WO2022053000A1 - Dérivé d'amide carbocyclique et son application en médecine - Google Patents

Dérivé d'amide carbocyclique et son application en médecine Download PDF

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WO2022053000A1
WO2022053000A1 PCT/CN2021/117545 CN2021117545W WO2022053000A1 WO 2022053000 A1 WO2022053000 A1 WO 2022053000A1 CN 2021117545 W CN2021117545 W CN 2021117545W WO 2022053000 A1 WO2022053000 A1 WO 2022053000A1
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alkyl
cyano
alkoxy
ethyl
methyl
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PCT/CN2021/117545
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English (en)
Chinese (zh)
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张晨
王健民
黄安邦
叶飞
黄正刚
唐平明
李瑶
倪佳
严庞科
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四川海思科制药有限公司
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Priority to CN202180058261.7A priority Critical patent/CN116157388A/zh
Publication of WO2022053000A1 publication Critical patent/WO2022053000A1/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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C07D249/18—Benzotriazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a compound of general formula (I) or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and intermediate and preparation method thereof , and the application in the preparation of medicines for treating diseases related to JAK3 kinase activity or expression.
  • Protein kinases are a class of intracellular messenger-dependent enzymes that catalyze the phosphorylation of specific proteins and complete the signal transmission process, mainly including tyrosine protein kinases, such as JAKs, Src, Abl, EGFR, FGFR, TOGFR, etc.; serine/threonine Acid protein kinases, such as PKC, MAPK, Rho kinase, etc.; dual-specificity protein kinases, such as MPKK, etc. and phosphatidylinositol kinases, such as PI3K.
  • tyrosine protein kinases such as JAKs, Src, Abl, EGFR, FGFR, TOGFR, etc.
  • serine/threonine Acid protein kinases such as PKC, MAPK, Rho kinase, etc.
  • dual-specificity protein kinases such as MPKK, etc.
  • Protein kinase phosphorylation/dephosphorylation processes can regulate a variety of biological processes in different cells, such as metabolism, cell differentiation, cell survival, apoptosis, organ formation, angiogenesis, immune response, etc. (Folia Biol. 2006, 52, 81-100.).
  • the Janus family (JAKs) consists of four members, including JAK1, JAK2, JAK3 and TYK2. Cytokines trigger the dimerization of the receptors by binding to the receptors in JAKs, resulting in the phosphorylation of tyrosine residues of the JAK kinases, resulting in JAK activation.
  • the phosphorylated JAKs kinases further bind and phosphorylate a variety of STAT (Signal Transducers and Activators of Transcription) proteins, inducing their dimerization and nuclear dissolution, directly regulating gene transcription and activating downstream disease signaling factors.
  • JAKs form critical signaling pathways in innate immunity, inflammation, and hematopoiesis; dysregulation of this pathway is associated with immune diseases and cancer, and JAKs are targets for the treatment of many disease indications (Immunol.Rev.2008, 223, 132-142.).
  • Tofacitinib pan-JAKs inhibitor
  • Tofacitinib pan-JAKs inhibitor
  • Tofacitinib has side effects including causing a decrease in the number of red and white blood cells and an increase in cholesterol levels, which may be related to its high JAK2 inhibitory activity (J. Med. Chem. 2012, 55, 6176-6193). Therefore, scientists from major pharmaceutical companies and other institutions have focused their attention on the research and discovery of selective JAK inhibitors.
  • JAK3 is mainly distributed in the bone marrow and lymphatic system.
  • IL-21 and other cytokine receptor complexes combine with the ⁇ co-chain ( ⁇ c) to regulate cell signaling.
  • JAK3 has become an attractive drug target for immune system-related diseases, and its inhibitors are in rheumatoid arthritis (RA), inflammatory bowel disease, Crohn's disease, systemic erythema It has important clinical application value in the treatment/prevention of lupus, multiple sclerosis, type I diabetes, psoriasis, allergic diseases, asthma, chronic obstructive pulmonary disease, leukemia, lymphoma, organ transplantation and other diseases (Trends Pharm Sci. 2004, 25, 558-562).
  • RA rheumatoid arthritis
  • inflammatory bowel disease Crohn's disease
  • Crohn's disease systemic erythema It has important clinical application value in the treatment/prevention of lupus, multiple sclerosis, type I diabetes, psoriasis, allergic diseases, asthma, chronic obstructive pulmonary disease, leukemia, lymphoma, organ transplantation and other diseases (Trends Pharm Sci. 2004, 25, 558-562).
  • One of the objects of the present invention is to provide a compound capable of inhibiting JAK3 kinase, or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and its intermediate and The preparation method and the application in the preparation of a medicine for treating diseases related to the activity or expression of JAK3.
  • the present invention provides a compound of general formula (I) or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
  • Y 1 , Y 2 , Y 3 are each independently selected from CH or N;
  • Y 1 , Y 2 are selected from CH, and Y 3 is selected from N;
  • Y 1 , Y 2 , Y 3 are selected from CH;
  • Y 1 , Y 2 are selected from N, and Y 3 is selected from N;
  • Y 1 is selected from N
  • Y 2 is selected from CH
  • Y 3 is selected from CH
  • Y 1 is selected from CH
  • Y 2 is selected from N
  • Y 3 is selected from CH
  • Y 1 is selected from CH, Y 2 is selected from N, and Y 3 is selected from N;
  • Ring A is selected from a 5- to 6-membered heterocyclic or heteroaromatic ring optionally further substituted with 0, 1, 2 or 3 R substituents,
  • the heterocyclic or heteroaromatic ring contains 1, 2, 3 or 4 heteroatoms selected from O, S, N;
  • selected from X 1 is selected from N or CR a ;
  • Ra is selected from H, F, Cl, cyano, NH2 , -NHCH3, -N( CH3 ) 2 , -C(O) NH2 , -C (O) NHCH3 , -C(O)N(CH 3 ) 2 , -C(O)NHCH 2 CH 3 , -C(O)N(CH 2 CH 3 ) 2 , -C(O)NHCH 2 CH 2 OCH 3 , - C(O)NH-cyclopropyl, -C(O)NH-cyclobutyl, -C(O)NH-cyclopentyl, -C(O)NH-cyclohexyl, -NHC(O)CH 3 , -NHC(O)CH 2 CH 3 , -NHC(O)-cyclopropyl, -NHC(O)-cyclobutyl, -NHC(O)-cyclopentyl, -NHC(O)-cyclohex
  • Ra is selected from H
  • Ring B is selected from C 3-10 carbocycles optionally further substituted with 0, 1, 2, 3 or 4 R b ;
  • Ring B is selected from the group consisting of C 3-6 saturated or unsaturated monocyclic carbocycles, C 5-10 saturated or unsaturated spirocyclic carbocycles, C 5-10 saturated or unsaturated and cyclic carbocycles, C 5-10 saturated or unsaturated bridged ring carbocycle optionally further substituted with 0, 1, 2, 3 or 4 R b ;
  • Ring B is selected from substituted or unsubstituted one of the following: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, bicyclo[1.1.1]pentyl , bicyclo[2.2.1]heptyl, cubic alkyl, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl, cyclopentacyclopentyl, bicyclo[4.2.0]octyl Alkyl, bicyclo[2.2.2]octyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclohexyl, when substituted, optionally further substituted with 0, 1, 2, 3 or 4 R b ;
  • Ring B is selected from one of the following groups, substituted or unsubstituted: When substituted, it is optionally further substituted by 0, 1, 2, 3 or 4 R b , the left side of which is connected to L 1 ;
  • Ring B is selected from Its left side is connected to L1 ;
  • each R b is independently selected from H, halo, cyano, C 1-6 alkyl or C 1-6 alkoxy optionally further substituted by O , 1, 2, 3 or 4 are selected from H, halogen, CF 3 , OH, cyano, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-8 cycloalkyl substituent;
  • R b is each independently selected from H, halo, cyano, C 1-4 alkyl or C 1-4 alkoxy optionally further substituted by O , 1, 2, 3 or 4 are selected from H, halogen, CF 3 , OH, cyano, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-8 cycloalkyl substituent;
  • each R b is independently selected from H, F, Cl, Br, I, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy, the methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy optionally further selected from 0, 1, 2, 3 or 4 From H, halogen, CF 3 , OH, cyano, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 Substituents of alkoxy or C 3-6 cycloalkyl;
  • each R b is independently selected from H, F, Cl, Br, I, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy, the methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy optionally further selected from 0, 1, 2, 3 or 4 From H, F, CF3 , OH, cyano, NH2 , -NHCH3 , -N( CH3 ) 2 , -NHCH2CH3, -N(CH2CH3)2 , methyl , ethyl , Substituted by substituents of isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl or cyclopentyl;
  • each R b is independently selected from H, F, Cl, cyano, methyl, ethyl, isopropyl, propyl, methoxy or ethoxy, the methyl, Ethyl, isopropyl, propyl, methoxy or ethoxy is optionally further selected by 0, 1, 2, 3 or 4 selected from H, F, CF3 , OH, cyano, NH2 , -N (CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , methyl, ethyl, isopropyl, propyl, cyclopropyl or cyclobutyl substituent;
  • L1 is selected from bond, -S (O) n- , -NR1a- , -CR1bR1c- , -O ( CR1bR1c ) s- , - ( CR1bR1c ) s O-, -NR 1a CR 1b R 1c -, -NR 1a S(O) n -, -S(O) n NR 1a -, -NR 1a C(O)-, -C(O)NR 1a -, -SCR 1b R 1c - or -CR 1b R 1c S-;
  • L 1 is selected from bond, -O-, -S(O) n -, -NR 1a -, -CR 1b R 1c -, -OCR 1b R 1c -, -O(CR 1b R 1c ) 2 -, -CR 1b R 1c O-, -NR 1a CR 1b R 1c -, -SCR 1b R 1c - or -CR 1b R 1c S-;
  • L1 is selected from bond, -O-, -S-, -NH-, -CH2- , -S(O) 2- , -OCH2-, -OCH( CH3 ) - , -OC(CH 3 ) 2 -, -OCH 2 CH 2 -, -CH 2 O-, -NHCH 2 - or -N(CH 3 )-;
  • L 1 is selected from -O-, -NH-, -OCH 2 -, -OC(CH 3 ) 2 -, -CH 2 O- or -NHCH 2 -;
  • L 1 is selected from -O-, -OCH 2 -, -OC(CH 3 ) 2 - or -CH 2 O-;
  • R 1a , R 1b or R 1c are each independently selected from H, C 1-4 alkyl or -(CH 2 ) p -C 3-6 carbocycle, said alkyl or carbon
  • the ring is optionally further substituted with 0, 1 , 2, 3 or 4 substituents selected from H, halogen, OH, CF3 , cyano, C1-4alkyl or C1-4alkoxy;
  • R 1b , R 1c together with the carbon atoms to which they are directly attached form a 3-membered carbocyclic ring;
  • selected from X 1 is selected from N or CR a ; the right side is directly connected to L 1 ;
  • selected from X 1 is selected from N or CH; the right side is directly connected with L 1 ;
  • selected from The right side is directly connected to L 1 ;
  • Ring C is selected from 5-6 membered heteroaryl or phenyl optionally further substituted with 0, 1, 2, 3 or 4 R c ;
  • Ring C is selected from pyridine optionally further substituted with 0, 1, 2 or 3 R c ;
  • each R c is independently selected from R 1 , R 2 , R 3 or R 4 ;
  • R 1 , R 2 are each independently selected from H, F, Cl, OH, CF 3 , cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy , ethoxy or propoxy;
  • R3 is selected from H, F, Cl, OH, CF3 , -CN, -CH2CN, -CH2CH2CN , NH2 , -N ( CH3 ) 2 , -N (CH 2 CH 3 ) 2 , -C(O)NH 2 , -CH 2 C(O)NH 2 , -C(O)NHCH 3 , -NHC(O)CH 3 , methyl, ethyl, isopropyl radical, propyl, butyl, methoxy, ethoxy or propoxy;
  • R4 is selected from H, F, OH, CF3 , NH2 , -CN, -CH2CN , -CH2CH2CN , -NHCH3, -N ( CH3 ) 2 , -C(O) -NH2 , -CH2C (O) -NH2 , -CH2CH2C (O) -NH2 , -C (O) NHCH3 , -C(O)N( CH3 ) 2 , -NHC(O)CH 3 , methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, -CH 2 -cyclopropyl, cyclobutyl , -CH 2 -cyclobutyl, cyclopentyl, -CH 2 -cyclopentyl, cyclohexyl, -CH 2 -cyclohexyl, a
  • R 1 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl, or methoxy;
  • R 2 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl, or methoxy;
  • R3 is selected from H, F, Cl, cyano, CF3 , methyl, ethyl, or methoxy;
  • R4 is selected from H, F, Cl, cyano, CF3 , methyl, ethyl, or methoxy;
  • R a1 , R a2 , R 3a , R 3b are each independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 Alkoxy, C 3-12 carbocyclyl or 3- to 12-membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl optionally further replaced by 0, 1 , 2, 3 or 4 substituents selected from H, halogen, CF 3 , OH, cyano, COOH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy, the hetero
  • the cyclic group contains 1, 2 or 3 heteroatoms selected from O, S, N;
  • R a1 , R a2 , R 3a , R 3b are each independently selected from H, C 1-4 alkyl, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, the The alkyl, carbocyclyl or heterocyclyl is optionally further selected by 0, 1, 2, 3 or 4 groups selected from H, halogen, CF3 , OH, cyano, COOH, NH2 , C1-4 alkyl or C 1-4 alkoxy substituent, the heterocyclic group contains 1, 2 or 3 heteroatoms selected from O, S, N;
  • R a1 , R a2 , R 3a , R 3b are each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopropyl Amyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl, the methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclopropyl Butyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl are optionally further substituted by 0, 1, 2, 3 or 4 selected from H, halogen, CF 3.
  • R 3a , R 3b are each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Azacyclobutyl, oxetanyl, pyrrolidinyl or piperidinyl, said methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl optionally further selected by 0, 1, 2, 3 or 4 selected from H, F, CF3 , OH, cyano , COOH, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy or propoxy substituents;
  • R 5 is selected from
  • R 5 is selected from
  • R 5 is selected from
  • R 5 is selected from
  • R 5 is selected from
  • R 5 is selected from
  • R 5 is selected from
  • R 5 is selected from
  • R 5 is selected from
  • R 5 is selected from
  • R 5 is selected from
  • R 5 is selected from
  • R 5 is selected from
  • R 5 is selected from
  • R 5b and R 5c can form a chemical bond
  • R 5d and R 5e are each independently selected from H, C 1-6 alkyl, C 3-8 carbocyclyl or 3- to 10-membered heterocyclyl, said alkyl, carbocyclic
  • the heterocyclyl group contains 1, 2 or 3 heteroatoms selected from O, S, N;
  • the heterocyclyl group contains 1, 2 or 3 heteroatoms selected from O, S, N;
  • R 5d and R 5e are each independently selected from H, C 1-4 alkyl, 3- to 6-membered carbocycle or 3- to 8-membered heterocycle, said alkyl, carbocycle or heterocycle
  • the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from O, S, N;
  • R 5f is selected from H or substituted or unsubstituted one of the following: methyl, ethyl, propyl, butyl, isopropyl, isobutyl, azetidine , azacyclopentyl, azacyclohexyl, piperazinyl, oxetanyl, oxolane, oxetanyl, morpholinyl, -CH 2 -azetidine, - CH 2 -azepanyl, -CH 2 -azepanyl, -CH 2 -piperazine, -CH 2 -oxetanyl, -CH 2 -oxolane, -CH 2 - Oxanyl, -CH 2 -morpholine, -CH 2 CH 2 -azepanyl, -CH 2 CH 2 -azepanyl, -CH 2 CH 2 -azepinyl, - CH 2 CH 2 -piperaz
  • R 5f is selected from H or substituted or unsubstituted one of the following: methyl, ethyl, propyl, butyl, isopropyl, isobutyl, azetidine , azacyclopentyl, azacyclohexyl, piperazinyl, oxetanyl, oxolane, oxetanyl, morpholinyl, -CH 2 -azetidine, - CH 2 -azepanyl, -CH 2 -azepanyl, -CH 2 -piperazine, -CH 2 -oxetanyl, -CH 2 -oxolane, -CH 2 - Oxanyl, -CH 2 -morpholine, -CH 2 CH 2 -azepanyl, -CH 2 CH 2 -azepanyl, -CH 2 CH 2 -azepinyl, - CH 2 CH 2 -piperaz
  • R 5f is selected from H, methyl, ethyl,
  • n and s are selected from 0, 1 or 2;
  • n, p, q are each independently selected from 0, 1, 2, 3 or 4.
  • Y 1 , Y 2 , and Y 3 are each independently selected from CH or N;
  • Ring A is selected from a 5- to 6-membered heterocyclic or heteroaromatic ring optionally further substituted by 0, 1, 2 or 3 R a substituents, the heterocyclic or heteroaromatic ring
  • the aromatic ring contains 1, 2, 3 or 4 heteroatoms selected from O, S, N;
  • Ring B is selected from C 3-10 carbocycles optionally further substituted by 0, 1, 2, 3 or 4 R b ;
  • R b is each independently selected from H, halogen, cyano, C 1-6 alkyl or C 1-6 alkoxy, said alkyl or alkoxy optionally further modified by 0, 1, 2, 3 or 4 selected from H, halogen, CF 3 , OH, cyano, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-8 cycloalkyl substituent;
  • L 1 is selected from bond, -S(O) n -, -NR 1a -, -CR 1b R 1c -, -O(CR 1b R 1c ) s -, -(CR 1b R 1c ) s O-, -NR 1a CR 1b R 1c -, -NR 1a S(O) n -, -S(O) n NR 1a -, -NR 1a C(O)-, -C(O)NR 1a -, -SCR 1b R 1c -or-CR 1b R 1c S-;
  • R 1a , R 1b or R 1c are each independently selected from H, C 1-4 alkyl or -(CH 2 ) p -C 3-6 carbocycle, wherein said alkyl or carbocycle is optionally further substituted by O, 1, 2, 3 or 4 substituents selected from H, halogen, OH, CF 3 , cyano, C 1-4 alkyl or C 1-4 alkoxy;
  • R 1b and R 1c together with the carbon atoms to which they are directly connected form a 3-membered carbocyclic ring;
  • Ring C is selected from 5-6 membered heteroaryl or phenyl, and said heteroaryl or phenyl is optionally further substituted by 0, 1, 2, 3 or 4 R c ;
  • R a1 , R a2 , R 3a , R 3b are each independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3- 12 -carbocyclyl or 3- to 12-membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl optionally further replaced by 0, 1, 2, 3 or 4 substituted with a substituent selected from H, halogen, CF 3 , OH, cyano, COOH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy, and the heterocyclic group contains 1, 2 or 3 heteroatoms selected from O, S, N;
  • R 5 is selected from
  • R 5b and R 5c may form a chemical bond
  • the cyclic group contains 1, 2 or 3
  • n and s are selected from 0, 1 or 2;
  • n, p, q are each independently selected from 0, 1, 2, 3 or 4.
  • the right side is directly connected to L 1 ;
  • X 1 is selected from N or CR a ;
  • Ring B is selected from C 3-6 saturated or unsaturated monocyclic carbocycle, C 5-10 saturated or unsaturated spirocyclic carbocycle, C 5-10 saturated or unsaturated and cyclic carbocycle, C 5-10 saturated or unsaturated A saturated bridged ring carbocycle optionally further substituted with 0, 1, 2 , 3 or 4 R;
  • R b is each independently selected from H, halogen, cyano, C 1-4 alkyl or C 1-4 alkoxy, said alkyl or alkoxy optionally further modified by 0, 1, 2, 3 or 4 selected from H, halogen, CF 3 , OH, cyano, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-8 cycloalkyl substituent;
  • L 1 is selected from bond, -O-, -S(O) n -, -NR 1a -, -CR 1b R 1c -, -OCR 1b R 1c -, -O(CR 1b R 1c ) 2 -, -CR 1b R 1c O-, -NR 1a CR 1b R 1c -, -SCR 1b R 1c - or -CR 1b R 1c S-;
  • R a1 , R a2 , R 3a , R 3b are each independently selected from H, C 1-4 alkyl, C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl is optionally further selected from 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 , OH, cyano, COOH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy substituted by the substituent of the group, the heterocyclic group contains 1, 2 or 3 heteroatoms selected from O, S, N;
  • R 5b and R 5c may form a chemical bond
  • L 1 is selected from bond, -O-, -S-, -NH-, -CH 2 -, -S(O) 2 -, -OCH 2 -, -OCH(CH 3 )-, -OC(CH 3 ) 2- , -OCH2CH2-, -CH2O- , -NHCH2- or -N( CH3 ) - ;
  • Ring B is selected from one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1] Heptyl, cubic alkyl, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl, cyclopentacyclopentyl, bicyclo[4.2.0]octyl, bicyclo[2.2.
  • R b is each independently selected from H, F, Cl, Br, I, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy, the The methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy groups are optionally further substituted by 0, 1, 2, 3 or 4 selected from H, halogen, CF 3 , OH, cyano, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3- 6 cycloalkyl substituents are substituted;
  • R a1 , R a2 , R 3a , R 3b are each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, nitrogen Heterobutyl, oxetanyl, pyrrolidinyl or piperidinyl, the methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl is optionally further selected by 0, 1, 2, 3 or 4 selected from H, halogen, CF3 , OH, cyano, Substituents of COOH, C 1-4 alkyl or C 1-4 alkoxy;
  • R 5 is selected from
  • R 5b and R 5c may form a chemical bond
  • R 5d , R 5e together with the nitrogen atom to which they are directly attached form an azetidine, pyrrolyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl or thiomorpholinyl group, the nitrogen Heterocyclobutyl, pyrrolyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl or thiomorpholinyl optionally further selected by 0, 1, 2, 3 or 4 selected from H, halogen, CF 3.
  • Substituent substitution of O, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy or -C 1-4 alkylene-C 1-4 alkoxy;
  • R 5f is selected from H or substituted or unsubstituted one of the following groups: methyl, ethyl, propyl, butyl, isopropyl, isobutyl, azetidinyl, azacyclopentyl, Azacyclohexyl, piperazinyl, oxetanyl, oxolanyl, oxanyl, morpholinyl, -CH2 -azetidinyl, -CH2 -azepanyl base, -CH 2 -azepanyl, -CH 2 -piperazine, -CH 2 -oxetanyl, -CH 2 -oxolane, -CH 2 -oxane, - CH2 - morpholine, -CH2CH2 - azetidine, -CH2CH2 - azacyclopentyl, -CH2CH2 -azacyclohexyl,
  • Ring B is selected from one of the following groups, substituted or unsubstituted: When substituted, it is optionally further substituted by 0, 1, 2, 3 or 4 R b , the left side of which is connected to L 1 ;
  • R b is each independently selected from H, F, Cl, Br, I, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy, the The methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy groups are optionally further selected by 0, 1, 2, 3 or 4 selected from H, F, CF 3 , OH, cyano, NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 2 CH 3 ) 2 , methyl, ethyl, isopropyl, propyl, Substituents of butyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl or cyclopentyl;
  • Ra is selected from H, F, Cl, cyano, NH2 , -NHCH3, -N( CH3 ) 2 , -C(O) NH2 , -C (O) NHCH3 , -C(O)N (CH 3 ) 2 , -C(O)NHCH 2 CH 3 , -C(O)N(CH 2 CH 3 ) 2 , -C(O)NHCH 2 CH 2 OCH 3 , -C(O)NH-ring Propyl, -C(O)NH-cyclobutyl, -C(O)NH-cyclopentyl, -C(O)NH-cyclohexyl, -NHC(O)CH 3 , -NHC(O)CH 2 CH 3 , -NHC(O)-cyclopropyl, -NHC(O)-cyclobutyl, -NHC(O)-cyclopentyl, -NHC(O)-cyclohexy
  • R 3a and R 3b are each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, oxygen Heterocyclobutyl, pyrrolidinyl or piperidinyl, said methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azacyclo
  • the butyl, oxetanyl, pyrrolidinyl or piperidinyl groups are optionally further substituted by 0, 1, 2, 3 or 4 selected from H, F, CF3 , OH, cyano, COOH, methyl, ethyl substituted with substituents of radical, isopropyl, propyl, methoxy, ethoxy or propoxy
  • R 5 is selected from
  • R 5 is selected from
  • R 5 is selected from
  • R 5 is selected from
  • L 1 is selected from -O-, -NH-, -OCH 2 -, -OC(CH 3 ) 2 -, -CH 2 O- or -NHCH 2 -;
  • R b is each independently selected from H, F, Cl, cyano, methyl, ethyl, isopropyl, propyl, methoxy or ethoxy, the methyl, ethyl, isopropyl, Propyl, methoxy or ethoxy optionally further selected by 0, 1, 2, 3 or 4 selected from H, F, CF3 , OH, cyano, NH2 , -N( CH3 ) 2 , - N(CH 2 CH 3 ) 2 , methyl, ethyl, isopropyl, propyl, cyclopropyl or cyclobutyl substituent;
  • X 1 is selected from N or CH;
  • R 1 , R 2 are each independently selected from H, F, Cl, OH, CF 3 , cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy base;
  • R3 is selected from H, F, Cl, OH, CF3 , -CN, -CH2CN , -CH2CH2CN , NH2 , -N( CH3 ) 2 , -N ( CH2CH3 ) 2 , -C(O)NH 2 , -CH 2 C(O)NH 2 , -C(O)NHCH 3 , -NHC(O)CH 3 , methyl, ethyl, isopropyl, propyl, butyl , methoxy, ethoxy or propoxy;
  • R4 is selected from H, F, OH, CF3 , NH2 , -CN, -CH2CN , -CH2CH2CN , -NHCH3 , -N( CH3 ) 2 , -C (O)-NH 2 , -CH 2 C(O)-NH 2 , -CH 2 CH 2 C(O)-NH 2 , -C(O)NHCH 3 , -C(O)N(CH 3 ) 2 , -NHC(O ) CH3 , methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, -CH2 -cyclopropyl, cyclobutyl, -CH2 -cyclo Butyl, cyclopentyl, -CH2 -cyclopentyl, cyclohexyl, -CH2 -cyclohexyl, azetidinyl
  • R 5 is selected from
  • R 5 is selected from
  • R 5 is selected from
  • R 5 is selected from
  • L 1 is selected from -O-, -OCH 2 -, -OC(CH 3 ) 2 - or -CH 2 O-;
  • Ring B is selected from Its left side is connected to L1 ;
  • R 5 is selected from
  • R 5 is selected from
  • R 5 is selected from
  • R 5 is selected from
  • R 1 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy;
  • R 2 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy;
  • R3 is selected from H, F, Cl, cyano, CF3 , methyl, ethyl or methoxy;
  • R 4 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy;
  • R 5 is selected from
  • R 5f is selected from H or substituted or unsubstituted one of the following groups: methyl, ethyl, propyl, butyl, isopropyl, isobutyl, azetidinyl, azacyclopentyl, Azacyclohexyl, piperazinyl, oxetanyl, oxolanyl, oxanyl, morpholinyl, -CH2 -azetidinyl, -CH2 -azepanyl base, -CH 2 -azepanyl, -CH 2 -piperazine, -CH 2 -oxetanyl, -CH 2 -oxolane, -CH 2 -oxane, - CH2 - morpholine, -CH2CH2 - azetidine, -CH2CH2 - azacyclopentyl, -CH2CH2 -azacyclohexyl,
  • L 1 is selected from -O-, -OCH 2 -, -OC(CH 3 ) 2 - or -CH 2 O-;
  • Ring B is selected from Its left side is connected to L1 ;
  • R 1 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy;
  • R 2 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy;
  • R3 is selected from H, F, Cl, cyano, CF3 , methyl, ethyl or methoxy;
  • R 4 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy;
  • the compound represented by the following general formula (Ia) or (Ib) or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic the compound represented by the following general formula (Ia) or (Ib) or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic,
  • each group is consistent with any one of the second, third, fourth, fifth, sixth, seventh or eighth embodiments of the present invention.
  • L 1 is selected from -O-, -OCH 2 -, -OC(CH 3 ) 2 - or -CH 2 O-;
  • Ring B is selected from Its left side is connected to L1 ;
  • R 1 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy;
  • R 2 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy;
  • R3 is selected from H, F, Cl, cyano, CF3 , methyl, ethyl or methoxy;
  • R 4 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy;
  • R 5 is selected from
  • Y 1 and Y 2 are selected from CH, and Y 3 is selected from N or C;
  • L 1 is selected from -O-, -OCH 2 -;
  • Ring B is selected from Its left side is connected to L1 ;
  • R 1 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy;
  • R 2 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy;
  • R3 is selected from H, F, Cl, cyano, CF3 , methyl, ethyl or methoxy;
  • R 4 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy;
  • R 5 is the same as the eleventh embodiment.
  • the present invention provides the compounds shown below or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof,
  • Y 1 , Y 2 and Y 3 are each independently selected from C, CH or N.
  • Y 1 and Y 2 are selected from CH, and Y 3 is selected from N.
  • Y 1 , Y 2 and Y 3 are selected from CH.
  • Y 1 and Y 2 are selected from CH, and Y 3 is selected from C.
  • Y 1 and Y 2 are selected from N, and Y 3 is selected from N.
  • Y 1 is selected from N
  • Y 2 is selected from CH
  • Y 3 is selected from C.
  • Y 1 is selected from CH
  • Y 2 is selected from N
  • Y 3 is selected from C.
  • Y 1 is selected from CH
  • Y 2 is selected from N
  • Y 3 is selected from N.
  • ring A is selected from 5- to 6-membered heterocycles or heteroaromatic rings, and the heterocyclic or heteroaromatic rings are any optionally further substituted with 0, 1, 2 or 3 R a substituents, said heterocyclic or heteroaromatic ring containing 1 to 4 heteroatoms selected from O, S, N.
  • the present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), selected from
  • the present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), selected from X 1 is selected from N or CR a .
  • the present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), selected from
  • the present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), selected from
  • R a is selected from H, F, Cl, cyano, NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -C(O)NH 2 , -C(O)NHCH 3 , -C(O)N(CH 3 ) 2 , -C(O)NHCH 2 CH 3 , -C(O)N(CH 2 CH 3 ) 2 , -C(O)NHCH 2 CH 2 OCH 3 , -C(O)NH-cyclopropyl, -C(O)NH-cyclobutyl, -C(O)NH-cyclopentyl, -C(O)NH-cyclohexyl, -NHC(O) CH3 , -NHC(O) CH2CH3 , -NHC(O ) -cyclopropyl, -NHC(O)-cyclobut
  • R a is selected from H.
  • ring B is selected from C 3-10 carbocyclic rings, which are optionally further substituted by 0, 1, 2 , 3 or 4 R b substitutions.
  • ring B is selected from C 3-6 saturated or unsaturated monocyclic carbocycle, C 5-10 saturated or unsaturated Spirocyclic carbocycles, C5-10 saturated or unsaturated and cyclic carbocycles, C5-10 saturated or unsaturated bridged carbocycles optionally further surrounded by 0, 1, 2, 3 or 4 R b replaces.
  • ring B is selected from one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentane Alkyl, cyclohexyl, adamantyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, cubic alkyl, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl Alkyl, cyclopentyl and cyclopentyl, bicyclo[4.2.0]octyl, bicyclo[2.2.2]octyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutyl Spirocyclohexyl, cyclopentylspirocyclohexyl, when substituted, are optionally further
  • ring B is selected from one of the following substituted or unsubstituted groups: When substituted, it is optionally further substituted with 0, 1, 2, 3 or 4 R b , the left side of which is attached to L 1 .
  • ring B is selected from Its left side is connected to L1 .
  • R b is each independently selected from H, halogen, cyano, C 1-6 alkyl or C 1-6 Alkoxy, said alkyl or alkoxy optionally further selected by 0, 1, 2, 3 or 4 selected from H, halogen, CF 3 , OH, cyano, NH 2 , -NH(C 1- 4 alkyl), -N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-8 cycloalkyl substituent.
  • R b is each independently selected from H, halogen, cyano, C 1-4 alkyl or C 1-4 Alkoxy, said alkyl or alkoxy is optionally further selected by 0, 1, 2, 3 or 4 selected from H, halogen, CF 3 , OH, cyano, NH 2 , -NH(C 1- 4 alkyl), -N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-8 cycloalkyl substituent.
  • R b is independently selected from H, F, Cl, Br, I, cyano, methyl, ethyl , isopropyl, propyl, butyl, methoxy, ethoxy or propoxy, the methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or Propoxy is optionally further selected by 0, 1, 2, 3 or 4 selected from H, halogen, CF3 , OH, cyano, NH2 , -NH( C1-4alkyl ), -N( C1 -4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituent.
  • R b is independently selected from H, F, Cl, Br, I, cyano, methyl, ethyl , isopropyl, propyl, butyl, methoxy, ethoxy or propoxy, the methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or Propoxy is optionally further selected by 0, 1, 2 , 3 or 4 selected from H, F, CF3 , OH, cyano, NH2 , -NHCH3, -N( CH3 ) 2 , -NHCH2CH 3 , -N(CH 2 CH 3 ) 2 , methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl or cyclopentyl substituted by the
  • R b is independently selected from H, F, Cl, cyano, methyl, ethyl, isopropyl , propyl, methoxy or ethoxy, the methyl, ethyl, isopropyl, propyl, methoxy or ethoxy optionally further selected from 0, 1, 2, 3 or 4 From H, F, CF3 , OH, cyano, NH2 , -N( CH3 ) 2 , -N( CH2CH3 )2 , methyl, ethyl, isopropyl, propyl, cyclopropyl or cyclobutyl substituents.
  • L 1 is selected from bond, -S(O) n -, -NR 1a -, -CR 1b R 1c - , -O(CR 1b R 1c ) s -, -(CR 1b R 1c ) s O-, -NR 1a CR 1b R 1c -, -NR 1a S(O) n -, -S(O) n NR 1a -, -NR 1a C(O)-, -C(O)NR 1a -, -SCR 1b R 1c - or -CR 1b R 1c S-.
  • L 1 is selected from bond, -O-, -S(O) n -, -NR 1a -, -CR 1b R 1c -, -OCR 1b R 1c -, -O(CR 1b R 1c ) 2 -, -CR 1b R 1c O-, -NR 1a CR 1b R 1c -, -SCR 1b R 1c - or -CR 1b R 1c S-.
  • L 1 is selected from bond, -O-, -S-, -NH-, -CH 2 -, -S (O) 2 -, -OCH 2 -, -OCH(CH 3 )-, -OC(CH 3 ) 2 -, -OCH 2 CH 2 -, -CH 2 O-, -NHCH 2 - or -N(CH 3 )-.
  • the present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), L 1 is selected from -O-, -NH-, -OCH 2 -, -OC(CH 3 ) 2 - , -CH 2 O- or -NHCH 2 -.
  • the present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), L 1 is selected from -O-, -OCH 2 -, -OC(CH 3 ) 2 - or -CH 2 O-.
  • R 1a , R 1b or R 1c are each independently selected from H, C 1-4 alkyl or -(CH 2 ) p -C 3-6 carbocyclic ring, the alkyl or carbocyclic ring is optionally further selected from 0, 1, 2, 3 or 4 by 0, 1, 2, 3 or 4 selected from H, halogen, OH, CF 3 , cyano, C 1- 4 alkyl or C 1-4 alkoxy substituent.
  • R 1b and R 1c together with the carbon atoms to which they are directly connected form a 3-membered carbocyclic ring.
  • the present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), selected from X 1 is selected from N or CR a , and the right side is directly connected to L 1 .
  • the present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), selected from X 1 is selected from N or CH, and the right side is directly connected to L 1 .
  • the present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), selected from The right side is directly connected to L 1
  • ring C is selected from 5-6 membered heteroaryl or phenyl, and said heteroaryl or phenyl is any Select is further substituted with 0, 1, 2, 3 or 4 Rcs.
  • ring C is selected from pyridine, and said pyridine is optionally further substituted by 0, 1, 2 or 3 R c .
  • the present invention relates to some embodiments of the compound represented by the general formula (I), selected from
  • R c is each independently selected from R 1 , R 2 , R 3 or R 4 .
  • R 1 and R 2 are each independently selected from H, F, Cl, OH, CF 3 , cyano, methyl radical, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy.
  • R 3 is selected from H, F, Cl, OH, CF 3 , -CN, -CH 2 CN, -CH 2CH2CN, NH2 , -N( CH3 ) 2 , -N( CH2CH3 ) 2 , -C (O) NH2 , -CH2C (O) NH2 , -C (O)NHCH 3 , -NHC(O) CH3 , methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy.
  • R 4 is selected from H, F, OH, CF 3 , NH 2 , -CN, -CH 2 CN, - CH2CH2CN, -NHCH3 , -N( CH3 ) 2 , -C (O) -NH2 , -CH2C (O) -NH2 , -CH2CH2C ( O) -NH2 , -C(O)NHCH 3 , -C(O)N(CH 3 ) 2 , -NHC(O)CH 3 , methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, Propoxy, cyclopropyl, -CH2 -cyclopropyl, cyclobutyl, -CH2 -cyclobutyl, cyclopentyl, -CH2 -cyclopentyl, cyclo
  • R 1 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy .
  • R 2 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy .
  • R 3 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy .
  • R 4 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy.
  • the present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R a1 , R a2 , R 3a , R 3b are each independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-12 carbocyclyl or 3- to 12-membered heterocyclyl, the alkyl, alkenyl, alkynyl, Alkoxy, carbocyclyl or heterocyclyl is optionally further selected by 0, 1, 2, 3 or 4 groups selected from H, halogen, CF3 , OH, cyano, COOH, NH2 , C1-4alkyl or C 1-4 alkoxy substituent, the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, N.
  • R a1 , R a2 , R 3a , R 3b are each independently selected from H, C 1-6 alkyl, C 2-6 alkenyl,
  • the present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R a1 , R a2 , R 3a , R 3b are each independently selected from H, C 1-4 alkyl, C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, the alkyl, carbocyclyl or heterocyclyl is optionally further selected by 0, 1, 2, 3 or 4 selected from H, halogen, CF 3 , OH, cyano, COOH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy substituent, the heterocyclic group contains 1 to 3 selected from O, S, N of heteroatoms.
  • the present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R a1 , R a2 , R 3a , R 3b are each independently selected from H, methyl, ethyl, propyl base, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl, the methyl, Ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl optionally further Substituted with 0, 1, 2, 3 or 4 substituents selected from H, halogen, CF3 , OH,
  • R 3a and R 3b are each independently selected from H, methyl, ethyl, propyl, isopropyl, Butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl, the methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl optionally further modified by 0, 1, 2 , 3 or 4 substituents selected from H, F, CF 3 , OH, cyano, COOH, methyl, ethyl, is
  • the present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 5 is selected from
  • the present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 5 is selected from
  • the present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 5 is selected from
  • the present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 5 is selected from
  • the present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 5 is selected from
  • the present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 5 is selected from
  • the present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 5 is selected from
  • the present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 5 is selected from
  • the present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 5 is selected from
  • the present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 5 is selected from
  • the present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 5 is selected from
  • the present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 5 is selected from
  • the present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 5 is selected from
  • the present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 5 is selected from
  • R 5b and R 5c can form a chemical bond.
  • the present invention relates to some embodiments of the compounds represented by the general formulae (I), (Ia) and (Ib), R 5d and R 5e together with their directly connected nitrogen atoms form a 4- to 8-membered heterocyclic group, the heterocyclic ring
  • the heterocyclyl group contains 1, 2 or 3 heteroatoms selected from O, S and N.
  • R 5a , R 5b and R 5c are each independently selected from H, F, Cl, Br, I, cyano , methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, oxetanyl, pyrrolidinyl or piperidinyl, said methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, ring Butyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl are optionally further selected by 0,
  • the present invention relates to some embodiments of the compounds represented by the general formulae (I), (Ia) and (Ib), R 5d and R 5e together with their directly connected nitrogen atoms form azetidine, pyrrolyl, pyrrolidinyl , piperazinyl, piperidinyl, morpholinyl or thiomorpholinyl, said azetidine, pyrrolyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl or thiomorpholine
  • R 5f is selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, the alkane
  • R 5f is selected from H or one of the following substituted or unsubstituted groups: methyl, ethyl, propyl Base, Butyl, Isopropyl, Isobutyl, Azacyclobutyl, Azacyclopentyl, Azacyclohexyl, Piperazinyl, Oxetanyl, Oxolatyl, Oxane Hexyl, morpholinyl, -CH 2 -azetidinyl, -CH 2 -azepanyl, -CH 2 -azepinyl, -CH 2 -piperazine, -CH 2 -oxa Cyclobutyl, -CH 2 -oxolane, -CH 2 -oxane, -CH 2 -morpholine, -CH 2 CH 2 -azetidinyl, -
  • R 5f is selected from H, C 1-4 alkyl or C 3-6 cycloalkyl, the alkane
  • R 5f is selected from H, methyl, ethyl,
  • n and s are selected from 0, 1 or 2.
  • m, p and q are each independently selected from 0, 1, 2, 3 or 4.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising any of the above compounds or their stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, and a pharmaceutically acceptable carrier.
  • the present invention relates to the use of any of the above-mentioned compounds or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof for the preparation of a medicament for prophylaxis or In drugs for treating diseases related to JAK3 kinase activity or expression level.
  • the disease is selected from immune system related diseases.
  • the disease is selected from rheumatoid arthritis (RA), inflammatory bowel disease, Crohn's disease.
  • RA rheumatoid arthritis
  • Crohn's disease rheumatoid arthritis
  • the present invention provides a method of preventing or treating a disease associated with JAK kinase activity or expression level, such as those described above, comprising the steps of: adding a preventive or therapeutically effective amount of the The compound, or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, or a pharmaceutical composition thereof, is administered to an individual in need thereof.
  • the term "individual” refers to a human or non-human animal.
  • references and monographs in the field detail the synthesis of reactants useful in the preparation of the compounds described herein, or provide references for articles describing such preparations. These references and monographs include: “Synthetic Organic Chemistry,” John Wiley & Sons, Inc., New York; SRSandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; HOHouse, “Modern Synthetic Reactions", 2nd Ed., WA Benjamin, Inc. Menlo Park, Calif. 1972; TLGilchrist, “Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J.
  • R 10 is selected from halogen or OH
  • R 11 is selected from halogen, preferably from Br, Cl;
  • R 12 is selected from amino protecting group or H
  • PG 1 is selected from amino protecting groups
  • the compound of general formula (Ia-1) is obtained by nucleophilic substitution reaction or coupling reaction to obtain the compound of general formula (Ia-2);
  • the compound of general formula (Ia-2) is obtained by coupling reaction to obtain the compound of general formula (Ia-3); or the compound of general formula (Ia-2) is obtained by coupling reaction first, and then by removing the hydroxyl protecting group to obtain the compound of general formula (Ia- 3) Compounds;
  • the compound of general formula (Ia-3) is obtained by removing the amino protecting group to obtain the compound of general formula (Ia-4);
  • the compound of general formula (Ia-4) can be obtained by condensation reaction or nucleophilic substitution reaction to obtain the compound of general formula (I).
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention all include their isotopic conditions, and the carbons involved in the groups and compounds of the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein isotopes of carbon include 12 C, 13 C and 14 C, and isotopes of hydrogen include protium (H), deuterium (D, Also known as heavy hydrogen), tritium (T, also known as super-heavy hydrogen), the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, and the isotopes of nitrogen include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
  • isotopes of carbon include 12 C, 13 C
  • Halogen means F, Cl, Br or I.
  • Alkyl refers to a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, even more preferably is an alkyl group of 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and its various branched chain isomers; the alkyl group can be optionally further selected from 0 to 6 groups selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, Amido, alkenyl, alkynyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, 3- to 8-membered carbocyclyl, 3- to 8-membered heterocyclyl, 3- to Substituents substituted by 8-membered carbocyclyloxy, 3- to 8-membered heterocyclyloxy, carboxyl or carboxylate groups
  • Alkylene refers to linear and branched divalent saturated hydrocarbon groups, including -(CH 2 ) v - (v is an integer from 1 to 10).
  • alkylene include but are not limited to methylene, methylene Ethyl, propylene and butylene, etc.; the alkylene group can be optionally further selected from 0 to 5 groups selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, alkyl Substituted by amino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate substituents . Alkylene groups appearing herein are defined in accordance with this definition.
  • Cycloalkyl refers to a monovalent saturated carbocyclic hydrocarbon group, usually having 3 to 10 carbon atoms, non-limiting examples including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, and the like.
  • the cycloalkyl group can be optionally further selected from 0 to 5 groups selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, Substituents of hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate. Cycloalkyl groups appearing herein are as defined above.
  • alkenyl refers to linear and branched monovalent unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon double bonds, and the main chain includes 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms in the backbone
  • alkenyl groups include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl , 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2- Methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-Methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-he
  • Alkynyl refers to linear and branched monovalent unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, and the main chain includes 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms in the backbone
  • alkynyl groups include, but are not limited to, ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl Alkynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-Methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl base,
  • Alkoxy refers to -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyl oxy and cyclobutoxy.
  • the alkoxy group can be optionally further selected from 0 to 5 groups selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, Substituents of hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate. Alkoxy groups appearing herein are defined in accordance with this definition.
  • Carbocyclyl or “carbocycle” refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which may be a 3- to 8-membered monocyclic, 4- to 12-membered A bicyclic or 10- to 15-membered tricyclic ring system, the carbocyclic group can be attached to an aromatic ring or a non-aromatic ring, and the aromatic or non-aromatic ring is optionally monocyclic, bridged or spirocyclic.
  • Heterocyclyl or “heterocycle” refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring
  • the aromatic or non-aromatic ring may be a 3- to 8-membered monocyclic, 4- to 12-membered Bicyclic or 10- to 15-membered tricyclic ring system, and contains 1 to 3 heteroatoms selected from N, O or S, preferably a 3- to 8-membered heterocyclic group, the N, S optionally substituted in the ring of the heterocyclic group can be oxidized into various oxidation states.
  • the heterocyclyl group can be attached to a heteroatom or a carbon atom, the heterocyclyl group can be attached to an aromatic ring or a non-aromatic ring, the heterocyclyl group can be attached to a bridged ring or a spiro ring, non-limiting examples include oxirane , azetidine, oxetanyl, azetidine, 1,3-dioxolane, 1,4-dioxolane, 1,3-dioxanyl, nitrogen Heterocycloheptyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpho Linyl, 1,3-Dithiyl, Dihydrofuranyl, Dihydropyranyl, Dithiopenyl
  • R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro, or bicyclyl.
  • the spiro rings appearing herein are defined in accordance with this definition.
  • Paracyclic refers to a polycyclic group in which each ring in a system shares an adjacent pair of atoms with other rings in the system, wherein one or more rings may contain zero or more double bonds and may be substituted
  • Non-limiting examples include:
  • R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro, or bicyclyl. Conjunctions appearing in this document are defined in accordance with this definition.
  • the ring atoms contain 5 to 20 atoms, preferably 5 to 14 atoms, more preferably 5 to 12 atoms, still more preferably 5 to 10 atoms.
  • Non-limiting examples include and adamantane.
  • R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro, or bicyclyl. Bridged rings appearing herein are defined in accordance with this definition.
  • Carbospiro refers to a “spirocycle” in which the ring system consists of only carbon atoms.
  • Carbospiro refers to a "spirocycle” in which the ring system consists of only carbon atoms.
  • Carbospiro refers to a "spirocycle” in which the ring system consists of only carbon atoms.
  • Carbospiro refers to a "spirocycle” in which the ring system consists of only carbon atoms.
  • Carbospiro refers to a "spirocycle” in which the ring system consists of only carbon atoms.
  • Carbospiro refers to a "spirocycle” in which the ring system consists of only carbon atoms.
  • Carbospiro refers to a "spirocycle” in which the ring system consists of only carbon atoms.
  • Carbospiro refers to a "spirocycle
  • Carbon-bridged ring refers to a “bridged ring” in which the ring system consists only of carbon atoms.
  • “Carbon-bridged ring”, “bridged-ring carbocyclyl”, “bridged carbocyclyl” or “carbon-bridged cyclyl” appearing herein are defined in accordance with this definition.
  • Heterocyclyl refers to a “heterocyclyl” or “heterocycle” of a monocyclic ring system, heterocyclyl, “monocyclic heterocyclyl” appearing herein group” or “heteromonocyclyl”, as defined herein.
  • Heterocyclyl refers to a “heterocyclyl” containing a heteroatom.
  • heterocyclyl refers to a “heterocyclyl” containing a heteroatom.
  • Heterospirocycle refers to a “spirocycle” containing a heteroatom.
  • heterospirocycle refers to a “spirocycle” containing a heteroatom.
  • heterospirocycle refers to a “spirocycle” containing a heteroatom.
  • Heterobridged ring refers to a “bridged ring” containing a heteroatom.
  • a heterobridged ring refers to a “bridged ring” containing a heteroatom.
  • a heterobridged ring refers to a “bridged ring” containing a heteroatom.
  • a heterobridged ring refers to a “bridged ring” containing a heteroatom.
  • R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro, or bicyclyl.
  • Aryl groups or aromatic rings appearing herein are defined in accordance with this definition.
  • heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, Benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, etc.
  • the heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples include
  • R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro, or bicyclyl.
  • Heteroaryl groups appearing herein are defined in accordance with this definition.
  • Constants 1 to 5 heteroatoms selected from O, S, N means containing 1, 2, 3, 4 or 5 heteroatoms selected from O, S, N.
  • Substituted with 0 to X substituents means substituted with 0, 1, 2, 3 . . . X substituents, and X is selected from any integer between 1 and 10.
  • substituted with 0 to 4 substituents means substituted with 0, 1, 2, 3 or 4 substituents.
  • substituted with 0 to 5 substituents means substituted with 0, 1, 2, 3, 4 or 5 substituents.
  • heterobridged ring is optionally further substituted with 0 to 4 substituents selected from H or F” means that the heterobridged ring is optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H or F base substituted.
  • the ring of XY members (X is selected from an integer less than Y and greater than or equal to 3, and Y is selected from any integer between 4 and 12) includes X+1, X+2, X+3, X+4....Y-membered ring ring.
  • Rings include heterocycles, carbocycles, aromatic rings, aryl, heteroaryl, cycloalkyl, heteromonocycles, heterocycles, heterospirocycles, or heterobridged rings.
  • 4--7 membered heteromonocycle refers to a 4-membered, 5-membered, 6-membered or 7-membered heteromonocycle
  • 5--10 membered heterocyclic ring refers to 5-membered, 6-membered, 7-membered, 8-membered , 9- or 10-membered heterocyclic ring.
  • alkyl optionally substituted by F means that the alkyl group may but not necessarily be substituted by F, and the description includes the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.
  • “Pharmaceutically acceptable salt” or “a pharmaceutically acceptable salt thereof” means that a compound of the present invention retains the biological effectiveness and properties of a free acid or free base that is treated with a non-toxic inorganic base or Organic bases, said free bases are salts obtained by reacting with non-toxic inorganic or organic acids.
  • “Pharmaceutical composition” refers to a mixture of one or more of the compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof and other chemical components, wherein “other chemical components” refers to pharmaceutically acceptable Accepted carriers, excipients and/or one or more other therapeutic agents.
  • Carrier refers to a material that is not appreciably irritating to the organism and that does not abrogate the biological activity and properties of the administered compound.
  • Excipient refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound.
  • Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binding agents agent and disintegrant.
  • a “prodrug” refers to a compound of the present invention that can be metabolized in vivo into a biologically active compound.
  • the prodrugs of the present invention are prepared by modifying the amino or carboxyl groups in the compounds of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound.
  • the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.
  • Co-crystal refers to a crystal formed by the combination of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, wherein the pure states of API and CCF are both at room temperature solid, and there is a fixed stoichiometric ratio between the components.
  • a co-crystal is a multicomponent crystal that includes both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between neutral solids and salts or solvates.
  • Animal is meant to include mammals such as humans, companion animals, zoo animals and domestic animals, preferably humans, horses or dogs.
  • Steps refer to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • HPLC HPLC-based high pressure liquid chromatograph
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm-0.20mm, and the specification used for TLC separation and purification products is 0.4mm -0.5mm;
  • the known starting materials of the present invention can be synthesized by using or according to methods known in the art, or can be purchased from Titan Technology, Annagy Chemical, Shanghai Demer, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Bailingwei Technology, etc. company;
  • reaction solution was washed successively with water (30 mL ⁇ 1) and saturated brine (30 mL ⁇ 1), the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 1B, a pale yellow solid (0.647 g), which was directly used for next reaction.
  • trans-4-dimethylaminocrotonate hydrochloride 0.093 g, 0.56 mmol
  • 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt in this order acid (0.216 g, 1.13 mmol)
  • 1-hydroxybenzotriazole 0.098 g, 0.73 mmol
  • N,N-dimethylformamide 40 mL
  • trans-3-Boc aminocyclobutanol 0.5 g, 2.6 mmol
  • triethylamine 0.51 g, 5 mmol
  • dichloromethane 10 mL
  • reaction solution was washed with water (30 mL ⁇ 1) and saturated brine (30 mL ⁇ 1) in turn, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 2B, a crude product, a pale yellow solid (0.67 g), which was used directly with in the next reaction.
  • trans-4-dimethylaminocrotonate hydrochloride 0.093 g, 0.56 mmol
  • 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt in this order acid (0.216 g, 1.13 mmol)
  • 1-hydroxybenzotriazole 0.098 g, 0.73 mmol
  • N,N-dimethylformamide 40 mL
  • reaction solution was washed with water (30 mL ⁇ 1) and saturated brine (30 mL ⁇ 1) in turn, the organic layer was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 3B, a crude product, a pale yellow solid (0.51 g), which was used directly with in the next reaction.
  • Water (50 mL) was added to the reaction solution, then extracted with ethyl acetate (50 mL ⁇ 2), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (PE/EA 3/1) to give 3D as a pale yellow solid (0.66 g, 92% yield).
  • trans-4-dimethylaminocrotonate hydrochloride (0.131 g, 0.79 mmol)
  • 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt in this order acid (0.232 g, 1.22 mmol)
  • 1-hydroxybenzotriazole (0.109 g, 0.81 mmol)
  • N,N-dimethylformamide (20 mL) were added and stirred at room temperature for 10 min.
  • N , N-diisopropylethylamine (0.47 g, 3.65 mmol) was added and stirred at room temperature for 50 minutes.
  • reaction solution was washed successively with water (30 mL ⁇ 1) and saturated brine (30 mL ⁇ 1), the organic layer was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 4B, a pale yellow solid (0.677 g), which was directly used for next reaction.
  • Water (50 mL) was added to the reaction solution, then extracted with ethyl acetate (50 mL ⁇ 2), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (PE/EA 3/1) to give 4D as a pale yellow solid (0.75 g, 98% yield).
  • trans-4-dimethylaminocrotonate hydrochloride 0.161 g, 0.97 mmol
  • 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt in this order acid 0.288 g, 1.5 mmol
  • 1-hydroxybenzotriazole 0.132 g, 1.0 mmol
  • N,N-dimethylformamide 40 mL
  • reaction solution was washed with water (30 mL ⁇ 1) and saturated brine (30 mL ⁇ 1) in turn, the organic layer was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 5B, a pale yellow solid (0.72 g), which was used directly for next reaction.
  • Step 2 N-[1-[(6-Bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxymethyl]-3-bicyclo[1.1.1]pentyl] tert-Butyl carbamate (5C)
  • trans-4-dimethylaminocrotonate hydrochloride (0.047 g, 0.283 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt in this order acid (0.084 g, 0.438 mmol), 1-hydroxybenzotriazole (0.038 g, 0.283 mmol) and N,N-dimethylformamide (40 mL), stir at room temperature for 10 min after addition, add N , N-diisopropylethylamine (0.58 g, 4.5 mmol) was added and stirred at room temperature for 50 minutes.
  • the first step trans-tert-butyl(3-((6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-(tetrahydro-2H-pyran-2 -yl)-1H-indazol-4-yl)oxy)cyclobutyl)carbamate (6A)
  • the second step trans-tert-butyl (3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)- 1H-Indazole-4-ethoxy)cyclobutylcarbamate (6B)
  • the third step trifluoroacetic acid of trans-4-(4-((3-aminocyclobutoxy)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (6C) Salt
  • the first step trans-N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]-N-methyl-carbamic acid tertiary Butyl ester (7A)
  • trans-4-dimethylaminocrotonate hydrochloride (0.024g, 0.145mmol), 6-chlorobenzotriazole-1,1,3,3-tetramethyl Urea hexafluorophosphate (0.071 g, 0.172 mmol) and DMF (10 mL) were added and stirred at room temperature for 30 minutes, then the DMF (5 mL) solution of the residue obtained in the previous step was added, and after the addition was completed, stirred at room temperature for 10 minutes minutes, N,N-diisopropylethylamine (0.102 g, 0.79 mmol) was added, and the mixture was stirred at room temperature for 50 minutes after the addition.
  • reaction solution was washed successively with water (30 mL ⁇ 1) and saturated brine (30 mL ⁇ 1), the organic layer was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 8B, a pale yellow solid (1.17 g), which was used directly for next reaction.
  • trans-4-dimethylaminocrotonate hydrochloride 0.066g, 0.397mmol
  • 6-chlorobenzotriazole-1,1,3,3-tetramethyl Urea hexafluorophosphate 0.194 g, 0.172 mmol
  • DMF 10 mL
  • reaction solution was washed successively with water (30 mL ⁇ 1) and saturated brine (30 mL ⁇ 1), the organic layer was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 9B, a pale yellow solid (1 g), which was directly used in the next step. one-step reaction.
  • trans-4-dimethylaminocrotonate hydrochloride 0.05g, 0.38mmol
  • 6-chlorobenzotriazole-1,1,3,3-tetramethyl Urea hexafluorophosphate 0.194 g, 0.172 mmol
  • DMF 10 mL
  • reaction solution was washed successively with water (30 mL ⁇ 1) and saturated brine (30 mL ⁇ 1), the organic layer was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 10B, a pale yellow solid (0.67 g), which was directly used for next reaction.
  • trans-4-dimethylaminocrotonate hydrochloride (0.146 g, 0.88 mmol)
  • 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt in this order acid 0.335 g, 1.74 mmol
  • 1-hydroxybenzotriazole (0.116 g, 0.86 mmol)
  • N,N-dimethylformamide 40 mL
  • Step 2 N-[(1S,3S)-3-[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-1-tetrahydropyran-2-yl-indazole- tert-Butyl 4-yl]oxycyclopentyl]carbamate (11B)
  • trans-4-dimethylaminocrotonate hydrochloride (0.19 g, 1.15 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in this order acid salt (0.604 g, 3.15 mmol), 1-hydroxybenzotriazole (0.212 g, 1.57 mmol) and N,N-dimethylformamide (40 mL), stir at room temperature for 10 min after addition, add N , N-diisopropylethylamine (0.814 g, 6.3 mmol) was added and stirred at room temperature for 50 minutes.
  • trans-4-dimethylaminocrotonate hydrochloride (0.15 g, 1.17 mmol)
  • 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt in this order acid (0.30 g, 1.56 mmol)
  • 1-hydroxybenzotriazole (0.16 g, 1.17 mmol)
  • N,N-dimethylformamide (10 mL) were added and stirred at room temperature for 10 min.
  • N , N-diisopropylethylamine (0.6 g, 4.68 mmol) was added and stirred at room temperature for 50 minutes.
  • tert-butyl trans-(3-hydroxycyclobutyl)carbamate 224.5 mg, 1.2 mmol
  • DMF 5 mL
  • sodium hydrogen 48 mg, 60 wt% was added under ice-water cooling.
  • 1.6 mmol the reaction was stirred at room temperature for 30 minutes after the addition; cooled with ice water, a DMF solution (5 mL) of 13E (215 mg, 1 mmol) was added dropwise, and the reaction was stirred at room temperature for 3 hours.
  • the completion of the reaction was monitored by TLC, ethyl acetate (100 mL) and water (100 mL) were added, and the layers were separated.
  • the seventh step trans-tert-butyl(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy )cyclobutyl)carbamate (13H)
  • the eighth step trans-4-(8-((3-aminocyclobutoxy)imidazo[1,5-a]pyridin-6-yl)-5-ethyl-2-fluorophenol (13I) Trifluoroacetate
  • N,N-diisopropylethylamine (101mg, 0.78mmol) is dissolved in 1mL N,N-dimethylformamide and added dropwise to the above reaction
  • the solution was stirred at 0°C for 3h, quenched with saturated sodium bicarbonate solution (5mL), extracted with ethyl acetate (20*3mL), concentrated under reduced pressure, and the residue was prepared by preparative liquid phase (instrument: waters 2767; chromatographic column) : SunFire@Prep C18 (19mm ⁇ 150mm); mobile phase composition: mobile phase A: acetonitrile mobile phase B: water (containing 5 mM ammonium acetate)) separation and purification to obtain compound 13 (6.8 mg, yield 13.3%).
  • the first step trans-tert-butyl (3-((6-(4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)carbamate (14A)
  • Step 2 Trifluoroacetate salt of trans-4-(8-((3-aminocyclobutoxy)imidazo[1,5-a]pyridin-6-yl)phenol (14B)
  • the first step cis-N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]-N-methyl-carbamic acid tertiary Butyl ester (16A)
  • trans-4-dimethylaminocrotonate hydrochloride (0.15g, 0.915mmol)
  • 6-chlorobenzotriazole-1,1,3,3-tetramethyl Urea hexafluorophosphate 0.378 g, 0.915 mmol
  • DMF 10 mL
  • the first step trans-tert-butyl-3-((6-(3-fluoro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole- 4-yl)oxy)cyclobutyl)carbamate (17A)
  • trans-4-dimethylaminocrotonate hydrochloride (0.015 g, 0.117 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt in this order acid (0.030 g, 0.156 mmol), 1-hydroxybenzotriazole (0.016 g, 0.117 mmol) and N,N-dimethylformamide (10 mL) were added and stirred at room temperature for 10 min.
  • N , N-diisopropylethylamine (0.06 g, 0.468 mmol
  • trans-4-dimethylaminocrotonate hydrochloride 0.062 g, 0.37 mmol
  • 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt in this order acid (0.165 g, 0.858 mmol)
  • 1-hydroxybenzotriazole 0.058 g, 0.429 mmol
  • N,N-dimethylformamide 20 mL
  • the first step trans-tert-butyl(3-((((6-(4-hydroxy-2-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indium azol-4-yl)oxy)cyclobutyl)carbamate (19A)
  • trans-4-dimethylaminocrotonate hydrochloride 0.096 g, 0.58 mmol
  • 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt in this order acid salt (0.222 g, 1.156 mmol)
  • 1-hydroxybenzotriazole (0.102 g, 0.75 mmol)
  • N,N-dimethylformamide (20 mL)
  • the first step trans-tert-butyl-3-((6-(2-chloro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole- 4-yl)oxy)cyclobutyl)carbamate (20A)
  • trans-4-dimethylaminocrotonate hydrochloride (0.015 g, 0.117 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt in this order acid (0.030 g, 0.156 mmol), 1-hydroxybenzotriazole (0.016 g, 0.117 mmol) and N,N-dimethylformamide (10 mL) were added and stirred at room temperature for 10 min.
  • N , N-diisopropylethylamine (0.06 g, 0.468 mmol
  • the first step cis-tert-butyl(-3-((6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutane yl) (ethyl) carbamate (21A)
  • Step 2 cis-N-ethyl-N-[3-[(6-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole- 4-yl)oxy]cyclobutyl]carbamate tert-butyl ester (21B)
  • trans-4-dimethylaminocrotonate hydrochloride 0.162g, 0.98mmol
  • DMF 1 drop in a 5mL disposable plastic dropper
  • dichloromethane 3mL
  • dropwise oxalyl chloride 0.25 g, 1.97 mmol
  • add the residue obtained in the previous step in dichloromethane 5 mL
  • N,N-diisopropylethylamine 0.79 g, 6.1 mmol
  • the first step cis-N-[3-[[6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy]cyclobutyl] -N-(Cyclopropylmethyl)carbamate tert-butyl (22A)
  • the reaction solution was concentrated to dryness under reduced pressure, and the residue was washed with MTBE (10 mL ⁇ 3), then concentrated to dryness under reduced pressure, added with dichloromethane (5 mL) and N,N-diisopropylethylamine (0.574 g, 4.44 mmol) and stirred 10 minutes is for the reaction solution I to be used.
  • Trans-4-dimethylaminocrotonate hydrochloride 0.331 g, 2.0 mmol
  • diisopropylethylamine 775 mg, 6.0 mmol, 1.0 mL
  • dichloromethane 9.0 mL
  • acetonitrile 1.0 mL
  • tripyrrolidinophosphonium bromide hexafluorophosphate 0.32 g, 2 mmol
  • reaction intermediate solution II (4.88 mL) was slowly added dropwise to the above-mentioned reaction solution I, and stirred at room temperature for 60 minutes after the addition.
  • the first step trans-tert-butyl(3-((6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl )(2-(dimethylamino)ethyl)carbamate (23A)
  • 2-chloroethyldimethylamine (0.66 g, 6.16 mmol) was added, and the temperature was raised to 50° C.
  • Crotonic acid 0.028 g, 0.32 mmol
  • diisopropylethylamine 83 mg, 0.64 mmol
  • tripyrrolidinophosphonium bromide was added.
  • Fluorophosphate (0.15 g, 0.32 mmol) stirred at room temperature for 20 minutes.
  • the reaction solution was slowly added dropwise to the above-mentioned acetonitrile solution to be used, and stirring was continued for 1 h.
  • the third step hydrochloride of (2E)-3-[((2R)-1-methylpyrrolidin-2-yl]prop-2-enoic acid (25C)
  • the third step hydrochloride of (2E)-3-[((2S)-1-methylpyrrolidin-2-yl]prop-2-enoic acid (26C)
  • Example 28 trans-(E)-N-((3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-4-(pyrrole Alk-1-yl)but-2-enamide; acetate salt (compound 28)
  • the first step hydrochloride of (E)-4-(pyrrolidin-1-yl)but-2-enoic acid (28A)

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Abstract

L'invention concerne un composé représenté par la formule générale (I) ou un stéréoisomère, un deutérium, un solvate, un promédicament, un métabolite et un sel ou co-cristal pharmaceutiquement acceptable de celui-ci, un produit intermédiaire correspondant ainsi qu'un procédé de préparation de ce composé, et une application dans la préparation de médicaments destinés à traiter des maladies liées à l'activité ou à l'expression de la JAK3 kinase.
PCT/CN2021/117545 2020-09-10 2021-09-10 Dérivé d'amide carbocyclique et son application en médecine WO2022053000A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015148867A1 (fr) * 2014-03-28 2015-10-01 Calitor Sciences, Llc Composés hétéroaryle substitués et procédés d'utilisation
CN105837577A (zh) * 2015-02-02 2016-08-10 四川大学 1-(嘧啶-4-基)3-胺基哌啶衍生物及其制备方法和用途
WO2016201370A1 (fr) * 2015-06-12 2016-12-15 Dana-Farber Cancer Institute, Inc. Thérapie d'association utilisant des inhibiteurs de transcription et des inhibiteurs de kinases
CN109843858A (zh) * 2016-08-15 2019-06-04 润新生物公司 某些化学实体、组合物及方法
CN111032646A (zh) * 2017-08-01 2020-04-17 施万生物制药研发Ip有限责任公司 作为jak激酶抑制剂的吡唑并和三唑并双环化合物
WO2020154350A1 (fr) * 2019-01-23 2020-07-30 Theravance Biopharma R&D Ip, Llc Imidazo[1,5-a]pyridine,1,2,4-triazolo[4,3-a]pyridine et imidazo[1,5-a]pyrazine utilisées en tant qu'inhibiteurs de jak

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015148867A1 (fr) * 2014-03-28 2015-10-01 Calitor Sciences, Llc Composés hétéroaryle substitués et procédés d'utilisation
CN105837577A (zh) * 2015-02-02 2016-08-10 四川大学 1-(嘧啶-4-基)3-胺基哌啶衍生物及其制备方法和用途
WO2016201370A1 (fr) * 2015-06-12 2016-12-15 Dana-Farber Cancer Institute, Inc. Thérapie d'association utilisant des inhibiteurs de transcription et des inhibiteurs de kinases
CN109843858A (zh) * 2016-08-15 2019-06-04 润新生物公司 某些化学实体、组合物及方法
CN111032646A (zh) * 2017-08-01 2020-04-17 施万生物制药研发Ip有限责任公司 作为jak激酶抑制剂的吡唑并和三唑并双环化合物
WO2020154350A1 (fr) * 2019-01-23 2020-07-30 Theravance Biopharma R&D Ip, Llc Imidazo[1,5-a]pyridine,1,2,4-triazolo[4,3-a]pyridine et imidazo[1,5-a]pyrazine utilisées en tant qu'inhibiteurs de jak

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