WO2020108516A1 - Régulateur de dérivé d'hétéroaryle contenant un nitrogène, son procédé de préparation et ses applications - Google Patents

Régulateur de dérivé d'hétéroaryle contenant un nitrogène, son procédé de préparation et ses applications Download PDF

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WO2020108516A1
WO2020108516A1 PCT/CN2019/121205 CN2019121205W WO2020108516A1 WO 2020108516 A1 WO2020108516 A1 WO 2020108516A1 CN 2019121205 W CN2019121205 W CN 2019121205W WO 2020108516 A1 WO2020108516 A1 WO 2020108516A1
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group
substituted
unsubstituted
amino
heteroaryl
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PCT/CN2019/121205
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English (en)
Chinese (zh)
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曾蜜
高鹏
程宇
黄胜爱
蔡家强
包如迪
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江苏豪森药业集团有限公司
上海翰森生物医药科技有限公司
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Priority to CN201980003771.7A priority Critical patent/CN111601804B/zh
Publication of WO2020108516A1 publication Critical patent/WO2020108516A1/fr

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    • 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
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system

Definitions

  • the invention belongs to the field of drug synthesis, and in particular relates to a JAK inhibitor, its preparation method and application.
  • Janus kinase is an intracellular non-receptor tyrosine kinase that mediates signaling and activation of various cytokines.
  • the JAK kinase family contains four subfamily members of JAK1, JAK2, JAK3 and TYK2. Members of each subfamily mediate different types of cytokine signaling pathways. JAK1, JAK2 and TYK2 are expressed in various tissues and cells of the human body, and JAK3 is mainly expressed In each hematopoietic tissue cell.
  • the common feature of cytokine receptors is that the receptor itself does not have kinase activity, but the intracellular segment of the receptor has a binding site for tyrosine kinase JAK.
  • the cytokine receptor When the cytokine receptor binds to its ligand, it activates JAKs coupled to the receptor, which in turn causes the receptor to be phosphorylated.
  • the phosphorylated tyrosine site can bind to the STAT protein containing the SH2 domain, thereby causing STAT Receptors are recruited and phosphorylated by JAKs.
  • Phosphotyrosine mediates STAT dimerization.
  • the activated STAT dimer is transferred into the nucleus and activates the transcription of its target gene, thereby regulating the growth, activation, and Differentiation and other functions.
  • the JAK/STAT signaling pathway mediates the signaling of most cytokines in cells and plays a key role in biological processes such as immune regulation and immune cell proliferation.
  • the JAK/STAT signaling pathway has a wide range of functions and participates in many important biological processes such as cell proliferation, differentiation, apoptosis, and immune regulation.
  • JAK/STAT signaling pathway is closely related to neoplastic diseases such as myelofibrosis, polycythemia vera, and primary thrombocythemia, mutation of JAK molecule itself It can also cause tumor diseases such as acute myeloid cell leukemia (AML), acute lymphocytic leukemia (ALL), breast ductal carcinoma, and non-small cell lung cancer (NSCLC).
  • AML acute myeloid cell leukemia
  • ALL acute lymphocytic leukemia
  • NSCLC non-small cell lung cancer
  • Inflammatory bowel disease is a chronic intestinal inflammatory disease, including ulcerative colitis (UC) and Crohn' disease (CD).
  • the drugs for treating inflammatory bowel disease mainly include aminosalicylic acid preparations, glucocorticoids, immunosuppressive agents, antibiotics, and the like.
  • the main principle of UC treatment is to regulate immune response and suppress inflammation.
  • sulfasalazine is mainly used in the treatment of mild to moderate UC.
  • the current commonly used drugs for moderate to severe UC include glucocorticoids, but because the risk is greater than the benefit, it will not be used as a long-term treatment.
  • Monoclonal antibodies have drugs, high costs, the production of drug antibodies affects the safety and effectiveness of drugs, and the inconvenient way of intravenous administration. There are still unmet medical needs in this field. Many patients who have received treatment have not yet been relieved, and up to 80% of Crohn's disease patients and 30% of UC patients will eventually need surgery.
  • Tofacitinib (Xeljanz) is the first oral JAK inhibitor for the treatment of moderate to severely active UC adult patients. It has significant inhibitory activity against JAK 1, 2, and 3 subtypes, which increases the efficacy of tofacitinib, but it also brings More serious side effects. Adverse reactions include infection, tuberculosis, tumor, anemia, liver damage, and increased cholesterol. Tofacitinib's manual has many black box signs: serious infections (tuberculosis, bacteria, fungi, viruses) and malignant tumors (lymphomas, etc.). Due to the wide range of JAK-mediated functions, these side effects are caused by the drug inhibiting multiple JAKs simultaneously. Because JAK is widely involved in the regulation of immune cells, JAK inhibitors inevitably cause side effects related to immunosuppression, such as serious infections and even tumors. Even with many highly selective inhibitors currently under study, such side effects caused by the inhibition of targets are inevitable.
  • the object of the present invention is to provide a compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the structure of the compound represented by the general formula (I) is as follows:
  • L is selected from the group consisting of a bond, an alkylene group, an alkenylene group, an alkynyl group, a cycloalkyl group, a heterocyclic group, -(CH 2 ) n1 -or -(CH 2 ) n1 S(O) m1 -;
  • G is selected from NR aa or CR aa ;
  • M is selected from S or CR 4 ;
  • Ring A is selected from heteroaryl, wherein the heteroaryl is optionally further selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl group, halogen, hydroxyl group, substituted or unsubstituted amino group, oxo group, nitrate Group, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or Unsubstituted heterocyclic group, substituted or unsubstituted aryl group and substituted, unsubstituted heteroaryl group, -(CH 2 ) n1 -, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR
  • R 2 hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, hydroxyalkyl group, halogenated alkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group or alkynyl group;
  • R 3 hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, hydroxyalkyl group, halogenated alkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group, ring Alkyl, heterocyclic, aryl, heteroaryl, -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa R bb , -( CH 2
  • R 4 hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, hydroxyalkyl group, halogenated alkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group or alkynyl group;
  • R aa , R bb , R cc and R dd are the same or different, and are independently selected from hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, hydroxyalkyl group, haloalkoxy group, Halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy Group, hydroxyalkyl group, haloalkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally further selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl group, Halogen, hydroxyl, substituted or unsubstituted amino, o
  • R aa and R bb are linked to form a cycloalkyl, heterocyclic group, aryl group and heteroaryl group, wherein the cycloalkyl, heterocyclic group, aryl group and heteroaryl group are optionally further selected from deuterium Atom, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, thio, nitro, cyano, Hydroxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted Heterocyclic group, substituted or unsubstituted aryl
  • n is an integer of 0, 1, 2 or 3;
  • n is an integer of 0, 1, 2, 3, 4 or 5;
  • n 1 is an integer of 0, 1, or 2;
  • n 2 is an integer of 0, 1, or 2;
  • n 1 is an integer of 0, 1, 2, 3, 4, or 5.
  • the present invention also relates to a preferred embodiment, wherein the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II) and its stereoisomer Body or its pharmaceutically acceptable salt:
  • Rings A, L, R 1 to R 5 , m and n are as described in the general formula (I).
  • the present invention also relates to a preferred embodiment, which is a compound represented by the general formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof:
  • L is selected from bond, C 0-8 alkylene, C 2-8 alkenylene, C 2-8 alkynyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, -(CH 2 ) n1 -Or- (CH 2 ) n1 S(O) m1 -, the hetero atom in the heterocyclic group is selected from one or more of N, O, S, P;
  • Ring A is selected from C 5-12 heteroaryl, wherein the heteroaryl is optionally further selected from hydrogen atom, deuterium atom, substituted or unsubstituted C 0-8 alkyl, halogen, hydroxyl, substituted or unsubstituted Amino, oxo, nitro, cyano, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted C 0-8 alkoxy, Substituted or unsubstituted C 0-8 hydroxyalkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 3-8 heterocyclic, substituted or unsubstituted C 5-12 aryl And substituted or unsubstituted C 5-12 heteroaryl, -(CH 2 ) n1 -, -(CH 2 ) n1 R aa ,
  • R 2 is selected from a hydrogen atom, C 0-8 alkyl, C 0-8 deuterated alkyl, C 0-8 haloalkyl, C 0-8 alkoxy, C 0-8 hydroxyalkyl, C 0-8 Haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-8 alkenyl or C 2-8 alkynyl;
  • R 3 is selected from a hydrogen atom, a deuterium atom, C 0-8 alkyl, C 0-8 deuterated alkyl, C 0-8 haloalkyl, C 0-8 alkoxy, C 0- 8 hydroxyalkyl, C 0-8 haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 5-12 aryl, C 5-12 heteroaryl, -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR a
  • R 4 is selected from a hydrogen atom, a deuterium atom, C 0-8 alkyl, C 0-8 deuterated alkyl, C 0-8 haloalkyl, C 0-8 alkoxy, C 0- 8 hydroxyalkyl, C 0-8 haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-8 alkenyl or C 2-8 alkynyl;
  • the present invention also relates to a preferred embodiment, which is a compound represented by the general formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof:
  • L is selected from the group consisting of bond, C 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, -(CH 2 ) n1 -Or- (CH 2 ) n1 S(O) m1 -the hetero atom in the heterocyclic group is selected from one or more of N, O, and S;
  • Ring A is selected from C 5-10 heteroaryl, wherein the heteroaryl is optionally further selected from hydrogen atom, deuterium atom, substituted or unsubstituted C 1-3 alkyl, halogen, hydroxyl, substituted or unsubstituted Amino, oxo, nitro, cyano, substituted or unsubstituted C 2-3 alkenyl, substituted or unsubstituted C 2-3 alkynyl, substituted or unsubstituted C 1-3 alkoxy, Substituted or unsubstituted C 1-3 hydroxyalkyl, substituted or unsubstituted C 1-3 cycloalkyl, substituted or unsubstituted C 3-6 heterocyclic, substituted or unsubstituted C 5-10 aryl And substituted or unsubstituted C 5-10 heteroaryl, -(CH 2 ) n1 -, -(CH 2 ) n1 R aa , -(CH 2
  • R 2 is selected from hydrogen atom, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 1-3 Haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-3 alkenyl or C 2-3 alkynyl;
  • R 3 is selected from a hydrogen atom, a deuterium atom, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1- 3 hydroxyalkyl, C 1-3 haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 5-10 aryl, C 5-10 heteroaryl, -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb ,
  • R 4 is selected from a hydrogen atom, a deuterium atom, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1- 3 hydroxyalkyl, C 1-3 haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-3 alkenyl or C 2-3 alkynyl;
  • the present invention also relates to a preferred embodiment, which is a compound represented by the general formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof:
  • L is selected from bond, C 1-3 alkylene, (CH 2 ) n1 -or -(CH 2 ) n1 S(O) m1 -;
  • Ring A is selected from C 5-6 heteroaryl, wherein the heteroaryl is optionally further selected from hydrogen atom, methyl, ethyl, F, Cl, Br, hydroxyl, substituted or unsubstituted amino, oxo Group, nitro group, cyano group, substituted or unsubstituted C 3-6 heterocyclic group, substituted or unsubstituted C 5-10 aryl group and substituted or unsubstituted C 5-10 heteroaryl group, -(CH 2 ) n1 -, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2
  • R 1 is selected from a hydrogen atom, C 1-3 alkyl, amino, cyano, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 5-10 aryl, C 5-10 heteroaryl, -(CH 2 ) n1 R aa , (CH 2 ) n1 C(O)R aa , --(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb or -(CH 2 ) n1 C(O)NR aa R bb , the hetero atom in the heterocyclic group and heteroaryl group is selected from one or more of N, O and S Wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from amino, cyano, -(CH 2 ) n1 R cc or -(CH 2
  • R 2 is selected from hydrogen atom, methyl, ethyl, halomethyl, haloethyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, halomethoxy, halo Ethoxy, F, Cl, Br, amino, nitro, hydroxyl, cyano, vinyl, propenyl, ethynyl, propynyl
  • R 3 is selected from hydrogen atom, C 1-3 alkyl group, C 1-3 hydroxyalkyl group, C 3-6 heterocyclic group, C 5-10 aryl group, C 5-10 heteroaryl group, -(CH 2 ) n1 C(O)R aa or -(CH 2 ) one or more of n1 C(O)NR aa R bb , optionally substituted by one or more substituents, heterocyclic and heteroaryl Is selected from one or more of N, O, S;
  • R 4 is selected from hydrogen atom, methyl, ethyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, F, Cl, Br, amino, nitro, hydroxy, cyano, vinyl or ethynyl ;
  • the present invention also relates to a preferred embodiment, which is a compound represented by the general formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof:
  • L is selected from bond, methylene, -(CH 2 ) 2 -or -S(O) 2 -;
  • Ring A is selected from
  • R 1 is selected from cyano
  • R 2 is selected from hydrogen atom, methyl, ethyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, F, Cl, amino, hydroxy, cyano, vinyl, propenyl, ethynyl, propylene Alkynyl
  • R 3 is selected from hydrogen atom, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, azetidine, oxetane, phenyl, benzyl, pyridine, -C (O)NH2;
  • R 4 is selected from hydrogen atom, methyl, ethyl, methoxy, hydroxymethyl, F, Cl, amino, hydroxyl, cyano, vinyl or ethynyl;
  • R5 is selected from methyl, methoxy, hydroxy, hydroxymethyl, F,
  • n 0, 1 or 2;
  • n 0, 1, or 2.
  • the present invention also relates to a preferred embodiment.
  • the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III) and its stereoisomer Body or its pharmaceutically acceptable salt:
  • Rings A, L, R 1 to R 5 , m and n are as described in the general formula (I).
  • the present invention also relates to a preferred embodiment, which is a compound represented by the general formula (III), its stereoisomer or a pharmaceutically acceptable salt thereof,
  • L is selected from bond, C 0-8 alkylene, C 2-8 alkenylene, C 2-8 alkynyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, -(CH 2 ) n1 -Or- (CH 2 ) n1 S(O) m1 -, the hetero atom in the heterocyclic group is selected from one or more of N, O, S, P;
  • Ring A is selected from C 5-12 heteroaryl, wherein the heteroaryl is optionally further selected from hydrogen atom, deuterium atom, substituted or unsubstituted C 0-8 alkyl, halogen, hydroxyl, substituted or unsubstituted Amino, oxo, nitro, cyano, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted C 0-8 alkoxy, Substituted or unsubstituted C 0-8 hydroxyalkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 3-8 heterocyclic, substituted or unsubstituted C 5-12 aryl And substituted or unsubstituted C 5-12 heteroaryl, -(CH 2 ) n1 -, -(CH 2 ) n1 R aa ,
  • R 2 is selected from a hydrogen atom, C 0-8 alkyl, C 0-8 deuterated alkyl, C 0-8 haloalkyl, C 0-8 alkoxy, C 0-8 hydroxyalkyl, C 0-8 Haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-8 alkenyl or C 2-8 alkynyl;
  • R 3 is selected from a hydrogen atom, a deuterium atom, C 0-8 alkyl, C 0-8 deuterated alkyl, C 0-8 haloalkyl, C 0-8 alkoxy, C 0- 8 hydroxyalkyl, C 0-8 haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 5-12 aryl, C 5-12 heteroaryl, -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR a
  • the present invention also relates to a preferred embodiment, which is a compound represented by the general formula (III), its stereoisomer or a pharmaceutically acceptable salt thereof,
  • L is selected from bond, C 1-3 alkylene, (CH 2 ) n1 -or -(CH 2 ) n1 S(O) m1 -;
  • Ring A is selected from C 5-6 heteroaryl, wherein the heteroaryl is optionally further selected from hydrogen atom, methyl, ethyl, F, Cl, Br, hydroxyl, substituted or unsubstituted amino, oxo Group, nitro group, cyano group, substituted or unsubstituted C 3-6 heterocyclic group, substituted or unsubstituted C 5-10 aryl group and substituted or unsubstituted C 5-10 heteroaryl group, -(CH 2 ) n1 -, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2
  • R 1 is selected from a hydrogen atom, C 1-3 alkyl, amino, cyano, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 5-10 aryl, C 5-10 heteroaryl, -(CH 2 ) n1 R aa , (CH 2 ) n1 C(O)R aa , --(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb or -(CH 2 ) n1 C(O)NR aa R bb , the hetero atom in the heterocyclic group and heteroaryl group is selected from one or more of N, O and S Wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from amino, cyano, -(CH 2 ) n1 R cc or -(CH 2
  • R 2 is selected from hydrogen atom, methyl, ethyl, halomethyl, haloethyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, halomethoxy, halo Substituted ethoxy, F, Cl, Br, amino, nitro, hydroxyl, cyano, vinyl, propenyl, ethynyl, propynyl;
  • R 3 is selected from hydrogen atom, C 1-3 alkyl group, C 1-3 hydroxyalkyl group, C 3-6 heterocyclic group, C 5-10 aryl group, C 5-10 heteroaryl group, -(CH 2 ) n1 C(O)R aa or -(CH 2 ) one or more of n1 C(O)NR aa R bb , optionally substituted by one or more substituents, heterocyclic and heteroaryl Is selected from one or more of N, O, S;
  • the present invention also relates to a preferred embodiment, which is a compound represented by the general formula (III), its stereoisomer or a pharmaceutically acceptable salt thereof,
  • L is selected from bond, methylene, -(CH 2 ) 2 -or -S(O) 2 -;
  • Ring A is selected from
  • R 1 is selected from cyano
  • R 2 is selected from hydrogen atom, methyl, ethyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, F, Cl, amino, hydroxy, cyano, vinyl, propenyl, ethynyl, propylene Alkynyl
  • R 3 is selected from hydrogen atom, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, azetidine, oxetane, phenyl, benzyl, pyridine, -C (O)NH2;
  • R5 is selected from methyl, methoxy, hydroxy, hydroxymethyl, F,
  • n 0, 1 or 2;
  • n 0, 1, or 2.
  • the present invention also relates to a preferred embodiment.
  • the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IV) and its stereoisomer Body or its pharmaceutically acceptable salt:
  • Ring A, R 2 to R 5 , m and n are as described in the general formula (I).
  • the present invention also relates to a preferred embodiment.
  • the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is represented by the general formulas (IV-A) and (IV-B)
  • Ring A, R 2 to R 5 , m and n are as described in the general formula (I).
  • the present invention also relates to a preferred embodiment.
  • the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (V) and its stereoisomer Body or its pharmaceutically acceptable salt:
  • Ring A, R 2 to R 5 and n are as described in the general formula (I).
  • the present invention also relates to a preferred embodiment, the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (VA) and (VB), Its stereoisomer or its pharmaceutically acceptable salt:
  • Ring A, R 2 to R 5 and n are as described in the general formula (I).
  • the present invention also relates to a preferred embodiment, the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (VI) and (VIA), Its stereoisomer or its pharmaceutically acceptable salt:
  • E, W and G are the same or different, each independently selected from a nitrogen atom or a carbon atom;
  • R 2 to R 5 and n are as described in the general formula (I).
  • the present invention also relates to a preferred embodiment.
  • the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (VII) and (VIIA), Its stereoisomer or its pharmaceutically acceptable salt:
  • L, R 2 to R 5 , m and n are as described in the general formula (I).
  • the present invention also relates to a preferred embodiment, the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (VIII) and (VIIIA), Its stereoisomer or its pharmaceutically acceptable salt:
  • L, R 1 to R 5 , m and n are as described in the general formula (I).
  • the present invention also relates to a preferred embodiment, the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IX) and (IXA), Its stereoisomer or its pharmaceutically acceptable salt:
  • R 2 to R 5 , m and n are as described in the general formula (I).
  • the present invention also relates to a preferred embodiment, the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (X) and (XA), Its stereoisomer or its pharmaceutically acceptable salt:
  • R 2 to R 5 and n are as described in the general formula (I).
  • the present invention also relates to a preferred solution, wherein the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IX) and its stereoisomer Body or its pharmaceutically acceptable salt:
  • J 1 and J 2 are the same or different, and are independently selected from carbon atom, nitrogen atom, oxygen atom and sulfur atom;
  • R 3 to R 5 and n are as described in the general formula (I).
  • the present invention also relates to a preferred solution, each of the general formulas, stereoisomers or pharmaceutically acceptable salts thereof according to any one of the claims, characterized in that
  • Ring A is selected from the following groups:
  • the present invention also relates to a preferred solution, each of the general formulas, stereoisomers or pharmaceutically acceptable salts thereof according to any one of the claims, characterized in that
  • L is -(CH 2 ) n1 -or-(CH 2 ) n1 S(O) m1 -;
  • R 1 is a cyano group or a 3-8 membered heterocyclic group, wherein the heterocyclic group is optionally further substituted with one or more substituents selected from a hydrogen atom and a cyano group;
  • R 2 hydrogen atom or C 1-6 alkyl group; preferably hydrogen atom or C 1-3 alkyl group; more preferably hydrogen atom or methyl group;
  • R 3 is selected from hydrogen atom, cyano group, halogen, C 1-6 alkyl group, C 1-6 haloalkyl group, C 1-6 hydroxyalkyl group, C 3-8 cycloalkyl group, 3-8 membered heterocyclic group, -(CH 2 ) n1 OR aa or -C(O)NR aa R bb ;
  • R 4 is selected from hydrogen atom or halogen
  • R 5 is selected from a hydrogen atom, halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, 3-8 membered heterocyclic group, 5-10 membered heteroaryl, -(CH 2 ) n1 OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 P(O) m2 R aa R bb , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa (CH 2 ) m1 R bb , -(CH 2 ) n1 P(O) m1 R aa R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb , where the Heterocyclic group and heteroaryl group are optionally further substituted by hydrogen atom, C 1-6
  • R aa , R bb , R cc and R dd are the same or different, and are each independently selected from a hydrogen atom, a C 1-6 alkyl group, an amino group, or a 3-8 membered heterocyclic group; wherein the C 1-6 alkane
  • the group, the amino group, and the 3-8 membered heterocyclic group are optionally further substituted with one or more substituents among a hydrogen atom, a hydroxyl group, and a 5-10 membered heteroaryl group.
  • the invention further relates to the use of any compound of the general formula (I), its stereoisomer or its pharmaceutically acceptable salt, or the pharmaceutical composition in the preparation of JAK kinase inhibitors.
  • the present invention also relates to a method for the treatment of prevention and/or treatment of pre-prepared treatment of conditions mediated by JAK kinase inhibitors, which comprises administering to the patient a therapeutically effective dose of a compound represented by general formula (I) and its stereoisomer Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective dose of a compound represented by general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable Accepted carriers, diluents or excipients.
  • the present invention also relates to the use of the compound of general formula (I), its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition in the preparation of drugs for treating inflammatory diseases and tumor diseases.
  • the invention also relates to a method for treating inflammatory diseases and a method for treating tumor diseases, which comprises administering to the patient a therapeutically effective dose of a pharmaceutical composition.
  • the inflammatory diseases mentioned above are selected from rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel disease (ulcerative colitis and Crohn's disease), and the neoplastic diseases are selected from myelofibrosis and true Polycythemia and primary thrombocythemia, sex myeloid leukemia (AML), acute lymphocytic leukemia (ALL), breast ductal carcinoma, and non-small cell lung cancer (NSCLC), in which gastrointestinal inflammation is chronic intestinal disease Inflammatory diseases are more preferably ulcerative colitis and Crohn's disease.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a linear or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms
  • the alkyl group is most preferably an alkyl group of 1 to 3 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Group, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl, etc.
  • the alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any usable connection point.
  • the substituent is preferably one or more of the following groups, which are independently selected from Group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxygen, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate groups, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl in the present invention , Deuterated alkyl, alkoxy substituted alkyl and hydroxy substituted alkyl.
  • alkylene means that a hydrogen atom of the alkyl group is further substituted, for example: "methylene” means -CH 2 -, "ethylene” means -(CH 2 ) 2 -, "propylene” Refers to -(CH 2 ) 3 -, "butylene” refers to -(CH 2 ) 4 -and so on.
  • alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3 -Butenyl, etc. The alkenyl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 Carbon atoms, most preferably containing 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused and bridged cycloalkyls, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl, more preferably cyclopropyl Group, cyclobutyl and cyclopentyl.
  • spirocycloalkyl refers to a polycyclic group that shares a carbon atom (called a spiro atom) between 5- to 20-membered monocycles, which may contain one or more double bonds, but none of the rings is fully conjugated ⁇ electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. According to the number of spiro atoms shared between rings, spirocycloalkyl groups are classified into monospirocycloalkyl groups, dispirocycloalkyl groups or polyspirocycloalkyl groups, preferably monospirocycloalkyl groups and dispirocycloalkyl groups. More preferably, it is 4 member/4 member, 4 member/5 member, 4 member/6 member, 5 member/5 member, or 5 member/6 member monospirocycloalkyl.
  • Non-limiting examples of spirocycloalkyl include:
  • a spirocyclic alkyl group that also contains a single spirocyclic alkyl group and a heterocyclic alkyl group sharing a spiro atom non-limiting examples include:
  • fused ring alkyl refers to a 5- to 20-membered, all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, where one or more rings may contain one or Multiple double bonds, but no ring has a completely conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cyclic alkyl groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 4 members/4 members, 5 members/5 members or 5 members/6 members Bicycloalkyl.
  • fused cycloalkyl include:
  • bridged cycloalkyl refers to a 5- to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has a complete Conjugated ⁇ electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic.
  • bridged cycloalkyls include:
  • the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Group, benzocycloheptyl, etc.
  • the cycloalkyl group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxyl or carboxylate groups.
  • heterocyclic group refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen, boron, phosphorus S(O) m (where m is an integer from 0 to 2) or P(O) n (where n is an integer from 0 to 2) heteroatom, but does not include the ring portion of -OO-, -OS- or -SS- ,
  • the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 8 ring atoms; most preferably 3 to 8 ring atoms.
  • Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, Dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably oxetanyl, oxetanyl Alkyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl and pyranyl.
  • Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups involved are optionally linked to other groups through a single bond or through a ring Any two or more atoms of the above are further connected to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups in parallel.
  • spiroheterocyclyl refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 3 and 20 membered single rings, where one or more ring atoms are nitrogen, oxygen, boron, phosphorus, S (O) m (where m is an integer from 0 to 2) or a hetero atom of P(O) n (where n is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a completely conjugated ⁇ electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan.
  • Spiro heterocyclic groups are classified into mono-spiro heterocyclic groups, di-spiro heterocyclic groups or poly-spiro heterocyclic groups according to the number of spiro atoms shared between the rings, preferably mono-spiro heterocyclic groups and di-spiro heterocyclic groups. More preferably, it is 3 member/5 member, 4 member/5 member, 4 member/6 member, 5 member/5 member, or 5 member/6 member monospiro heterocyclic group.
  • Non-limiting examples of spiro heterocyclic groups include:
  • fused heterocyclic group refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system.
  • One or more rings may contain one or more Double bond, but none of the rings has a completely conjugated ⁇ -electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), and the remaining rings
  • the atom is carbon. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic condensed heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 3 member/5 member, 4 member/5 member or 5 member/6 member Bicyclic fused heterocyclic group.
  • fused heterocyclic groups include:
  • bridged heterocyclic group refers to a 5- to 14-membered, polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a complete common
  • one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic bridge heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic.
  • bridged heterocyclic groups include:
  • the heterocyclic ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples thereof include:
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxyl or carboxylate groups.
  • aryl refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups with a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene And naphthyl. More preferred is phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:
  • the aryl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate groups.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen.
  • the heteroaryl group is preferably 5- to 10-membered, more preferably 5- or 6-membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl , Pyridyl, pyrimidinyl, thiadiazole, oxadiazole, pyrazinyl, etc., preferably oxazolyl, oxadiazole, tetrazole, triazolyl, thienyl, imidazolyl, pyridyl, pyrazine Group, pyrimidinyl, pyrazolyl, thiazole, thiadiazole, pyrazolyl, pyrazolyl
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate groups.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), where alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate groups.
  • Haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • Haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
  • Hydroalkyl refers to an alkyl group substituted with a hydroxy group, where alkyl is as defined above.
  • alkenyl refers to alkenyl, also known as alkenyl, where the alkenyl can be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkyl Amino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio Group, carboxyl group or carboxylate group.
  • Alkynyl means (CH ⁇ C- or -C ⁇ C-), wherein the alkynyl group may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio Group, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, carboxyl or carboxylate groups.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • Amino refers to -NH 2 .
  • Niro refers to -NO 2 .
  • Carboxy refers to -C(O)OH.
  • THF tetrahydrofuran
  • EtOAc means ethyl acetate
  • MeOH refers to methanol
  • DMF N,N-dimethylformamide
  • DIPEA diisopropylethylamine
  • TFA trifluoroacetic acid
  • DMA refers to N,N-dimethylacetamide.
  • Et 2 O refers to diethyl ether
  • DCE 1,2 dichloroethane
  • DIPEA N,N-diisopropylethylamine
  • NBS N-bromosuccinimide
  • NIS N-iodosuccinimide
  • Cbz-Cl refers to benzyl chloroformate
  • Dppf refers to 1,1'-bisdiphenylphosphinoferrocene.
  • HATU refers to 2-(7-benzobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.
  • KHMDS refers to potassium hexamethyldisilazide
  • LiHMDS refers to lithium bistrimethylsilylamine.
  • MeLi refers to methyl lithium
  • N-BuLi refers to n-butyl lithium
  • X is selected from A, B, or C
  • X is selected from A, B, and C
  • X is A, B, or C
  • X is A, B, and C
  • other different terms all express the same Meaning, that is, X can be any one or more of A, B, and C.
  • the hydrogen atoms described in the present invention can be replaced by their isotope deuterium, and any hydrogen atom in the compounds of the examples involved in the present invention can also be replaced by deuterium atoms.
  • heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted refers to one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only at their possible chemical positions, and those skilled in the art can determine (through experiment or theory) possible or impossible substitutions without undue effort. For example, an amino group or hydroxyl group having free hydrogen may be unstable when bonded to a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein or a physiological/pharmaceutically acceptable salt or prodrug thereof with other chemical components, and other components such as physiological/pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert the biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of the compound of the present invention. Such salt is safe and effective when used in mammals, and has proper biological activity.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts ( ⁇ ) are given in parts per million (ppm). The measurement of NMR was performed by Bruker AVANCE-400 nuclear magnetic instrument. The solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ). Methylsilane (TMS).
  • Liquid chromatography-mass spectrometry LC-MS was measured with an Agilent 1200 Infinity Series mass spectrometer. HPLC was measured using Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150 ⁇ 4.6mm chromatographic column) and Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18 150 ⁇ 4.6mm chromatographic column).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specifications adopted by TLC are 0.15mm ⁇ 0.20mm, and the specifications adopted by thin layer chromatography separation and purification products are 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Yellow Sea silica gel 200-300 mesh silica gel as a carrier.
  • the starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized using or following methods known in the art.
  • reaction solution was extracted with EA (15mL ⁇ 3), washed with saturated aqueous sodium chloride solution (15mL ⁇ 3), the organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure to give the title compound as a pale yellow solid (200mg, 93 %).
  • Step 4 3-((3-exo)-3-((4-methoxy-6-((5-methyl-1hydro-pyrazol-3-yl)amino)pyrimidin-2-yl) Preparation of amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
  • Step 2 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-morpholinopyrimidin-2-yl)amino )-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
  • Second step 2-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-6-(( Preparation of 5-methyl-1H-pyrazol-3-yl)amino)pyrimidine-4-carboxamide
  • Example 1 1-(((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-(1H-pyrazol-4-yl)
  • the preparation of pyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl)azetidine-3-carbonitrile is referred to Example 1.
  • reaction solution was diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by silica gel column chromatography to obtain the title compound (50 mg , 6%).
  • Step 3 3-((3-exo)-3-((6-((5-methyl-1H-pyrazol-3-yl)amino)-2-morpholinopyrimidin-4-yl)amino )-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
  • the second step (3-((2-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-1H-pyrazol-5-yl) methanol preparation
  • the third step tert-butyl(3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-(1-methyl- Preparation of 1H-pyrazol-4-yl)pyrimidin-2-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate
  • Test compound inhibits JAK kinase activity
  • Test Example 1 Determination of the inhibitory effect of the compounds of the present invention on JAK kinase activity
  • the purpose of this test case is to test the activity of the compound against the inhibition of JAK kinase activity.
  • centrifuge (5702R) was purchased from Eppendorf company, pipette was purchased from Eppendorf or Rainin company, microplate reader was purchased from American BioTek company, model is SynergyH1 full-function microplate reader.
  • TR-FRET test fluorescence resonance energy transfer
  • the kinase reaction was carried out in a white 384-well plate (PerkinElmer). 1-5 ⁇ L of compounds of different concentrations diluted with DMSO and ddH 2 O were added to each well. 1-5 ⁇ L of the corresponding vehicle was added to the positive control well, and then 1-5 ⁇ L was added to each well Kinase buffer (HEPES 50-250 mM, MgCl 2 5-20 mM, etc.) diluted 0.1-20 nM JAK kinase solution, add 1-5 ⁇ L of kinase buffer to the negative control well, add 1-5 ul of substrate containing peptide substrate and ATP Mix the solution and incubate at room temperature for 0.5 to 5 hours, add 10ul of EDTA and the detection solution containing the labeled antibody, incubate at room temperature for 1 to 24 hours, use the BioTek Synergy H1 microplate reader to measure the fluorescence signal value of each plate well at about 620nm and 665nm The
  • Test Example 2 Determination of the inhibitory effect of compounds of the present invention on JAK-STAT signaling pathway
  • the purpose of the experiment is to test the activity of the compound on the inhibition of JAK-STAT signaling pathway in cells.
  • Microplate oscillator (88880024) was purchased from Thermo Scientific TM
  • the centrifuge (5702R) was purchased from Eppendorf,
  • the microplate reader was purchased from the United States BioTek company, the model is SynergyH1 full-function microplate reader.
  • mice study compounds 1, 4, 7, 9, 12, 15, 16, 18, 21, 23, 27, 32, 33, 38, 42, 49, 53, 54, 57 , 58, 60, 68, 69, 70, 71, 72, 73, 74, 76, 77, 78, 82, 83, 84, 88, 90, 92, 93, orally administered at a dose of 5 mg/kg in small Pharmacokinetic behavior in mice (plasma and colon, ileum tissue), by analyzing the drug concentration of colon and ileum, as well as colon/ileal drug concentration, colon/plasma drug concentration ratio, screening compounds with excellent PK for further research .
  • mice There are 12 Balb/C mice in each group, male; p.o. after fasting overnight, the dose is 5 mg/kg, and the administration volume is 10 mL/kg.
  • mice were sacrificed with CO 2 at 0 , 0.5, 1, 2 , 3, 5 and 7 hours, and 0.2 mL of blood was collected from the heart, placed in an EDTA-K 2 test tube, and centrifuged at 6000 rpm at 4°C. 6 Plasma is separated in minutes and stored at -80°C; the ileum is taken close to the cecum end with a length of about 4-5cm; the colon is also taken close to the cecum end with a length of about 2-3cm, taken out and weighed, placed in a 2mL centrifuge tube Store at °C.
  • Plasma samples were precipitated by adding 160uL of acetonitrile to 40uL, and centrifuged at 3500 ⁇ g for 5-20 minutes after mixing.

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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un composé de dérivé d'hétéroaryle contenant un nitrogène de formule générale (I), son procédé de préparation et sa composition pharmaceutique le contenant. Le composé peut servir comme inhibiteur JAK et est indiqué pour la préparation de médicaments destinés à traiter des maladies inflammatoires et tumeurs.
PCT/CN2019/121205 2018-11-27 2019-11-27 Régulateur de dérivé d'hétéroaryle contenant un nitrogène, son procédé de préparation et ses applications WO2020108516A1 (fr)

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US11155549B2 (en) 2019-04-24 2021-10-26 Theravance Biopharma R&D Ip, Llc Ester and carbonate pyrimidine compounds as JAK kinase inhibitors
WO2022083687A1 (fr) * 2020-10-21 2022-04-28 南京明德新药研发有限公司 Composés hétérocycliques de sélénium et leur application
EP3889152A4 (fr) * 2018-11-30 2022-09-07 Jiangsu Hansoh Pharmaceutical Group Co., Ltd. Dérivés hétéroaromatiques destinés à être utilisés comme régulateurs, leur procédé de préparation et leur utilisation
US11439641B2 (en) 2019-04-24 2022-09-13 Theravance Biopharma R&D Ip, Llc Pyrimidine JAK inhibitors for the treatment of skin diseases
WO2023279105A1 (fr) * 2021-07-01 2023-01-05 Aerie Pharmaceuticals, Inc. Azétidinyl pyrimidines et utilisations associées
WO2023011359A1 (fr) * 2021-08-05 2023-02-09 南京明德新药研发有限公司 Composé cyclique ponté et son utilisation
WO2023159307A1 (fr) * 2022-02-23 2023-08-31 Repare Therapeutics Inc. Inhibiteurs de kinase 4 de type polo (plk4), compositions pharmaceutiques, leurs procédés de préparation et leurs utilisations
WO2023202706A1 (fr) * 2022-04-21 2023-10-26 南京明德新药研发有限公司 Forme saline et forme cristalline de composé hétérocyclique de sélénium et leur application
US11932648B2 (en) 2021-06-28 2024-03-19 Blueprint Medicines Corporation CDK2 inhibitors

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CN117886801B (zh) * 2024-03-14 2024-05-17 中国药科大学 吡啶酮嘧啶类cdk抑制剂及其制备方法和应用

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WO2008005538A2 (fr) * 2006-07-05 2008-01-10 Exelixis, Inc. Procédés d'utilisation de modulateurs de kinase igf1r et abl
WO2016191524A1 (fr) * 2015-05-28 2016-12-01 Theravance Biopharma R&D Ip, Llc Composés de naphtyridine en tant qu'inhibiteurs de la kinase jak
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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3889152A4 (fr) * 2018-11-30 2022-09-07 Jiangsu Hansoh Pharmaceutical Group Co., Ltd. Dérivés hétéroaromatiques destinés à être utilisés comme régulateurs, leur procédé de préparation et leur utilisation
US11155549B2 (en) 2019-04-24 2021-10-26 Theravance Biopharma R&D Ip, Llc Ester and carbonate pyrimidine compounds as JAK kinase inhibitors
US11439641B2 (en) 2019-04-24 2022-09-13 Theravance Biopharma R&D Ip, Llc Pyrimidine JAK inhibitors for the treatment of skin diseases
US11845747B2 (en) 2019-04-24 2023-12-19 Theravance Biopharma R&D Ip, Llc Ester and carbonate pyrimidine compounds as JAK kinase inhibitors
WO2022083687A1 (fr) * 2020-10-21 2022-04-28 南京明德新药研发有限公司 Composés hétérocycliques de sélénium et leur application
US11932648B2 (en) 2021-06-28 2024-03-19 Blueprint Medicines Corporation CDK2 inhibitors
US11970498B2 (en) 2021-06-28 2024-04-30 Blueprint Medicines Corporation CDK2 inhibitors
WO2023279105A1 (fr) * 2021-07-01 2023-01-05 Aerie Pharmaceuticals, Inc. Azétidinyl pyrimidines et utilisations associées
WO2023011359A1 (fr) * 2021-08-05 2023-02-09 南京明德新药研发有限公司 Composé cyclique ponté et son utilisation
WO2023159307A1 (fr) * 2022-02-23 2023-08-31 Repare Therapeutics Inc. Inhibiteurs de kinase 4 de type polo (plk4), compositions pharmaceutiques, leurs procédés de préparation et leurs utilisations
WO2023202706A1 (fr) * 2022-04-21 2023-10-26 南京明德新药研发有限公司 Forme saline et forme cristalline de composé hétérocyclique de sélénium et leur application

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