyclopentyl, hydroxycyclohexyl, cyclohexyl, methoxyphenyl, methoxybenzyl, methylsulfonylphenyl, (4- Methylpiperazinyl)-phenyl, triazolyl, or
  • R 2 together with X form unsubstituted or substituted by one or two oxo, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy substituted ureido, pyrazolyl, pyrrolidinyl, imidazolidinyl, Pyrrolinyl, piperidinyl, morpholinyl or piperazinyl.
  • Y 2 is N or CH
  • X is NH or O
  • R 2 is selected from H, methoxyphenyl, methoxybenzyl, methylsulfonylphenyl, (4-methylpiperazinyl)-phenyl, triazolyl, or
  • R 2 together with X form morpholinyl, tert-butylureido, pyrazolyl or (3-oxo)-piperazinyl.
  • the compound of formula (II-1) has the following three-dimensional structure of formula (II-1a):
  • each group has the corresponding definition given above in any of the embodiments of the compound of formula (I) or formula (II-1).
  • the compound of formula (I) can be selected from the compounds exemplified in Table 1 below and their pharmaceutically acceptable salts:
  • the pharmaceutically acceptable salt of the compound of the present invention may be an acid addition salt or a base addition salt.
  • it may be an acid addition salt formed with the following inorganic or organic acids: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid , Formic acid, acetic acid, tartaric acid, fumaric acid, citric acid, malic acid, oxalic acid, ascorbic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, etc., or may be combined with sodium ion, potassium ion, calcium ion, Salts formed by ammonium ions, etc. It can be specifically as follows.
  • the present invention also provides a preparation method of the compound of formula (I), which can be one of the following schemes:
  • R 2 ' is R 2 -X
  • R 3 ' is R 3 -W
  • Nu is a nucleophilic group
  • R 1 , R 2 , R 3 , X and W are as described above in any of the embodiments Definition.
  • Option 1 includes the following steps 1a and 1b:
  • the Lewis base can be selected from triethylamine, diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide, Any one or two or more of sodium hydroxide, or an excess of the nucleophile containing R 3 'as the Lewis base;
  • the reaction can be carried out in the presence or absence of a solvent.
  • the solvent may be an organic solvent, and the organic solvent is preferably selected from methanol, ethanol, isopropanol, tert-butanol, acetonitrile, tetrahydrofuran, dioxane, dimethylformamide, dimethyl One or more of sulfoxide, acetone and dichloromethane;
  • the molar ratio of the compound SM-1A to the nucleophile containing R 3 ' may be 1:(0.8 ⁇ 10); the molar ratio of the compound SM-1A to the Lewis base may be 1:(0.8 ⁇ 5 );
  • the weight-volume ratio of the compound SM-1A to the organic solvent can be 1:(0-100)g/ml, preferably 1:(3-100)g/ml; the reaction can be at -10°C ⁇ 40°C It is carried out at -10°C to 40°C; the reaction time can be 1 to 24 hours.
  • IM-1A reacts with a nucleophile containing R 2 'under the action of a Lewis base to generate corresponding products or intermediates;
  • the Lewis base can be selected from triethylamine, diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide, Any one or two or more of sodium hydroxide, or an excess of the nucleophile containing R 2 ′ as the Lewis base;
  • the reaction can be carried out in the presence or absence of a solvent.
  • the solvent may be an organic solvent, and the organic solvent is preferably selected from methanol, ethanol, isopropanol, tert-butanol, acetonitrile, tetrahydrofuran, dioxane, dimethylformamide, dimethyl One or more of sulfoxide, acetone and dichloromethane;
  • the molar ratio of the compound SM-1A to the nucleophile containing R 2 ' may be 1:(0.8 ⁇ 10); the molar ratio of the compound SM-1A to the Lewis base may be 1:(0.8 ⁇ 5 );
  • the weight-volume ratio of the compound SM-1A to the organic solvent can be 1:(0-100)g/ml, preferably 1:(3-100)g/ml; the reaction can be at 20°C ⁇ 150°C It is preferably carried out at 50°C to 150°C; the reaction time can be 1 to 24 hours.
  • R 1 ' is R 1 or a group derivable to R 1 , R 2 ' is R 2 -X, R 3 'is R 3 -W, Nu is a nucleophilic group, R 1 , R 2 , R 3.
  • X and W have the definitions described above in any of the embodiments.
  • Scheme 2 includes the following steps 2a-2d:
  • reaction conditions can be conventionally selected.
  • the molar ratio of the compound SM-1B to the sodium methyl mercaptan can be 1:(0.8-5);
  • the reaction can be carried out in the presence or absence of a solvent.
  • the solvent may be an organic solvent, and the organic solvent is preferably selected from methanol, ethanol, isopropanol, tert-butanol, acetonitrile, tetrahydrofuran, dioxane, dimethylformamide, dimethyl One or more of sulfoxide, acetone and dichloromethane;
  • the weight-volume ratio of the compound SM-1B to the organic solvent can be 1:(0-100)g/ml, preferably 1:(3-100)g/ml; the reaction can be carried out at -10°C ⁇ 100°C It is preferably carried out at -10°C to 40°C; the reaction time can be 1 to 24 hours.
  • IM-1B reacts with the nucleophile containing R 2 'under the action of Lewis base to generate IM-2B;
  • the Lewis base can be selected from triethylamine, diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide, Any one or two or more of sodium hydroxide, or an excess of the nucleophile containing R 2 ′ as the Lewis base;
  • the reaction can be carried out in the presence or absence of a solvent.
  • the solvent may be an organic solvent, and the organic solvent is preferably selected from methanol, ethanol, isopropanol, tert-butanol, acetonitrile, tetrahydrofuran, dioxane, dimethylformamide, dimethyl One or more of sulfoxide, acetone and dichloromethane;
  • the molar ratio of the compound SM-1B to the nucleophile containing R 2 ' may be 1:(0.8 ⁇ 10); the molar ratio of the compound SM-1B to the Lewis base may be 1:(0.8 ⁇ 5 );
  • the weight-volume ratio of the compound SM-1B to the organic solvent can be 1:(0-100)g/ml, preferably 1:(3-100)g/ml; the reaction can be at 10°C ⁇ 150°C It is preferably carried out at 50°C to 150°C; the reaction time can be 1 to 24 hours.
  • reaction conditions can be conventionally selected.
  • the molar ratio of the compound IM-2B to the m-chloroperoxybenzoic acid can be 1:(0.8-10);
  • the reaction can be carried out in the presence or absence of a solvent.
  • the solvent may be an organic solvent, and the organic solvent is preferably selected from methanol, ethanol, isopropanol, tert-butanol, acetonitrile, tetrahydrofuran, dioxane, dimethylformamide, dimethyl One or more of sulfoxide, acetone and dichloromethane;
  • the weight-volume ratio of the compound IM-2B to the organic solvent can be 1:(0-100)g/ml, preferably 1:(3-100)g/ml; the reaction can be carried out at -20°C ⁇ 150°C It is preferably carried out at -20°C to 40°C; the reaction time can be 1 to 24 hours.
  • IM-3B reacts with a nucleophile containing R 3 'under the action of a Lewis base to generate corresponding products or intermediates; optionally, further derivatization reaction can be carried out;
  • the Lewis base can be selected from triethylamine, diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide, Any one or two or more of sodium hydroxide, or an excess of the nucleophile containing R 3 'as the Lewis base;
  • the reaction can be carried out in the presence or absence of a solvent.
  • the solvent may be an organic solvent, and the organic solvent is preferably selected from methanol, ethanol, isopropanol, tert-butanol, acetonitrile, tetrahydrofuran, dioxane, dimethylformamide, dimethyl One or more of sulfoxide, acetone and dichloromethane;
  • the molar ratio of the compound IM-3B and the nucleophile containing R 3 ' may be 1:(0.8 ⁇ 10); the molar ratio of the compound IM-3B and the Lewis base may be 1:(0.8 ⁇ 5 );
  • the weight-volume ratio of the compound IM-3B and the organic solvent can be 1:(0-100)g/ml, preferably 1:(3-100)g/ml; the reaction can be at 20°C ⁇ 150°C It is preferably carried out at 50°C to 150°C; the reaction time can be 1 to 24 hours.
  • R 2 has the definition described above in any of the embodiments.
  • Scheme 3 includes the following steps 3a-3c:
  • the Lewis base can be selected from triethylamine, diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide, Any one or two or more of sodium hydroxide, or excess SM-2C as the Lewis base;
  • the reaction can be carried out in the presence or absence of a solvent.
  • the solvent may be an organic solvent, and the organic solvent is preferably selected from methanol, ethanol, isopropanol, tert-butanol, acetonitrile, tetrahydrofuran, dioxane, dimethylformamide, dimethyl One or more of sulfoxide, acetone and dichloromethane;
  • the molar ratio of the compound SM-1C to the SM-2C can be 1:(0.8 ⁇ 10); the molar ratio of the compound SM-1C to the Lewis base can be 1:(0.8 ⁇ 5); the compound
  • the weight-volume ratio of SM-1C to organic solvent can be 1:(0-100)g/ml, preferably 1:(3-100)g/ml; the reaction can be carried out at 10°C ⁇ 150°C, preferably 25 It is carried out at °C ⁇ 120°C; the reaction time can be 1 ⁇ 24h.
  • the Lewis base can be selected from triethylamine, diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide, Any one or two or more of sodium hydroxide, or excess R 2 NH 2 as the Lewis base;
  • the reaction can be carried out in the presence or absence of a solvent.
  • the solvent may preferably be an organic solvent, and the organic solvent is preferably selected from the group consisting of methanol, ethanol, isopropanol, tert-butanol, acetonitrile, tetrahydrofuran, dioxane, dimethylformamide, and dimethylformamide.
  • a solvent preferably be an organic solvent
  • the organic solvent is preferably selected from the group consisting of methanol, ethanol, isopropanol, tert-butanol, acetonitrile, tetrahydrofuran, dioxane, dimethylformamide, and dimethylformamide.
  • sulfoxide, acetone and dichloromethane One or more of sulfoxide, acetone and dichloromethane;
  • the molar ratio of the compound IM-1C and R 2 NH 2 may be 1:(0.8 ⁇ 10); the molar ratio of the compound IM-1C and the Lewis base may be 1:(0.8 ⁇ 5); the compound IM
  • the weight-volume ratio of -1C to the organic solvent can be 1:(0-100)g/ml, preferably 1:(3-100)g/ml; the reaction can be carried out at 20°C ⁇ 150°C, preferably at 50°C It is carried out at ⁇ 150°C; the reaction time can be 1 ⁇ 24h.
  • the Lewis base can be selected from triethylamine, diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide, Any one or two or more of sodium hydroxide;
  • the reaction can be carried out in the presence or absence of a solvent.
  • the solvent may be an organic solvent, and the organic solvent is preferably selected from the group consisting of water, methanol, ethanol, isopropanol, tert-butanol, acetonitrile, tetrahydrofuran, dioxane, dimethylformamide, two One or more of methyl sulfoxide, acetone and dichloromethane;
  • the molar ratio of the compound IM-2C and H 2 O 2 may be 1: (0.8-20); the molar ratio of the compound IM-2C and the Lewis base may be 1: (0.8-5); the compound IM
  • the weight-volume ratio of -2C to the solvent can be 1:(0-100)g/ml, preferably 1:(3-100)g/ml; the reaction can be carried out at -78°C ⁇ 100°C, preferably at -78 It is carried out at °C ⁇ 20°C; the reaction time can be 1 ⁇ 24h.
  • the compound represented by formula (I), its racemates, stereoisomers, tautomers, and nitrogen oxides can be used as raw materials or intermediates to prepare the compounds represented by formula (I) Pharmaceutically acceptable salts of the compounds, racemates, stereoisomers, tautomers, and nitrogen oxides thereof.
  • the present invention also provides compounds represented by formula (I), their racemates, stereoisomers, tautomers, and nitrogen oxides in the preparation of compounds represented by formula (I), their racemates , Stereoisomers, tautomers, and pharmaceutically acceptable salts of nitrogen oxides.
  • the present invention also provides compounds represented by formula I, their racemates, stereoisomers, tautomers, nitrogen oxides, isotope markers, solvates, polymorphs, metabolites, esters, pharmaceutically At least one of the acceptable salts or prodrugs is used in the preparation of medicines, which are inhibitors of protein kinases.
  • the medicine is used to treat, prevent or ameliorate diseases in animals or humans, including pulmonary fibrosis or liver fibrosis.
  • the compound is active against protein kinases, especially JNK1 and/or JNK2.
  • the method provided herein includes combining an effective amount of the compound of the present invention (including the compound represented by formula (I), its racemate, stereoisomer, tautomer, nitrogen oxide or their pharmaceutically acceptable salt , The same below) give to those who need it.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by formula (I), its racemate, stereoisomer, tautomer, nitrogen oxide, isotope label, solvate, Polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs.
  • the pharmaceutical composition may also optionally include pharmaceutically acceptable excipients, such as carriers and excipients.
  • the auxiliary material may be one or more selected from the group consisting of disintegrants, glidants, lubricants, diluents or fillers, binders, and colorants.
  • the present invention also provides a method for modulating the function of JNK kinase, which comprises administering an effective amount of one or more compounds of the present invention, or a pharmaceutical composition containing the compounds, to an individual in need thereof.
  • the present invention provides a method of inhibiting the kinase in a cell expressing a kinase, comprising contacting the cell with an effective amount of a compound of the present invention.
  • the kinase is JNK1, JNK2, or a mutant or equivalent thereof, or a combination thereof, and the compound is one or more compounds of formula (I), such as compounds from Table 1.
  • liver fibrotic diseases such as non-alcoholic steatohepatitis, steatosis (ie fatty liver), liver cirrhosis, primary sclerosing cholangitis, primary biliary Liver cirrhosis, hepatitis, hepatocellular carcinoma, and liver fibrosis accompanied by long-term or repeated alcohol intake (alcoholic hepatitis), accompanied by infection (e.g. viral infection such as HCV), accompanied by liver transplantation, or accompanied by drug-induced liver
  • a method of injury includes administering an effective amount of a compound of the present invention to a subject in need thereof.
  • liver or lung fibrotic diseases such as non-alcoholic steatohepatitis, steatosis (ie fatty liver), liver cirrhosis, primary sclerosing cholangitis, primary
  • the method for diabetic or metabolic syndrome of biliary cirrhosis and hepatitis includes administering an effective amount of the compound of the present invention to a subject in need thereof.
  • idiopathic pulmonary fibrosis IPF
  • systemic sclerosis e.g., scleroderma
  • chronic allograft nephropathy antibodies
  • the method of mediated rejection or lupus disorder includes administering an effective amount of the compound of the present invention to a subject in need thereof.
  • the lupus is lupus erythematosus (e.g., discoid lupus erythematosus or cutaneous lupus erythematosus) or systemic lupus erythematosus.
  • a method for treating or preventing a condition treatable or preventable by inhibiting JNK1 and/or JNK2 comprising administering to a subject in need thereof an effective amount of a compound of the present invention.
  • Such conditions include rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis; asthma, bronchitis; allergic rhinitis; chronic obstructive pulmonary disease; cystic fibrosis; inflammatory bowel disease; allergic Bowel syndrome (irritable bowel syndrome); mucinous colitis; ulcerative colitis; Crohn's disease; Huntington's disease; hepatitis; pancreatitis; nephritis; multiple sclerosis; lupus erythematosus; II Type diabetes; obesity; atherosclerosis; restenosis after angioplasty; left ventricular hypertrophy; myocardial infarction; stroke; ischemic injury of heart, lung, intestine,
  • a compound of formula (I) for use in modulating JNK kinase function including administering an effective amount of one or more compounds of the present invention to an individual in need thereof, or a compound containing said compound Pharmaceutical composition.
  • the present invention provides a compound of formula (I) for use in a method for inhibiting the kinase in a cell expressing a kinase, comprising contacting the cell with an effective amount of the compound of the present invention.
  • the kinase is JNK1, JNK2, or a mutant or equivalent thereof, or a combination thereof, and the compound is one or more compounds of formula (I), such as compounds from Table 1.
  • liver fibrotic diseases such as non-alcoholic steatohepatitis, steatosis (ie fatty liver), liver cirrhosis, primary sclerosing cholangitis , Primary biliary cirrhosis, hepatitis, hepatocellular carcinoma and liver fibrosis accompanied by long-term or repeated alcohol intake (alcoholic hepatitis), accompanied by infection (e.g. viral infection such as HCV), accompanied by liver transplantation or
  • the method accompanied by drug-induced liver injury includes administering an effective amount of the compound of the present invention to a subject in need thereof.
  • liver or lung fibrotic diseases such as non-alcoholic steatohepatitis, steatosis (ie fatty liver), liver cirrhosis, primary sclerosing cholangitis, primary
  • the method for diabetic or metabolic syndrome of biliary cirrhosis and hepatitis includes administering an effective amount of the compound of the present invention to a subject in need thereof.
  • a compound of formula (I) for use in the treatment or prevention of one or more selected from idiopathic pulmonary fibrosis (IPF), systemic sclerosis, scleroderma, chronic allogeneic
  • the method of graft nephropathy, antibody-mediated rejection or lupus disorder includes administering an effective amount of the compound of the present invention to a subject in need thereof.
  • the lupus is lupus erythematosus (eg, discoid lupus erythematosus or cutaneous lupus erythematosus) or systemic lupus erythematosus.
  • a compound of formula (I) for use in a method of treating or preventing a condition treatable or preventable by inhibiting JNK1 and/or JNK2, the method comprising administering to a subject in need thereof an effective amount of Compounds of the invention.
  • Such conditions include rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis; asthma, bronchitis; allergic rhinitis; chronic obstructive pulmonary disease; cystic fibrosis; inflammatory bowel disease; allergic Bowel syndrome; mucinous colitis; ulcerative colitis; Crohn's disease; Huntington's disease; hepatitis; pancreatitis; nephritis; multiple sclerosis; lupus erythematosus; type II diabetes; obesity; atherosclerosis; angioplasty Postoperative restenosis; left ventricular hypertrophy; myocardial infarction; stroke; ischemic injury of heart, lung, intestine, kidney, liver, pancreas, spleen and brain; acute or chronic organ transplant rejection; preservation of transplanted organs ; Organ failure or limb defect (for example, including but not limited to caused by ischemia-reperfusion injury, trauma, whole body injury, car accident
  • halogen refers to F, Cl, Br, and I. In other words, F, Cl, Br, and I can be described as “halogen" in this specification.
  • C 1-40 alkyl should be understood to preferably mean a straight or branched chain saturated monovalent hydrocarbon group having 1 to 40 carbon atoms, preferably a C 1-10 alkyl group and a C 1-6 alkyl group.
  • C 1-10 alkyl should be understood to preferably mean a straight or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • C 1-6 alkyl is understood to preferably mean a straight or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Group, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, 1,2-dimethylbutyl, etc.
  • the group has 1, 2, 3, 4, 5 or 6 carbon atoms (ie, C 1-6 alkyl), such as methyl, ethyl, propyl, butyl, isopropyl, Isobutyl, sec-butyl, tert-butyl, more particularly, the group has 1, 2 or 3 carbon atoms (ie, C 1-3 alkyl), such as methyl, ethyl, n-propyl Or isopropyl.
  • C 1-3 alkyl such as methyl, ethyl, n-propyl Or isopropyl.
  • C 1-40 alkoxy refers to the group -OR, where R is a substituted or unsubstituted C 1-40 alkyl group, where "C 1-40 alkyl” has the definition given above.
  • C 1-10 alkoxy refers to the group -OC 1-10 alkyl
  • C 1-6 alkoxy refers to the group -OC 1-6 alkyl
  • C 1-3 alkyl The oxy group refers to the group -OC 1-3 alkyl, where "C 1-10 alkyl", “C 1-6 alkyl” and “C 1-3 alkyl” have the definitions given above.
  • alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, N-hexyloxy and 1,2-dimethylbutoxy.
  • C 2-40 alkenyl should be understood to preferably mean a straight or branched monovalent hydrocarbon group, which contains one or more double bonds and has 2 to 40 carbon atoms, preferably “C 2-10 alkenyl” .
  • C 2-10 alkenyl should be understood to preferably mean a straight or branched monovalent hydrocarbon group, which contains one or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10
  • One carbon atom for example, has 2, 3, 4, 5, or 6 carbon atoms (ie, C 2-6 alkenyl), and has 2 or 3 carbon atoms (ie, C 2-3 alkenyl). It should be understood that where the alkenyl group contains more than one double bond, the double bonds may be separated from each other or conjugated.
  • the alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)- But-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z) -Pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-ene Group, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3- Alkenyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-eny
  • C 2-40 alkynyl should be understood to mean a straight or branched monovalent hydrocarbon group, which contains one or more triple bonds and has 2-40 carbon atoms, preferably "C 2-10 alkynyl".
  • C 2-10 alkynyl should be understood to preferably mean a straight or branched monovalent hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example, having 2, 3, 4, 5, or 6 carbon atoms (ie, "C 2-6 alkynyl”), having 2 or 3 carbon atoms ("C 2-3 -alkynyl ").
  • the alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl , Pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, Hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl , 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpentyl -4-ynyl, 2-methylpent-3-yn
  • C 3-20 cycloalkyl should be understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring, which may be a spiro ring or a bridged ring, which has 3 to 20 carbon atoms, preferably "C 3-10 cycloalkane base".
  • C 3-10 cycloalkyl should be understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring, which may be a spiro ring or a bridged ring, which has 3, 4, 5, 6, 7, 8, 9 or 10 Carbon atoms.
  • the C 3-10 cycloalkyl group may be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic group. Hydrocarbon groups such as decalin ring.
  • C 3-6 cycloalkyl should be understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring, which may be a spiro ring or a bridged ring, which has 3, 4, 5 or 6 carbon atoms.
  • the C 3-6 cycloalkyl group may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.0]butyl, spiropentyl, spiro[2.3]hexyl, bicyclo[ 1.1.1]Pentyl, bicyclo[2.1.0]pentyl, bicyclo[2.1.1]hexyl or bicyclo[3.1.0]hexyl.
  • 3-20 membered heterocyclic group means a monovalent group of a 3 to 20 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms.
  • the non-aromatic ring system may be saturated or contain One or more double bonds, which can be monocyclic, bicyclic, spirocyclic or bridged, wherein each ring heteroatom is independently selected from N, O, S, B, P, and Si.
  • the "3-20 membered heterocyclic group” may be, for example, “3-10 membered heterocyclic group", “3-7 membered heterocyclic group” or "5-6 membered heterocyclic group”.
  • 3-10 membered heterocyclic group means a monovalent group of a 3 to 10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms.
  • the non-aromatic ring system can be monocyclic or bicyclic. , Spiro ring or bridged ring, wherein each ring heteroatom is independently selected from N, O, S, B, P and Si, and preferably contains 1-3 heteroatoms selected from N, O and S.
  • 3-7 membered heterocyclic group means a monovalent group of 3 to 7 non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms.
  • the non-aromatic ring system can be monocyclic, bicyclic, Spiro or bridged rings, wherein each ring heteroatom is independently selected from N, O, S, B, P, and Si, and preferably contains 1-3 heteroatoms selected from N, O, and S.
  • the term "5-6 membered heterocyclic group” means a monovalent group of 5 to 6 non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms.
  • the non-aromatic ring system is usually a monocyclic ring, wherein each Each ring heteroatom is independently selected from N, O, S, B, P and Si, and preferably contains 1-3 heteroatoms selected from N, O and S.
  • the heterocyclic group may be connected to the rest of the molecule through any of the carbon atoms or the nitrogen atom (if present). Regardless of whether the heterocyclic group is modified with "substituted", each atom of the heterocyclic group is independently optionally substituted, for example, by 1 to 5 substituents, 1 to 3 substituents or 1 substituent, Suitable substituents include, but are not limited to, hydroxyl, amino, oxo, halogen, cyano, nitro, C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, and the like.
  • the heterocyclic group may include, but is not limited to: a 3-membered ring, such as aziridinyl, oxiranyl, and thiiridine; a 4-membered ring, such as azetidinyl, oxygen Etanyl and thietanyl; 5-membered ring, such as dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, dioxolyl, pyrrolidinyl, dihydro Pyrrolyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, dioxolanyl, oxasulfuranyl, disulfuranyl, oxazolidine- 2-keto, triazolinyl, oxadiazolinyl and thiadiazolinyl; or 6-membered ring, such as dihydropyranyl, tetrahydropyranyl,
  • Bicyclic heterocyclic group such as but not limited to 5,5 membered ring, such as hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or 5,6 membered bicyclic ring, such as hexahydropyrrolo[1,2 -a] Pyrazine-2(1H)-yl ring.
  • the ring containing nitrogen atoms may be partially unsaturated, that is, it may contain one or more double bonds, such as but not limited to 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadi Azinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl, or it may be benzo-fused, such as but not limited to dihydroisoquinolinyl.
  • C 6-20 aryl should be understood to preferably mean a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, preferably “C 6-14 aryl” .
  • the term “C 6-14 aryl” should be understood as preferably meaning a monocyclic, bicyclic or partially aromatic monocyclic or partially aromatic monocyclic or partially aromatic having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms
  • a tricyclic hydrocarbon ring (“C 6-14 aryl"), especially a ring having 6 carbon atoms (“C 6 aryl”), such as phenyl; or biphenyl, or one having 9 carbon atoms Ring (“C 9 aryl”), such as indanyl or indenyl, or a ring with 10 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, Either a ring having 13 carbon
  • 5-20 membered heteroaryl should be understood to include such a monovalent monocyclic, bicyclic or tricyclic aromatic ring system which has 5-20 ring atoms and contains 1-5 independently selected from N, O And S heteroatoms, for example "5-14 membered heteroaryl".
  • the term “5-14 membered heteroaryl” should be understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially 5 or 6 or 9 or 10 carbon atoms, and it contains 1-5, preferably 1-3 heteroatoms each independently selected from N, O and S and, additionally in each case The bottom can be benzo-fused.
  • heteroaryl should be understood as a monovalent monocyclic aromatic ring system having 5 or 6 ring atoms, which contains 1-3 heteroatoms each independently selected from N, O and S, and which It can be benzo-fused in each case.
  • the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiol Diazolyl, thio-4H-pyrazolyl, etc.
  • heterocyclic group, heteroaryl group or heteroarylene group includes all possible isomeric forms thereof, such as positional isomers thereof. Therefore, for some illustrative non-limiting examples, pyridinyl or pyridinylene includes pyridin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, pyridin-4-yl And pyridin-4-yl; thienyl or thienylene includes thiophen-2-yl, thiophen-2-yl, thiophen-3-yl, and thiophen-3-yl.
  • alkyl such as “C 1-40 alkyl” is also applicable to other terms containing “C 1-40 alkyl”, such as the terms “C 1-40 alkoxy”, “C 1 -40 alkylsilyl” and “C 1-40 alkylsilyloxy” and the like.
  • leaving group shall mean a charged or uncharged atom or group that is released during a substitution or displacement reaction. Suitable examples include, but are not limited to, H, F, Br, Cl, I, mesylate, tosylate, and the like.
  • any method for preparing the compounds of the present invention it may be necessary and/or desirable to protect sensitive or reactive groups on any relevant molecules. This can be achieved by conventional protecting groups, such as those described in textbooks or reference books in the field.
  • the protecting group can be removed at a convenient subsequent stage using methods known in the art.
  • other reagents can be used for this deprotection step, including but not limited to Pd/C, Pd(OH) 2 , PdCl 2 , Pd(OAc) 2 / Et 3 SiH, Raney nickel, appropriately selected acid, appropriately selected base, fluoride, etc.
  • “optionally further” means that subsequent steps or operations can be carried out or not carried out as required.
  • “optionally further salt formation” means that the salt formation step may be carried out, or the salt formation step may not be carried out.
  • the target compound can be separated according to a known method, for example, extraction, filtration, or column chromatography.
  • the compound of the present invention may be chiral, and therefore may exist in various enantiomeric forms. Therefore, these compounds may exist in racemate form or optically active form.
  • the compounds of the present invention or intermediates thereof can be separated into enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in synthesis in this form. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with optically active resolving reagents.
  • Suitable resolution reagents are optically active acids such as R and S forms of tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid, appropriate N-protected amino acids (e.g., N- Benzoyl proline or N-benzenesulfonyl proline) or various optically active camphor sulfonic acids.
  • optically active resolving reagents such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers
  • Suitable eluents for this purpose are aqueous or alcohol-containing solvent mixtures, for example, hexane/isopropanol/acetonitrile.
  • the synthetic methods for preparing heterocyclic and tertiary amine N-oxides are well known to those skilled in the art, and the synthetic methods include the use of peroxyacids such as peroxyacetic acid and m-chloroperoxybenzoic acid (MCPBA), peroxy Hydrogen oxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate and dioxirane (dioxirane) such as dimethyldioxirane oxidize heterocycles and tertiary amines.
  • MCPBA peroxyacids
  • alkyl hydroperoxides such as tert-butyl hydroperoxide
  • sodium perborate and dioxirane (dioxirane) such as dimethyldioxirane oxidize heterocycles and tertiary amines.
  • the pharmaceutically acceptable salt may be, for example, an acid addition salt of the compound of the present invention that has a nitrogen atom in the chain or ring and is sufficiently basic, for example, an acid addition salt formed with the following inorganic acids: for example, hydrochloric acid, hydrofluorine Acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid, or hydrogen sulfate, or acid addition salts formed with the following organic acids: for example, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid , Propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphor acid, cinnamic acid, cyclopentane Propionic acid, digluconic acid, 3-hydroxy-2-nap
  • an alkali metal salt such as a sodium salt or potassium salt
  • an alkaline earth metal salt such as a calcium salt or a magnesium salt
  • an ammonium salt or salts formed with organic bases that provide physiologically acceptable cations, such as salts formed with sodium ions, potassium ions, N-methylglucamine, dimethylglucamine, ethylglucosamine, Lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucosamine, meglumine, sarcosine, serinol, trihydroxymethylaminomethane, aminopropanediol, 1-amino-2 ,3,4-Butanetriol.
  • an alkali metal salt such as a sodium salt or potassium salt
  • an alkaline earth metal salt such as a calcium salt or a magnesium salt
  • an ammonium salt or salts formed with organic bases that provide physiologically acceptable cations, such as salts formed with sodium ions, potassium ions, N-methyl
  • the pharmaceutically acceptable salt includes the salt formed by the group -COOH with the following substances: sodium ion, potassium ion, calcium ion, magnesium ion, N-methylglucamine, dimethylglucamine, Ethyl glucosamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucosamine, meglumine, sarcosine, serinol, trishydroxymethylaminomethane, aminopropanediol , 1-amino-2,3,4-butanetriol; when 1 , 2 , or 3 of M 1, M 2, and M 3 of the present invention are H, the pharmaceutically acceptable salt of the present invention includes, for example, -OP (O)(OM 1 )(OM 2 ), -P(O)(OM 1 )(OM 2 ), -OS(O) 2 OM 3 , -S(O) 2 OM 3 and the salt formed with the following substances :
  • basic nitrogen-containing groups can be quaternized with the following reagents: lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates, such as sulfuric acid Dimethyl, diethyl sulfate, dibutyl sulfate and dipentyl sulfate; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl Halides such as benzyl and phenethyl bromide.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides
  • dialkyl sulfates such as sulfuric acid Dimethyl, diethyl sulfate, dibutyl sulfate and dipentyl
  • pharmaceutically acceptable salts include hydrochloride, sulfate, nitrate, bisulfate, hydrobromide, acetate, oxalate, citrate, methanesulfonate, formate, or Meglumine salt and so on.
  • the "pharmaceutically acceptable salt” includes not only the salt formed at one salt-forming site of the compound of the present invention, but also 2, 3 or all of them.
  • the salt formed at the salt-forming site can be varied within a relatively large range, for example, it can be 4 :1 ⁇ 1:4, such as 3:1, 2:1, 1:1, 1:2, 1:3, etc.
  • pharmaceutically acceptable anions include anions selected from the ionization of inorganic acids or organic acids.
  • the "inorganic acid” includes, but is not limited to, hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, or nitric acid.
  • the "organic acid” includes but is not limited to formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid , 2-(4-Hydroxybenzoyl)benzoic acid, camphor acid, cinnamic acid, cyclopentane propionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, hexanoic acid, pectinic acid , Persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid,
  • ionized anion includes all the anion forms of the inorganic acid and organic acid that may be generated by ionization, for example, different anions can be generated through primary ionization, secondary ionization or tertiary ionization.
  • phosphoric acid can generate dihydrogen phosphate through primary ionization, hydrogen phosphate through secondary ionization, or phosphate through tertiary ionization; sulfuric acid can generate hydrogen sulfate through primary ionization, or through secondary ionization.
  • Grade ionization generates sulfate.
  • the compound of formula (I) of the present invention can share a multivalent anion generated by multi-stage ionization by multiple molecules. All of these possible anions are included in the scope of the anion of the present invention.
  • tautomer refers to an isomer of a functional group resulting from the rapid movement of an atom in a molecule at two positions.
  • the compounds of the present invention may exhibit tautomerism.
  • Tautomeric compounds can exist in two or more mutually convertible species.
  • Proton shift tautomers result from the migration of covalently bonded hydrogen atoms between two atoms.
  • Tautomers generally exist in an equilibrium form. An attempt to separate a single tautomer usually produces a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties of the molecule.
  • the ketone type is dominant; in phenol, the enol type is dominant.
  • the present invention encompasses all tautomeric forms of the compound.
  • the term "effective amount” or “therapeutically effective amount” refers to the amount of the compound of the present invention sufficient to achieve the intended application (including but not limited to the treatment of diseases as defined below).
  • the therapeutically effective amount may vary depending on the following factors: the intended application (in vitro or in vivo), or the subject to be treated and the disease condition such as the weight and age of the subject, the severity of the disease condition and the mode of administration, etc. It can be easily determined by a person of ordinary skill in the art.
  • the specific dosage will vary depending on the following factors: the particular compound selected, the dosing regimen on which it is based, whether it is administered in combination with other compounds, the timing of administration, the tissue to be administered, and the physical delivery system carried.
  • excipients refers to pharmaceutically acceptable inert ingredients.
  • examples of the types of excipients include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of the pharmaceutical preparation, that is, make the preparation more suitable for direct compression by increasing fluidity and/or adhesion.
  • Examples of typical pharmaceutically acceptable carriers suitable for the above formulations are: sugars, such as lactose, sucrose, mannitol, and sorbitol; starches, such as corn starch, tapioca starch, and potato starch; cellulose and its derivatives, For example, sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; calcium phosphates, such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinylpyrrolidone; polyvinyl alcohol; stearic acid; hard Fatty acid alkaline earth metal salts, such as magnesium stearate and calcium stearate; stearic acid; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; nonionic, cationic and anionic surfactants; B Glycol polymers; fatty alcohols; and grain hydrolyzed solids and other non-toxic compatible fillers, binders, dis
  • the compound provided by the present invention has excellent JNK inhibitory activity.
  • the compounds of the present invention have better safety and metabolic stability.
  • the preparation method of the compound of the present invention is simple and easy to purify, so it has good application prospects.
  • the raw materials and reagents used in the following examples are all commercially available products, or can be prepared by known methods.
  • N,N-diisopropylethylamine ie DIEA, 0.15g, 1.18mmol
  • DIEA N,N-diisopropylethylamine
  • hydroxylamine hydrochloride 114 mg, 1.65 mmol
  • triethylamine 166 mg, 1.65 mmol
  • the temperature was raised to 80°C, heated for 2 hours, then cooled to room temperature, concentrated under reduced pressure, purified by preparative high performance liquid chromatography (ammonium bicarbonate method), and freeze-dried to obtain 100 mg of white solid with a yield of 90%.
  • the 5-bromouracil (CAS: 51-20-7, 3g, 0.015mol), benzyl mercaptan (2.1g, 0.017mol), tetrabutylammonium hydrogen sulfate (CAS: 32503-27-8, 1.3g, 0.25mol) and potassium carbonate (4.5g, 0.033mol) were dissolved in 20ml DMF and reacted at 60°C overnight (about 16 hours). Liquid chromatography monitors the end of the reaction. The reaction liquid was filtered, and the filtrate was concentrated under reduced pressure, and then slurried with petroleum ether to obtain 2.1 g of white solid, with a yield of 57.2%.
  • Iron powder (361mg, 6.46mmol) and ammonium chloride (348mg, 6.46mmol) were added to a mixture of QR053044A (300mg, 0.92mmol) in ethanol (10ml) and water (2ml), and reacted at 80°C for 3 hours. After filtration, the filtrate was concentrated under reduced pressure and extracted with water and ethyl acetate. The organic phase was dried and concentrated to obtain 250 mg of a yellow oily substance with a yield of 93%. 50mg of the crude product was purified by preparative high performance liquid chromatography (ammonium bicarbonate method), and 5.8mg of yellow solid was obtained after freeze-drying.
  • DIEA 0.3g, 2.2mmol
  • (1R, 2R, 5R)-5-amino-2-methylcyclohexane were added to the DMF (3ml) solution of compound T067-3 (0.2g, 0.7mmol) Alcohol (0.12g, 0.7mmol), after the addition, heat to 110°C and react for 16 hours.
  • the completion of the reaction was monitored by liquid chromatography. Concentrated under reduced pressure, purified by preparative high performance liquid chromatography (ammonium bicarbonate method), and freeze-dried to obtain 50 mg of white solid, with a yield of 21.2%.
  • JNK1 activity screening A 96-well (Cisbio, 66PL96025) time-resolved fluorescence assay was used to detect JNK1 activity.
  • the JNK1 assay is run in the following assay buffers: 10mM MgCl2 (Sigma, M1028), 1mM MnCl2 (Sigma, M1787), 1mM DTT (Sigma, D0632) and 1X Enzymatic buffer/kinase (Cisbio, 62EZBFDC).
  • assay buffer first transfer 3 ⁇ l of 0.1ng/ ⁇ l JNK1 kinase (Carna Biosciences, 04-163) to a 96-well plate, and then transfer 4 ⁇ l of appropriately diluted compound with 2.5% DMSO content, and incubate at room temperature for 0.5h. In order to start the reaction, the assay buffer is also used. After mixing 0.003 ⁇ M ATP (Aladdin, A7699) and 30 ⁇ M substrate ATF2-GST fusion (Cisbio, 64CUS000AFPEB), add 3 ⁇ l of the mixed solution to the microwell plate, and continue to incubate at room temperature for 2.5 h.
  • HTRF detection buffer Gibco, 62SDBRDD
  • MAb Anti GST-XL665 Cisbio, 61GSTXLA
  • PAb Anti-phospho ATF2-K Cisbio, 61P12KAZ
  • RAW264.7 phosphorylated c-jun whole cell assay RAW264.7 (ATCC TIB-71) cells were purchased from Suzhou BeNa Culture Collection (BeNa Culture Collection) and contained 10% fetal bovine serum (Gibco) and 1% penicillin-streptomycin (Gibco). Maintained in sugar DMEM medium (Gibco). All cells were cultured at 37°C in 95% air and 5% CO 2 . The cells were seeded into 120 ⁇ l cell culture medium in a 96-well plate at a density of 2 ⁇ 10 5 cells per well. The compound stock solution (15mM) was serially diluted in DMSO (Sigma) and further diluted in growth medium.
  • Jurkat T cells (clone E6-1) were purchased from the China Center for Type Culture Collection (China Center for Type Culture Collection), and contained 10% fetal bovine serum (Gibco), 1% penicillin-streptomycin (Gibco) ) Is maintained in RPMI1640 (Gibco). All cells were cultured at 37°C in 95% air and 5% CO 2 . The cells were seeded into 120 ⁇ l cell culture medium in a 96-well plate at a density of 1 ⁇ 10 5 cells per well. The compound stock solution (15mM) was serially diluted in DMSO (Sigma) and further diluted in growth medium.
  • DMSO DMSO
  • the compounds in Table 6 below have been tested by enzymatic and cellular methods in the JNK1 biochemical test, and it is found that the compounds of the present invention have good activity.
  • a compound with IC 50 lower than 100 nM is recorded as activity level A
  • IC 50 between 100 nM and 500 nM is recorded as activity level B
  • IC 50 between 500 nM and 1 ⁇ M is recorded as activity level C
  • IC 50 greater than 1 ⁇ M is recorded as the activity level D.
  • a compound with IC 50 lower than 100 nM is recorded as activity level A
  • IC 50 between 100 nM and 500 nM is recorded as activity level B
  • IC 50 between 500 nM and 1 ⁇ M is recorded as activity level C
  • IC 50 greater than 1 ⁇ M is recorded as the activity level D.

Abstract

本文提供下式（I）所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、多晶型物、氮氧化物或它们药学上可接受的盐，其可用作JNK抑制剂。还提供了式（I）所示化合物的制备方法，包含式（I）所示化合物的药物组合物，以及式（I）所示化合物用于制备药物的用途，所述药物用于治疗可通过抑制JNK活性而得以治疗的疾病。

Description

JNK抑制剂、其药物组合物和用途
本申请要求2019年9月30日向中国国家知识产权局提交的专利申请号为201910942775.3，发明名称为“JNK抑制剂、其药物组合物和用途”的在先申请的优先权。该在先申请的全文通过引用的方式结合于本申请中。
技术领域
本发明涉及药物领域，具体涉及可抑制JNK活性的化合物、其药物组合物和用途。
背景技术
促分裂原活化蛋白激酶(mitogen-activated protein kinases,MAPK)是真核生物信号传递网络中的重要途径之一。MAPK链由3类蛋白激酶MAP3K-MAP2K-MAPK组成，通过依次磷酸化将上游信号传递至下游应答分子。在哺乳动物机体中，包括三大MAPK信号转导通路：ERK(细胞外信号调节激酶)1/2、JNK(c-Jun N-末端激酶)和p38信号通路，其中ERK1/2信号转导通路调控细胞生长和分化，JNK和p38MAPK信号转导通路在炎症与细胞凋亡等应激反应中发挥重要作用。JNK是MAPK家族的重要成员，它可由应激信号激活，因此又被称为应激活化蛋白激酶(stress-activated protein kinase,SAPK)。JNK参与广泛的生物学过程包括胚胎发育，细胞凋亡/存活，癌基因表达细胞的转化血管生成，T细胞激活、B细胞增殖、细胞因子的产生和炎症的发生等。
目前，已鉴定了三种截然不同的基因(JNK1，JNK2和JNK3)，它们编码10种剪接变体。JNK1和JNK2在广泛多样的组织中表达，而JNK3主要在神经元中表达，较小程度地在心脏和睾丸中表达。JNK家族的成员通过促炎细胞因子如肿瘤坏死因子α(TNF-α)和白介素-1β(IL-1β)以及环境应激而活化。JNK的活化通过它的上游激酶——MKK4和MKK7，经由Thr-183和Tyr-185的双磷酸化而介导。已经显示，MKK4和MMK7可以通过不同的上游激酶激活，所述不同的上游激酶包括MEKK1和MEKK4，这取决于外部刺激和细胞环境。JNK信号传导的特异性是通过使用被称为JNK-相互作用蛋白的支架蛋白而形成JNK-特异性信号传导复合物来实现的，所述复合物含有激酶级联的多个组分。通过磷酸化特异性底物，JNK已经显示在炎症、T细胞功能、细胞凋亡和存活中发挥重要作用，所述底物包括转录因子如c-Jun、激活蛋白-1(AP1)家族成员和ATF2，以及非转录因子如IRS-1和Bcl-2。据认为，JNK的过度活化是自身免疫、炎性、代谢、神经学疾病以及癌症中的重要机制。一些研究表明，JNK信号转导通路在肺纤维化和肝纤维化中被激活，调控细胞炎症、增殖、分化和凋亡等，其可由TGF-β1诱导。
特发性肺间质纤维化(Idiopathic interstitial pulmonary fibrosis，IPF)，是一种原因不明的以普通间质性肺炎为特征性病理改变的慢性、弥漫性肺间质疾病，其组织病理学及影像学多显示为普通间质性肺炎的表现。因其发病机制复杂，病情呈不可逆性进展，早期诊断困难；确诊后患者生存率随时间推移显著下降，其3年生存率为50％，5年生存率仅为20％，比多数癌症(例如：白血病、乳腺癌、结肠癌、子宫瘤、肾癌等)的生存率都低，被称为“不是癌症的癌症”。
肝纤维化是慢性肝病向肝硬化进展的共同环节。既往相关研究局限于避免纤维化发生、延缓乃至阻断纤维化进展。但近年来多项实验均提示，无论是消除致病因素还是应用有效的抗纤维化药物，都可能部分或完全逆转患者及模型动物中的肝纤维化，即肝纤维化在一定程度上是可逆的。然而，肝纤维化的逆转过程十分复杂，众多信号通路如已知的MAPK/EKR信号通路以及SAPK/JNK和MEK5等MAPK信号通路，以及PI3K/Akt、Notch等非MAPK信号通路都在其中发挥重要作用。
目前，尚无JNK抑制途径治疗包括纤维化在内的众多病症的药物上市。因此，开发新的JNK抑制剂化合物对于上述疾病的治疗具有积极意义。
发明内容
为改善现有技术中存在的问题，本发明提供如下技术方案：
一种式(I)所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、多晶型物、氮氧化物或它们药学上可接受的盐：
Figure PCTCN2020116617-appb-000001
其中，
Y 1、Y 2独立地为CR 4或N；
X、W独立地选自CR 5R 6、O或NR 7；
R 1选自H、羟基、卤素、氰基、硝基、NR 11R 12、C(O)NR 11R 12、C(＝S)NR 11R 12、S(O) 2NR 11R 12、C(＝NR 13)NR 11R 12、NHC(O)NR 11R 12、P(O) 2NR 11R 12、P(O)R 13NR 11R 12、C(O)R 14、NHC(O)R 14、C(O)OR 15、或者未取代的或任选被一个、两个或更多个R a取代的如下基团：C 1-40烷基、C 2-40烯基、C 2-40炔基、C 1-40烷氧基、C 3-20环烷基、3-20元杂环基、C 6-20芳基或5-20元杂芳基；
R 2选自H、或者未取代的或任选被一个、两个或更多个R b取代的如下基团：C 1-40烷基、C 2-40烯基、C 2-40炔基、C 1-40烷氧基、C 3-20环烷基、3-20元杂环基、C 6-20芳基、C 6-20芳基-C 1-40烷基、5-20元杂芳基或5-20元杂芳基-C 1-40烷基；或者
R 2连同X一起形成未取代的或任选被一个、两个或更多个R b取代的如下基团：NHC(O)NR 11R 12、C 3-20环烷基、3-20元杂环基、C 6-20芳基或5-20元杂芳基；
R 3选自H、或者未取代的或任选被一个、两个或更多个R c取代的如下基团：NR 11R 12、C(O)NR 11R 12、C(O)R 14、C 1-40烷基、C 2-40烯基、C 2-40炔基、C 1-40烷氧基、C 3-20环烷基、3-20元杂环基、C 6-20芳基或5-20元杂芳基；或者
R 3连同W一起形成未取代的或任选被一个、两个或更多个R c取代的如下基团：NHC(O)NR 11R 12、C 3-20环烷基、3-20元杂环基、C 6-20芳基或5-20元杂芳基；
R 4选自H、羟基、卤素、氰基、硝基、氨基、或者未取代的或任选被一个、两个或更多个R d取代的如下基团：C 1-40烷基、C 2-40烯基、C 2-40炔基或C 1-40烷氧基；
R 5、R 6各自独立地选自H、羟基、卤素、氰基、或者未取代或任选被一个、两个或更多个R d取代的C 1-40烷基、C 2-40烯基、C 2-40炔基或C 1-40烷氧基；条件是R 5和R 6不同时为羟基、氰基或C 1-40烷氧基；或者，R 5、R 6与所连接的碳原子一起形成羰基，即，CR 5R 6为C(＝O)；
R 7选自H、或者未取代的或任选被一个、两个或更多个R e取代的如下基团：C 1-40烷基、C 2-40烯基、C 2-40炔基、C 1-40烷氧基、C 3-20环烷基、3-20元杂环基、C 6-20芳基或5-20元杂芳基；
R 11、R 12各自独立地选自H、或者未取代的或任选被一个、两个或更多个R e取代的如下基团：C(O)R 14、C 1-40烷基、C 2-40烯基、C 2-40炔基、C 1-40烷氧基、C 3-20环烷基、3-20元杂环基、C 6-20芳基或5-20元杂芳基；或者
R 11和R 12连同它们所连接的氮原子一起形成未取代的或任选被一个、两个或更多个R e取代的3-20元杂环基或5-20元杂芳基；
R 13选自H、羟基、氰基、或者未取代的或任选被一个、两个或更多个R e取代的C 1-40烷基或C 1-40烷氧基；
R 14选自H、羟基、卤素、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-40烷基、C 2-40烯基、C 2-40炔基、C 1-40烷氧基、C 3-20环烷基、3-20元杂环基、C 6-20芳基或5-20元杂芳基；
R 15选自H、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-20环烷基、3-20元杂环基、C 6-20芳基或5-20元杂芳基；
每一个R a独立地选自CN、卤素、OH、NH 2、氧代、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-40烷基或C 1-40烷氧基；
每一个R b独立地选自CN、卤素、OH、NH 2、COOH、NO 2、氧代、S(O) 2CH 3、C(O)NHCH 2CH 3、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-40烷基、C 1-40烷氧基、C 3-20环烷基、3-20元杂环基、C 6-20芳基或5-20元杂芳基；
每一个R c独立地选自CN、卤素、OH、NH 2、COOH、NO 2、C(O)NH 2、C(O)NHOH、C(O)N(OH)CH 3、氧代、C(O)CH 2COOH、C(O)CH 2CN、C(O)CH 2Cl、C(O)CH 2F或C(O)CH 2Br、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-40烷基、C 1-40烷氧基、C 3-20环烷基、3-20元杂环基、C 6-20芳基或5-20元杂芳基；
每一个R d、R e、R f相同或不同，各自独立地选自CN、卤素、OH、NH 2、氧代、S(O) 2CH 3、C 1-40烷基、卤代C 1-40烷基、C 1-40烷氧基或卤代C 1-40烷氧基。
根据本发明的一个实施方案，在式(I)所示的化合物中，
Figure PCTCN2020116617-appb-000002
其中，Y 1、Y 2独立地为CR 4或N；
X、W独立地选自CR 5R 6、O或NR 7；
R 1选自H、羟基、卤素、氰基、硝基、NR 11R 12、C(O)NR 11R 12、C(＝S)NR 11R 12、S(O) 2NR 11R 12、C(＝NR 13)NR 11R 12、NHC(O)NR 11R 12、P(O) 2NR 11R 12、P(O)R 13NR 11R 12、C(O)R 14、NHC(O)R 14、C(O)OR 15、或者未取代的或任选被一个、两个或更多个R a取代的如下基团：C 1-10烷基、C 2-10烯基、C 2-10炔基、C 1-10烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
R 2选自H、或者未取代的或任选被一个、两个或更多个R b取代的如下基团：C 1-10烷基、C 2-10烯基、C 2-10炔基、C 1-10烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基、C 6-14芳基-C 1-10烷基、5-14元杂芳基或或5-14元杂芳基-C 1-10烷基；或者
R 2连同X一起形成未取代的或任选被一个、两个或更多个R b取代的如下基团：NHC(O)NR 11R 12、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
R 3选自H、或者未取代的或任选被一个、两个或更多个R c取代的如下基团：NR 11R 12、C(O)NR 11R 12、C(O)R 14、C 1-10烷基、C 2-10烯基、C 2-10炔基、C 1-10烷氧基、C 3-10环烷基、3-10 元杂环基、C 6-14芳基或5-14元杂芳基；或者
R 3连同W一起形成未取代的或任选被一个、两个或更多个R c取代的如下基团：NHC(O)NR 11R 12、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
R 4选自H、羟基、卤素、氰基、硝基、氨基、或者未取代的或任选被一个、两个或更多个R d取代的如下基团：C 1-10烷基、C 2-10烯基、C 2-10炔基、C 1-10烷氧基；
R 5、R 6各自独立地选自H、羟基、卤素、氰基、或者未取代或任选被一个、两个或更多个R d取代的C 1-10烷基、C 2-10烯基、C 2-10炔基或C 1-10烷氧基；条件是R 5和R 6不同时为羟基、氰基或C 1-10烷氧基；或者，R 5、R 6与所连接的碳原子一起形成羰基，即，CR 5R 6为C(＝O)；
R 7选自H、或者未取代的或任选被一个、两个或更多个R e取代的如下基团：C 1-10烷基、C 2-10烯基、C 2-10炔基、C 1-10烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
R 11、R 12各自独立地选自H、或者未取代的或任选被一个、两个或更多个R e取代的如下基团：C(O)R 14、C 1-10烷基、C 2-10烯基、C 2-10炔基、C 1-10烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；或者
R 11和R 12连同它们所连接的氮原子一起形成未取代的或任选被一个、两个或更多个R e取代的3-10元杂环基或5-14元杂芳基；
R 13选自H、羟基、氰基、或者未取代的或任选被一个、两个或更多个R e取代的C 1-10烷基或C 1-10烷氧基；
R 14选自H、羟基、卤素、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-10烷基、C 2-10烯基、C 2-10炔基、C 1-10烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
R 15选自H、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-10烷基、C 2-10烯基、C 2-10炔基、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
每一个R a独立地选自CN、卤素、OH、NH 2、氧代、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-10烷基或C 1-10烷氧基；
每一个R b独立地选自CN、卤素、OH、NH 2、COOH、NO 2、氧代、S(O) 2CH 3、C(O)NHCH 2CH 3、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
每一个R c独立地选自CN、卤素、OH、NH 2、COOH、NO 2、C(O)NH 2、C(O)NHOH、C(O)N(OH)CH 3、氧代、C(O)CH 2COOH、C(O)CH 2CN、C(O)CH 2Cl、C(O)CH 2F、C(O)CH 2Br、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
每一个R d、R e、R f相同或不同，各自独立地选自CN、卤素、OH、NH 2、氧代、S(O) 2CH 3、C 1-10烷基、卤代C 1-10烷基、C 1-10烷氧基或卤代C 1-10烷氧基。
根据本发明的一个实施方案，在式(I)所示的化合物中，
Figure PCTCN2020116617-appb-000003
其中，Y 1、Y 2独立地为CR 4或N；
X、W独立地选自CR 5R 6、O或NR 7；
R 1选自H、羟基、卤素、氰基、硝基、NR 11R 12、C(O)NR 11R 12、C(＝S)NR 11R 12、S(O) 2NR 11R 12、C(＝NR 13)NR 11R 12、NHC(O)NR 11R 12、P(O) 2NR 11R 12、P(O)R 13NR 11R 12、C(O)R 14、NHC(O)R 14、C(O)OR 15、或者未取代的或任选被一个、两个或更多个R a取代的如下基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
R 2选自H、或者未取代的或任选被一个、两个或更多个R b取代的如下基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基、C 6-14芳基-C 1-6烷基、5-14元杂芳基或5-14元杂芳基-C 1-6烷基；或者
R 2连同X一起形成未取代的或任选被一个、两个或更多个R b取代的如下基团：NHC(O)NR 11R 12、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
R 3选自H、或者未取代的或任选被一个、两个或更多个R c取代的如下基团：NR 11R 12、C(O)NR 11R 12、C(O)R 14、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；或者
R 3连同W一起形成未取代的或任选被一个、两个或更多个R c取代的如下基团：NHC(O)NR 11R 12、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
R 4选自H、羟基、卤素、氰基、硝基、氨基、或者未取代的或任选被一个、两个或更多个R d取代的如下基团：C 1-6烷基、C 2-6烯基、C 2-6炔基或C 1-6烷氧基；
R 5、R 6各自独立地选自H、羟基、卤素、氰基、或者未取代或任选被一个、两个或更多个R d取代的C 1-6烷基、C 2-6烯基、C 2-6炔基或C 1-6烷氧基；条件是R 5和R 6不同时为羟基、氰基或C 1-6烷氧基；或者，R 5、R 6与所连接的碳原子一起形成羰基，即，CR 5R 6为C(＝O)；
R 7选自H、或者未取代的或任选被一个、两个或更多个R e取代的如下基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
R 11、R 12各自独立地选自H、或者未取代的或任选被一个、两个或更多个R e取代的如下基团：C(O)R 14、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；或者
R 11和R 12连同它们所连接的氮原子一起形成未取代的或任选被一个、两个或更多个R e取代的3-10元杂环基或5-14元杂芳基；
R 13选自H、羟基、氰基、或者未取代的或任选被一个、两个或更多个R e取代的C 1-6烷基或C 1-6烷氧基；
R 14选自H、羟基、卤素、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
R 15选自H、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
每一个R a独立地选自CN、卤素、OH、NH 2、氧代、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-6烷基或C 1-6烷氧基；
每一个R b独立地选自CN、卤素、OH、NH 2、COOH、NO 2、氧代、S(O) 2CH 3、C(O)NHCH 2CH 3、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-6烷基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
每一个R c独立地选自CN、卤素、OH、NH 2、COOH、NO 2、C(O)NH 2、C(O)NHOH、C(O)N(OH)CH 3、氧代、C(O)CH 2COOH、C(O)CH 2CN、C(O)CH 2Cl、C(O)CH 2F、C(O)CH 2Br、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-6烷基、C 1-6烷氧基、C 3-10 环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
每一个R d、R e、R f相同或不同，各自独立地选自CN、卤素、OH、NH 2、氧代、S(O) 2CH 3、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基。
根据本发明的一个实施方案，在式(I)所示的化合物中，
Figure PCTCN2020116617-appb-000004
其中，Y 1、Y 2独立地为CR 4或N；
X、W独立地为O或NR 7；
R 1选自H、羟基、卤素、氰基、硝基、NR 11R 12、C(O)NR 11R 12、C(＝S)NR 11R 12、S(O) 2NR 11R 12、C(＝NR 13)NR 11R 12、NHC(O)NR 11R 12、P(O) 2NR 11R 12、P(O)R 13NR 11R 12、C(O)R 14、NHC(O)R 14、C(O)OR 15、或者未取代的或任选被一个、两个或更多个R a取代的如下基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-6环烷基、3-7元杂环基或5-6元杂芳基；
R 2选自H、或者未取代的或任选被一个、两个或更多个R b取代的如下基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-6环烷基、3-7元杂环基、苯基、苄基、5-6元杂芳基或5-6元杂芳基-C 1-6烷基；或者
R 2连同X一起形成未取代的或任选被一个、两个或更多个R b取代的NHC(O)NR 11R 12、3-7元杂环基或5-6元杂芳基；
R 3选自H、或者未取代的或任选被一个、两个或更多个R c取代的如下基团：NR 11R 12、C(O)NR 11R 12、C(O)R 14、C 1-6烷基、C 3-6环烷基、3-7元杂环基、苯基或5-6元杂芳基；或者
R 3连同W一起形成未取代的或任选被一个、两个或更多个R c取代的NHC(O)NR 11R 12、3-7元杂环基或5-6元杂芳基；
R 4选自H、羟基或卤素；
R 7为H；
R 11、R 12各自独立地选自H、或者未取代的或任选被一个、两个或更多个R e取代的如下基团：C 1-6烷基、C 2-6烯基或C 2-6炔基；或者
R 11和R 12连同它们所连接的氮原子一起形成未取代的或任选被一个、两个或更多个R e取代的3-7元杂环基或5-6元杂芳基；
R 13选自H、氰基、甲基或羟基；
R 14选自H、羟基、卤素、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基或C 3-6环烷基；
R 15选自H、或者未取代的或任选被一个、两个或更多个R f取代的C 1-6烷基；
每一个R a独立地选自CN、卤素、OH、NH 2、氧代、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-6烷基或C 1-6烷氧基；
每一个R b独立地选自CN、卤素、OH、NH 2、COOH、NO 2、氧代、S(O) 2CH 3、C(O)NHCH 2CH 3、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、3-7元杂环基、苯基或5-6元杂芳基；
每一个R c独立地选自CN、卤素、OH、NH 2、COOH、NO 2、C(O)NH 2、C(O)NHOH、C(O)N(OH)CH 3、氧代、C(O)CH 2COOH、C(O)CH 2CN、C(O)CH 2Cl、C(O)CH 2F或C(O)CH 2Br、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-6烷基、C 1-6 烷氧基、3-7元杂环基或5-6元杂芳基；
每一个R e、R f相同或不同，各自独立地选自CN、卤素、OH、NH 2、氧代、S(O) 2CH 3、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基。
根据本发明的一个实施方案，在式(I)所示的化合物中，
Figure PCTCN2020116617-appb-000005
其中，Y 1、Y 2独立地为CR 4或N；
X、W独立地为O或NR 7；
R 1选自H、羟基、卤素、氰基、硝基、NR 11R 12、C(O)NR 11R 12、C(＝S)NR 11R 12、S(O) 2NR 11R 12、C(＝NR 13)NR 11R 12、NHC(O)NR 11R 12、P(O) 2NR 11R 12、P(O)R 13NR 11R 12、C(O)R 14、NHC(O)R 14、C(O)OR 15、或者未取代的或任选被一个、两个或更多个R a取代的如下基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、氧杂环丁基、氮杂环丁基、咪唑基、吡唑基、三唑基、噁二唑基、异噁二唑基、噻二唑基、异噻二唑基、四氮唑基、吡咯基、呋喃基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、吡喃基或噻吩基；
R 2选自H、或者未取代的或任选被一个、两个或更多个R b取代的如下基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-6环烷基、氧杂环丁基、哌啶基、哌嗪基、吗啉基、吡咯烷基、苯基、苄基、咪唑基、吡唑基、三唑基、噁二唑基、异噁二唑基、噻二唑基、异噻二唑基、四氮唑基、吡咯基、呋喃基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、吡喃基、噻吩基或
Figure PCTCN2020116617-appb-000006
或者
R 2连同X一起形成未取代的或任选被一个、两个或更多个R b取代的如下基团：NHC(O)NR 11R 12、氮杂环丁基、氧杂环丁基、哌啶基、哌嗪基、吗啉基、吡咯烷基、咪唑烷基、吡咯啉基、吡喃基、咪唑基、吡唑基、三唑基、噁二唑基、异噁二唑基、噻二唑基、异噻二唑基、四氮唑基、吡咯基、呋喃基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、嘧啶基、哒嗪基或吡嗪基；
R 3选自H、或者未取代的或任选被一个、两个或更多个R c取代的如下基团：C(O)NR 11R 12、C(O)R 14、C 1-6烷基、环戊基、环己基、哌啶基、吡咯烷基、苯基、咪唑基、吡唑基、三唑基、吡咯基、呋喃基、哌嗪基、吗啉基、吡喃基、噁二唑基、异噁二唑基、噻二唑基、异噻二唑基、四氮唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻唑基或噻吩基；或者
R 3连同W一起形成未取代的或任选被一个、两个或更多个R c取代的如下基团：NHC(O)NR 11R 12、哌啶基、哌嗪基、吗啉基、吡咯烷基、咪唑烷基、吡咯啉基、氮杂环丁基、氧杂环丁基、吡喃基、咪唑基、吡唑基、三唑基、噁二唑基、异噁二唑基、噻二唑基、异噻二唑基、四氮唑基、吡咯基、呋喃基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、嘧啶基、哒嗪基或吡嗪基；
R 4选自H、羟基或卤素；
R 7为H；
R 11、R 12各自独立地选自H、或者未取代的或任选被一个、两个或更多个R e取代的C 1-6 烷基；或者
R 11和R 12连同它们所连接的氮原子一起形成未取代的或任选被一个、两个或更多个R e取代的3-7元氮杂环烷基；
R 13选自H、氰基、甲基或羟基；
R 14选自H、羟基、卤素、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基或C 3-6环烷基；
R 15选自H、或者未取代的或任选被一个、两个或更多个R f取代的C 1-6烷基；
每一个R a独立地选自CN、卤素、OH、NH 2、氧代、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基或CH 2CH 2S(O) 2CH 3；
每一个R b独立地选自CN、卤素、OH、NH 2、COOH、NO 2、氧代、S(O) 2CH 3、C(O)NHCH 2CH 3、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-6烷基、C 1-6烷氧基、苯基或哌啶基；
每一个R c独立地选自CN、卤素、OH、NH 2、COOH、NO 2、C(O)NH 2、C(O)NHOH、C(O)N(OH)CH 3、氧代、C(O)CH 2COOH、C(O)CH 2CN、C(O)CH 2Cl、C(O)CH 2F或C(O)CH 2Br、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-6烷基、C 1-6烷氧基、5元杂环基或5元杂芳基；
每一个R e和R f相同或不同，各自独立地选自CN、卤素、OH、NH 2、氧代、S(O) 2CH 3、C 1-6烷基、卤代C 1-6烷基、卤代C 1-6烷氧基或C 1-6烷氧基。
根据本发明的一个实施方案，在式(I)所示的化合物中，
Figure PCTCN2020116617-appb-000007
其中，Y 1和Y 2均为N，或者Y 1为N且Y 2为CH；
X和W均为NH，或者X为O且W为NH；
R 1选自H、羟基、卤素、氰基、硝基、NH 2、C(O)NH 2、C(＝S)NH 2、C(＝NH)NH 2、C(＝NOH)NH 2、C(＝NCN)NH 2、C(＝NCH 3)NH 2、S(O) 2NH 2、NHC(O)NH 2、NHC(O)CH 3、甲基、单氟甲基、二氟甲基、三氟甲基、甲氧基、羟基丙基、乙炔基、丙炔基、乙烯基、烯丙基、甲基羰基、环丙基羰基、乙基羰基、异丙基羰基、甲氧基羰基、单氟甲基羰基、二氟甲基羰基、三氟甲基羰基、咪唑基、吡唑基、三唑基、噁二唑基、噁唑基、异噁唑基、
Figure PCTCN2020116617-appb-000008
Figure PCTCN2020116617-appb-000009
R 2选自H、叔丁基、(1-乙基氨基酰基)-哌啶基、羟基乙基、异丙基、氟丙基、C(CH 3) 2CF 3、环丙基、羟基环丙基、环丁基、羟基环丁基、环戊基、羟基环戊基、环己基、羟基环己基、甲氧基苯基、甲氧基苄基、甲基磺酰基苯基、(4-甲基哌嗪基)-苯基、三唑基、
Figure PCTCN2020116617-appb-000010
Figure PCTCN2020116617-appb-000011
R 2优选自甲氧基苯基、甲氧基苄基、甲基磺酰基苯基、(4-甲基哌嗪基)-苯基、三唑基、
Figure PCTCN2020116617-appb-000012
或者
R 2连同X一起形成未取代或者被一个或两个氧代、羟基、C 1-6烷基、C 1-6烷氧基取代的脲基、吡唑基、吡咯烷基、咪唑烷基、吡咯啉基、哌啶基、吗啉基或哌嗪基；优选，R 2连同X一起形成吗啉基、叔丁脲基、吡唑基或(3-氧代)-哌嗪基；
R 3选自H、(3-羟基-4-甲基)-环己基、甲酰基、二甲基环己基、乙烯基羰基、(1-氯甲基羰基)-哌啶基、(1-羧基甲基羰基)-哌啶基、羧基苯基、(1-氰基甲基羰基)-哌啶基、(1-酰胺基)-哌啶基、哌啶酮基、羟乙基哌啶酮基、哌啶基、羟基哌啶基、羟甲基苯基、1-(2-甲基磺酰基乙基)-吡唑基、或者
Figure PCTCN2020116617-appb-000013
或者
R 3连同W一起形成脲基、羟基哌啶基、羟甲基哌啶基、羟甲基吡咯烷基、
Figure PCTCN2020116617-appb-000014
Figure PCTCN2020116617-appb-000015
或(2-羟基-2-丙基)-氮杂环丁基。
根据本发明的一个实施方案，在式(I)所示的化合物中，
Figure PCTCN2020116617-appb-000016
其中，Y 1和Y 2均为N，或者Y 1为N且Y 2为CH；
X和W均为NH，或者X为O且W为NH；
R 1选自H、羟基、卤素、硝基、NH 2、C(＝S)NH 2、C(＝NH)NH 2、C(＝NOH)NH 2、S(O) 2NH 2、C(＝NCN)NH 2、C(＝NCH 3)NH 2、NHC(O)NH 2、NHC(O)CH 3、甲基、单氟甲基、二氟甲基、三氟甲基、甲氧基、羟基丙基、丙炔基、乙炔基、乙烯基、烯丙基、甲基羰基、环丙基羰基、乙基羰基、异丙基羰基、甲氧基羰基、单氟甲基羰基、二氟甲基羰基、三氟甲基羰基、咪唑基、吡唑基、三唑基、噁二唑基、噁唑基、异噁唑基、
Figure PCTCN2020116617-appb-000017
R 2和R 3具有上文在任一个实施方案中所给出的定义。
根据本发明的一个实施方案，在式(I)所示的化合物中，
Figure PCTCN2020116617-appb-000018
其中，Y 1和Y 2均为N，或者Y 1为N且Y 2为CH；
X和W均为NH，或者X为O且W为NH；
R 1选自H、羟基、卤素、硝基、NH 2、C(＝S)NH 2、C(＝NH)NH 2、C(＝NOH)NH 2、S(O) 2NH 2、C(＝NCN)NH 2、C(＝NCH 3)NH 2、NHC(O)NH 2、NHC(O)CH 3、甲基、单氟甲基、二氟甲基、三氟甲基、甲氧基、羟基丙基、丙炔基、乙炔基、乙烯基、烯丙基、甲基羰基、环丙基羰基、乙基羰基、异丙基羰基、甲氧基羰基、单氟甲基羰基、二氟甲基羰基、三氟甲基羰基、咪唑基、吡唑基、三唑基、噁二唑基、噁唑基、异噁唑基、
Figure PCTCN2020116617-appb-000019
R 2选自H、叔丁基、(1-乙基氨基酰基)-哌啶基、羟基乙基、异丙基、氟丙基、C(CH 3) 2CF 3、环丙基、羟基环丙基、环丁基、羟基环丁基、环戊基、羟基环戊基、环己基、羟基环己基、甲氧基苯基、甲氧基苄基、甲基磺酰基苯基、(4-甲基哌嗪基)-苯基、三唑基、
Figure PCTCN2020116617-appb-000020
Figure PCTCN2020116617-appb-000021
或者
R 2连同X一起形成吗啉基、叔丁脲基、吡唑基或(3-氧代)-哌嗪基；
R 3选自H、(3-羟基-4-甲基)-环己基、甲酰基、二甲基环己基、乙烯基羰基、(1-氯甲基羰基)-哌啶基、(1-羧基甲基羰基)-哌啶基、羧基苯基、(1-氰基甲基羰基)-哌啶基、(1-酰胺基)-哌啶基、哌啶酮基、羟乙基哌啶酮基、哌啶基、羟基哌啶基、羟甲基苯基、1-(2-甲基磺酰基乙基)-吡唑基、或者
Figure PCTCN2020116617-appb-000022
或者
R 3连同W一起形成脲基、羟基哌啶基、羟甲基哌啶基、羟甲基吡咯烷基、
Figure PCTCN2020116617-appb-000023
Figure PCTCN2020116617-appb-000024
或(2羟基-2-丙基)-氮杂环丁基。
根据本发明的一个实施方案，在式(I)所示的化合物中，
Figure PCTCN2020116617-appb-000025
其中，Y 1和Y 2均为N，或者Y 1为N且Y 2为CH；
X为O且W为NH；
R 1、R 2和R 3具有上文在任一个实施方案中所给出的定义。
根据本发明的一个实施方案，在式(I)所示的化合物中，
Figure PCTCN2020116617-appb-000026
其中，Y 1和Y 2均为N，或者Y 1为N且Y 2为CH；
X为O且W为NH；
R 1选自H、羟基、卤素、氰基、硝基、NH 2、C(O)NH 2、C(＝S)NH 2、C(＝NH)NH 2、C(＝NOH)NH 2、C(＝NCN)NH 2、C(＝NCH 3)NH 2、S(O) 2NH 2、NHC(O)NH 2、NHC(O)CH 3、甲基、单氟甲基、二氟甲基、三氟甲基、甲氧基、羟基丙基、乙炔基、丙炔基、乙烯基、烯丙基、甲基羰基、环丙基羰基、乙基羰基、异丙基羰基、甲氧基羰基、单氟甲基羰基、二氟甲基羰基、三氟甲基羰基、咪唑基、吡唑基、三唑基、噁二唑基、噁唑基、异噁唑基、
Figure PCTCN2020116617-appb-000027
Figure PCTCN2020116617-appb-000028
R 2选自H、叔丁基、(1-乙基氨基酰基)-哌啶基、羟基乙基、异丙基、氟丙基、C(CH 3) 2CF 3、环丙基、羟基环丙基、环丁基、羟基环丁基、环戊基、羟基环戊基、环己基、羟基环己基、甲氧基苯基、甲氧基苄基、甲基磺酰基苯基、(4-甲基哌嗪基)-苯基、三唑基、
Figure PCTCN2020116617-appb-000029
Figure PCTCN2020116617-appb-000030
或者
R 2连同X一起形成吗啉基、叔丁脲基、吡唑基或(3-氧代)-哌嗪基；
R 3选自H、(3-羟基-4-甲基)-环己基、甲酰基、二甲基环己基、乙烯基羰基、(1-氯甲基羰基)-哌啶基、(1-羧基甲基羰基)-哌啶基、羧基苯基、(1-氰基甲基羰基)-哌啶基、(1-酰胺基)-哌啶基、哌啶酮基、羟乙基哌啶酮基、哌啶基、羟基哌啶基、羟甲基苯基、1-(2-甲基磺酰基乙基)-吡唑基、或者
Figure PCTCN2020116617-appb-000031
或者
R 3连同W一起形成脲基、羟基哌啶基、羟甲基哌啶基、羟甲基吡咯烷基、
Figure PCTCN2020116617-appb-000032
Figure PCTCN2020116617-appb-000033
或(2-羟基-2-丙基)-氮杂环丁基。
根据本发明的一个实施方案，在式(I)所示的化合物中，
Figure PCTCN2020116617-appb-000034
其中，Y 1和Y 2均为N，或者Y 1为N且Y 2为CH；
X和W均为NH，或者X为O且W为NH；
R 2连同X一起形成未取代或者被一个、两个或更多个氧代、羟基、C 1-6烷基、C 1-6烷氧基取代的脲基、5-6元杂环基或5-6元杂芳基；
优选地，R 2连同X一起形成未取代的或任选被一个、两个或更多个R b取代的如下基团：NHC(O)NR 11R 12、氮杂环丁基、哌啶基、哌嗪基、吗啉基、吡咯烷基、咪唑烷基、吡咯啉基、吡喃基、咪唑基、吡唑基、三唑基、噁二唑基、异噁二唑基、噻二唑基、异噻二唑基、四氮唑基、吡咯基、呋喃基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、嘧啶基、哒嗪基或吡嗪基；
R 1、R 3、R 11、R 12和R b具有上文在任一个实施方案中所给出的定义。
根据本发明的一个实施方案，在式(I)所示的化合物中，
Figure PCTCN2020116617-appb-000035
其中，Y 1和Y 2均为N，或者Y 1为N且Y 2为CH；
X和W均为NH，或者X为O且W为NH；
R 1选自H、羟基、卤素、氰基、硝基、NH 2、C(O)NH 2、C(＝S)NH 2、C(＝NH)NH 2、C(＝NOH)NH 2、C(＝NCN)NH 2、C(＝NCH 3)NH 2、S(O) 2NH 2、NHC(O)NH 2、NHC(O)CH 3、甲基、单氟甲基、二氟甲基、三氟甲基、甲氧基、羟基丙基、乙炔基、丙炔基、乙烯基、烯丙基、甲基羰基、环丙基羰基、乙基羰基、异丙基羰基、甲氧基羰基、单氟甲基羰基、二氟甲基羰基、三氟甲基羰基、咪唑基、吡唑基、三唑基、噁二唑基、噁唑基、异噁唑基、
Figure PCTCN2020116617-appb-000036
Figure PCTCN2020116617-appb-000037
R 2连同X一起形成被一个或两个氧代、羟基、C 1-6烷基、C 1-6烷氧基取代的脲基、吡咯烷基、咪唑烷基、吡咯啉基、吡唑基、咪唑基、哌啶基、吗啉基或哌嗪基；
R 3选自H、(3-羟基-4-甲基)-环己基、甲酰基、二甲基环己基、乙烯基羰基、(1-氯甲基羰基)-哌啶基、(1-羧基甲基羰基)-哌啶基、羧基苯基、(1-氰基甲基羰基)-哌啶基、(1-酰胺基)-哌啶基、哌啶酮基、羟乙基哌啶酮基、哌啶基、羟基哌啶基、羟甲基苯基、1-(2-甲基磺酰基乙基)-吡唑基、或者
Figure PCTCN2020116617-appb-000038
或者
R 3连同W一起形成脲基、羟基哌啶基、羟甲基哌啶基、羟甲基吡咯烷基、
Figure PCTCN2020116617-appb-000039
Figure PCTCN2020116617-appb-000040
或(2-羟基-2-丙基)-氮杂环丁基。
根据本发明的一个实施方案，在式(I)所示的化合物中，
Figure PCTCN2020116617-appb-000041
其中，Y 1和Y 2均为N，或者Y 1为N且Y 2为CH；
X和W均为NH，或者X为O且W为NH；
R 3连同W一起形成未取代的或被一个、两个或更多个C(O)NHOH、C(O)N(OH)CH 3、氧代、羟基、C 1-6烷基、羟基-C 1-6烷基、C 1-6烷氧基取代的如下基团：脲基或3-7元杂环基；
R 1和R 2具有上文在任一个实施方案中所给出的定义。
根据本发明的一个实施方案，在式(I)所示的化合物中，
Figure PCTCN2020116617-appb-000042
其中，Y 1和Y 2均为N，或者Y 1为N且Y 2为CH；
X和W均为NH，或者X为O且W为NH；
R 3连同W一起形成未取代的或被一个、两个或更多个C(O)NHOH、C(O)N(OH)CH 3、氧代、羟基、C 1-6烷基、羟基-C 1-6烷基、C 1-6烷氧基取代的如下基团：脲基、吡咯烷基、咪唑烷基、吗啉基、吡咯啉基、哌啶基、吡咯烷基或氮杂环丁基；
R 1和R 2具有上文在任一个实施方案中所给出的定义。
根据本发明的一个实施方案，在式(I)所示的化合物中，
Figure PCTCN2020116617-appb-000043
其中，Y 1和Y 2均为N，或者Y 1为N且Y 2为CH；
X和W均为NH，或者X为O且W为NH；
R 1选自H、羟基、卤素、氰基、硝基、NH 2、C(O)NH 2、C(＝S)NH 2、C(＝NH)NH 2、C(＝NOH)NH 2、C(＝NCN)NH 2、C(＝NCH 3)NH 2、S(O) 2NH 2、NHC(O)NH 2、NHC(O)CH 3、甲基、单氟甲基、二氟甲基、三氟甲基、甲氧基、羟基丙基、乙炔基、丙炔基、乙烯基、烯丙基、甲基羰基、环丙基羰基、乙基羰基、异丙基羰基、甲氧基羰基、单氟甲基羰基、二氟甲基羰基、三氟甲基羰基、咪唑基、吡唑基、三唑基、噁二唑基、噁唑基、异噁唑基、
Figure PCTCN2020116617-appb-000044
Figure PCTCN2020116617-appb-000045
R 2选自H、叔丁基、(1-乙基氨基酰基)-哌啶基、羟基乙基、异丙基、氟丙基、C(CH 3) 2CF 3、环丙基、羟基环丙基、环丁基、羟基环丁基、环戊基、羟基环戊基、环己基、羟基环己基、甲氧基苯基、甲氧基苄基、甲基磺酰基苯基、(4-甲基哌嗪基)-苯基、三唑基、
Figure PCTCN2020116617-appb-000046
Figure PCTCN2020116617-appb-000047
或者
R 2连同X一起形成吗啉基、叔丁脲基、吡唑基或(3-氧代)-哌嗪基；
R 3连同W一起形成羟基哌啶基、羟甲基哌啶基、羟甲基吡咯烷基、
Figure PCTCN2020116617-appb-000048
或(2-羟基-2-丙基)-氮杂环丁基。
根据本发明的一个实施方案，式(I)所示的化合物为下式(II)的化合物：
Figure PCTCN2020116617-appb-000049
其中，
Y 2、X、R 1和R 2具有上文在式(I)的任一个实施方案中所给出的定义；
Y 3为CR 8R 9或NR 10；
R 8和R 9相同或不同，彼此独立地选自H、羟基、卤素、氰基、或者未取代的或任选被一个、两个或更多个羟基或卤素取代的C 1-6烷基、C 1-6烷氧基、C 1-6烯基或C 1-6炔基；或者R 8、R 9与所连接的碳原子一起形成羰基，即，CR 8R 9为C(＝O)；
R 10选自H、C(O)NH 2、C(O)CH 2CN、C(O)CH 2COOH或者未取代的或任选被一个、两个或更多个羟基或卤素取代的C 1-6烷基、C 1-6烷氧基、C 1-6烯基或C 1-6炔基；
R 3a和R 3b相同或不同，且彼此独立地选自H、羟基、卤素、氰基、氧代、或者未取代的或任选被一个、两个或更多个羟基或卤素取代的C 1-6烷基、C 1-6烷氧基、C 1-6烯基或C 1-6炔基。
根据本发明的一个实施方案，在式(II)的化合物中，
Figure PCTCN2020116617-appb-000050
其中，
Y 2、X、R 1和R 2具有上文在式(I)的任一个实施方案中所给出的定义；
Y 3为CR 8R 9或NR 10；
R 8为H，且R 9选自H、羟基、卤素、氰基、或者未取代的或任选被一个、两个或更多 个羟基或卤素取代的C 1-6烷基、C 1-6烷氧基、C 1-6烯基或C 1-6炔基；或者R 8、R 9与所连接的碳原子一起形成羰基，即，CR 8R 9为C(＝O)；
R 10选自H、C(O)NH 2、C(O)CH 2CN、C(O)CH 2COOH、或者未取代的或任选被一个、两个或更多个羟基或卤素取代的C 1-6烷基；
R 3a和R 3b相同或不同，彼此独立地选自H、羟基、卤素、氰基、氧代、或者未取代的或任选被一个、两个或更多个羟基或卤素取代的C 1-6烷基、C 1-6烷氧基、C 1-6烯基或C 1-6炔基。
根据本发明的一个实施方案，在式(II)的化合物中，
Figure PCTCN2020116617-appb-000051
其中，
Y 2、X、R 1和R 2具有上文在式(I)的任一个实施方案中所给出的定义；
Y 3为CR 8R 9；
R 8为H，且R 9选自羟基、或者未取代的或任选被一个、两个或更多个羟基或卤素取代的C 1-6烷氧基；
R 3a位于环己基环的4位，且选自H、羟基、卤素、氰基、氧代、或者未取代的或任选被一个、两个或更多个羟基或卤素取代的C 1-6烷基、C 1-6烷氧基、C 1-6烯基或C 1-6炔基；且
R 3b选自H、羟基、卤素、氰基、氧代、或者未取代的或任选被一个、两个或更多个羟基或卤素取代的C 1-6烷基或C 1-6烷氧基。
根据本发明的一个实施方案，式(I)所示的化合物为下式(II-1)的化合物：
Figure PCTCN2020116617-appb-000052
其中，
Y 2、X、R 1、R 2各取代基定义如上述式(I)所定义。
根据本发明的一个实施方案，在所述式(II-1)的化合物中，
Y 2为N或CH；
X为NH或O；
R 1选自H、羟基、卤素、氰基、硝基、NR 11R 12、C(O)NR 11R 12、C(＝S)NR 11R 12、S(O) 2NR 11R 12、C(＝NR 13)NR 11R 12、NHC(O)NR 11R 12、P(O) 2NR 11R 12、P(O)R 13NR 11R 12、C(O)R 14、NHC(O)R 14、C(O)OR 15、或者未取代的或任选被一个、两个或更多个R a取代的如下基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
R 2选自H、或者未取代的或任选被一个、两个或更多个R b取代的如下基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基、C 6-14芳基C 1-10 烷基、5-14元杂芳基或5-14元杂芳基C 1-10烷基；或者
R 2连同X一起形成未取代的或任选被一个、两个或更多个R b取代的如下基团：NHC(O)NR 11R 12、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
R 11、R 12、R 13、R 14和R 15具有上文在式(I)化合物的任一个实施方案中所给出的定义；
每一个R a独立地选自CN、卤素、OH、NH 2、氧代、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-6烷基或C 1-6烷氧基；且
每一个R b独立地选自CN、卤素、OH、NH 2、COOH、NO 2、氧代、S(O) 2CH 3、C(O)NHCH 2CH 3、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-6烷基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
R f具有上文在式(I)化合物的任一个实施方案中所给出的定义。
根据本发明的一个实施方案，在所述式(II-1)的化合物中，
Y 2为N或CH；
X为NH或O；
R 1选自H、羟基、卤素、氰基、硝基、NR 11R 12、C(O)NR 11R 12、C(＝S)NR 11R 12、S(O) 2NR 11R 12、C(＝NR 13)NR 11R 12、NHC(O)NR 11R 12、P(O) 2NR 11R 12、P(O)R 13NR 11R 12、C(O)R 14、NHC(O)R 14、C(O)OR 15、或者未取代的或任选被一个、两个或更多个R a取代的如下基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-6环烷基、3-7元杂环基或5-6元杂芳基；
R 2选自H、或者未取代的或任选被一个、两个或更多个R b取代的如下基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-6环烷基、3-7元杂环基、苯基、苄基、5-6元杂芳基或5-6元杂芳基-C 1-6烷基；或者
R 2连同X一起形成未取代的或任选被一个、两个或更多个R b取代的NHC(O)NR 11R 12、3-7元杂环基或5-6元杂芳基；
R 11、R 12、R 13、R 14和R 15具有上文在式(I)化合物的任一个实施方案中所给出的定义；
每一个R a独立地选自CN、卤素、OH、NH 2、氧代、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-6烷基或C 1-6烷氧基；且
每一个R b独立地选自CN、卤素、OH、NH 2、COOH、NO 2、氧代、S(O) 2CH 3、C(O)NHCH 2CH 3、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、3-7元杂环基、苯基或5-6元杂芳基；
每一个R c独立地选自CN、卤素、OH、NH 2、COOH、NO 2、C(O)NH 2、C(O)NHOH、C(O)N(OH)CH 3、氧代、C(O)CH 2COOH、C(O)CH 2CN、C(O)CH 2Cl、C(O)CH 2F或C(O)CH 2Br、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-6烷基、C 1-6烷氧基、3-7元杂环基或5-6元杂芳基；
每一个R f相同或不同，各自独立地选自CN、卤素、OH、NH 2、氧代、S(O) 2CH 3、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基。
根据本发明的一个实施方案，在式(II-1)的化合物中，
Figure PCTCN2020116617-appb-000053
其中，Y 2为N或CH；
X为NH或O；
R 1选自H、羟基、卤素、氰基、硝基、NR 11R 12、C(O)NR 11R 12、C(＝S)NR 11R 12、S(O) 2NR 11R 12、C(＝NR 13)NR 11R 12、NHC(O)NR 11R 12、P(O) 2NR 11R 12、P(O)R 13NR 11R 12、C(O)R 14、NHC(O)R 14、C(O)OR 15、或者未取代的或任选被一个、两个或更多个R a取代的如下基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、咪唑基、吡唑基、三唑基、噁二唑基、氧杂环丁基、氮杂环丁基、异噁二唑基、噻二唑基、异噻二唑基、四氮唑基、吡咯基、呋喃基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、吡喃基或噻吩基；
R 2选自H、或者未取代的或任选被一个、两个或更多个R b取代的如下基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-6环烷基、苯基、苄基、哌啶基、哌嗪基、吗啉基、咪唑基、吡唑基、三唑基、噁二唑基、异噁二唑基、噻二唑基、异噻二唑基、四氮唑基、吡咯烷基、氧杂环丁基、吡咯基、呋喃基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、吡喃基、噻吩基或
Figure PCTCN2020116617-appb-000054
或者
R 2连同X一起形成未取代的或任选被一个、两个或更多个R b取代的如下基团：NHC(O)NR 11R 12、氮杂环丁基、哌啶基、哌嗪基、吗啉基、吡咯烷基、咪唑烷基、吡咯啉基、吡喃基、咪唑基、吡唑基、三唑基、噁二唑基、异噁二唑基、噻二唑基、异噻二唑基、四氮唑基、吡咯基、呋喃基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、嘧啶基、哒嗪基或吡嗪基；
R 11、R 12独立地选自H、或者未取代的或任选被一个、两个或更多个R e取代的C 1-6烷基；或者
R 11和R 12连同它们所连接的氮原子一起形成未取代的或任选被一个、两个或更多个R e取代的3-7元氮杂环烷基；
R 13选自H、氰基、甲基或羟基；
R 14选自H、羟基、卤素、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基或C 3-6环烷基；
R 15选自H、或者未取代的或任选被一个、两个或更多个R f取代的C 1-6烷基；
每一个R a独立地选自CN、卤素、OH、NH 2、氧代、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基或CH 2CH 2S(O) 2CH 3；且
每一个R b独立地选自CN、卤素、OH、NH 2、COOH、NO 2、氧代、S(O) 2CH 3、C(O)NHCH 2CH 3、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-6烷基、C 1-6烷氧基、苯基或哌啶基；
每一个R e和R f独立地选自CN、卤素、OH、NH 2、氧代、S(O) 2CH 3、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基。
根据本发明的一个实施方案，在式(II-1)的化合物中，
Figure PCTCN2020116617-appb-000055
其中，Y 2为N或CH；
X为NH或O；
R 1选自H、羟基、卤素、氰基、硝基、NH 2、C(O)NH 2、C(＝S)NH 2、C(＝NH)NH 2、C(＝NOH)NH 2、C(＝NCN)NH 2、C(＝NCH 3)NH 2、NHC(O)NH 2、S(O) 2NH 2、NHC(O)CH 3、甲基、单氟甲基、二氟甲基、三氟甲基、甲氧基、羟基丙基、乙炔基、乙烯基、丙炔基、烯丙基、甲基羰基、环丙基羰基、乙基羰基、异丙基羰基、甲氧基羰基、单氟甲基羰基、二氟甲基羰基、三氟甲基羰基、咪唑基、吡唑基、三唑基、噁二唑基、噁唑基、异噁唑基、
Figure PCTCN2020116617-appb-000056
Figure PCTCN2020116617-appb-000057
R 2选自H、叔丁基、(1-乙基氨基酰基)-哌啶基、羟基乙基、异丙基、氟丙基、C(CH 3) 2CF 3、环丙基、羟基环丙基、环丁基、羟基环丁基、羟基环戊基、环戊基、羟基环己基、环己基、甲氧基苯基、甲氧基苄基、甲基磺酰基苯基、(4-甲基哌嗪基)-苯基、三唑基、
Figure PCTCN2020116617-appb-000058
Figure PCTCN2020116617-appb-000059
或者
R 2连同X一起形成未取代或者被一个或两个氧代、羟基、C 1-6烷基、C 1-6烷氧基取代的脲基、吡唑基、吡咯烷基、咪唑烷基、吡咯啉基、哌啶基、吗啉基或哌嗪基。
根据本发明的一个实施方案，在式(II-1)的化合物中，
Figure PCTCN2020116617-appb-000060
其中，Y 2为N或CH；
X为NH或O；
R 1选自H、羟基、卤素、氰基、硝基、NH 2、C(O)NH 2、C(＝S)NH 2、C(＝NH)NH 2、C(＝NOH)NH 2、C(＝NCN)NH 2、C(＝NCH 3)NH 2、S(O) 2NH 2、NHC(O)NH 2、NHC(O)CH 3、甲基、单氟甲基、二氟甲基、三氟甲基、甲氧基、羟基丙基、乙炔基、丙炔基、乙烯基、烯丙 基、甲基羰基、环丙基羰基、乙基羰基、异丙基羰基、甲氧基羰基、单氟甲基羰基、二氟甲基羰基、三氟甲基羰基、咪唑基、吡唑基、三唑基、噁二唑、噁唑、异噁唑、
Figure PCTCN2020116617-appb-000061
R 2选自H、甲氧基苯基、甲氧基苄基、甲基磺酰基苯基、(4-甲基哌嗪基)-苯基、三唑基、
Figure PCTCN2020116617-appb-000062
或者
R 2连同X一起形成吗啉基、叔丁脲基、吡唑基或(3-氧代)-哌嗪基。
根据本发明的一个实施方案，式(II-1)的化合物具有以下式(II-1a)的立体结构：
Figure PCTCN2020116617-appb-000063
其中各基团具有上文在式(I)或式(II-1)的化合物的任一个实施方案中所给出的相应定义。
作为实例，式(I)化合物可选自下面表1中例示的化合物及其药学上可接受的盐：
表1
Figure PCTCN2020116617-appb-000064
Figure PCTCN2020116617-appb-000065
Figure PCTCN2020116617-appb-000066
Figure PCTCN2020116617-appb-000067
Figure PCTCN2020116617-appb-000068
Figure PCTCN2020116617-appb-000069
Figure PCTCN2020116617-appb-000070
Figure PCTCN2020116617-appb-000071
Figure PCTCN2020116617-appb-000072
Figure PCTCN2020116617-appb-000073
Figure PCTCN2020116617-appb-000074
Figure PCTCN2020116617-appb-000075
Figure PCTCN2020116617-appb-000076
Figure PCTCN2020116617-appb-000077
本发明化合物药学上可接受的盐可以是酸加成盐，也可以是碱加成盐，例如，可以是与以下的无机酸或有机酸形成的酸加成盐：盐酸、硫酸、硝酸、磷酸、甲酸、乙酸、酒石酸、富马酸、柠檬酸、苹果酸、草酸、抗坏血酸、琥珀酸、甲磺酸、乙磺酸、苯磺酸等，或者可以是与钠离子、钾离子、钙离子、铵离子等形成的盐。可以具体如下所示。
本发明还提供式(I)化合物的制备方法，其可以为以下几种方案之一：
Figure PCTCN2020116617-appb-000078
方案1：
Figure PCTCN2020116617-appb-000079
其中，R 2’为R 2-X，R 3’为R 3-W，Nu为亲核基团，R 1、R 2、R 3、X和W具有上文在任何一个实施方案中所述的定义。
方案1包括以下步骤1a和1b：
(1a)SM-1A与含R 3’的亲核试剂在路易斯碱的作用下反应，生成IM-1A；
上述反应条件可为常规选择，例如，所述路易斯碱可以选自三乙胺、二异丙基乙胺、吡啶、碳酸钾、碳酸钠、叔丁醇钾、叔丁醇钠、氢氧化钾、氢氧化钠中的任意一种或两种以上，或以过量的所述含R 3’的亲核试剂作为路易斯碱；
所述反应可以在存在溶剂或不存在溶剂的情况下进行。当存在溶剂时，所述溶剂可以为有机溶剂，所述有机溶剂优选选自甲醇、乙醇、异丙醇、叔丁醇、乙腈、四氢呋喃、二氧六环、二甲基甲酰胺、二甲基亚砜、丙酮、二氯甲烷中的一种或两种以上；
所述化合物SM-1A与所述含R 3’的亲核试剂的摩尔比可以为1:(0.8～10)；所述化合物SM-1A与路易斯碱的摩尔比可以为1:(0.8～5)；所述化合物SM-1A与有机溶剂的重量体积比可以为1:(0～100)g/ml，优选为1:(3～100)g/ml；反应可以于-10℃～40℃下进行，优选于-10℃～40℃下进行；反应时间可以为1～24h。
(1b)IM-1A与含R 2’的亲核试剂在路易斯碱的作用下反应，生成相应产物或中间体；
上述反应条件可为常规选择，例如，所述路易斯碱可以选自三乙胺、二异丙基乙胺、吡啶、碳酸钾、碳酸钠、叔丁醇钾、叔丁醇钠、氢氧化钾、氢氧化钠中的任意一种或两种以上，或以过量的所述含R 2’的亲核试剂作为路易斯碱；
所述反应可以在存在溶剂或不存在溶剂的情况下进行。当存在溶剂时，所述溶剂可以为有机溶剂，所述有机溶剂优选选自甲醇、乙醇、异丙醇、叔丁醇、乙腈、四氢呋喃、二氧六环、二甲基甲酰胺、二甲基亚砜、丙酮、二氯甲烷中的一种或两种以上；
所述化合物SM-1A与所述含R 2’的亲核试剂的摩尔比可以为1:(0.8～10)；所述化合物SM-1A与路易斯碱的摩尔比可以为1:(0.8～5)；所述化合物SM-1A与有机溶剂的重量体积比可以为1:(0～100)g/ml，优选为1:(3～100)g/ml；反应可以于20℃～150℃下进行，优选于50℃～150℃下进行；反应时间可以为1～24h。
方案2：
Figure PCTCN2020116617-appb-000080
其中，R 1’为R 1或可衍生为R 1的基团，R 2’为R 2-X，R 3’为R 3-W，Nu为亲核基团，R 1、R 2、R 3、X和W具有上文在任何一个实施方案中所述的定义。
方案2包括以下步骤2a-2d：
(2a)SM-1B与甲硫醇钠生成IM-1B，可以任选对IM-1B中的R 1’进行衍生反应后继续进行后续步骤；
上述反应条件可为常规选择，例如，所述化合物SM-1B与所述甲硫醇钠的摩尔比可以为1:(0.8～5)；
所述反应可以在存在溶剂或不存在溶剂的情况下进行。当存在溶剂时，所述溶剂可以为有机溶剂，所述有机溶剂优选选自甲醇、乙醇、异丙醇、叔丁醇、乙腈、四氢呋喃、二氧六环、二甲基甲酰胺、二甲基亚砜、丙酮、二氯甲烷中的一种或两种以上；
所述化合物SM-1B与有机溶剂的重量体积比可以为1:(0～100)g/ml，优选为1:(3～100)g/ml；反应可以于-10℃～100℃下进行，优选于-10℃～40℃下进行；反应时间可以为1～24h。
(2b)IM-1B与含R 2’的亲核试剂在路易斯碱的作用下反应，生成IM-2B；
上述反应条件可为常规选择，例如，所述路易斯碱可以选自三乙胺、二异丙基乙胺、吡啶、碳酸钾、碳酸钠、叔丁醇钾、叔丁醇钠、氢氧化钾、氢氧化钠中的任意一种或两种以上，或以过量的所述含R 2’的亲核试剂作为路易斯碱；
所述反应可以在存在溶剂或不存在溶剂的情况下进行。当存在溶剂时，所述溶剂可以为 有机溶剂，所述有机溶剂优选选自甲醇、乙醇、异丙醇、叔丁醇、乙腈、四氢呋喃、二氧六环、二甲基甲酰胺、二甲基亚砜、丙酮、二氯甲烷中的一种或两种以上；
所述化合物SM-1B与所述含R 2’的亲核试剂的摩尔比可以为1:(0.8～10)；所述化合物SM-1B与路易斯碱的摩尔比可以为1:(0.8～5)；所述化合物SM-1B与有机溶剂的重量体积比可以为1:(0～100)g/ml，优选为1:(3～100)g/ml；反应可以于10℃～150℃下进行，优选于50℃～150℃下进行；反应时间可以为1～24h。
(2c)IM-2B与间氯过氧苯甲酸作用，生成IM-3B；
上述反应条件可为常规选择，例如，所述化合物IM-2B与所述含间氯过氧苯甲酸的摩尔比可以为1:(0.8～10)；
所述反应可以在存在溶剂或不存在溶剂的情况下进行。当存在溶剂时，所述溶剂可以为有机溶剂，所述有机溶剂优选选自甲醇、乙醇、异丙醇、叔丁醇、乙腈、四氢呋喃、二氧六环、二甲基甲酰胺、二甲基亚砜、丙酮、二氯甲烷中的一种或两种以上；
所述化合物IM-2B与有机溶剂的重量体积比可以为1:(0～100)g/ml，优选为1:(3～100)g/ml；反应可以于-20℃～150℃下进行，优选于-20℃～40℃下进行；反应时间可以为1～24h。
(2d)IM-3B与含R 3’的亲核试剂在路易斯碱的作用下反应，生成相应产物或中间体；可任选进一步进行衍生化反应；
上述反应条件可为常规选择，例如，所述路易斯碱可以选自三乙胺、二异丙基乙胺、吡啶、碳酸钾、碳酸钠、叔丁醇钾、叔丁醇钠、氢氧化钾、氢氧化钠中的任意一种或两种以上，或以过量的所述含R 3’的亲核试剂作为路易斯碱；
所述反应可以在存在溶剂或不存在溶剂的情况下进行。当存在溶剂时，所述溶剂可以为有机溶剂，所述有机溶剂优选选自甲醇、乙醇、异丙醇、叔丁醇、乙腈、四氢呋喃、二氧六环、二甲基甲酰胺、二甲基亚砜、丙酮、二氯甲烷中的一种或两种以上；
所述化合物IM-3B与所述含R 3’的亲核试剂的摩尔比可以为1:(0.8～10)；所述化合物IM-3B与路易斯碱的摩尔比可以为1:(0.8～5)；所述化合物IM-3B与有机溶剂的重量体积比可以为1:(0～100)g/ml，优选为1:(3～100)g/ml；反应可以于20℃～150℃下进行，优选于50℃～150℃下进行；反应时间可以为1～24h。
方案3：
Figure PCTCN2020116617-appb-000081
其中，R 2具有上文在任何一个实施方案中所述的定义。
方案3包括以下步骤3a-3c：
(3a)SM-1C与SM-2C在路易斯碱的作用下反应，生成IM-1C；
上述反应条件可为常规选择，例如，所述路易斯碱可以选自三乙胺、二异丙基乙胺、吡啶、碳酸钾、碳酸钠、叔丁醇钾、叔丁醇钠、氢氧化钾、氢氧化钠中的任意一种或两种以上，或以过量的SM-2C作为路易斯碱；
所述反应可以在存在溶剂或不存在溶剂的情况下进行。当存在溶剂时，所述溶剂可以为有机溶剂，所述有机溶剂优选选自甲醇、乙醇、异丙醇、叔丁醇、乙腈、四氢呋喃、二氧六环、二甲基甲酰胺、二甲基亚砜、丙酮、二氯甲烷中的一种或两种以上；
所述化合物SM-1C与所述SM-2C的摩尔比可以为1:(0.8～10)；所述化合物SM-1C与路易斯碱的摩尔比可以为1:(0.8～5)；所述化合物SM-1C与有机溶剂的重量体积比可以为1:(0～100)g/ml，优选为1:(3～100)g/ml；反应可以于10℃～150℃下进行，优选于25℃～120℃下进行；反应时间可以为1～24h。
(3b)IM-1C与R 2NH 2在路易斯碱的作用下反应，生成相应产物或中间体；
上述反应条件可为常规选择，例如，所述路易斯碱可以选自三乙胺、二异丙基乙胺、吡啶、碳酸钾、碳酸钠、叔丁醇钾、叔丁醇钠、氢氧化钾、氢氧化钠中的任意一种或两种以上，或以过量的R 2NH 2作为路易斯碱；
所述反应可以在存在溶剂或不存在溶剂的情况下进行。当存在溶剂时，所述溶剂优选可以为有机溶剂，所述有机溶剂优选选自甲醇、乙醇、异丙醇、叔丁醇、乙腈、四氢呋喃、二氧六环、二甲基甲酰胺、二甲基亚砜、丙酮、二氯甲烷中的一种或两种以上；
所述化合物IM-1C与R 2NH 2的摩尔比可以为1:(0.8～10)；所述化合物IM-1C与路易斯碱的摩尔比可以为1:(0.8～5)；所述化合物IM-1C与有机溶剂的重量体积比可以为1:(0～100)g/ml，优选为1:(3～100)g/ml；反应可以于20℃～150℃下进行，优选于50℃～150℃下进行；反应时间可以为1～24h。
(3c)IM-2C与H 2O 2在路易斯碱的作用下反应，生成相应产物；
上述反应条件可为常规选择，例如，所述路易斯碱可以选自三乙胺、二异丙基乙胺、吡啶、碳酸钾、碳酸钠、叔丁醇钾、叔丁醇钠、氢氧化钾、氢氧化钠中的任意一种或两种以上；
所述反应可以在存在溶剂或不存在溶剂的情况下进行。当存在溶剂时，所述溶剂可以为有机溶剂，所述有机溶剂优选选自水、甲醇、乙醇、异丙醇、叔丁醇、乙腈、四氢呋喃、二氧六环、二甲基甲酰胺、二甲基亚砜、丙酮、二氯甲烷中的一种或两种以上；
所述化合物IM-2C与H 2O 2的摩尔比可以为1:(0.8～20)；所述化合物IM-2C与路易斯碱的摩尔比可以为1:(0.8～5)；所述化合物IM-2C与溶剂的重量体积比可以为1:(0～100)g/ml，优选为1:(3～100)g/ml；反应可以于-78℃～100℃下进行，优选于-78℃～20℃下进行；反应时间可以为1～24h。
本领域技术人员应当理解，式(I)所示的化合物、其消旋体、立体异构体、互变异构体、氮氧化物可以作为原料或中间体，以制备式(I)所示的化合物、其消旋体、立体异构体、互变异构体、氮氧化物的药学上可接受的盐。为此，本发明还提供式(I)所示的化合物、其消旋体、立体异构体、互变异构体、氮氧化物在制备式(I)所示的化合物、其消旋体、立体异构体、互变异构体、氮氧化物的药学上可接受的盐中的用途。
本发明还提供式I所示的化合物、其消旋体、立体异构体、互变异构体、氮氧化物、同位素标记物、溶剂化物、多晶型物、代谢产物、酯、药学上可接受的盐或前药中的至少一种在制备药物中用途，所述药物为蛋白质激酶的抑制剂。所述药物用来治疗、预防或改善动物或人的病症，所述病症包括肺部纤维化或肝脏纤维化等。此外，所述化合物针对蛋白激酶、特别是JNK1和/或JNK2有活性。本文提供的方法包括将有效量的本发明化合物(包括式(I)所示的化合物、其消旋体、立体异构体、互变异构体、氮氧化物或它们药学上可接受的盐，下同)给予有其需要的对象。
本发明还提供药物组合物，其包含治疗有效量的式(I)所示的化合物、其消旋体、立体异构体、互变异构体、氮氧化物、同位素标记物、溶剂化物、多晶型物、代谢产物、酯、药学上可接受的盐或前药。所述药物组合物还可任选包含药学上可接受的辅料，例如载体、赋形剂。作为实例，所述辅料可以为选自下列中的一种或多种：崩解剂、助流剂、润滑剂、稀释剂或填充剂、粘合剂、着色剂。
本发明还提供一种调节JNK激酶功能的方法，包括向有此需要的个体给予有效量的一种或更多种本发明的化合物，或者包含所述化合物的药物组合物。
再一个方面，本发明提供抑制表达激酶的细胞中的所述激酶的方法，包括使所述细胞接触有效量的本发明化合物。在一个实施方案中，所述激酶是JNK1、JNK2或其突变体或同等型，或它们的组合，所述化合物是一种或更多种式(I)的化合物，例如来自表1的化合物。
在另一个方面，本文提供的是用于治疗或预防肝脏纤维化疾病例如非酒精性脂肪性肝炎、脂肪变性(即脂肪肝)、肝硬化、原发性硬化性胆管炎、原发性胆汁性肝硬化、肝炎、肝细胞癌和肝纤维化同时伴有长期或反复酒精摄入(酒精性肝炎)、伴有感染(例如病毒性感染例如HCV)、伴有肝脏移植或伴有药物诱发的肝损伤(例如对乙酰氨基酚毒性)的方法，包括给予有其需要的对象有效量的本发明化合物。在有些方面，本文提供的是用于治疗或预防导致肝脏或肺部纤维化疾病例如非酒精性脂肪性肝炎、脂肪变性(即脂肪肝)、肝硬化、原发性硬化性胆管炎、原发性胆汁性肝硬化和肝炎的糖尿病或代谢综合症的方法，包括给予有其需要的对象有效量的本发明化合物。
在另一个方面，本文提供的是用于治疗或预防一种或多种选自特发性肺纤维化(IPF)、系统性硬化病、硬皮病、慢性同种异体移植物肾病变、抗体介导的排斥或狼疮的紊乱的方法，包括给予有其需要的对象有效量的本发明化合物。在有些这样的实施方案中，所述狼疮是红 斑狼疮(例如，盘状红斑狼疮或皮肤红斑狼疮)或系统性狼疮。
在另一个方面，本文提供的是用于治疗或预防通过抑制JNK1和/或JNK2可治疗或可预防的病症的方法，所述方法包括给予有其需要的对象有效量的本发明化合物。此类病症的实例包括类风湿性关节炎；类风湿性脊椎炎；骨关节炎；哮喘、支气管炎；变应性鼻炎；慢性阻塞性肺疾病；囊性纤维化；炎症性肠疾病；过敏性肠综合症(irritable bowel syndrome)；粘液性结肠炎；溃疡性结肠炎；克罗恩病(Crohn's disease)；亨廷顿病(Huntington's disease)；肝炎；胰腺炎；肾炎；多发性硬化；红斑狼疮；II型糖尿病；肥胖症；动脉粥样硬化；血管成形术后再狭窄；左心室肥大；心肌梗塞；脑卒中；心、肺、肠、肾、肝、胰、脾和脑的缺血性损伤；急性或慢性器官移植排斥；用于移植的器官的保存；器官衰竭或肢缺损(例如，包括但不限于由缺血-再灌注损伤、创伤、全身受伤、车祸、挤压伤或移植失败所致的)；移植物抗宿主病；内毒素性休克；多器官衰竭；银屑病；暴露于火、化学品或辐射所致的烧伤；湿疹；皮炎；皮肤移植；局部缺血；与外科手术或创伤性损伤(例如车辆事故、枪弹伤或肢轧碎(limb crush))相关的缺血病症；癫痫；阿尔茨海默病(Alzheimer's disease)；帕金森病(Parkinson's disease)；对细菌或病毒感染的免疫应答；恶病质；血管生成性和增殖性疾病；实体肿瘤；和各种组织例如结肠、直肠、前列腺、肝脏、肺、支气管、胰腺、脑、头、颈、胃、皮肤、肾脏、宫颈、血液、喉、食管、口、咽、膀胱、卵巢或子宫的癌症。
在另一个方面，本文提供式(I)的化合物，其用于调节JNK激酶功能，包括向有此需要的个体给予有效量的一种或更多种本发明的化合物，或者包含所述化合物的药物组合物。
在又一个方面，本发明提供式(I)的化合物，其用于抑制表达激酶的细胞中的所述激酶的方法，包括使所述细胞接触有效量的本发明化合物。在一个实施方案中，所述激酶是JNK1、JNK2或其突变体或同等型，或它们的组合，所述化合物是一种或更多种式(I)的化合物，例如来自表1的化合物。
在又一个方面，本文提供式(I)的化合物，其用于治疗或预防肝脏纤维化疾病例如非酒精性脂肪性肝炎、脂肪变性(即脂肪肝)、肝硬化、原发性硬化性胆管炎、原发性胆汁性肝硬化、肝炎、肝细胞癌和肝纤维化同时伴有长期或反复酒精摄入(酒精性肝炎)、伴有感染(例如病毒性感染例如HCV)、伴有肝脏移植或伴有药物诱发的肝损伤(例如对乙酰氨基酚毒性)的方法，包括给予有其需要的对象有效量的本发明化合物。在有些方面，本文提供的是用于治疗或预防导致肝脏或肺部纤维化疾病例如非酒精性脂肪性肝炎、脂肪变性(即脂肪肝)、肝硬化、原发性硬化性胆管炎、原发性胆汁性肝硬化和肝炎的糖尿病或代谢综合症的方法，包括给予有其需要的对象有效量的本发明化合物。
在又一个方面，本文提供式(I)的化合物，其用于治疗或预防一种或多种选自特发性肺纤维化(IPF)、系统性硬化病、硬皮病、慢性同种异体移植物肾病变、抗体介导的排斥或狼疮的紊乱的方法，包括给予有其需要的对象有效量的本发明化合物。在有些这样的实施方案中，所述狼疮是红斑狼疮(例如，盘状红斑狼疮或皮肤红斑狼疮)或系统性狼疮。
在又一个方面，本文提供式(I)的化合物，其用于治疗或预防通过抑制JNK1和/或JNK2可治疗或可预防的病症的方法，所述方法包括给予有其需要的对象有效量的本发明化合物。此类病症的实例包括类风湿性关节炎；类风湿性脊椎炎；骨关节炎；哮喘、支气管炎；变应性鼻炎；慢性阻塞性肺疾病；囊性纤维化；炎症性肠疾病；过敏性肠综合症；粘液性结肠炎；溃疡性结肠炎；克罗恩病；亨廷顿病；肝炎；胰腺炎；肾炎；多发性硬化；红斑狼疮；II型糖尿病；肥胖症；动脉粥样硬化；血管成形术后再狭窄；左心室肥大；心肌梗塞；脑卒中；心、肺、肠、肾、肝、胰、脾和脑的缺血性损伤；急性或慢性器官移植排斥；用于移植的器 官的保存；器官衰竭或肢缺损(例如，包括但不限于由缺血-再灌注损伤、创伤、全身受伤、车祸、挤压伤或移植失败所致的)；移植物抗宿主病；内毒素性休克；多器官衰竭；银屑病；暴露于火、化学品或辐射所致的烧伤；湿疹；皮炎；皮肤移植；局部缺血；与外科手术或创伤性损伤(例如车辆事故、枪弹伤或肢轧碎)相关的缺血病症；癫痫；阿尔茨海默病；帕金森病；对细菌或病毒感染的免疫应答；恶病质；血管生成性和增殖性疾病；实体肿瘤；和各种组织例如结肠、直肠、前列腺、肝脏、肺、支气管、胰腺、脑、头、颈、胃、皮肤、肾脏、宫颈、血液、喉、食管、口、咽、膀胱、卵巢或子宫的癌症。
术语定义和说明
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本申请说明书记载的范围内。
本申请说明书和权利要求书记载的数值范围，当该数值范围被定义为“整数”时，应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如，“0～10的整数”应当理解为记载了0、1、2、3、4、5、6、7、8、9和10的每一个整数。当该数值范围被定义为“数”时，应当理解为记载了该范围的两个端点、该范围内的每一个整数以及该范围内的每一个小数。例如，“0～10的数”应当理解为不仅记载了0、1、2、3、4、5、6、7、8、9和10的每一个整数，还至少记载了其中每一个整数分别与0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9的和。
除非另有说明，当本文中使用“本发明化合物”或“本发明的化合物”时，旨在涵盖式(I)所示的三氮唑衍生物、其消旋体、立体异构体、互变异构体、氮氧化物或它们药学上可接受的盐。
术语“卤素”指F、Cl、Br和I。换言之，F、Cl、Br和I在本说明书中可描述为“卤素”。
术语“C 1-40烷基”应理解为优选表示具有1～40个碳原子的直连或支链饱和一价烃基，优选为C 1-10烷基和C 1-6烷基。“C 1-10烷基”应理解为优选表示具有1、2、3、4、5、6、7、8、9或10个碳原子的直连或支链饱和一价烃基。“C 1-6烷基”应理解为优选表示具有1、2、3、4、5或6个碳原子的直连或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。特别地，所述基团具有1、2、3、4、5或6个碳原子(即，C 1-6烷基)，例如甲基、乙基、丙基、丁基、异丙基、异丁基、仲丁基、叔丁基，更特别地，所述基团具有1、2或3个碳原子(即，C 1-3烷基)，例如甲基、乙基、正丙基或异丙基。
术语“C 1-40烷氧基”指基团-OR，其中R为取代或未取代的C 1-40烷基，其中“C 1-40烷基”具有上文给出的定义。类似地，术语“C 1-10烷氧基”指基团-OC 1-10烷基，“C 1-6烷氧基”指基团-OC 1-6烷基，“C 1-3烷氧基”指基团-OC 1-3烷基，其中“C 1-10烷基”、“C 1-6烷基”和“C 1-3烷基”具有上文给出的定义。具体的所述烷氧基包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、仲丁氧基、正戊氧基、正己氧基和1,2-二甲基丁氧基。
术语“C 2-40烯基”应理解为优选表示直连或支链的一价烃基，其包含一个或多个双键并且具有2～40个碳原子，优选“C 2-10烯基”。“C 2-10烯基”应理解为优选表示直连或支链的一价烃 基，其包含一个或多个双键并且具有2、3、4、5、6、7、8、9或10个碳原子，例如，具有2、3、4、5或6个碳原子(即，C 2-6烯基)，具有2或3个碳原子(即，C 2-3烯基)。应理解，在所述烯基包含多于一个双键的情况下，所述双键可相互分离或者共轭。所述烯基是例如乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基、戊-4-烯基、(E)-戊-3-烯基、(Z)-戊-3-烯基、(E)-戊-2-烯基、(Z)-戊-2-烯基、(E)-戊-1-烯基、(Z)-戊-1-烯基、己-5-烯基、(E)-己-4-烯基、(Z)-己-4-烯基、(E)-己-3-烯基、(Z)-己-3-烯基、(E)-己-2-烯基、(Z)-己-2-烯基、(E)-己-1-烯基、(Z)-己-1-烯基、异丙烯基、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基、(E)-1-甲基丙-1-烯基、(Z)-1-甲基丙-1-烯基、3-甲基丁-3-烯基、2-甲基丁-3-烯基、1-甲基丁-3-烯基、3-甲基丁-2-烯基、(E)-2-甲基丁-2-烯基、(Z)-2-甲基丁-2-烯基、(E)-1-甲基丁-2-烯基、(Z)-1-甲基丁-2-烯基、(E)-3-甲基丁-1-烯基、(Z)-3-甲基丁-1-烯基、(E)-2-甲基丁-1-烯基、(Z)-2-甲基丁-1-烯基、(E)-1-甲基丁-1-烯基、(Z)-1-甲基丁-1-烯基、1,1-二甲基丙-2-烯基、1-乙基丙-1-烯基、1-丙基乙烯基、1-异丙基乙烯基。
术语“C 2-40炔基”应理解为表示直连或支链的一价烃基，其包含一个或多个三键并且具有2～40个碳原子，优选“C 2-10炔基”。术语“C 2-10炔基”应理解为优选表示直连或支链的一价烃基，其包含一个或多个三键并且具有2、3、4、5、6、7、8、9或10个碳原子，，例如，具有2、3、4、5或6个碳原子(即，“C 2-6炔基”)，具有2或3个碳原子(“C 2-3-炔基”)。所述炔基是例如乙炔基、丙-1-炔基、丙-2-炔基、丁-1-炔基、丁-2-炔基、丁-3-炔基、戊-1-炔基、戊-2-炔基、戊-3-炔基、戊-4-炔基、己-1-炔基、己-2-炔基、己-3-炔基、己-4-炔基、己-5-炔基、1-甲基丙-2-炔基、2-甲基丁-3-炔基、1-甲基丁-3-炔基、1-甲基丁-2-炔基、3-甲基丁-1-炔基、1-乙基丙-2-炔基、3-甲基戊-4-炔基、2-甲基戊-4-炔基、1-甲基戊-4-炔基、2-甲基戊-3-炔基、1-甲基戊-3-炔基、4-甲基戊-2-炔基、1-甲基戊-2-炔基、4-甲基戊-1-炔基、3-甲基戊-1-炔基、2-乙基丁-3-炔基、1-乙基丁-3-炔基、1-乙基丁-2-炔基、1-丙基丙-2-炔基、1-异丙基丙-2-炔基、2,2-二甲基丁-3-炔基、1,1-二甲基丁-3-炔基、1,1-二甲基丁-2-炔基或3,3-二甲基丁-1-炔基。特别地，所述炔基是乙炔基、丙-1-炔基或丙-2-炔基。
术语“C 3-20环烷基”应理解为表示饱和的一价单环或双环烃环，可以是螺环或桥环，其具有3～20个碳原子，优选“C 3-10环烷基”。术语“C 3-10环烷基”应理解为表示饱和的一价单环或双环烃环，可以是螺环或桥环，其具有3、4、5、6、7、8、9或10个碳原子。所述C 3-10环烷基可以是单环烃基，如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基，或者是双环烃基如十氢化萘环。术语“C 3-6环烷基”应理解为表示饱和的一价单环或双环烃环，可以是螺环或桥环，其具有3、4、5或6个碳原子。所述C 3-6环烷基可以是，例如，环丙基、环丁基、环戊基、环己基、双环[1.1.0]丁基、螺戊基、螺[2.3]己基、双环[1.1.1]戊基、双环[2.1.0]戊基、双环[2.1.1]己基或双环[3.1.0]己基。
术语“3-20元杂环基”意指具有环碳原子和1至5个环杂原子的3至20元非芳香环系的一价基团，该非芳香环系可以是饱和的或者含有一个或更多个双键，其可以为单环、双环、螺环或桥环，其中每个环杂原子独立地选自N、O、S、B、P和Si。所述“3-20元杂环基”可以是例如，“3-10元杂环基”、“3-7元杂环基”或“5-6元杂环基”。术语“3-10元杂环基”意指具有环碳原子和1至5个环杂原子的3至10元非芳香环系的一价基团，该非芳香环系可以为单环、双环、螺环或桥环，其中每个环杂原子独立地选自N、O、S、B、P和Si，优选包含1-3个选自N、O和S的杂原子。术语“3-7元杂环基”意指具有环碳原子和1至3个环杂原子的3至7非芳香环系的一价基团，该非芳香环系可以为单环、双环、螺环或桥环，其 中每个环杂原子独立地选自N、O、S、B、P和Si，优选包含1-3个选自N、O和S的杂原子。术语“5-6元杂环基”意指具有环碳原子和1至3个环杂原子的5至6非芳香环系的一价基团，该非芳香环系通常为单环，其中每个环杂原子独立地选自N、O、S、B、P和Si，优选包含1-3个选自N、O和S的杂原子。所述杂环基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。不论杂环基前是否修饰有“取代的”，杂环基的每个原子独立地任选被取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代，适当的取代基包括但不限于羟基、氨基、氧代、卤素、氰基、硝基、C 1-40烷基、C 2-40烯基、C 2-40炔基等。特别地，所述杂环基可以包括但不限于：3元环，如氮杂环丙烷基、氧杂环丙烷基和硫杂环丙烷基；4元环，如氮杂环丁烷基、氧杂环丁烷基和硫杂环丁烷基；5元环，如二氢呋喃基、四氢呋喃基、二氢噻吩基、四氢噻吩基、二氧杂环戊烯基、吡咯烷基、二氢吡咯基、咪唑烷基、吡唑烷基、吡咯啉基、二氧杂环戊烷基、氧硫杂环戊烷基(oxasulfuranyl)、二硫杂环戊烷基(disulfuranyl)、噁唑烷-2-酮、三唑啉基、噁二唑啉基和噻二唑啉基；或6元环，如二氢吡喃基、四氢吡喃基、哌啶基、吗啉基、二氢吡啶基、硫杂环己烷基、二噻烷基、硫代吗啉基、哌嗪基、二硫杂环己烷基、二噁烷基和三噻烷基；或7元环，如二氮杂环庚烷基、氮杂环庚烷基、氧杂环庚烷基和硫杂环庚烷基。双环杂环基，例如但不限于5,5元环，如六氢环戊并[c]吡咯-2(1H)-基环，或者5,6元双环，如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。含氮原子的环可以是部分不饱和的，即它可以包含一个或多个双键，例如但不限于2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢噁唑基或4H-[1,4]噻嗪基，或者，它可以是苯并稠合的，例如但不限于二氢异喹啉基。
术语“C 6-20芳基”应理解为优选表示具有6～20个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环，优选“C 6-14芳基”。术语“C 6-14芳基”应理解为优选表示具有6、7、8、9、10、11、12、13或14个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环(“C 6-14芳基”)，特别是具有6个碳原子的环(“C 6芳基”)，例如苯基；或联苯基，或者是具有9个碳原子的环(“C 9芳基”)，例如茚满基或茚基，或者是具有10个碳原子的环(“C 10芳基”)，例如四氢化萘基、二氢萘基或萘基，或者是具有13个碳原子的环(“C 13芳基”)，例如芴基，或者是具有14个碳原子的环(“C 14芳基”)，例如蒽基。
术语“5-20元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系：其具有5～20个环原子且包含1-5个独立选自N、O和S的杂原子，例如“5-14元杂芳基”。术语“5-14元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系：其具有5、6、7、8、9、10、11、12、13或14个环原子，特别是5或6或9或10个碳原子，且其包含1-5个，优选1-3各独立选自N、O和S的杂原子并且，另外在每一种情况下可为苯并稠合的。术语“5-6元杂芳基”应理解为具有5或6个环原子的一价单环芳族环系，其包含1-3各独立选自N、O和S的杂原子，并且其在每一种情况下可为苯并稠合的。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基、噻-4H-吡唑基等以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基、异吲哚基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及它们的苯并衍生物，例如喹啉基、喹唑啉基、异喹啉基等；或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基等。
除非另有说明，杂环基、杂芳基或亚杂芳基包括其所有可能的异构形式，例如其位置异构体。因此，对于一些说明性的非限制性实例，吡啶基或亚吡啶基包括吡啶-2-基、亚吡啶-2- 基、吡啶-3-基、亚吡啶-3-基、吡啶-4-基和亚吡啶-4-基；噻吩基或亚噻吩基包括噻吩-2-基、亚噻吩-2-基、噻吩-3-基和亚噻吩-3-基。
上述对术语“烷基”，如“C 1-40烷基”的定义同样适用于含有“C 1-40烷基”的其他术语，例如术语“C 1-40烷氧基”、“C 1-40烷基硅基”和“C 1-40烷基硅基氧基”等。同样地，上述对术语“C 2-40烯基”、“C 2-40炔基”、“C 3-20环烷基”、“C 5-20环烯基”、“3-20元杂环基”、“C 6-20芳基”和“5-20元杂芳基”的定义相应地同样适用于含有其的其他术语，如术语“C 2-40烯基氧基”、C 2-40炔基氧基”、“C 3-20环烷基氧基”、“3-20元杂环基”、“3-20元杂环基氧基”、“C 6-20芳基氧基”、“C 6-20芳基烷基”和“5-20元杂芳基烷基”等。
除非另外指明，否则本文所用的术语“离去基团”应意指在取代或置换反应过程中脱离的带电或不带电的原子或基团。合适的例子包括但不限于H、F、Br、Cl、I、甲磺酸酯基、甲苯磺酸酯基等。
在任何用于制备本发明化合物的方法中，可能必需和/或期望保护任何有关分子上的敏感或反应性基团。这可通过常规的保护基来实现，如本领域教科书或工具书描述的保护基。可使用本领域已知的方法在方便的后续阶段移除保护基团。本领域技术人员将认识到，取决于具体的保护基团，可将其他试剂用于该去保护步骤，包括但不限于Pd/C、Pd(OH) 2、PdCl 2、Pd(OAc) 2/Et 3SiH、兰尼镍、适当选择的酸、适当选择的碱、氟化物等等。
根据本发明的制备方法，“任选进一步”意指后续的步骤或操作可以根据需要进行或不进行。例如，“可任选进一步成盐”表示可以进行成盐步骤，也可以不进行成盐步骤。本领域技术人员能够根据目标化合物的需要确定是否进行所述步骤或操作。
可以根据已知的方法，例如通过萃取、过滤或柱色谱来分离目标化合物。
根据其分子结构，本发明的化合物可以是手性的，因此可能存在各种对映异构体形式。因而这些化合物可以以消旋体形式或光学活性形式存在。本发明的化合物或其中间体可以通过本领域技术人员公知的化学或物理方法分离为对映异构体化合物，或者以此形式用于合成。在外消旋的胺的情况中，通过与光学活性的拆分试剂反应，从混合物制得非对映异构体。适当的拆分试剂的示例是光学活性的酸，例如R和S形式的酒石酸、二乙酰酒石酸、二苯甲酰酒石酸、扁桃酸、苹果酸、乳酸、适当的N-保护的氨基酸(例如N-苯甲酰脯氨酸或N-苯磺酰基脯氨酸)或各种光学活性的樟脑磺酸。借助光学活性的拆分试剂(例如固定在硅胶上的二硝基苯甲酰基苯基甘氨酸、三乙酸纤维素或其它碳水化合物的衍生物或手性衍生化的异丁烯酸酯聚合物)，也可有利地进行色谱对映体拆分。用于此目的的适当的洗脱剂是含水或含醇的溶剂混合物，例如，己烷/异丙醇/乙腈。
本领域技术人员将理解，由于氮需要具有可用的孤对电子用于被氧化为氧化物，因此并非所有的含氮杂环都可以形成N-氧化物；本领域技术人员将识别能够形成N-氧化物的含氮杂环。本领域技术人员还将认识到叔胺能够形成N-氧化物。制备杂环和叔胺的N-氧化物的合成方法对于本领域技术人员而言是熟知的，所述合成方法包括用过氧酸如过氧乙酸和间氯过氧苯甲酸(MCPBA)、过氧化氢、烷基氢过氧化物如叔丁基氢过氧化物、过硼酸钠和双环氧乙烷(dioxirane)如二甲基双环氧乙烷氧化杂环和叔胺。这些制备N-氧化物的方法已在文献中广泛地描述和综述。
药学上可接受的盐可以是例如在链或环中具有氮原子的具有足够碱性的本发明的化合物的酸加成盐，例如与如下无机酸形成的酸加成盐：例如盐酸、氢氟酸、氢溴酸、氢碘酸、硫酸、焦硫酸、磷酸或硝酸，或硫酸氢盐、或者与如下有机酸形成的酸加成盐：例如甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、 水杨酸、2-(4-羟基苯甲酰基)苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡糖酸、3-羟基-2-萘甲酸、烟酸、扑酸、果胶酯酸、过硫酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、氨基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、藻酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚酸、甘油磷酸、天冬氨酸、磺基水杨酸、半硫酸或硫氰酸。
另外，具有足够酸性的本发明的化合物的另一种适合的药学上可接受的盐是碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如钙盐或镁盐)、铵盐，或与提供生理学可接受的阳离子的有机碱形成的盐，例如与如下物质形成的盐：钠离子、钾离子、N-甲基葡糖胺、二甲基葡糖胺、乙基葡糖胺、赖氨酸、二环己基胺、1,6-己二胺、乙醇胺、葡糖胺、葡甲胺、肌氨酸、丝氨醇、三羟基甲基氨基甲烷、氨基丙二醇、1-氨基-2,3,4-丁三醇。作为实例，所述药学上可接受的盐包括基团-COOH与如下物质形成的盐：钠离子、钾离子、钙离子、镁离子、N-甲基葡糖胺、二甲基葡糖胺、乙基葡糖胺、赖氨酸、二环己基胺、1,6-己二胺、乙醇胺、葡糖胺、葡甲胺、肌氨酸、丝氨醇、三羟基甲基氨基甲烷、氨基丙二醇、1-氨基-2,3,4-丁三醇；当本发明M 1、M 2、M 3中的1、2或3个为H时，本发明药学上可接受的盐包括例如-OP(O)(OM 1)(OM 2)、-P(O)(OM 1)(OM 2)、-OS(O) 2OM 3、-S(O) 2OM 3与与如下物质形成的盐：钠离子、钾离子、钙离子、镁离子、N-甲基葡糖胺、二甲基葡糖胺、乙基葡糖胺、赖氨酸、二环己基胺、1,6-己二胺、乙醇胺、葡糖胺、葡甲胺、肌氨酸、丝氨醇、三羟基甲基氨基甲烷、氨基丙二醇、1-氨基-2,3,4-丁三醇。
另外，碱性含氮基团可用如下试剂季铵化：低级烷基卤化物，例如甲基、乙基、丙基和丁基氯化物、溴化物和碘化物；硫酸二烷基酯，例如硫酸二甲酯、硫酸二乙酯、硫酸二丁酯和硫酸二戊酯；长链卤化物，例如癸基、月桂基、肉豆蔻基和硬脂基氯化物、溴化物和碘化物；芳烷基卤化物如苄基和苯乙基溴化物等。作为实例，药学上可接受的盐包括盐酸盐、硫酸盐、硝酸盐、硫酸氢盐、氢溴酸盐、醋酸盐、草酸盐、柠檬酸盐、甲磺酸盐、甲酸盐或葡甲胺盐等。
由于本发明的化合物可存在多个成盐位点，所述“药学上可接受的盐”不仅包括本发明化合物其中1个成盐位点上形成的盐，而且还包括其中2、3或全部成盐位点上形成的盐。为此，所述“药学上可接受的盐”中式(I)化合物与成盐所需的酸的根离子(阴离子)或碱的阳离子摩尔比可以在较大的范围内变化，例如可以是4:1～1:4，如3:1、2:1、1:1、1:2、1:3等。
根据本发明，药学上可接受的阴离子包括选自由无机酸或有机酸电离生成的阴离子。所述“无机酸”包括但不限于盐酸、氢氟酸、氢溴酸、氢碘酸、硫酸、焦硫酸、磷酸或硝酸。所述“有机酸”包括但不限于甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡糖酸、3-羟基-2-萘甲酸、烟酸、扑酸、果胶酯酸、过硫酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、氨基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、藻酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚酸、甘油磷酸、天冬氨酸、磺基水杨酸、半硫酸或硫氰酸。
术语“电离生成的阴离子”包括所述无机酸和有机酸所有可能由电离生成的阴离子形式，例如可经过一级电离、二级电离或三级电离而生成不同的阴离子。作为实例，磷酸可经一级电离生成磷酸二氢根，可经二级电离生成磷酸氢根，也可经三级电离生成磷酸根；硫酸可经 一级电离生成硫酸氢根，也可经二级电离生成硫酸根。本发明式(I)化合物可以多个分子共用一个经过多级电离所生成的多价态阴离子。这些所有可能生成的阴离子都涵盖在本发明阴离子的范围内。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发明包含化合物的所有互变异构形式。
术语“有效量”或者“治疗有效量”是指足以实现预期应用(包括但不限于如下定义的疾病治疗)的本发明所述化合物的量。治疗有效量可以取决于以下因素而改变：预期应用(体外或者体内)，或者所治疗的受试者和疾病病症如受试者的重量和年龄、疾病病症的严重性和给药方式等，其可以由本领域普通技术人员容易地确定。具体剂量将取决于以下因素而改变：所选择的特定化合物、所依据的给药方案、是否与其它化合物组合给药、给药的时间安排、所给药的组织和所承载的物理递送系统。
术语“辅料”是指可药用惰性成分。赋形剂种类的实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性，即通过增加流动性和/或粘着性使制剂更适于直接压缩。适用于上述制剂的典型的药学上可接受的载体的实例为：糖类，例如乳糖、蔗糖、甘露醇和山梨醇；淀粉类，例如玉米淀粉、木薯淀粉和土豆淀粉；纤维素及其衍生物，例如羧甲基纤维素钠，乙基纤维素和甲基纤维素；磷酸钙类，例如磷酸二钙和磷酸三钙；硫酸钠；硫酸钙；聚乙烯吡咯烷酮；聚乙烯醇；硬脂酸；硬脂酸碱土金属盐，例如硬脂酸镁和硬脂酸钙；硬脂酸；植物油类，例如花生油、棉籽油、芝麻油、橄榄油和玉米油；非离子、阳离子和负离子表面活性剂；乙二醇聚合物；脂肪醇类；和谷物水解固形物以及其它无毒的可相容的填充剂、粘合剂、崩解剂、缓冲剂、防腐剂、抗氧剂、润滑剂、着色剂等在药物制剂中常用到的辅料。
本发明的有益效果包括：
本发明提供的化合物具有优异的JNK抑制活性。此外，本发明化合物具有较好的安全性和代谢稳定性。本发明的化合物制备方法简单、易于提纯，因此具有良好的应用前景。
具体实施方式
下文将结合具体实施例对本发明的通式化合物及其制备方法和应用做更进一步的详细说明。下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
<制备实施例>
实施例1：化合物(T001A)和(T001)的制备
Figure PCTCN2020116617-appb-000082
1.1化合物(T001-2)的制备
常温下，向5-溴-2,4-二氯嘧啶(4g,17.4mmol)的乙腈溶液中(40ml)加入甲硫醇钠(2.4g,34.8mmol)。加毕，室温搅拌过夜。加入水，并用乙酸乙酯萃取。收集有机相，干燥减压浓缩后，用硅胶柱色谱纯化(EA/PE＝1/50)得白色固体3.48g，收率82.8％。
1H NMR(400MHz,CDCl 3):δ＝8.31(s,1H),2.59(s,3H)。
1.2化合物(T001-3)的制备
向封管中加入化合物T001-2(3.48g,14.54mmol)、二氧六环(10ml)和叔丁胺(6.38g,87.2mmol)。加毕，封管密封后，100℃反应72小时。TLC板监测反应完毕(PE/EA＝10/1，Rf值＝0.6)，冷却至室温，减压浓缩后，硅胶柱色谱纯化(EA/PE＝1/20)得白色固体2.35g，收率59％。
1H NMR(400MHz,DMSO-d 6):δ＝8.08(s,1H),7.04(s,1H),1.44(s,3H),1.38(s,9H)。
1.3化合物(T001-4)的制备
常温下，向微波管中加入化合物T001-3(2g,7.2mmol)、DMF(5ml)、氰化锌(1.7g,14.5mmol)和四(三苯基磷)钯(0.84g,0.72mmol)。加毕，充氮气密封后微波下使用温度模式于120℃反应1.5小时。冷却至室温，减压浓缩后硅胶柱色谱纯化(EA/PE＝1/20)得白色固体1.48g，收率91％。
1.4化合物(T001-5)的制备
冰浴下，向化合物T001-4(1.48g,6.63mmol)的二氯甲烷(30ml)溶液中分批加入间氯过氧苯甲酸(4g,19.9mmol)。加完之后在室温下搅拌4个小时，监测反应完毕。用饱和碳酸氢钠溶液洗去多余的间氯过氧苯甲酸，有机相水洗后干燥，减压浓缩，硅胶柱色谱纯化(EA/PE＝3/20)得白色固体0.44g，收率26.2％。
1.5化合物(T001A)的制备
常温下，向化合物T001-5(0.2g,0.787mmol)的乙醇(3ml)溶液中加入N,N-二异丙基乙胺(即DIEA，0.15g,1.18mmol)，(1R,2R,5R)-5-氨基-2-甲基环己醇盐酸盐(CAS：1403864-98-1，0.13g,0.787mmol)，加完之后在90℃下加热0.5个小时，液相色谱监测反应完毕。减压浓缩，用硅胶柱色谱纯化(EA/PE＝3/10)得白色固体80mg，收率33.4％。
1H NMR(400MHz,CD 3OD):δ＝8.04(s,1H),4.14-4.07(m,1H),3.16-3.10(m,1H),2.22-2.19(m,1H),1.93-1.89(m,1H),1.81-1.77(m,1H),1.44(s,9H),1.39-1.29(m,3H),1.12-1.05(m,1H),1.02(d,J＝6.8Hz,3H).Rt＝3.629min,[M+H]+＝304.2.
1.6化合物(T001)的制备
常温下，向微波管中加入化合物T001A(80mg,0.264mmol)、DMF(1ml)、甲醇(1ml)以及硫化铵水溶液(20％,0.8ml,0.246mmol)。加毕，充氮气密封后，微波下使用温度模式于100℃反应1小时，冷却到室温，减压浓缩后用制备型高效液相色谱(碳酸氢铵方法)纯化，冷冻干燥后得白色固体19mg，收率21.3％。
1H NMR(400MHz,CD 3OD):δ＝8.15(s,1H),4.08-4.02(m,1H),3.16-3.09(m,1H),2.36-2.33(m,1H),2.07-2.04(m,1H),1.81-1.77(m,1H),1.46(s,9H),1.35-1.24(m,3H),1.13-1.06(m,1H),1.03(d,J＝6Hz,3H)；Rt＝3.569min,[M+H]+＝338.1。
实施例2：化合物(T002)的制备
常温下，向化合物T001A(100mg,0.33mmol)的乙醇(2ml)溶液中加入盐酸羟胺(114mg,1.65mmol)以及三乙胺(166mg,1.65mmol)。升温到80℃，加热2个小时后，降到室温，减压浓缩，制备型高效液相色谱(碳酸氢铵方法)纯化、冷冻干燥后得到100mg白色固体，收率90％。
1H NMR(400MHz,DMSO-d 6):δ＝9.48(s,1H),8.43-8.34(m,1H),8.09(s,1H),6.17(s,1H),5.72(s,1H),4.57-4.56(m,1H),3.90-3.87(m,1H),2.98-2.96(m,1H),2.17-2.14(m,1H),1.95-1.92(m,1H),1.69-1.65(m,1H),1.36(s,9H),1.23-0.98(m,4H),0.94(d,J＝6Hz,3H)；Rt＝3.214min,[M+H]+＝337.2。
实施例3：化合物(T003)的制备
Figure PCTCN2020116617-appb-000083
常温下，向化合物T002(50mg,0.148mmol)的甲醇(3ml)溶液中加入2滴醋酸、2滴醋酸酐以及湿钯碳(约10mg)。加毕，氮气置换，再用氢气置换，室温搅拌过夜。减压浓缩后用制备型高效液相色谱(碳酸氢铵方法)纯化，冷冻干燥后得黄色固体17.1mg，收率35.8％。
1H NMR(400MHz,DMSO-d 6):δ＝10.62-10.60(br,1H),6.17(s,1H),6.57-6.28(brs,1H),6.24-6.07(brs,1H),6.04-5.96(brs,2H),4.55-4.54(m,1H),3.87-3.84(m,1H),2.98-2.93(m,1H),2.15-2.12(m,1H),1.92-1.90(m,1H),1.67-1.63(m,1H),1.36(s,9H),1.20-0.97(m,4H),0.93(d,J＝6.4Hz,3H)；Rt＝2.846min,[M+H]+＝321.2。
实施例4：化合物(T004)的制备
Figure PCTCN2020116617-appb-000084
4.1化合物(T004-2)的制备
在冰水浴搅拌下，将五氯化磷(29.6g,142mmol)分批慢慢加入到2,4-二羟基嘧啶-5-甲酸(CAS：23945-44-0，6.2g,40mmol)的三氯氧磷(30ml)溶液中,在冰浴下搅拌30min。然后梯度升温到回流(油浴温度120℃)。回流16个小时后，降到室温。小心地减压浓缩，馏出物为三氯氧磷，用温水淬灭。残留物用二氯甲烷溶解后，过滤。母液再次浓缩后，得到油状物6.7g，粗品收率78.8％。直接用于下一步反应。
4.2化合物(T004-3)的制备
在-20℃搅拌下，将氨水(14ml)滴加到化合物T004-2(8.8g,41.5mmol)的二氯甲烷(30ml)溶液中，有白色的固体出现。在-20℃下搅拌30min。过滤，水洗，干燥得到白色固体2.8g,收率35％。
4.3化合物(T004-4)的制备
在冰浴和搅拌下，向T004-3(384mg，2.0mmol)和(1R,2R,5R)-5-氨基-2-甲基环己醇盐酸盐(397mg，2.4mmol)的异丙醇(10ml)溶液中滴加二异丙基乙基胺(516mg，4.0mmol)。室温搅拌过夜后，反应结束。减压浓缩，加入水，并用乙酸乙酯萃取，有机相用饱和盐水洗涤，用无水硫酸钠干燥。减压浓缩后，用二氯甲烷打浆，过滤得到白色固体500mg，收率88％。
4.4化合物(T004)的制备
将化合物T004-4(50mg，0.175mmol)、4-氨基-1,2,4-三氮唑(29.4mg，0.35mmol)，Pd 2(dba) 3(10mg，0.075mmol)、Xantphos(13mg，0.026mmol)和叔丁醇钾(39.2mg，0.35mmol)分散在无水甲苯(5ml)中。氮气置换后，加热到110℃回流12小时。冷却到室温，减压浓缩，用制备型高效液相色谱(碳酸氢铵方法)纯化，冷冻干燥后得得到白色固体17mg，收率29％。
1HNMR(400MHz，DMSO-d 6)δ10.57(s，1H),9.03(d,J＝7.6Hz,1H),8.64(s，1H)，8.44(s,1H),7.81(brs,1H),7.23(brs,1H),4.54(d,J＝5.6Hz,1H),3.57(brs,1H),2.89-2.85(m,1H),2.02-1.97(m,1H),1.78-1.75(m,1H),1.60-1.56(m,1H),1.19-0.99(m,3H),0.88-0.79(m,4H).LCMS:Rt＝2.207min,[M+H]+＝333.1。
实施例5：化合物(T005)和(T005A)的制备
Figure PCTCN2020116617-appb-000085
5.1化合物(T005-3)的制备
冰浴下，向化合物T001-3(4g,14.5mmol)的二氯甲烷(80ml)溶液中分批加入间氯过氧苯甲酸(7.5g,43.6mmol)，加完之后在室温下搅拌3个小时，液相色谱法监测反应完之后用碳酸氢钠水溶液洗，二氯甲烷萃取，收集有机相干燥减压浓缩后得到化合物T005-2粗品。
常温下，向化合物T005-2(粗品)的DMF(40ml)溶液中加入DIEA(3.75g,29.0mmol)，(1R,2R,5R)-5-氨基-2-甲基环己醇盐酸盐(2.4g,14.5mmol)，加完之后在120℃下搅拌过夜，液相色谱法监测反应完毕，减压浓缩干，正相过柱机纯化(EA/PE＝1/5)得黄色油状物1.637g，两步收率31.5％。
5.2化合物(T005A)的制备
常温下，向高压釜中加入化合物T005-3(300mg,0.84mmol)，三乙胺(254mg,2.52mmol)，双三苯基磷二氯化钯(61mg,0.084mmol)以及甲醇(20ml)，加完之后通一氧化碳气体置换，加压到1.5MPa在100℃下搅拌过夜，液相色谱法监测反应完毕，减压浓缩干，正相过柱机纯化(EA/PE＝1/5)得黄色油状物267mg，收率94.6％。
1H NMR(400MHz,CD 3OD):δ＝8.40(s,1H),4.08-4.06(m,1H),3.79(s,3H),3.17-3.11(m,1H),2.33-2.30(m,1H),2.05-2.00(m,1H),1.82-1.77(m,1H),1.46(s,9H),1.35-1.25(m,3H),1.11-1.07(m,1H),1.03(d,J＝6.4Hz,3H).Rt＝3.861min,[M+H]+＝338.2。
5.3化合物(T005)的制备
冰浴下，向化合物T005A(100mg,0.297mmol)的四氢呋喃(3ml)溶液中缓慢滴加甲基锂的乙醚溶液(1.6M)(1.8ml,2.97mmol)，加完之后升温至室温搅拌过夜，液相色谱法监测反应完之后用氯化铵水溶液淬灭，并用乙酸乙酯萃取，收集有机相，干燥，减压浓缩后，用制备型高效液相色谱(碳酸氢铵方法)纯化，冷冻干燥后得白色固体50mg，收率33.3％。
1H NMR(400MHz,DMSO-d 6):δ＝7.54(s,1H),6.92(d,J＝7.6Hz,1H),5.73(s,1H),5.34(s,1H),4.56(d,J＝5.6Hz,1H),3.88-3.83(m,1H),2.99-2.93(m,1H),2.17-2.11(m,1H), 1.94-1.91(m,1H),1.68-1.64(m,1H),1.40(s,6H),1.34(s,9H),1.24-0.98(m,4H),0.94(d,J＝6.8Hz,3H).Rt＝3.005min,[M+H]+＝337.2。
实施例6：化合物(T006)的制备
Figure PCTCN2020116617-appb-000086
6.1化合物(T006-2)的制备
在冰水浴搅拌下，将五氯化磷(29.6g,142mmol)分批慢慢加入到2,4-二羟基嘧啶-5-甲酸(CAS：38324-83-3，6.2g,40mmol)的三氯氧磷(30ml)溶液中,在冰浴下搅拌30min。然后梯度升温到回流(油浴温度120℃)。回流16个小时后，降到室温。小心地减压浓缩，馏出物为三氯氧磷，用温水淬灭。残留物用二氯甲烷溶解后，过滤。母液再次浓缩后，得到油状物6.7g，粗品收率78.8％。直接用于下一步反应。
6.2化合物(T006-3)的制备
在-20℃搅拌下，将氨水(14ml)滴加到化合物T006-2(8.8g,41.5mmol)的二氯甲烷(30ml)溶液中，有白色的固体出现。在-20℃下搅拌30min。过滤，水洗，干燥得到白色固体2.8g,收率35％。
6.3化合物(T006-4)的制备
在冰浴和搅拌下，向化合物T006-3(192mg，1.0mmol)和4-羟基哌啶(CAS：5382-16-1，111mg，1.1mmol)的异丙醇(5ml)溶液中滴加二异丙基乙基胺(193mg，1.5mmol)。搅拌2h后，反应结束。减压浓缩，加入水，并乙酸乙酯萃取，有机相用饱和盐水洗涤，经无水硫酸钠干燥。减压浓缩后，用二氯甲烷打浆，过滤得到白色固体54mg，收率21％。
6.4化合物(T006)的制备
玻璃封管中加入化合物T006-4(54mg，0.21mmol)，叔丁胺(438mg)和乙腈(5ml)。封管密封后加热到90℃。反应12h后，冷却到室温，浓缩后，经制备型高效液相色谱(碳酸氢铵方法)纯化，冷冻干燥得到白色固体27mg，收率44％。
1HNMR(400MHz，CD 3OD)δ8.09(s，1H),3.87-3.93(m,3H),3.19-3.25(m,2H),1.91-1.96(m,2H),1.55-1.59(m,2H),1.46(s,9H).LCMS:Rt＝2.22min,[M+H]+＝294.1。
实施例7：化合物(T007)的制备
Figure PCTCN2020116617-appb-000087
7.1化合物(T007-2)的制备
室温下，将化合物3-叔丁氧羰基氨基哌啶(CAS：172603-05-3，1g,4.98mmol)、氰乙酸(636mg,7.4mmol)和三乙胺(1.0g,9.96mmol)溶于20ml二氯甲烷中,加入2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲氟磷酸酯(2.26g,5.96mmol),室温搅拌下过夜。后处理加水，二氯甲烷萃取，有机相减压浓缩，粗品过正相柱得到黄色的固体898mg,收率69％。
7.2化合物(T007-3)的制备
室温下，将化合物T007-2(848mg,3.17mmol)溶于2ml盐酸乙酸乙酯中,搅拌4小时减压浓缩得到白色固体380mg,收率71％。
7.3化合物(T007-4)的制备
将化合物T007-3(350mg,2.09mmol)和化合物T006-3(482mg,2.5mmol)溶于10ml异丙醇中，在冰浴和搅拌下滴加DIEA(808mg,6.27mmol)，室温搅拌下过夜。减压浓缩，加入水，并用乙酸乙酯萃取，有机相用饱和盐水洗涤，经无水硫酸钠干燥。浓缩后的残余物用二氯甲烷打浆，过滤得到300mg白色固体T007-4，收率44.6％。将滤液浓缩，经高效液相色谱(碳酸氢铵方法)制备得到70mg氰基水解的副产物T007-5。
7.4化合物(T007)的制备
封管中加入化合物T007-4(200mg,0.62mmol)、2ml乙腈和1ml叔丁胺。封管密封后加热至90℃反应过夜。冷却到室温，浓缩后，经制备型高效液相色谱(碳酸氢铵方法)纯化，冷冻干燥后得到白色固体15mg，收率6.7％。
1H NMR(400MHz，DMSO-d6):δ8.27(d，J＝7.6Hz,1H),8.02(s,1H),7.49(s,1H),7.13s, 1H),6.61(br,1H),3.76-3.74(m,2H),3.63(s,2H),3.60-3.56(m,1H),3.04-2.94(m,2H),1.83-1.81(m,1H),1.68-1.69(m,1H),1.58-1.36(m,2H),1.36(s,9H).LCMS:Rt＝3.992min,[M+H]+＝360.2。
实施例8：化合物(T008)的制备
将化合物T007-5(70mg,0.185mmol)溶于1ml乙腈中，再加入1ml叔丁胺用封管加热至90℃反应过夜。冷却到室温，浓缩后，经制备型高效液相色谱(碳酸氢铵方法)纯化，冷冻干燥后得到白色固体8.7mg，收率11.5％。
1H NMR(400MHz，DMSO-d6):δ8.28-8.26(m,1H),4.25-4.20(m,1H),3.90-3.85(m,1H),3.70-3.30(m,4H),2.05-1.95(m,1H),1.8-1.60(m,4H),1.36(s,9H).LCMS:Rt＝2.688min,[M+H]+＝378.2。
实施例9：化合物(T009)的制备
Figure PCTCN2020116617-appb-000088
9.1化合物(T009-2)的制备
在冰浴和搅拌下，向化合物T006-3(384mg，2.0mmol)和5-氨甲基-2-吡咯烷酮(272mg，2.4mmol)的异丙醇(10ml)溶液中滴加DIEA(516mg，4.0mmol)。加完后室温继续搅拌4小时，反应结束。有白色固体析出。过滤水洗得到白色产物400mg，收率74％。
9.2化合物(T009)的制备
向封管中加入化合物T009-2(210mg，0.73mmol)、叔丁胺(730mg，7.4mmol)和N,N-二甲基甲酰胺(5ml)。封管密封后加热到90℃，反应12h。冷却到室温，减压浓缩，用制备型高效液相色谱(碳酸氢铵方法)纯化，冷冻干燥后得得到白色固体67mg，收率30％。
1HNMR(400MHz，CD 3OD)δ8.30(s,1H),4.01-3.95(m,1H),3.74-3.71(m,1H),3.70-3.56(m,1H),2.44-2.23(m,3H),1.94-1.85(m,1H),1.48(s,9H).LCMS:Rt＝2.673min,[M+H]+＝307.1。
实施例10：化合物(T010)的制备
Figure PCTCN2020116617-appb-000089
室温下，向化合物T004-4(80mg,0.282mmol)和对甲氧基苯胺(42mg,0.338mmol)的异丙醇(10ml)混合液中加入一水合对甲苯磺酸(134mg,0.705mmol)。反应体系用氮气置换后， 加热回流16小时。冷却到室温，析出白色固体，过滤，用异丙醇洗涤后抽真空干燥得到纯产物65mg，收率62％。
1H NMR(400MHz,CD 3OD):δ8.27(s,1H),7.38-7.36(m,2H),7.02-7.00(m,2H),4.02-3.98(m,1H),3.83(s,3H),3.13-3.07(m,1H),2.30-2.27(m,1H),2.00-1.97(m,1H),1.81-1.77(m,1H),1.38-1.29(m,4H),1.02(d,J＝6.4Hz,3H).Rt＝3.012min,[M+H]+＝372.1。
实施例11：化合物(T011)的制备
Figure PCTCN2020116617-appb-000090
11.1化合物(T011-2)的制备
2,6-二氯-烟酰胺(500mg,2.6mmol，CAS：62068-78-4)的异丙醇(5ml)溶液中加入3-胺基-苯甲酸甲酯(474mg,3.1mmol，CAS：4518-10-9)和DIEA(503mg,3.9mmol)，然后加热回流反应16小时。液相色谱监测反应完毕。反应液过滤，减压浓缩得化合物T011-2粗品(600mg),直接用于下一步反应。LCMS:Rt＝1.450min,[M+H]+＝306.8。
11.2化合物(T011-3)的制备
化合物T011-2(150mg,0.49mmol)的DMF(0.5ml)溶液中加入叔丁胺(0.5ml)，封管在100℃下反应18小时，色谱监测反应完毕。减压浓缩后得化合物T011-3的粗品约200mg，直接用于下一步反应。LCMS:Rt＝1.572min,[M+H]+＝343.9.
11.3化合物(T011)的制备
化合物T011-3(粗品，0.49mmol)的THF(1.5ml)溶液中加入水(0.3ml)和氢氧化锂(100mg,2.5mmol),然后室温搅拌12小时。液相色谱监测反应完毕。反应液用1mol/L的盐酸调pH＝4.0，旋干，用DMF(2ml)溶解，过滤除去不溶物，用制备型高效液相色谱(碳酸氢铵方法)纯化，冷冻干燥后得得到白色固体24mg,三步收率为15％。
1H NMR(400MHz,DMSO-d 6):δ＝12.89(br,1H),11.72(brs,1H),8.58(s,1H),8.27(s,1H),7.88-7.72(m,2H),7.61(d,J＝7.8Hz,1H),7.43(t,J＝8Hz,1H),7.27(br,1H),7.05(brs,1H),1.38(s,9H).LCMS:Rt＝2.623min,[M+H]+＝330.1。
实施例12：化合物(T012)的制备
Figure PCTCN2020116617-appb-000091
12.1化合物(T012-2)的制备
常温下，向2,4-二氯-5-氟嘧啶(500mg，2.5mmol，CAS：2927-71-1)的异丙醇(10ml)溶液中加入DIEA(997mg,7.7mmol)和(1R,2R,5R)-5-氨基-2-甲基环己醇盐酸盐(467mg,2.8mmol)，室温下反应3小时，液相色谱监测反应完毕。减压浓缩，用硅胶柱色谱纯化(EA/PE＝1/3)得黄色固体510mg，收率69.1％。
12.2化合物(T012)的制备
常温下，向封管中加入化合物T012-2(510mg,1.78mmol)、二氧六环(5ml)和叔丁胺(2ml)。加毕，封管密封后加热到90℃反应3小时。冷却到室温，减压浓缩后，用水和乙酸乙酯萃取，有机相经干燥和浓缩后得粗产物420mg，为黄色固体，收率72.7％。
1H NMR(400MHz,DMSO-d 6):δ＝8.82(s,1H),8.52(d,J＝7.6Hz,1H),7.96(s,1H),8.52(d,J＝5.2Hz,1H),4.10-4.06(m,1H),3.06-3.01(m,1H),2.13-2.10(m,1H),1.88-1.85(m,1H),1.74-1.70(m,1H),1.45-1.36(m,10H),1.29-1.23(m,2H),1.03-0.93(m,4H).Rt＝4.064min,[M+H]+＝324.1。
实施例13：化合物(T013)的制备
Figure PCTCN2020116617-appb-000092
13.1化合物(T013-2)的制备
室温下，将化合物2,4,5-三氯嘧啶(CAS:5750-76-5，366mg,2mmol)，甲硫醇钠(154mg,2.2mmol)溶于50ml四氢呋喃中，室温搅拌过夜，LC-MS确认反应完成，经柱色谱纯化得到335mg白色固体，收率86.3％。
13.2化合物(T013-3)的制备
将化合物T013-2(340mg,1.75mmol)溶于3ml二氧六环中，加入1.5ml叔丁胺，在封管 中在100℃反应过夜。冷却后浓缩，经柱色谱纯化得到110mg白色固体，收率27％。
13.3化合物(T013-4)的制备
将化合物T013-3(110mg，0.47mmol)溶于20ml二氯甲烷中，冰浴下分批加入m-CPBA(246mg，1.42mmol)，加毕恢复到室温，继续搅拌过夜。加入30ml二氯甲烷稀释，用饱和碳酸氢钠溶液洗涤后，有机相用无水硫酸钠干燥，柱色谱得到60毫克白色固体，收率48.8％。
13.4化合物(T013)的制备
将化合物T013-4(60mg，0.228mmol)溶于10ml二氧六环中，加入(1R,2R,5R)-5-氨基-2-甲基环己醇盐酸盐(56.5mg，0.342mmol)，二异丙基乙基胺(88.3mg，0.684mmol)，于100℃搅拌反应20小时。反应液浓缩后由制备型高效液相色谱(碳酸氢铵方法)纯化，冷冻干燥后得白色固体20mg，收率28％。
1H NMR(400MHz，CDCl 3)δ7.73(s,1H),5.07(br,1H),4.91(s,1H),3.99-3.95(m,1H),3.32-3.26(m,1H),2.39-2.35(m,1H),2.06-2.02(m,1H),1.83-1.77(m,1H),1.38(s,9H),1.38-1.25(m,3H),1.15-1.05(m,1H),1.03(d,J＝6.6Hz,3H).LCMS:Rt＝4.524min,[M+H]+＝313.1。
实施例14：化合物(T014)的制备
Figure PCTCN2020116617-appb-000093
14.1化合物(T014-2)的制备
将化合物T001-3(230mg，0.836mmol)、甲基硼酸(251mg,4.18mmol)、碳酸钾(346mg，0.250mmol)和Pd(dppf)Cl 2(50mg，0.068mmol)分散在二氧六环(5ml)和水(2ml)混合溶液中。氮气置换，加热到回流反应4小时，液相色谱监测反应结束。反应液减压浓缩后，柱色谱纯化得到油状物130mg，收率74％。
14.2化合物(T014-3)的制备
在冰浴和搅拌下，向化合物T014-2(180mg，0.853mmol)的二氯甲烷(2ml)溶液加3-氯苯并过氧酸(296mg，1.70mmol)。室温搅拌4小时后，反应结束。加入二氯甲烷稀释后过滤，有机相用碳酸氢钠溶液洗涤后，低温减压浓缩，柱色谱纯化得到白色固体150mg，收率72％。
14.3化合物(T014)的制备
向8ml微波管中加入化合物T014-3(50mg，0.205mmol)、异丙醇(2ml)、(1R,3R,4R)-5- 氨基-2-甲基环己醇盐酸盐(34mg，0.205mmol)和DIEA(53mg，0.41mmol)。微波管密封后在微波反应器中于140℃反应2小时。冷却到室温，减压浓缩，用制备型高效液相色谱(碳酸氢铵方法)纯化，冷冻干燥后得到白色固体8.1mg，收率13.5％。
1H NMR(400MHz，CD 3OD)δ7.43(s，1H),4.23-4.17(m,1H),3.20-3.14(m,1H),2.24-2.21(m,1H),2.20(s,3H),1.96-1.92(m,1H),1.86-1.82(m,1H),1.55-1.52(m,11H),1.48-1.36(m,1H),1.09-1.07(m,1H),1.04(d,J＝6.4Hz,3H).LCMS:Rt＝3.168min,[M+H]+＝293.2。
同类型其他化合物的制备
参考上述实施例1-14的工艺路线和操作方法，制备得到下面表2中的如下化合物：
表2
实施例 化合物编号 Ms+1
15 T015 362.1
16 T016 307.1
17 T017 351.1
18 T018 308.1
19 T019 294.2
20 T020 308.2
21 T021 336.3
22 T022 336.1
23 T023 349.1
24 T024 420.1
25 T025 293.3
26 T026 316.1
27 T027 348.3
28 T028 329.1
29 T029 309.1
30 T030 311.1
实施例31：化合物(T031)的制备
Figure PCTCN2020116617-appb-000094
31.1化合物(T031-2)的制备
将5-溴尿嘧啶(CAS:51-20-7，3g,0.015mol)、苄硫醇(2.1g,0.017mol)、四丁基硫酸氢铵(CAS:32503-27-8，1.3g,0.25mol)和碳酸钾(4.5g,0.033mol)溶于20ml DMF中，60℃反应过夜(约16小时)。液相色谱监测反应结束。反应液过滤，滤液减压浓缩后，用石油醚打浆得白色固体2.1g，收率57.2％。
LCMS:Rt＝0.964min,[M+H]+＝235.1。
31.2化合物(T031-3)的制备
化合物T031-2溶于三氯氧磷中，110℃反应过夜。液相色谱监测反应结束，反应液减压浓缩，浓缩液加入碳酸氢钠水溶液和乙酸乙酯，分液，有机相浓缩后用硅胶柱色谱纯化(PE)得黄色油状物420mg，收率24.7％。
1H NMR(400MHz，CD 3OD):δ8.74(s，1H),7.43(d，J＝8.4Hz,2H)，7.35(t，J＝7.2Hz,2H)，7.31-7.26(m,1H),4.46(s,2H)。
31.3化合物(T031-4)的制备
2M盐酸溶液(0.3ml)溶于10ml乙腈中，冰浴下加入N-氯代丁二酰亚胺(即NCS，CAS:128-09-6；635mg，4.74mmol)搅拌5分钟，将化合物T031-3(320mg，1.18mmol)的乙腈溶液滴加到反应中，冰浴下反应30分钟，液相色谱监测反应结束。反应液减压浓缩，浓缩液加入水和乙酸乙酯，分液，有机相浓缩得到300mg粗品，直接用于下一步反应。
31.4化合物(T031-5)的制备
化合物T031-4粗品溶于四氢呋喃溶液中，冰浴下滴加氨水(0.3ml)，0℃反应5分钟。液相色谱监测反应结束，反应液减压浓缩，浓缩液加入水和乙酸乙酯，分液，有机相浓缩后用硅胶柱色谱纯化(EA/PE＝1/3)得黄色油状物190mg，二步收率71.1％。
LCMS:Rt＝1.390min,[M-H]-＝225.9。
31.5化合物(T031-6)的制备
常温下，向化合物T031-5(190mg，0.84mmol)的异丙醇(4ml)溶液中加入DIEA(325mg,2.52mmol)和化合物(1R,2R,5R)-5-氨基-2-甲基环己醇盐酸盐(166mg,100mmol)，室温下反应3小时。液相色谱监测反应完毕。减压浓缩，用硅胶柱色谱纯化(EA/PE＝1/1)得黄色油状物110mg，收率40.8％。
LCMS:Rt＝1.036min,[M+H]+＝320.8。
31.6化合物(T031)的制备
常温下，向封管中加入化合物T031-6(90mg,0.28mmol)，乙腈(2ml)和叔丁胺(0.5ml)。 加毕，封管密封后加热到90℃反应6小时。冷却到室温，减压浓缩后用制备型高效液相色谱(氨水方法)纯化、冷冻干燥后得白色固体2.2mg，收率2.2％。
1H NMR(400MHz，CD 3OD):δ8.75(s，1H),4.13-4.07(m,1H),3.10-3.03(m,1H),2.23-2.20(m,1H),1.94-1.91(m,1H),1.75-1.70(m,1H),1.37(s，9H),1.32-1.18(m,3H),1.05-0.97(m,1H),0.95(d,J＝6.4Hz,3H).LCMS:Rt＝3.060min,[M+H]+＝358.1。
实施例32：化合物(T032)的制备
参考实施例31的工艺路线和操作方法，以苯甲醇替换苄硫醇，先取代后脱苄，制备得到化合物T032，[M+H]+＝295.3。
实施例33：化合物(T033)的制备
Figure PCTCN2020116617-appb-000095
33.1化合物(T033-2)的制备
常温下，向化合物5-溴-2,4-二氯嘧啶(150mg,0.658mmol)的异丙醇(2ml)溶液中加入(1R,2R,5R)-5-氨基-2-甲基环己醇盐酸盐(119.8mg,0.724mmol)以及DIEA(169.8mg,1.316mmol)。加毕，加热到70℃反应1小时。冷却到室温，减压浓缩，正相过柱机纯化(EA/PE＝3/10)得无色油状物377mg，收率89.5％。
33.2化合物(T033)的制备
常温下，向封管中加入化合物T033-2(377mg,1.178mmol)，二氧六环(1.2ml)，叔丁胺(517mg,7.068mmol)。加毕，封管密封后加热到100℃反应72小时。冷却到室温，减压浓缩后，用制备型高效液相色谱(碳酸氢铵方法)纯化、冷冻干燥后得白色固体61mg，收率14.5％。
1H NMR(400MHz,DMSO-d 6):δ＝7.80(s,1H),6.28-6.26(m,1H),4.64-4.63(m,1H),3.95-3.93(m,1H),2.98-2.95(m,1H),2.01-1.98(m,1H),1.76-1.65(m,2H),1.43-1.18(m,13H),0.98-0.90(m,3H).Rt＝2.918min,[M+H]+＝359.1。
实施例34：化合物(T034)的制备
Figure PCTCN2020116617-appb-000096
将化合物T005-3(210mg,0.58mmol)、咪唑(47.6mg,0.7mmol)、碳酸钾(296mg,2.32mmol)、L-脯氨酸(66.7mg,0.58mmol)和碘化亚铜(55.1mg,0.29mmol)溶于3ml二甲基亚砜中。氮气保护下，120℃反应过夜，液相色谱监测反应结束。反应液过滤，加入水，并用乙酸乙酯萃取，有机相经无水硫酸钠干燥，减压浓缩，用制备型高效液相色谱(碳酸氢铵方法)纯化，冷冻干燥后得白色固体8.8mg，收率4％。
1H NMR(400MHz，CD 3OD):δ7.67(s,1H),7.62(s,1H),7.15-713(m,2H),4.11-4.04(m,1H),3.15-3.09(m,1H),2.19-2.14(m,1H),1.90-1.86(m,1H),1.77-1.73(m,1H),1.46(s,9H),1.33-1.25(m,3H),1.07-1.00(d,J＝6.4Hz,3H).LCMS:Rt＝3.244min,[M+H]+＝345.2。
实施例35：化合物(T035)的制备
参考上述实施例34的工艺路线和操作方法，以1，2，4-三氮唑替换咪唑，制备得到化合物T035，[M+H]+＝346.3。
实施例36：化合物(T036)的制备
参考上述实施例34的工艺路线和操作方法，以1，2，3-三氮唑替换咪唑，制备得到化合物T036，[M+H]+＝346.3。
实施例37：化合物(T037)的制备
Figure PCTCN2020116617-appb-000097
37.1化合物(T037-2)的制备
室温下，将二氯亚砜(5.76g,48.3mmol)缓慢滴加到2-羟乙基甲砜(CAS：15205-66-0，2g, 16.1mmol)和吡啶(1.27g,16.1mmol)的甲苯(20ml)溶液中。加毕，反应液加热到80℃反应10小时。冷却至室温，饱和碳酸氢钠水溶液(50ml)淬灭，分液分出甲苯层，水层用乙酸乙酯萃取。合并有机相，经干燥和浓缩后得粗产物1-氯-2-甲磺酰基乙烷1.5g，为棕黄色的油，收率66％。
1H NMR(400MHz,CDCl3):δ3.93(t,J＝6.4Hz,2H),3.45(t,J＝6.4Hz,2H),3.04(s,3H)。
37.2化合物(T037-3)的制备
在Biotage微波管中加入T037-2(377mg,2.65mmol)、3-硝基吡唑(250mg,2.21mmol)、碳酸钾(460mg,3.31mmol)、碘化钾(约5mg，催化量)和DMF(3ml)。充氮气密封后微波下使用温度模式于150℃反应3小时。冷却到室温后加水稀释，用乙酸乙酯萃取后浓缩。用硅胶柱色谱纯化(PE/EA＝25％to 40％)得到产物160mg，为黄色固体，收率33％。
1H NMR(400MHz,CDCl 3):δ7.63(d,J＝2.4Hz,1H),6.92(d,J＝2.4Hz,1H),4.72(t,J＝6.4Hz,2H),3.69(t,J＝6.4Hz,2H),2.78(s,3H)。
37.3化合物(T037-4)的制备
将化合物T037-3(160mg，0.727mmol)和Pd/C(含水，约30mg)分散在乙酸乙酯(40ml)和甲醇(10ml)中，用气球常压氢化，在室温下反应16小时。过滤，干燥和浓缩后得粗产物(160mg),为棕色的油。
37.4化合物(T037-5)的制备
在Biotage微波管中加入化合物T037-4(160mg，0.73mmol)、2,4-二氯嘧啶(91mg,0.615mmol)、DIEA(0.33ml,1.845mmol)和DMF(2ml)。充氮气密封后微波下使用温度模式于140℃反应2小时。反应液减压浓缩后，用制备硅胶板分离(PE/EA＝1:1)，得产物140mg,为黄色固体，收率75％。
37.5化合物(T037)的制备
在Biotage微波管中加入化合物T037-5(120mg,0.397mmol)、反式-4-氨基环己醇(91mg,0.795mmol)、DIEA(0.14ml,0.795mmol)和正丁醇(3ml)。充氮气密封后微波下使用温度模式于165℃反应2小时。反应液减压浓缩后用甲醇(2.5ml)溶解过滤，送制备型高效液相色谱(TFA方法)纯化，冷冻干燥后得产物25.2mg，为白色固体，收率17％。
1H NMR(400MHz,CD 3OD):δ7.70(s,2H),6.76(s,1H),6.28(s,1H),4.58(t,J＝6.4Hz,2H),3.93-3.87(m,1H),3.69(t,J＝6.4Hz,2H),3.63-3.58(m,1H),2.80(s,3H),2.08-2.00(m,4H),1.46-1.37(m,4H).LCMS:Rt＝3.311min,[M+H]+＝381.1。
实施例38：化合物(T038)的制备
Figure PCTCN2020116617-appb-000098
38.1化合物(T038-2)的制备
将1H-吡唑-3-甲酸(CAS：1621-91-6，2g,17.85mmol)和浓硫酸(2.9ml,53.56mmol)的乙醇溶液(80ml)加热回流14小时。冷却到室温后，减压蒸馏去除乙醇，加乙酸乙酯(50ml)，饱和碳酸氢钠水溶液萃取洗涤，有机相干燥后浓缩得产物1.7g，为白色固体，收率68％。
38.2化合物(T038-3)的制备
室温下，向化合物T038-2(1.6g,11.43mmol)和化合物T037-2(1.95g,13.71mmol)的DMF溶液(50ml)中加入碳酸钾(2.06g,14.86mmol)和碘化钾(190mg,1.14mmol)。加热反应体系到120℃，反应16小时。反应液减压浓缩后使用硅胶柱色谱纯化(PE/EA＝55％)，得到2个位置异构体。经NOE二维核磁谱确认，较小极性的较低转化率的异构体为目标产物(190mg)，为白色固体，收率6.7％。
1H NMR(400MHz,CDCl 3):δ7.52(d,J＝2.0Hz,1H),6.86(d,J＝2.0Hz,1H),5.04(t,J＝6.8Hz,2H),4.40-4.34(m,2H),3.58(t,J＝6.8Hz,2H),2.86(s,3H),1.40-1.35(m,3H).
38.3化合物(T038-4)的制备
室温下，向化合物T038-3(190mg,0.77mmol)的乙醇(5ml)和水(2ml)溶液中加入氢氧化钠(37mg,0.92mmol)。室温下搅拌16小时。浓缩除去乙醇后加入5ml水稀释，用盐酸(1M)酸化到pH值为1，白色固体析出，过滤后得到产物(140mg)，收率84％。
38.4化合物(T038-5)的制备
室温下，向化合物T038-4(120mg,0.55mmol)的叔丁醇(无水，10ml)溶液中加入DPPA(227mg,0.82mmol)和三乙胺(112mg,1.1mmol)。反应体系加热到90℃，反应16小时。减压浓缩后用制备硅胶板纯化(DCM/MeOH＝20:1)，得粗产物160mg,为棕色的固体，收率100％。
38.5化合物(T038-6)的制备
化合物T038-5(160mg,0.55mmol)的盐酸二氧六环(4M,10ml)溶液室温下搅拌2小时。减压浓缩后得到粗产物盐酸盐(110mg),为黄色的胶状物，收率89％。
38.6化合物(T038-7)的制备
在Biotage微波管中加入化合物T038-6(110mg,0.489mmol)，2,4-二氯嘧啶(61mg,0.407mmol),DIEA(0.37ml,2.035mmol)和DMF(2ml)。充氮气密封后微波下使用温度模式于145℃反应3小时。冷却到室温后加水稀释，用乙酸乙酯萃取后浓缩。用制备硅胶板纯化(PE/EA＝40％)得到产物30mg，为黄色固体，收率24％。
38.7化合物(T038)的制备
在Biotage微波管中加入化合物T038-7(30mg,0.1mmol),反式-4-氨基环己醇(23mg,0.2mmol),DIEA(40mg,0.3mmol)和正丁醇(1ml)。充氮气密封后微波下使用温度模式于165℃反应3小时。反应液减压浓缩后用甲醇(1ml)溶解过滤，送制备型高效液相色谱(碳酸氢铵方法)纯化，冷冻干燥后得产物3.5mg，为黄色固体，收率9.2％。
1H NMR(400MHz,CD 3OD):δ7.85-7.83(m,1H),7.52-7.49(m,1H),8.28-8.24(m,1H),6.01.5.99(m,1H),4.49(t,J＝6.4Hz,2H),3.68-3.64(m,2H),3.60-3.52(m,2H),2.77(s,3H),1.99-1.92(m,4H),1.36-1.26(m,4H).LCMS:Rt＝2.349min,[M+H]+＝381.1。
实施例39：化合物(T039)的制备
Figure PCTCN2020116617-appb-000099
冰浴下，向化合物T004-4(143mg,1.232mmol)的THF(15ml)悬浮液中分次加入氢化钠(60％,94mg,2.46mmol)。加毕，冰浴下搅拌30分钟后加入反式-1,4-环己二醇(CAS：6995-79-5，70mg,0.246mmol)。缓慢升温至回流反应14小时。冷却到室温，加甲醇和氯化铵水溶液淬灭。减压浓缩后用制备型高效液相色谱(TFA方法和碳酸氢铵方法)纯化2次，冷冻干燥后得白色固体16mg，收率18％。
1H NMR(400MHz,CD 3OD):δ8.43(s,1H),4.84-4.91(m,1H),4.00-3.98(m,1H),3.69-3.66(m,1H),3.19-3.14(m,1H),2.34-2.31(m,1H),2.18-2.15(m,2H),2.03-2.00(m,3H),1.82-1.77(m,1H),1.60-1.55(m,2H),1.47-1.41(m,2H),1.35-1.24(m,4H),1.18-1.09(m,1H),1.04(d,J＝6.4Hz,3H).Rt＝2.576min,[M+H]+＝365.2。
实施例40：化合物(T040)的制备
Figure PCTCN2020116617-appb-000100
室温下，向化合物T004-4(80mg,0.282mmol)和对羟基苯甲醚(CAS：150-76-5，38mg,0.309mmol)的DMF(5ml)混合液中加入碳酸钾(78mg,0.564mmol)。反应体系氮气置换后加热到80℃反应16小时。冷却到室温，加入水和乙酸乙酯萃取。经制备型高效液相色谱(碳酸氢铵方法)纯化，冷冻干燥后得到白色固体60mg,收率57％。
1H NMR(400MHz,CD 3OD):δ8.49(s,1H),7.08-7.05(m,2H),6.97-6.93(m,2H),3.80(s,3H),3.61-3.55(m,1H),2.94-2.88(m,1H),2.15-2.11(m,1H),1.83-1.80(m,1H),1.66-1.61(m,1H),1.22-1.08(m,3H),0.97(d,J＝6.0Hz,3H),0.90-0.78(m,1H).Rt＝2.576min,[M+H]+＝365.2.
实施例41：化合物(T041)的制备
Figure PCTCN2020116617-appb-000101
41.1化合物(T041-2)的制备
在冰浴和搅拌下，向化合物T001-2(60mg，0.251mmol)的N,N-二甲基甲酰胺(2ml)溶液加叔丁醇钾(56mg，0.50mmol)。室温搅拌过夜后，反应结束。加入水，并用乙酸乙酯萃取，有机相用饱和盐水洗涤，经无水硫酸钠干燥。减压浓缩后，柱色谱，得到无色液体60mg，收率86％。
1HNMR(400MHz，DMSO-d 6)δ8.40(s，1H),2.55(s,3H),1.54(s，9H)。
41.2化合物(T041-3)的制备
在冰浴和搅拌下，向化合物T041-2(1.5g，5.41mmol)的二氯甲烷(20ml)溶液加3-氯苯并过氧酸(1.9g，10.8mmol)。室温搅拌7小时后，反应结束。加入二氯甲烷稀释后过滤，水相用碳酸氢钠溶液洗涤后，低温减压浓缩，柱色谱纯化得到白色固体700mg，收率42％。该化合物不稳定，需要立即使用。
41.3化合物(T041)的制备
在室温和搅拌下，向化合物T041-3(100mg，0.342mmol)的异丙醇(3ml)溶液加入(1R,3R,4R)-5-氨基-2-甲基环己醇盐酸盐(57mg，0.342mmol)和DIEA(132mg，1.026mmol)。室温搅拌3小时后，反应结束。加入水，并用乙酸乙酯萃取，有机相用饱和盐水洗涤，经无水硫酸钠干燥。减压浓缩后，用制备型高效液相色谱(碳酸氢铵方法)纯化，冷冻干燥后得得 到白色固体40mg，收率34％。该化合物也不太稳定，容易受酸碱水汽等影响变质。
1H NMR(400MHz，CD 3OD)δ7.97(s,1H),4.09-4.03(m,1H),3.20-3.15(m,1H),2.25-2.21(m,1H),1.96-1.92(m,1H),1.85-1.81(m,1H),1.55(s,9H),1.50-1.32(m,3H),1.17-1.08(m,1H),1.04(d,J＝6.4Hz,3H).LCMS:Rt＝4.113min,[M+H]+＝358.1，340.1。
实施例42：化合物(T042)的制备
Figure PCTCN2020116617-appb-000102
42.1化合物(T042-2)的制备
在氮气保护下，冰浴搅拌，向环丙醇(70mg，1.20mmol)的N,N-二甲基甲酰胺(3ml)溶液中加氢化钠(96mg，60％，2.4mmol)。冰浴下搅拌1小时后，将化合物T001-2(288mg，1.2mmol)加入到反应液中，室温继续搅拌过夜。室温下加入氯化铵溶液淬灭，并用乙酸乙酯萃取，有机相经干燥和浓缩后，经柱色谱得到无色液体150mg，收率40％。
LCMS:Rt＝1.730min,[M+H]+＝261.0。
42.2化合物(T042-3)的制备
在冰浴和搅拌下，向化合物T042-2(30mg，0.114mmol)的二氯甲烷(2ml)溶液加3-氯苯并过氧酸(59mg，0.343mmol)。室温搅拌3小时后，反应结束。加入二氯甲烷稀释后过滤，水相用碳酸氢钠溶液洗涤后，低温减压浓缩，柱色谱纯化得到白色固体30mg，收率88％。
42.3化合物(T042-4)的制备
在室温和搅拌下，向化合物T042-3(100mg，0.342mmol)的异丙醇(3ml)溶液加(1R,3R,4R)-5-氨基-2-甲基环己醇盐酸盐(57mg，0.342mmol)和DIEA(132mg，1.026mmol)。室温搅拌过夜后，反应结束。反应液减压浓缩后，过柱，得到白色固体50mg，收率43％。LCMS:Rt＝1.523min,[M+H]+＝341.1，343.1.
42.4化合物(T042-5)的制备
将化合物T042-4(40mg，0.30mmol)和氰化亚铜(104mg，1.17mmol)分散在2ml DMF中。加热到150℃反应5小时，液相色谱监测反应结束。冷却到室温，加入水，并用乙酸乙酯萃取。有机相用无水硫酸钠干燥后减压浓缩，经柱色谱纯化得到白色固体30mg，收率88％。
42.5化合物(T042)的制备
在室温和搅拌下，向化合物T042-5(40mg，0.30mmol)的2ml水溶液滴加市售30％双氧水(0.5ml)和氢氧化钠水溶液(0.2ml,1M)。加完后室温搅拌2小时，液相色谱监测反应结束。过滤，滤液用制备型高效液相色谱(碳酸氢铵方法)纯化，冷冻干燥后得得到白色固体10mg，收率27％。
1H NMR(400MHz，CD 3OD)δ8.46(s，1H),4.32-4.28(m,1H),4.12-4.06(m,1H),3.20-3.14(m,1H),2.41-2.37(m,1H),2.10-2.07(m,1H),1.82-1.78(m,1H),1.35-1.19(m,3H),1.16-1.12(m,1H),1.04(d,J＝6.0Hz,3H),0.84-0.79(m,4H).LCMS:Rt＝2.722min,[M+H]+＝307.1。
实施例43：化合物(T043)的制备
参考上述实施例41-42的工艺路线和操作方法，制备得到化合物T043，[M+H]+＝323.1。
实施例44：化合物(T044)的制备
44.1化合物(T044-2)的制备
室温下，向4,6-二氯烟腈(CAS:166526-03-0；200mg,1.16mmol)和(1R,2R,5R)-5-氨基-2-甲基环己醇盐酸盐(180mg,1.39mmol)的异丙醇(10ml)悬浮液中加入DIEA(300mg,2.32mmol),加热至60℃反应过夜。冷却至室温，减压浓缩除去异丙醇，加入乙酸乙酯，水萃取，有机相用饱和盐水洗，有机相经干燥和浓缩后，用硅胶柱色谱纯化(PE/EA＝1/1)得到白色固体，收率55％。
44.2化合物(T044)的制备
Figure PCTCN2020116617-appb-000103
室温下，在封管中加入化合物T044-2(200mg,0.75mmol)、Cs 2CO 3(490mg,1.5mmol),Pd 2(dba) 3(68mg,0.075mmol)、BINAP(46mg,0.075mmol)、二氧六环(3ml)和叔丁胺(1ml)。氮气置换2分钟后密封，加热至100℃反应24小时。冷却至室温，减压浓缩除去二氧六环，加入乙酸乙酯和水萃取，有机相用饱和盐水洗，有机相经干燥和浓缩后，用薄层色谱制备板纯化(DCM/MeOH＝10/1)得到黄色固体130mg粗品，收率57％。
1H NMR(400MHz,DMSO-d 6):δ＝8.00(s,1H),6.87(d,J＝7.6Hz,1H),5.89(s,1H),4.86(s,1H),4.52(d,J＝5.6Hz,1H),3.71(s,1H),2.99-2.93(m,1H),2.09-2.07(m,1H),1.83(d,J＝12.4Hz,1H),1.64-1.60(m,1H),1.36(s,9H),1.17-0.95(m,4H),0.93(d,J＝6.0Hz,3H).Rt＝3.440min,[M+H]+＝303.1。
实施例45：化合物(T045)的制备
Figure PCTCN2020116617-appb-000104
室温下，化合物T044(90mg,0.3mmol)的DMSO(0.5ml)溶液中加入碳酸钾(124mg,0.9mmol)和30％过氧化氢(0.15ml,约1.2mmol)。室温反应5分钟，加入饱和亚硫酸钠溶液淬灭。过滤，滤液用制备型高效液相色谱纯化(碳酸氢铵方法)，冷冻干燥后得到白色固体18.3mg，收率19％。
1H NMR(400MHz,DMSO-d 6):δ＝8.65(s,1H),8.17(s,1H),7.50(br,1H),6.78(br,1H),6.35(d,J＝8.0Hz,1H),5.72(s,1H),4.51(d,J＝5.2Hz,1H),3.66(s,1H),3.00-2.94(m,1H),2.10-2.07(m,1H),1.85-1.82(m,1H),1.64-1.60(m,1H),1.32(s,9H),1.16-0.99(m,4H),0.93(d,J＝6.4Hz,3H).Rt＝2.918min；[M+H]+＝321.2。
实施例46：化合物(T046)的制备
Figure PCTCN2020116617-appb-000105
46.1化合物(T046-2)的制备
化合物4,6二氯烟腈(CAS:166526-03-0，100mg,0.578mmol)、(1R,3R,4R)-5-氨基-2-甲基环己醇盐酸盐(95.4mg，0.578mmol)和DIEA(149mg，1.156mmol)分散在异丙醇(5ml)中。反应液在60℃下搅拌两个小时，液相色谱监测反应结束。反应液中加入水和乙酸乙酯，萃取分层。有机相经干燥和浓缩后得到黄色的粗产物130mg，收率85％。
46.2化合物(T046-3)的制备
将化合物T046-2(100mg，0.377mmol)、2-氨基乙醇(1ml)和DIEA(97mg,0.75mmol)混 合均匀。该混合物加热到120℃，搅拌2个小时，液相色谱监测反应结束。反应液浓缩后用制备型高效液相色谱(碳酸氢铵方法)纯化，得到白色的固体20mg，收率18％。
46.3化合物(T046)的制备
将化合物T046-3(20mg，0.075mmol)和碳酸钾(20.7mg，0.15mmol)分散在DMSO(1ml)中。冰浴冷却下加入市售30％双氧水(0.5ml)。混合物恢复到室温继续搅拌1小时，液相色谱监测反应结束。反应液过滤，用制备型高效液相色谱(碳酸氢铵方法)纯化，冷冻干燥后得得到白色固体6.0mg，收率26％。
1HNMR(400MHz，CD 3OD):δ8.15(s,1H),5.62(s,1H),3.77-3.74(m,2H),3.70-3.67(m,1H),3.33-3.26(m,2H),3.23-3.17(m,1H),2.29-2.25(m,1H),1.99-1.96(m,1H),1.78-1.74(m,1H),1.32-1.13(m,4H),1.05(d,J＝6.0Hz,3H).LCMS:Rt＝2.759min；[M+H]+＝309.1。
参考上述实施例46的工艺路线和操作方法，制备得到下面表3中的如下化合物：
表3
实施例 化合物编号 Ms+1
47 T047 307.2
48 T048 349.1
49 T049 319.1
50 T050 335.1
51 T051 335.1
52 T052 363.1
53 T053 363.1
54 T054 347.2
55 T055 349.2
56 T056 333.1
57 T057 325.1
58 T058 305.1
59 T059 321.1
60 T060 317.2
实施例61：化合物(T062)的制备
Figure PCTCN2020116617-appb-000106
61.1化合物(T062-2)的制备
常温下，向2,4-二氯-5-氟嘧啶(500mg，2.5mmol，CAS：49845-33-2)的异丙醇(10ml)溶液中加入DIEA(997mg,7.7mmol)和(1R,2R,5R)-5-氨基-2-甲基环己醇盐酸盐(467mg,2.8mmol)，室温下反应3小时，液相色谱监测反应完毕。减压浓缩，用硅胶柱色谱纯化(EA/PE＝1/3)得黄色固体510mg，收率69.1％。
61.2化合物(T062)的制备
常温下，向封管中加入化合物T062-2(510mg,1.78mmol)、乙腈(5ml)和叔丁胺(2ml)。加毕，封管密封后加热到90℃反应3小时。冷却到室温，减压浓缩后用水和乙酸乙酯萃取，有机相经干燥和浓缩后得粗产物420mg，为黄色固体，收率72.7％。
1H NMR(400MHz,DMSO-d 6):δ＝8.82(s,1H),8.52(d,J＝7.6Hz,1H),7.96(s,1H),8.52(d,J＝5.2Hz,1H),4.10-4.06(m,1H),3.06-3.01(m,1H),2.13-2.10(m,1H),1.88-1.85(m,1H),1.74-1.70(m,1H),1.45-1.36(m,10H),1.29-1.23(m,2H),1.03-0.93(m,4H).Rt＝4.064min,[M+H]+＝324.1。
实施例62：化合物(T063)的制备
Figure PCTCN2020116617-appb-000107
向化合物QR053044A(300mg,0.92mmol)的乙醇(10ml)和水(2ml)混合液中加入铁粉(361mg,6.46mmol)和氯化铵(348mg,6.46mmol)，80℃反应3小时。过滤，滤液减压浓缩后用水和乙酸乙酯萃取，有机相经干燥和浓缩后得黄色油状物250mg，收率93％。取50mg粗产物经制备型高效液相色谱(碳酸氢胺方法)纯化，冷冻干燥后得黄色固体5.8mg。
1H NMR(400MHz,CD 3OD):δ＝7.37(s,1H),4.15-4.10(m,1H),3.40-3.36(m,1H),2.43-2.40(m,1H),2.12-2.08(m,1H),1.84-1.80(m,1H),1.51(s,9H),1.46-1.34(m,3H),1.25-1.22(m,1H),1.13(d,J＝8.8Hz,3H).Rt＝2.362min,[M+H]+＝294.2.
实施例63：化合物(T064)的制备
Figure PCTCN2020116617-appb-000108
63.1化合物(T064-2)的制备
常温下，向化合物T001-3(500mg,1.8mmol)的N,N-二甲基甲酰胺溶液中加入三乙胺(551 mg,5.4mmol)、双二苯基磷二氯化钯(382mg,0.54mmol)、碘化亚铜(104mg,0.54mmol)和三异丙基硅乙炔(497mg,2.7mmol)，加完之后氮气置换，在130℃下搅拌过夜，液相色谱法监测反应完毕，减压浓缩后硅胶拌样柱色谱纯化(EA/PE＝1/5)得黄色油状物236mg，收率34.3％。
63.2化合物(T064-4)的制备
冰浴下，向化合物T064-2(236mg,0.624mmol)的二氯甲烷(3ml)溶液中分批加入间氯过氧苯甲酸(189mg,0.936mmol)，加完之后在室温下搅拌过夜，液相色谱法监测反应完之后，用碳酸氢钠水溶液洗，二氯甲烷萃取(20ml*3)，收集有机相干燥减压浓缩后得到化合物T064-3粗品。
常温下，向化合物T064-3(粗品)的DMF(3ml)溶液中加入DIEA(96.7mg,0.75mmol)和(1R,2R,5R)-5-氨基-2-甲基环己醇盐酸盐(82.5mg,0.5mmol)，加完之后在110℃下搅拌过夜，液相色谱法监测反应完毕，减压浓缩干，柱色谱纯化(EA/PE＝1/3)得黄色油状物100mg，两步收率43.8％。
63.3化合物(T064)的制备
冰浴下，向化合物T064-4(95mg,0.198mmol)的THF(3ml)溶液中加入四丁基氟化铵的四氢呋喃溶液(0.2ml)，加完之后在室温下搅拌过夜，液相色谱法监测反应完毕，减压浓缩后用制备型高效液相色谱(碳酸氢铵方法)纯化、冷冻干燥后得白色固体15mg，收率25％。
1H NMR(400MHz,CD 3OD):δ＝7.82(s,1H),4.11-4.05(m,1H),3.80(s,1H),3.20-3.14(m,1H),2.30-2.25(m,1H),2.00-1.96(m,1H),1.84-1.78(m,1H),1.46(s,9H),1.43-1.33(m,3H),1.16-1.09(m,1H),1.05(d,J＝6.4Hz,3H).LCMS:Rt＝4.384min,[M+H]+＝303.2。
实施例64：化合物(T065)的制备
参考上述实施例64的工艺路线和操作方法，，以丙炔替换三异丙基硅基乙炔，制备得到化合物T065，[M+H]+＝317.1。
实施例65：化合物(T066)的制备
Figure PCTCN2020116617-appb-000109
常温下，向化合物T033(150mg,0.42mmol)的二氧六环溶液中加入碳酸钾(174mg,1.26mmol)，1,1,-双二苯基磷二茂铁二氯化钯(15.4mg,0.02mmol)以及乙烯基三氟硼酸钾(84.9mg,0.63mmol)，加完之后氮气置换，在105℃下搅拌过夜，液相色谱法监测反应完毕，减压浓缩后用制备型高效液相色谱(碳酸氢铵方法)纯化、冷冻干燥后得白色固体42mg，收率33％。
1H NMR(400MHz,CDCl 3):δ＝7.81(s,1H),6.42-6.35(m,1H),5.40-5.35(m,1H),5.14-5.11(m,1H),4.90(s,1H),4.78(br,1H),4.09-4.01(m,1H),3.34-3.28(m,1H),2.41-2.35(m,1H),2.07-2.04(m,1H),1.82-1.77(m,1H),1.43(s,9H),1.42-1.34(m,1H),1.27-1.08(m,3H),1.06(d,J＝6.8Hz,3H).LCMS:Rt＝3.301min,[M+H]+＝305.2。
实施例66：化合物(T067)的制备
Figure PCTCN2020116617-appb-000110
66.1化合物(T067-2)的制备
常温下，向化合物T001-3(1g,3.6mmol)的二氧六环(15ml)溶液中加入三丁基(1-乙氧基乙烯)锡(1.5g,4.3mmol)和双三苯基磷二氯化钯(1.2g,1.8mmol)。加毕，氮气置换后，于80℃反应16小时。液相色谱监测反应完毕。减压浓缩，柱色谱纯化(EA/PE＝1/5)得白色固体0.8g，收率91.7％。Rt＝1.652min,[M+H]+＝240.1.
66.2化合物(T067-3)的制备
冰浴下，向化合物T067-2(0.25g,1mmol)的二氯甲烷(5ml)溶液中分批加入间氯过氧苯甲酸(0.5g,2mmol)。加完之后撤走冰浴，在室温下搅拌4个小时，液相色谱监测反应完毕。用饱和碳酸氢钠溶液洗去多余的苯甲酸，有机相水洗后再干燥，减压浓缩得到粗品0.2g。Rt＝1.43min,[M+H]+＝272.5.
66.3化合物(T067)的制备
常温下，向化合物T067-3(0.2g,0.7mmol)的DMF(3ml)溶液中加入DIEA(0.3g,2.2mmol)和(1R,2R,5R)-5-氨基-2-甲基环己醇(0.12g,0.7mmol)，加完之后加热到110℃反应16小时。液相色谱监测反应完毕。减压浓缩，用制备型高效液相色谱(碳酸氢铵方法)纯化，冷冻干燥后得白色固体50mg，收率21.2％。
1H NMR(400MHz,CD 3OD):δ＝9.8.51(s,1H),4.13-4.07(m,1H),3.33-3.12(m,1H),2.42(s,3H),2.35-2.32(m,1H),2.06-2.03(m,1H),1.83-1.79(m,1H),1.48(s,9H),1.39-1.25(m,3H),1.16-1.09(m,1H),1.06(d,J＝6.4Hz,3H).Rt＝3.894min,[M+H]+＝321.2。
参考上述实施例66的工艺路线和操作方法，制备得到下面表4中的如下化合物：
表4
实施例 化合物编号 Ms+1
67 T068 347.1
68 T069 335.2
69 T070 349.2
70 T071 375.2
参考上述实施例10的工艺路线和操作方法，制备得到下面表5中的如下化合物：
表5
实施例 化合物编号 Ms+1
71 T072 420.1
72 T073 440.2
73 T074 386.2
<生物学活性测试试验>
激酶活性筛选
JNK1活性筛选。用96孔(Cisbio，66PL96025)时间分辨荧光测定法来检测JNK1活性。JNK1测定是在以下测定缓冲液中运行：10mM MgCl2(Sigma，M1028)、1mM MnCl2(Sigma，M1787)、1mM DTT(Sigma，D0632)和1X Enzymatic buffer/kinase(Cisbio，62EZBFDC)。采用测定缓冲液，先转3μl的0.1ng/μl JNK1激酶(Carna Biosciences，04-163)于96微孔板，再转适当稀释的4μl的化合物，DMSO含量2.5％，室温下孵育0.5h。为了启动反应，也使用测定缓冲液，将0.003μM ATP(阿拉丁，A7699)和30μM底物ATF2-GST fusion(Cisbio，64CUS000AFPEB)一起混合后，加入3μl混合液于微孔板，继续室温孵育2.5h。然后使用HTRF detection buffer(Gibco，62SDBRDD)配制5μg/mlMAb Anti GST-XL665(Cisbio，61GSTXLA)和0.045μg/mlPAb Anti-phospho ATF2-K(Cisbio，61P12KAZ)的混合物，转10μl混合物来终止反应。孵育约12h后，在Perkin-Elmer Envision阅读器上读板。
细胞评价法
1.RAW264.7磷酸化c-jun全细胞测定。RAW264.7(ATCC TIB-71)细胞购自苏州北纳创联生物技术有限公司(BeNa Culture Collection)，并在含10％胎牛血清(Gibco)、1％青霉素-链霉素(Gibco)高糖DMEM培养基(Gibco)中维持。所有的细胞在37℃下在95％空气在5％CO 2中培养。将细胞按照每孔2×10 5个细胞的密度接种到96孔板中的120μl细胞培养基中，将化合物贮液(15mM)在DMSO(Sigma)中连续稀释，在生长培养基中进一步稀释，然后以10×浓溶液15μl加至孔中，混匀与细胞一起孵育30min。所有孔中化合物溶媒(DMSO)浓度为0.2％。30min后细胞用25ng/ml的脂多糖(Sigma)激活。脂多糖作为10×浓溶液加入生长培养基中并按每孔加入15μl的体积添加。把细胞板培养1小时，然后弃去全部培养基。采用全细胞裂解试剂盒-磷酸化c-jun测定法(
Figure PCTCN2020116617-appb-000111
Phospho-c-Jun(Ser63)Sandwich ELISA Kit)(CST，7145C)，按照生产商的说明书测量在63位丝氨酸磷酸化的c-jun的蛋白水平。
2.Jurkat T细胞IL-2产生测定。Jurkat T细胞(克隆(clone)E6-1)购自中国典型培养物保 藏中心(China Center for Type Culture Collection)，并在含10％胎牛血清(Gibco)、1％青霉素-链霉素(Gibco)的RPMI1640(Gibco)中维持。所有的细胞在37℃下在95％空气在5％CO 2中培养。将细胞按照每孔1×10 5个细胞的密度接种到96孔板中的120μl细胞培养基中，将化合物贮液(15mM)在DMSO(Sigma)中连续稀释，在生长培养基中进一步稀释，然后以10×浓溶液15μl加至孔中，混匀与细胞一起孵育30min。所有孔中化合物溶媒(DMSO)浓度为0.2％。30min后细胞用PMA(乙酸肉豆蔻酸佛波醇酯；终浓度50ng/ml)(Sigma)和PHA(植物血凝素；终浓度1μg/ml)(Sigma)激活。PMA和PHA作为制得的作为10×浓溶液加入生长培养基中并按每孔加入15μl的体积添加。把细胞板培养6小时。用微孔板离心机(湘仪)将细胞沉淀下来，收集细胞上清置于-20℃保存。采用人类Il-2检测试剂盒(Human IL-2 ValukineTM ELISA Kit)(R&D Systems，VAL110)，按照生产商的说明书测量上清中IL-2的量。
下面表6中的各化合物都在JNK1生物化学试验中通过酶法与细胞法进行了测试，发现本发明的化合物具有良好的活性。在酶法试验中，化合物的IC 50低于100nM记为活性水平A，IC 50介于100nM和500nM之间记为活性水平B，IC 50介于500nM和1μM之间记为活性水平C，IC 50大于1μM记为活性水平D。在细胞法试验中，化合物的IC 50低于100nM记为活性水平A，IC 50介于100nM和500nM之间记为活性水平B，IC 50介于500nM和1μM之间记为活性水平C，IC 50大于1μM记为活性水平D。
表6
Figure PCTCN2020116617-appb-000112
Figure PCTCN2020116617-appb-000113
Figure PCTCN2020116617-appb-000114

Claims (10)

  1. 式(I)所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、多晶型物、氮氧化物或它们药学上可接受的盐：
    Figure PCTCN2020116617-appb-100001
    其中，
    Y 1、Y 2各自独立地为CR 4或N；
    X、W各自独立地选自CR 5R 6、O或NR 7；
    R 1选自H、羟基、卤素、氰基、硝基、NR 11R 12、C(O)NR 11R 12、C(＝S)NR 11R 12、S(O) 2NR 11R 12、C(＝NR 13)NR 11R 12、NHC(O)NR 11R 12、P(O) 2NR 11R 12、P(O)R 13NR 11R 12、C(O)R 14、NHC(O)R 14、C(O)OR 15、或者未取代的或任选被一个、两个或更多个R a取代的如下基团：C 1-40烷基、C 2-40烯基、C 2-40炔基、C 1-40烷氧基、C 3-20环烷基、3-20元杂环基、C 6-20芳基或5-20元杂芳基；
    R 2选自H、或者未取代的或任选被一个、两个或更多个R b取代的如下基团：C 1-40烷基、C 2-40烯基、C 2-40炔基、C 1-40烷氧基、C 3-20环烷基、3-20元杂环基、C 6-20芳基、C 6-20芳基-C 1-40烷基、5-20元杂芳基或5-20元杂芳基C 1-40烷基；或者
    R 2连同X一起形成未取代的或任选被一个、两个或更多个R b取代的如下基团：NHC(O)NR 11R 12、C 3-20环烷基、3-20元杂环基、C 6-20芳基或5-20元杂芳基；
    R 3选自H、或者未取代的或任选被一个、两个或更多个R c取代的如下基团：NR 11R 12、C(O)NR 11R 12、C(O)R 14、C 1-40烷基、C 2-40烯基、C 2-40炔基、C 1-40烷氧基、C 3-20环烷基、3-20元杂环基、C 6-20芳基或5-20元杂芳基；或者
    R 3连同W一起形成未取代的或任选被一个、两个或更多个R c取代的如下基团：NHC(O)NR 11R 12、C 3-20环烷基、3-20元杂环基、C 6-20芳基或5-20元杂芳基；
    R 4选自H、羟基、卤素、氰基、硝基、氨基、或者未取代的或任选被一个、两个或更多个R d取代的如下基团：C 1-40烷基、C 2-40烯基、C 2-40炔基或C 1-40烷氧基；
    R 5、R 6各自独立地选自H、羟基、卤素、氰基、或者未取代或任选被一个、两个或更多个R d取代的C 1-40烷基、C 2-40烯基、C 2-40炔基或C 1-40烷氧基；条件是R 5和R 6不同时为羟基、氰基或C 1-40烷氧基；或者，R 5、R 6与所连接的碳原子一起形成羰基；
    R 7选自H、或者未取代的或任选被一个、两个或更多个R e取代的如下基团：C 1-40烷基、C 2-40烯基、C 2-40炔基、C 1-40烷氧基、C 3-20环烷基、3-20元杂环基、C 6-20芳基或5-20元杂芳基；
    R 11、R 12各自独立地选自H、或者未取代的或任选被一个、两个或更多个R e取代的如下基团：C(O)R 14、C 1-40烷基、C 2-40烯基、C 2-40炔基、C 1-40烷氧基、C 3-20环烷基、3-20元杂环基、C 6-20芳基或5-20元杂芳基；或者
    R 11和R 12连同它们所连接的氮原子一起形成未取代的或任选被一个、两个或更多个R e取代的3-20元杂环基或5-20元杂芳基；
    R 13选自H、羟基、氰基、或者未取代的或任选被一个、两个或更多个R e取代的C 1-40烷基或C 1-40烷氧基；
    R 14选自H、羟基、卤素、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-40烷基、C 2-40烯基、C 2-40炔基、C 1-40烷氧基、C 3-20环烷基、3-20元杂环基、C 6-20芳基 或5-20元杂芳基；
    R 15选自H、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-20环烷基、3-20元杂环基、C 6-20芳基或5-20元杂芳基；
    每一个R a独立地选自CN、卤素、OH、NH 2、氧代、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-40烷基、C 1-40烷氧基；
    每一个R b独立地选自CN、卤素、OH、NH 2、COOH、NO 2、氧代、S(O) 2CH 3、C(O)NHCH 2CH 3、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-40烷基、C 1-40烷氧基、C 3-20环烷基、3-20元杂环基、C 6-20芳基或5-20元杂芳基；
    每一个R c独立地选自CN、卤素、OH、NH 2、COOH、NO 2、C(O)NH 2、C(O)NHOH、C(O)N(OH)CH 3、氧代、C(O)CH 2COOH、C(O)CH 2CN、C(O)CH 2Cl、C(O)CH 2F或C(O)CH 2Br、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-40烷基、C 1-40烷氧基、C 3-20环烷基、3-20元杂环基、C 6-20芳基或5-20元杂芳基；
    每一个R d、R e、R f相同或不同，各自独立地选自CN、卤素、OH、NH 2、氧代、S(O) 2CH 3、C 1-40烷基、卤代C 1-40烷基、C 1-40烷氧基或卤代C 1-40烷氧基。
  2. 权利要求1所述的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、多晶型物、氮氧化物或它们药学上可接受的盐，其中，
    Y 1、Y 2独立地为CR 4或N；
    X、W独立地选自CR 5R 6、O或NR 7；
    R 1选自H、羟基、卤素、氰基、硝基、NR 11R 12、C(O)NR 11R 12、C(＝S)NR 11R 12、S(O) 2NR 11R 12、C(＝NR 13)NR 11R 12、NHC(O)NR 11R 12、P(O) 2NR 11R 12、P(O)R 13NR 11R 12、C(O)R 14、NHC(O)R 14、C(O)OR 15、或者未取代的或任选被一个、两个或更多个R a取代的如下基团：C 1-10烷基、C 2-10烯基、C 2-10炔基、C 1-10烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
    R 2选自H、或者未取代的或任选被一个、两个或更多个R b取代的如下基团：C 1-10烷基、C 2-10烯基、C 2-10炔基、C 1-10烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基、C 6-14芳基-C 1-10烷基、5-14元杂芳基或或5-14元杂芳基-C 1-10烷基；或者
    R 2连同X一起形成未取代的或任选被一个、两个或更多个R b取代的如下基团：NHC(O)NR 11R 12、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
    R 3选自H、或者未取代的或任选被一个、两个或更多个R c取代的如下基团：NR 11R 12、C(O)NR 11R 12、C(O)R 14、C 1-10烷基、C 2-10烯基、C 2-10炔基、C 1-10烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；或者
    R 3连同W一起形成未取代的或任选被一个、两个或更多个R c取代的如下基团：NHC(O)NR 11R 12、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
    R 4选自H、羟基、卤素、氰基、硝基、氨基、或者未取代的或任选被一个、两个或更多个R d取代的如下基团：C 1-10烷基、C 2-10烯基、C 2-10炔基、C 1-10烷氧基；
    R 5、R 6各自独立地选自H、羟基、卤素、氰基、或者未取代或任选被一个、两个或更多个R d取代的C 1-10烷基、C 2-10烯基、C 2-10炔基或C 1-10烷氧基；条件是R 5和R 6不同时为羟基、氰基或C 1-10烷氧基；或者，R 5、R 6与所连接的碳原子一起形成羰基，即，CR 5R 6为C(＝O)；
    R 7选自H、或者未取代的或任选被一个、两个或更多个R e取代的如下基团：C 1-10烷基、C 2-10烯基、C 2-10炔基、C 1-10烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
    R 11、R 12各自独立地选自H、或者未取代的或任选被一个、两个或更多个R e取代的如下基团：C(O)R 14、C 1-10烷基、C 2-10烯基、C 2-10炔基、C 1-10烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；或者
    R 11和R 12连同它们所连接的氮原子一起形成未取代的或任选被一个、两个或更多个R e取代的3-10元杂环基或5-14元杂芳基；
    R 13选自H、羟基、氰基、或者未取代的或任选被一个、两个或更多个R e取代的C 1-10烷基或C 1-10烷氧基；
    R 14选自H、羟基、卤素、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-10烷基、C 2-10烯基、C 2-10炔基、C 1-10烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
    R 15选自H、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-10烷基、C 2-10烯基、C 2-10炔基、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
    每一个R a独立地选自CN、卤素、OH、NH 2、氧代、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-10烷基或C 1-10烷氧基；
    每一个R b独立地选自CN、卤素、OH、NH 2、COOH、NO 2、氧代、S(O) 2CH 3、C(O)NHCH 2CH 3、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
    每一个R c独立地选自CN、卤素、OH、NH 2、COOH、NO 2、C(O)NH 2、C(O)NHOH、C(O)N(OH)CH 3、氧代、C(O)CH 2COOH、C(O)CH 2CN、C(O)CH 2Cl、C(O)CH 2F、C(O)CH 2Br、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
    每一个R d、R e、R f相同或不同，各自独立地选自CN、卤素、OH、NH 2、氧代、S(O) 2CH 3、C 1-10烷基、卤代C 1-10烷基、C 1-10烷氧基或卤代C 1-10烷氧基。
  3. 权利要求1或2所述的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、多晶型物、氮氧化物或它们药学上可接受的盐，其中
    Y 1、Y 2独立地为CR 4或N；
    X、W独立地选自CR 5R 6、O或NR 7；
    R 1选自H、羟基、卤素、氰基、硝基、NR 11R 12、C(O)NR 11R 12、C(＝S)NR 11R 12、S(O) 2NR 11R 12、C(＝NR 13)NR 11R 12、NHC(O)NR 11R 12、P(O) 2NR 11R 12、P(O)R 13NR 11R 12、C(O)R 14、NHC(O)R 14、C(O)OR 15、或者未取代的或任选被一个、两个或更多个R a取代的如下基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
    R 2选自H、或者未取代的或任选被一个、两个或更多个R b取代的如下基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基、C 6-14芳基-C 1-6烷基、5-14元杂芳基或5-14元杂芳基-C 1-6烷基；或者
    R 2连同X一起形成未取代的或任选被一个、两个或更多个R b取代的如下基团：NHC(O)NR 11R 12、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
    R 3选自H、或者未取代的或任选被一个、两个或更多个R c取代的如下基团：NR 11R 12、C(O)NR 11R 12、C(O)R 14、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；或者
    R 3连同W一起形成未取代的或任选被一个、两个或更多个R c取代的如下基团： NHC(O)NR 11R 12、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
    R 4选自H、羟基、卤素、氰基、硝基、氨基、或者未取代的或任选被一个、两个或更多个R d取代的如下基团：C 1-6烷基、C 2-6烯基、C 2-6炔基或C 1-6烷氧基；
    R 5、R 6各自独立地选自H、羟基、卤素、氰基、或者未取代或任选被一个、两个或更多个R d取代的C 1-6烷基、C 2-6烯基、C 2-6炔基或C 1-6烷氧基；条件是R 5和R 6不同时为羟基、氰基或C 1-6烷氧基；或者，R 5、R 6与所连接的碳原子一起形成羰基，即，CR 5R 6为C(＝O)；
    R 7选自H、或者未取代的或任选被一个、两个或更多个R e取代的如下基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
    R 11、R 12各自独立地选自H、或者未取代的或任选被一个、两个或更多个R e取代的如下基团：C(O)R 14、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；或者
    R 11和R 12连同它们所连接的氮原子一起形成未取代的或任选被一个、两个或更多个R e取代的3-10元杂环基或5-14元杂芳基；
    R 13选自H、羟基、氰基、或者未取代的或任选被一个、两个或更多个R e取代的C 1-6烷基或C 1-6烷氧基；
    R 14选自H、羟基、卤素、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
    R 15选自H、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
    每一个R a独立地选自CN、卤素、OH、NH 2、氧代、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-6烷基或C 1-6烷氧基；
    每一个R b独立地选自CN、卤素、OH、NH 2、COOH、NO 2、氧代、S(O) 2CH 3、C(O)NHCH 2CH 3、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-6烷基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
    每一个R c独立地选自CN、卤素、OH、NH 2、COOH、NO 2、C(O)NH 2、C(O)NHOH、C(O)N(OH)CH 3、氧代、C(O)CH 2COOH、C(O)CH 2CN、C(O)CH 2Cl、C(O)CH 2F、C(O)CH 2Br、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-6烷基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环基、C 6-14芳基或5-14元杂芳基；
    每一个R d、R e、R f相同或不同，各自独立地选自CN、卤素、OH、NH 2、氧代、S(O) 2CH 3、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基。
  4. 权利要求1-3中任一项所述的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、多晶型物、氮氧化物或它们药学上可接受的盐，其中，
    Y 1、Y 2独立地为CR 4或N；
    X、W独立地为O或NR 7；
    R 1选自H、羟基、卤素、氰基、硝基、NR 11R 12、C(O)NR 11R 12、C(＝S)NR 11R 12、S(O) 2NR 11R 12、C(＝NR 13)NR 11R 12、NHC(O)NR 11R 12、P(O) 2NR 11R 12、P(O)R 13NR 11R 12、C(O)R 14、NHC(O)R 14、C(O)OR 15、或者未取代的或任选被一个、两个或更多个R a取代的如下基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-6环烷基、3-7元杂环基或5-6元杂芳基；
    R 2选自H、或者未取代的或任选被一个、两个或更多个R b取代的如下基团：C 1-6烷基、 C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-6环烷基、3-7元杂环基、苯基、苄基、5-6元杂芳基或5-6元杂芳基-C 1-6烷基；或者
    R 2连同X一起形成未取代的或任选被一个、两个或更多个R b取代的NHC(O)NR 11R 12、3-7元杂环基或5-6元杂芳基；
    R 3选自H、或者未取代的或任选被一个、两个或更多个R c取代的如下基团：NR 11R 12、C(O)NR 11R 12、C(O)R 14、C 1-6烷基、C 3-6环烷基、3-7元杂环基、苯基或5-6元杂芳基；或者
    R 3连同W一起形成未取代的或任选被一个、两个或更多个R c取代的NHC(O)NR 11R 12、3-7元杂环基或5-6元杂芳基；
    R 4选自H、羟基或卤素；
    R 7为H；
    R 11、R 12各自独立地选自H、或者未取代的或任选被一个、两个或更多个R e取代的如下基团：C 1-6烷基、C 2-6烯基或C 2-6炔基；或者
    R 11和R 12连同它们所连接的氮原子一起形成未取代的或任选被一个、两个或更多个R e取代的3-7元杂环基或5-6元杂芳基；
    R 13选自H、氰基、甲基或羟基；
    R 14选自H、羟基、卤素、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基或C 3-6环烷基；
    R 15选自H、或者未取代的或任选被一个、两个或更多个R f取代的C 1-6烷基；
    每一个R a独立地选自CN、卤素、OH、NH 2、氧代、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-6烷基或C 1-6烷氧基；
    每一个R b独立地选自CN、卤素、OH、NH 2、COOH、NO 2、氧代、S(O) 2CH 3、C(O)NHCH 2CH 3、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、3-7元杂环基、苯基或5-6元杂芳基；
    每一个R c独立地选自CN、卤素、OH、NH 2、COOH、NO 2、C(O)NH 2、C(O)NHOH、C(O)N(OH)CH 3、氧代、C(O)CH 2COOH、C(O)CH 2CN、C(O)CH 2Cl、C(O)CH 2F或C(O)CH 2Br、或者未取代的或任选被一个、两个或更多个R f取代的如下基团：C 1-6烷基、C 1-6烷氧基、3-7元杂环基或5-6元杂芳基；
    每一个R e、R f相同或不同，各自独立地选自CN、卤素、OH、NH 2、氧代、S(O) 2CH 3、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基。
  5. 权利要求1-4中任一项所述的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、多晶型物、氮氧化物或它们药学上可接受的盐，其中式(I)所示的化合物为下式(II)的化合物：
    Figure PCTCN2020116617-appb-100002
    其中，
    Y 2、X、R 1和R 2具有权利要求1至4中任一项所给出的定义；
    Y 3为CR 8R 9或NR 10；
    R 8和R 9相同或不同，彼此独立地选自H、羟基、卤素、氰基、或者未取代的或任选被一个、两个或更多个羟基或卤素取代的C 1-6烷基、C 1-6烷氧基、C 1-6烯基或C 1-6炔基；或者R 8、R 9与所连接的碳原子一起形成羰基，即，CR 8R 9为C(＝O)；
    R 10选自H、C(O)NH 2、C(O)CH 2CN、C(O)CH 2COOH或者未取代的或任选被一个、两个或更多个羟基或卤素取代的C 1-6烷基、C 1-6烷氧基、C 1-6烯基或C 1-6炔基；
    R 3a和R 3b相同或不同，且彼此独立地选自H、羟基、卤素、氰基、氧代、或者未取代的或任选被一个、两个或更多个羟基或卤素取代的C 1-6烷基、C 1-6烷氧基、C 1-6烯基或C 1-6炔基。
  6. 权利要求1-5中任一项所述的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、多晶型物、氮氧化物或它们药学上可接受的盐，其中式(I)所示的化合物选自式(II-1)的化合物：
    Figure PCTCN2020116617-appb-100003
    其中，
    Y 2、X、R 1和R 2具有权利要求1至5中任一项所给出的定义。
  7. 权利要求1-6中任一项所述的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、多晶型物、氮氧化物或它们药学上可接受的盐的制备方法，其为如下方案1-3之一：
    方案1：
    Figure PCTCN2020116617-appb-100004
    其中，R 2’为R 2-X，R 3’为R 3-W，Nu为亲核基团，R 1、R 2、R 3、X和W具有权利要求1至6中任一项所给出的定义；
    方案1包括以下步骤1a和1b：
    (1a)SM-1A与含R 3’的亲核试剂在路易斯碱的作用下反应，生成IM-1A；和
    (1b)IM-1A与含R 2’的亲核试剂在路易斯碱的作用下反应，生成相应产物或中间体；
    方案2：
    Figure PCTCN2020116617-appb-100005
    其中，R 1’为R 1或可衍生为R 1的基团，R 2’为R 2-X，R 3’为R 3-W，Nu为亲核基团，R 1、R 2、R 3、X和W具有权利要求1至6中任一项所给出的定义。
    方案2包括以下步骤2a-2d：
    (2a)SM-1B与甲硫醇钠生成IM-1B，可以任选对IM-1B中的R 1’进行衍生反应后继续进行后续步骤；
    (2b)IM-1B与含R 2’的亲核试剂在路易斯碱的作用下反应，生成IM-2B；
    (2c)IM-2B与间氯过氧苯甲酸作用，生成IM-3B；和
    (2d)IM-3B与含R 3’的亲核试剂在路易斯碱的作用下反应，生成相应产物或中间体；可任选进一步进行衍生化反应；
    方案3：
    Figure PCTCN2020116617-appb-100006
    其中，R 2具有权利要求1至6中任一项所给出的定义。
    方案3包括以下步骤3a-3c：
    (3a)SM-1C与SM-2C在路易斯碱的作用下反应，生成IM-1C；
    (3b)IM-1C与R 2NH 2在路易斯碱的作用下反应，生成相应产物或中间体；和
    (3c)IM-2C与H 2O 2在路易斯碱的作用下反应，生成相应产物。
  8. 一种药物组合物，包含治疗有效量的权利要求1-6中任一项所述的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、多晶型物、氮氧化物或它们药学上可接受的盐，以及一种或更多种药学上可接受的辅料，所述辅料可为选自下列中的一种或更多种：崩解剂、助流剂、润滑剂、稀释剂或填充剂、粘合剂、着色剂。
  9. 权利要求1-6中任一项所述的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、多晶型物、氮氧化物或它们药学上可接受的盐用于制备激酶抑制剂、特别是激酶JNK1和/或JNK2抑制剂的用途。
  10. 权利要求1-6中任一项所述的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、多晶型物、氮氧化物或它们药学上可接受的盐用于制备药物的用途，其中所述药物用于预防和/或治疗下列疾病或病症：类风湿性关节炎；类风湿性脊椎炎；骨关节炎；哮喘、支气管炎；变应性鼻炎；慢性阻塞性肺疾病；囊性纤维化；炎症性肠疾病；过敏性肠综合症；粘液性结肠炎；溃疡性结肠炎；克罗恩病；亨廷顿病；肝炎；胰腺炎；肾炎；多发性硬化；红斑狼疮；II型糖尿病；肥胖症；动脉粥样硬化；血管成形术后再狭窄；左心室肥大；心肌梗塞；脑卒中；心、肺、肠、肾、肝、胰、脾和脑的缺血性损伤；急性或慢性器官移植排斥；用于移植的器官的保存；器官衰竭或肢缺损(例如，包括但不限于由缺血-再灌注损伤、创伤、全身受伤、车祸、挤压伤或移植失败所致的)；移植物抗宿主病；内毒素性休克；多器官衰竭；银屑病；暴露于火、化学品或辐射所致的烧伤；湿疹；皮炎；皮肤移植；局部缺血；与外科手术或创伤性损伤(例如车辆事故、枪弹伤或肢轧碎)相关的缺血病症；癫痫；阿尔茨海默病；帕金森病；对细菌或病毒感染的免疫应答；恶病质；血管生成性和增殖性疾病；实体肿瘤；和各种组织例如结肠、直肠、前列腺、肝脏、肺、支气管、胰腺、脑、头、颈、胃、皮肤、肾脏、宫颈、血液、喉、食管、口、咽、膀胱、卵巢或子宫的癌症；
    特别地，所述药物用于预防和/或治疗下列疾病或病症：肝脏纤维化疾病和肺部纤维化疾病，例如非酒精性脂肪性肝炎、脂肪变性、肝硬化、原发性硬化性胆管炎、原发性胆汁性肝硬化、肝炎、肝细胞癌和肝纤维化同时伴有长期或反复酒精摄入、伴有感染、伴有肝脏移植或伴有药物诱发的肝损伤、特发性肺纤维化；系统性硬化病、硬皮病、慢性同种异体移植物肾病变、抗体介导的排斥或狼疮，例如红斑狼疮或系统性狼疮。
PCT/CN2020/116617 2019-09-30 2020-09-21 Jnk抑制剂、其药物组合物和用途 WO2021063207A1 (zh)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP20872098.7A EP4023642A4 (en) 2019-09-30 2020-09-21 JNK INHIBITOR, PHARMACEUTICAL COMPOSITION AND USE THEREOF
US17/754,333 US20230104283A1 (en) 2019-09-30 2020-09-21 Jnk inhibitor, and pharmaceutical composition and use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910942775.3 2019-09-30
CN201910942775.3A CN112574123A (zh) 2019-09-30 2019-09-30 Jnk抑制剂、其药物组合物和用途

Publications (1)

Publication Number Publication Date
WO2021063207A1 true WO2021063207A1 (zh) 2021-04-08

Family

ID=75116447

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/116617 WO2021063207A1 (zh) 2019-09-30 2020-09-21 Jnk抑制剂、其药物组合物和用途

Country Status (4)

Country Link
US (1) US20230104283A1 (zh)
EP (1) EP4023642A4 (zh)
CN (1) CN112574123A (zh)
WO (1) WO2021063207A1 (zh)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104098563A (zh) * 2013-04-02 2014-10-15 山东亨利医药科技有限责任公司 Jnk抑制剂化合物
WO2016123291A1 (en) * 2015-01-29 2016-08-04 Signal Pharmaceuticals, Llc Isotopologues of 2-(tert-butylamino)-4-((1r,3r,4r)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide
CN106170290A (zh) * 2013-12-20 2016-11-30 西格诺药品有限公司 取代的二氨基嘧啶基化合物、其组合物及其治疗方法
CN106946795A (zh) * 2011-04-22 2017-07-14 西格诺药品有限公司 取代的二氨基甲酰胺和二氨基甲腈嘧啶，其组合物，和用其治疗的方法
CN107108524A (zh) * 2014-12-16 2017-08-29 西格诺药品有限公司 2‑(叔丁基氨基)‑4‑((1r,3r,4r)‑3‑羟基‑4‑甲基环己基氨基)‑嘧啶‑5‑甲酰胺的配制物

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106946795A (zh) * 2011-04-22 2017-07-14 西格诺药品有限公司 取代的二氨基甲酰胺和二氨基甲腈嘧啶，其组合物，和用其治疗的方法
CN104098563A (zh) * 2013-04-02 2014-10-15 山东亨利医药科技有限责任公司 Jnk抑制剂化合物
CN106170290A (zh) * 2013-12-20 2016-11-30 西格诺药品有限公司 取代的二氨基嘧啶基化合物、其组合物及其治疗方法
CN107108524A (zh) * 2014-12-16 2017-08-29 西格诺药品有限公司 2‑(叔丁基氨基)‑4‑((1r,3r,4r)‑3‑羟基‑4‑甲基环己基氨基)‑嘧啶‑5‑甲酰胺的配制物
WO2016123291A1 (en) * 2015-01-29 2016-08-04 Signal Pharmaceuticals, Llc Isotopologues of 2-(tert-butylamino)-4-((1r,3r,4r)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide

Also Published As

Publication number Publication date
US20230104283A1 (en) 2023-04-06
CN112574123A (zh) 2021-03-30
EP4023642A1 (en) 2022-07-06
EP4023642A4 (en) 2023-11-08

Similar Documents

Publication Publication Date Title
CN109400625B (zh) 稠合双环类化合物及其在药物中的应用
CN107074859B (zh) 用于治疗癌症的作为吲哚胺-2,3-双加氧酶(ido)拮抗剂的环己基乙基取代的二氮杂-和三氮杂-三环化合物
WO2018056453A1 (ja) Ｇｌｐ－１受容体アゴニスト作用を持つピラゾロピリジン誘導体
WO2018157856A1 (zh) 酰胺类衍生物抑制剂及其制备方法和应用
JP2018083832A (ja) 核内輸送調節因子およびその使用
WO2018090869A1 (zh) 酰胺衍生物及其在药物中的应用
WO2020216190A1 (zh) 一种喹唑啉化合物及其在医药上的应用
WO2016169421A1 (zh) 咪唑并异吲哚类衍生物、其制备方法及其在医药上的应用
CN104918934A (zh) 3-取代的吡唑及其作为dlk抑制剂的用途
WO2023036285A1 (zh) 一种杂芳环类化合物及其应用
WO2021208918A1 (zh) 作为egfr抑制剂的三环化合物
AU2022401750A1 (en) Pyrazole derivative, and preparation method therefor and use thereof in medicine
CN108779115B (zh) 五元杂芳环并桥环类衍生物、其制备方法及其在医药上的应用
TW202110831A (zh) 吡啶酮類衍生物、其製備方法及其在醫藥上的應用
WO2020020385A1 (zh) 含三并环类衍生物抑制剂、其制备方法和应用
CN113698408A (zh) Jnk抑制剂、其药物组合物和用途
WO2021027647A1 (zh) 桥杂环基取代的嘧啶类化合物及其制备方法和医药用途
WO2021063207A1 (zh) Jnk抑制剂、其药物组合物和用途
CN108137544B (zh) 用于抑制蛋白酪氨酸激酶活性的氨基嘧啶类化合物
KR20230146639A (ko) 이미다졸 함유 축합고리계 유도체, 이의 제조방법 및 이의 의약적 용도
WO2022017442A1 (zh) 双功能蛋白降解靶向嵌合体类化合物及其制备方法和医药用途
CN113943276A (zh) 氮杂环类化合物及其用途
WO2021228216A1 (zh) 可用作RORγ调节剂的联芳基类化合物
WO2020211751A1 (zh) Rock抑制剂及其制备方法和用途
JP2021523920A (ja) キナーゼ阻害剤

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20872098

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2020872098

Country of ref document: EP

Effective date: 20220330