WO2022053000A1 - Carbocyclic amide derivative and application thereof in medicine - Google Patents

Carbocyclic amide derivative and application thereof in medicine Download PDF

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Publication number
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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Prior art keywords
alkyl
cyano
alkoxy
ethyl
methyl
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PCT/CN2021/117545
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French (fr)
Chinese (zh)
Inventor
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/en
Publication of WO2022053000A1 publication Critical patent/WO2022053000A1/en

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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)

Abstract

Provided are a compound of general formula (I) or a stereoisomer, deuterium, solvate, prodrug, metabolite, and pharmaceutically acceptable salt or co-crystal thereof, an intermediate thereof, and a preparation method therefor, and an application in the preparation of drugs for treating diseases related to JAK3 kinase activity or expression.

Description

一种碳环酰胺衍生物及其在医药上的应用A kind of carbocyclic amide derivative and its application in medicine 技术领域technical field
本发明涉及一种通式(I)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，及其中间体和制备方法，以及在制备治疗与JAK3激酶活性或表达量相关疾病的药物中的应用。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.
背景技术Background technique
蛋白激酶是一类胞内信使依赖的、催化特定蛋白磷酸化并完成信号传递过程的酶，主要包括酪氨酸蛋白激酶，如JAKs、Src、Abl、EGFR、FGFR、TOGFR等；丝氨酸/苏氨酸蛋白激酶，如PKC、MAPK、Rho激酶等；双特异性蛋白激酶，如MPKK等以及磷脂酰肌醇激酶，如PI3K。蛋白激酶磷酸化/去磷酸化过程能够调节不同细胞的多种生物学过程，如代谢、细胞分化、细胞存活、细胞凋亡、器官形成、血管生成、免疫应答等(Folia Biol.2006,52,81-100.)。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. 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.).
Janus家族(JAKs)由四个成员组成，包括JAK1、JAK2、JAK3和TYK2。细胞因子通过结合JAK中的受体引发受体的二聚，促使JAK激酶酪氨酸残基的磷酸化，从而使得JAK激活。磷酸化的JAKs激酶进一步结合和磷酸化多种STAT(Signal Transducers and Activators of Transcription)蛋白，诱导其发生二聚、细胞核内溶化，直接调节基因的转录和激活下游疾病信号因子。在先天免疫、炎症和造血生物功能中，JAKs形成了至关重要的信号通路；该通路失调与免疫疾病和癌症会形成关联，因此JAKs是治疗许多疾病适应症的靶标(Immunol.Rev.2008,223,132-142.)。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.).
2012年11月，Pfizer公司的pan-JAKs抑制剂Tofacitinib已获FDA批准用于治疗RA。然而，Tofacitinib具有包括引起红细胞与白细胞数量下降、胆固醇水平上升等副作用，这或许与其具有高JAK2抑制活性相关(J.Med.Chem.2012,55,6176-6193)。因此，各大制药公司等机构的科学家都将目光聚焦于选择性JAK抑制剂的研究与发现上。In November 2012, Pfizer's pan-JAKs inhibitor, Tofacitinib, was approved by the FDA for the treatment of RA. However, 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.
不同于JAK1、JAK2和TYK2广泛分布于人体的多种组织细胞中，JAK3主要分布于骨髓和淋巴系统中，JAK3通过与IL-2、IL-4、IL-7、IL-9、IL-15、IL-21等细胞因子受体复合物中的γ共链(γc)相结合，调节细胞信号传导。基于其功能特点和特殊的组织分布，JAK3成为针对免疫系统相关疾病极具吸引力的药物靶点，其抑制剂在类风湿性关节炎(RA)、炎症肠炎、克罗恩病、系统性红斑狼疮、多发性硬化症、I型糖尿病、银屑病、过敏性疾病、哮喘、慢性阻塞性肺病、白血病、淋巴瘤、器官移植和其它等疾病的治疗/预防方面具有重要的临床应用价值(Trends Pharm Sci.2004,25,558-562)。Unlike JAK1, JAK2 and TYK2, which are widely distributed in various tissues and cells of the human body, JAK3 is mainly distributed in the bone marrow and lymphatic system. , IL-21 and other cytokine receptor complexes combine with the γ co-chain (γc) to regulate cell signaling. Based on its functional characteristics and special tissue distribution, 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).
发明内容SUMMARY OF THE INVENTION
本发明的目的之一在于提供一种能够抑制JAK3激酶的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，及其中间体和制备方法，以及在制备治疗与JAK3活性或表达量相关疾病的药物中的应用。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.
本发明提供一种通式(I)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中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
Figure PCTCN2021117545-appb-000001
Figure PCTCN2021117545-appb-000001
在某些实施方案中，Y 1、Y 2、Y 3各自独立的选自CH或N； In certain embodiments, Y 1 , Y 2 , Y 3 are each independently selected from CH or N;
在某些实施方案中，Y 1、Y 2选自CH，Y 3选自N； In certain embodiments, Y 1 , Y 2 are selected from CH, and Y 3 is selected from N;
在某些实施方案中，Y 1、Y 2、Y 3选自CH； In certain embodiments, Y 1 , Y 2 , Y 3 are selected from CH;
在某些实施方案中，Y 1、Y 2选自N，Y 3选自N； In certain embodiments, Y 1 , Y 2 are selected from N, and Y 3 is selected from N;
在某些实施方案中，Y 1选自N，Y 2选自CH，Y 3选自CH； In certain embodiments, Y 1 is selected from N, Y 2 is selected from CH, and Y 3 is selected from CH;
在某些实施方案中，Y 1选自CH，Y 2选自N，Y 3选自CH； In certain embodiments, Y 1 is selected from CH, Y 2 is selected from N, and Y 3 is selected from CH;
在某些实施方案中，Y 1选自CH，Y 2选自N，Y 3选自N； In certain embodiments, Y 1 is selected from CH, Y 2 is selected from N, and Y 3 is selected from N;
在某些实施方案中，环A选自5至6元杂环或杂芳环，所述的杂环或杂芳环任选进一步被0、1、2或3个R a取代基所取代，所述的杂环或杂芳环含有1、2、3或4个选自O、S、N的杂原子； In certain embodiments, 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;
在某些实施方案中，
Figure PCTCN2021117545-appb-000002
选自
Figure PCTCN2021117545-appb-000003
In certain embodiments,
Figure PCTCN2021117545-appb-000002
selected from
Figure PCTCN2021117545-appb-000003
在某些实施方案中，
Figure PCTCN2021117545-appb-000004
选自
Figure PCTCN2021117545-appb-000005
X 1选自N或CR a； In certain embodiments,
Figure PCTCN2021117545-appb-000004
selected from
Figure PCTCN2021117545-appb-000005
X 1 is selected from N or CR a ;
在某些实施方案中，
Figure PCTCN2021117545-appb-000006
选自
Figure PCTCN2021117545-appb-000007
In certain embodiments,
Figure PCTCN2021117545-appb-000006
selected from
Figure PCTCN2021117545-appb-000007
在某些实施方案中，
Figure PCTCN2021117545-appb-000008
选自
Figure PCTCN2021117545-appb-000009
In certain embodiments,
Figure PCTCN2021117545-appb-000008
selected from
Figure PCTCN2021117545-appb-000009
在某些实施方案中，R a各自独立的选自H、＝O、卤素、氰基、C 1-6烷基、C 1-6烷氧基、-(CH 2) q-C(＝O)-NR a1R a2、-(CH 2) q-NR a1R a2、-(CH 2) qNR a1C(＝O)-R a2、-(CH 2) q-C 3-10碳环或-(CH 2) q-3至12元杂环，所述的CH 2、烷基、烷氧基、碳环或杂环任选进一步被0、1、2、3或4个选自H、卤素、CF 3、OH、氰基、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环含有1、2或3个选自O、S、N的杂原子； In certain embodiments, each R a is independently selected from H, =O, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, -(CH 2 ) q -C(=O )-NR a1 R a2 , -(CH 2 ) q -NR a1 R a2 , -(CH 2 ) q NR a1 C(=O)-R a2 , -(CH 2 ) q -C 3-10 carbocyclic or -(CH 2 ) q -3- to 12-membered heterocycle, said CH 2 , alkyl, alkoxy, carbocycle or heterocycle is optionally further selected from 0, 1, 2, 3 or 4 by H, Halogen, CF 3 , OH, cyano, COOH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy substituent, the heterocycle contains 1, 2 or 3 selected from O , S, N heteroatoms;
在某些实施方案中，R a选自H、卤素、氰基、C 1-4烷基、C 1-4烷氧基、-(CH 2) q-C(＝O)-NR a1R a2、-(CH 2) q-NR a1R a2、-(CH 2) qNR a1C(＝O)-R a2、-(CH 2) q-C 3-6碳环或-(CH 2) q-3至6元杂环，所述的CH 2、烷基、烷氧基、碳环或杂环任选进一步被0、1、2、3或4个选自H、卤素、CF 3、OH、氰基、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环含有1、2或3个选自O、S、N的杂原子； In certain embodiments, R a is selected from H, halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, -(CH 2 ) q -C(=O)-NR a1 R a2 , -(CH 2 ) q -NR a1 R a2 , -(CH 2 ) q NR a1 C(=O)-R a2 , -(CH 2 ) q -C 3-6 carbocyclic or -(CH 2 ) q -3- to 6-membered heterocycle, said CH2 , alkyl, alkoxy, carbocycle or heterocycle is optionally further selected from 0, 1, 2, 3 or 4 by 0, 1, 2, 3 or 4 selected from H, halogen, CF3 , OH , cyano, COOH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy substituents, the heterocycle contains 1, 2 or 3 heterocycles selected from O, S, N atom;
在某些实施方案中，R a选自H、F、Cl、Br、I、氰基、甲基、乙基、异丙基、丙基、甲氧基、乙氧基、丙氧基、-(CH 2) q-C(＝O)-NR a1R a2、-(CH 2) q-NR a1R a2、-(CH 2) qNR a1C(＝O)-R a2、环丙基、环丁基、环戊基、环己基、-CH 2-环丙基、-CH 2-环丁基、-CH 2-环戊基或-CH 2-环己基，所述的CH 2、甲基、乙基、异丙基、丙基、甲氧基、乙氧基、丙氧基、环丙基、环丁基或环戊基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、OH、氰基、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； In certain embodiments, Ra is selected from H, F, Cl, Br, I, cyano, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, - (CH 2 ) q -C(=O)-NR a1 R a2 , -(CH 2 ) q -NR a1 R a2 , -(CH 2 ) q NR a1 C(=O)-R a2 , cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl or -CH 2 -cyclohexyl, said CH 2 , methyl , ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl or cyclopentyl optionally further selected from 0, 1, 2, 3 or 4 H, halogen, CF 3 , OH, cyano, COOH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy substituent;
在某些实施方案中，R a选自H、F、Cl、氰基、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 2CH 3、-C(O)N(CH 2CH 3) 2、-C(O)NHCH 2CH 2OCH 3、-C(O)NH-环丙基、-C(O)NH-环丁基、-C(O)NH-环戊基、-C(O)NH-环已基、-NHC(O)CH 3、-NHC(O)CH 2CH 3、-NHC(O)-环丙基、-NHC(O)-环丁基、-NHC(O)-环戊基、-NHC(O)-环已基、环丙基、环丁基、环戊基、环己基、-CH 2-环丙基、-CH 2-环丁基、-CH 2-环戊基或-CH 2-环己基； In certain embodiments, 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)-cyclohexyl , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2 -cyclopropyl, -CH2 -cyclobutyl, -CH2 -cyclopentyl or -CH2 -cyclohexyl;
在某些实施方案中，R a选自H； In certain embodiments, Ra is selected from H;
在某些实施方案中，环B选自C 3-10碳环，所述的碳环任选进一步被0、1、2、3或4个R b取代； In certain embodiments, Ring B is selected from C 3-10 carbocycles optionally further substituted with 0, 1, 2, 3 or 4 R b ;
在某些实施方案中，环B选自C 3-6饱和或不饱和单环碳环、C 5-10饱和或不饱和螺环碳环、C 5-10饱和或不饱和并环碳环、C 5-10饱和或不饱和桥环碳环，所述碳环任选进一步被0、1、2、3或4个R b取代； In certain embodiments, 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 ;
在某些实施方案中，环B选自取代或者未取代的如下基团之一：环丙基、环丁基、环戊基、环己基、金刚烷基、双环[1.1.1]戊烷基、双环[2.2.1]庚烷基、立方烷基、双环[3.1.0]己烷基、双环[3.2.0]庚烷基、环戊基并环戊基、双环[4.2.0]辛烷基、双环[2.2.2]辛烷 基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环己基，当被取代时，任选进一步被0、1、2、3或4个R b取代； In certain embodiments, 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 ;
在某些实施方案中，环B选自取代的或者未取代的如下基团之一：
Figure PCTCN2021117545-appb-000010
Figure PCTCN2021117545-appb-000011
Figure PCTCN2021117545-appb-000012
当被取代时，任选进一步被0、1、2、3或4个R b取代，其左侧与L 1相连； In certain embodiments, Ring B is selected from one of the following groups, substituted or unsubstituted:
Figure PCTCN2021117545-appb-000010
Figure PCTCN2021117545-appb-000011
Figure PCTCN2021117545-appb-000012
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 ;
在某些实施方案中，环B选自
Figure PCTCN2021117545-appb-000013
Figure PCTCN2021117545-appb-000014
其左侧与L 1相连； In certain embodiments, Ring B is selected from
Figure PCTCN2021117545-appb-000013
Figure PCTCN2021117545-appb-000014
Its left side is connected to L1 ;
在某些实施方案中，R b各自独立的选自H、卤素、氰基、C 1-6烷基或C 1-6烷氧基，所述的烷基或烷氧基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、OH、氰基、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基或C 3-8环烷基的取代基所取代； In certain embodiments, 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;
在某些实施方案中，R b各自独立的选自H、卤素、氰基、C 1-4烷基或C 1-4烷氧基，所述的烷基或烷氧基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、OH、氰基、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基或C 3-8环烷基的取代基所取代； In certain embodiments, 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;
在某些实施方案中，R b各自独立的选自H、F、Cl、Br、I、氰基、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基或丙氧基，所述的甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基或丙氧基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、OH、氰基、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基所取代； In certain embodiments, 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;
在某些实施方案中，R b各自独立的选自H、F、Cl、Br、I、氰基、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基或丙氧基，所述的甲基、乙基、异丙基、丙基、丁基、 甲氧基、乙氧基或丙氧基任选进一步被0、1、2、3或4个选自H、F、CF 3、OH、氰基、NH 2、-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 2CH 3) 2、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基、丙氧基、环丙基、环丁基或环戊基的取代基所取代； In certain embodiments, 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;
在某些实施方案中，R b各自独立的选自H、F、Cl、氰基、甲基、乙基、异丙基、丙基、甲氧基或乙氧基，所述的甲基、乙基、异丙基、丙基、甲氧基或乙氧基任选进一步被0、1、2、3或4个选自H、F、CF 3、OH、氰基、NH 2、-N(CH 3) 2、-N(CH 2CH 3) 2、甲基、乙基、异丙基、丙基、环丙基或环丁基的取代基所取代； In certain embodiments, 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;
在某些实施方案中，L 1选自键、-S(O) n-、-NR 1a-、-CR 1bR 1c-、-O(CR 1bR 1c) s-、-(CR 1bR 1c) sO-、-NR 1aCR 1bR 1c-、-NR 1aS(O) n-、-S(O) nNR 1a-、-NR 1aC(O)-、-C(O)NR 1a-、-SCR 1bR 1c-或-CR 1bR 1cS-； In certain embodiments, 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-;
在某些实施方案中，L 1选自键、-O-、-S(O) n-、-NR 1a-、-CR 1bR 1c-、-OCR 1bR 1c-、-O(CR 1bR 1c) 2-、-CR 1bR 1cO-、-NR 1aCR 1bR 1c-、-SCR 1bR 1c-或-CR 1bR 1cS-； In certain embodiments, 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-;
在某些实施方案中，L 1选自键、-O-、-S-、-NH-、-CH 2-、-S(O) 2-、-OCH 2-、-OCH(CH 3)-、-OC(CH 3) 2-、-OCH 2CH 2-、-CH 2O-、-NHCH 2-或-N(CH 3)-； In certain embodiments, 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 )-;
在某些实施方案中，L 1选自-O-、-NH-、-OCH 2-、-OC(CH 3) 2-、-CH 2O-或-NHCH 2-； In certain embodiments, L 1 is selected from -O-, -NH-, -OCH 2 -, -OC(CH 3 ) 2 -, -CH 2 O- or -NHCH 2 -;
在某些实施方案中，L 1选自-O-、-OCH 2-、-OC(CH 3) 2-或-CH 2O-； In certain embodiments, L 1 is selected from -O-, -OCH 2 -, -OC(CH 3 ) 2 - or -CH 2 O-;
在某些实施方案中，R 1a、R 1b或R 1c各自独立的选自H、C 1-4烷基或-(CH 2) p-C 3-6碳环，所述的烷基或碳环任选进一步被0、1、2、3或4个选自H、卤素、OH、CF 3、氰基、C 1- 4烷基或C 1-4烷氧基的取代基所取代； In certain embodiments, 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;
在某些实施方案中，R 1b、R 1c与其直接相连的碳原子一起形成3元碳环； In certain embodiments, R 1b , R 1c together with the carbon atoms to which they are directly attached form a 3-membered carbocyclic ring;
在某些实施方案中，
Figure PCTCN2021117545-appb-000015
选自
Figure PCTCN2021117545-appb-000016
Figure PCTCN2021117545-appb-000017
X 1选自N或CR a；右侧与L 1直接连接； In certain embodiments,
Figure PCTCN2021117545-appb-000015
selected from
Figure PCTCN2021117545-appb-000016
Figure PCTCN2021117545-appb-000017
X 1 is selected from N or CR a ; the right side is directly connected to L 1 ;
在某些实施方案中，
Figure PCTCN2021117545-appb-000018
选自
Figure PCTCN2021117545-appb-000019
Figure PCTCN2021117545-appb-000020
X 1选自N或CH；右侧与L 1直接连接； In certain embodiments,
Figure PCTCN2021117545-appb-000018
selected from
Figure PCTCN2021117545-appb-000019
Figure PCTCN2021117545-appb-000020
X 1 is selected from N or CH; the right side is directly connected with L 1 ;
在某些实施方案中，
Figure PCTCN2021117545-appb-000021
选自
Figure PCTCN2021117545-appb-000022
Figure PCTCN2021117545-appb-000023
右侧与L 1直接连接； In certain embodiments,
Figure PCTCN2021117545-appb-000021
selected from
Figure PCTCN2021117545-appb-000022
Figure PCTCN2021117545-appb-000023
The right side is directly connected to L 1 ;
在某些实施方案中，环C选自5-6元杂芳基或苯基，所述的杂芳基或苯基任选进一步被0、1、2、3或4个R c取代； In certain embodiments, Ring C is selected from 5-6 membered heteroaryl or phenyl optionally further substituted with 0, 1, 2, 3 or 4 R c ;
在某些实施方案中，环C选自吡啶，所述的吡啶任选进一步被0、1、2或3个R c取代； In certain embodiments, Ring C is selected from pyridine optionally further substituted with 0, 1, 2 or 3 R c ;
在某些实施方案中，
Figure PCTCN2021117545-appb-000024
选自
Figure PCTCN2021117545-appb-000025
In certain embodiments,
Figure PCTCN2021117545-appb-000024
selected from
Figure PCTCN2021117545-appb-000025
在某些实施方案中，R c各自独立的选自H、卤素、OH、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、-(CH 2) m-C(＝O)-NR 3aR 3b、-(CH 2) m-NR 3aR 3b、-(CH 2) mNR 3aC(＝O)-R 3b、-(CH 2) m-C(＝O)R 3a、-(CH 2) m-C(＝O)OR 3a、-(CH 2) m-OC(＝O)R 3a、-(CH 2) m-3至12元杂环基或-(CH 2) m-C 3-10碳环基，所述的CH 2、烷基、烯基、炔基、烷氧基、碳环或杂环任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、-C 1-4亚烷基-羟基、C 3-6碳环基或3至8元杂环基的取代基所取代，所述的杂环基含有1、2或3个选自O、S、N的杂原子； In certain embodiments, each R c is independently selected from H, halogen, OH, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy base, -(CH 2 ) m -C(=O)-NR 3a R 3b , -(CH 2 ) m -NR 3a R 3b , -(CH 2 ) m NR 3a C(=O)-R 3b , - (CH 2 ) m -C(=O)R 3a , -(CH 2 ) m -C(=O)OR 3a , -(CH 2 ) m -OC(=O)R 3a , -(CH 2 ) m -3- to 12-membered heterocyclyl or -(CH 2 ) m -C 3-10 carbocyclyl, said CH 2 , alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle are optional is further selected from H, halogen, CF3 , =O, OH, cyano, COOH, NH2 , -NH( C1-4 alkyl), -N( C1 Substitution of -4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, -C 1-4 alkylene-hydroxy, C 3-6 carbocyclyl or 3- to 8-membered heterocyclyl The heterocyclic group contains 1, 2 or 3 heteroatoms selected from O, S, N;
在某些实施方案中，R c各自独立的选自R 1、R 2、R 3或R 4； In certain embodiments, each R c is independently selected from R 1 , R 2 , R 3 or R 4 ;
在某些实施方案中，R 1、R 2、R 3、R 4各自独立的选自H、卤素、OH、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、-(CH 2) m-C(＝O)-NR 3aR 3b、-(CH 2) m-NR 3aR 3b、- (CH 2) mNR 3aC(＝O)-R 3b、-(CH 2) m-C(＝O)R 3a、-(CH 2) m-C(＝O)OR 3a、-(CH 2) m-OC(＝O)R 3a、-(CH 2) m-3至12元杂环基或-(CH 2) m-C 3-10碳环基，所述的CH 2、烷基、烯基、炔基、烷氧基、碳环或杂环任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、-C 1-4亚烷基-羟基、C 3-6碳环基或3至8元杂环基的取代基所取代，所述的杂环基含有1、2或3个选自O、S、N的杂原子； In certain embodiments, R 1 , R 2 , R 3 , R 4 are each independently selected from H, halogen, OH, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, C 1-6 alkoxy, -(CH 2 ) m -C(=O)-NR 3a R 3b , -(CH 2 ) m -NR 3a R 3b , -(CH 2 ) m NR 3a C (=O)-R 3b , -(CH 2 ) m -C(=O)R 3a , -(CH 2 ) m -C(=O)OR 3a , -(CH 2 ) m -OC(=O) R 3a , -(CH 2 ) m -3- to 12-membered heterocyclyl or -(CH 2 ) m -C 3-10 carbocyclyl, said CH 2 , alkyl, alkenyl, alkynyl, alkoxy The radical, carbocycle or heterocycle is optionally further selected by 0, 1, 2, 3 or 4 groups selected from H, halogen, CF3 , =O, OH, cyano, COOH, NH2 , -NH( C1-4 alkyl), -N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, -C 1-4 alkylene-hydroxy, C 3-6 carbocyclyl or substituted by the substituents of 3- to 8-membered heterocyclic groups containing 1, 2 or 3 heteroatoms selected from O, S, N;
在某些实施方案中，R 1、R 2、R 3、R 4各自独立的选自H、卤素、OH、氰基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、-(CH 2) m-C(＝O)-NR 3aR 3b、-(CH 2) m-NR 3aR 3b、-(CH 2) mNR 3aC(＝O)-R 3b、-(CH 2) m-C(＝O)R 3a、-(CH 2) m-C(＝O)OR 3a、-(CH 2) m-OC(＝O)R 3a、-(CH 2) m-3至10元杂环或-(CH 2) m-C 3-8碳环，所述的CH 2、烷基、烯基、炔基、烷氧基、碳环或杂环任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、-C 1-4亚烷基-羟基、C 3-6环烷基或3至8元杂环基的取代基所取代，所述的杂环含有1、2或3个选自O、S、N的杂原子； In certain embodiments, R 1 , R 2 , R 3 , R 4 are each independently selected from H, halogen, OH, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 1-4 alkoxy, -(CH 2 ) m -C(=O)-NR 3a R 3b , -(CH 2 ) m -NR 3a R 3b , -(CH 2 ) m NR 3a C (=O)-R 3b , -(CH 2 ) m -C(=O)R 3a , -(CH 2 ) m -C(=O)OR 3a , -(CH 2 ) m -OC(=O) R 3a , -(CH 2 ) m -3- to 10-membered heterocycle or -(CH 2 ) m -C 3-8 carbocycle, said CH 2 , alkyl, alkenyl, alkynyl, alkoxy, The carbocycle or heterocycle is optionally further selected by 0, 1, 2, 3 or 4 from H, halogen, CF3 , =O, OH, cyano, COOH, NH2 , -NH( C1-4alkyl ), -N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, -C 1-4 alkylene-hydroxy, C 3-6 cycloalkyl or 3 to 8-membered heterocyclic group is substituted by the substituent, the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from O, S, N;
在某些实施方案中，R 1、R 2、R 3、R 4各自独立的选自H、F、Cl、Br、I、OH、氰基、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基、丙氧基、乙烯基、丙烯基、乙炔基、丙炔基、-(CH 2) m-C(＝O)-NR 3aR 3b、-(CH 2) m-NR 3aR 3b、-(CH 2) mNR 3aC(＝O)-R 3b、-(CH 2) m-环丙基、-(CH 2) m-环丁基、-(CH 2) m-环戊基、-(CH 2) m-环己基、-(CH 2) m-氮杂环丁基、-(CH 2) m-氧杂环丁基、-(CH 2) m-吡咯烷基、-(CH 2) m-四氢呋喃基、-(CH 2) m-哌啶基、-(CH 2) m-四氢吡喃基、-(CH 2) m-吗啉基、-(CH 2) m-哌嗪基或-(CH 2) m-氮杂环庚基，所述的CH 2、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基、丙氧基、环丙基、乙烯基、丙烯基、乙炔基、丙炔基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、四氢吡喃基、吗啉基、哌嗪基或氮杂环庚基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、-C 1-4亚烷基-羟基、C 3-6环烷基或3至8元杂环基的取代基所取代，所述的杂环含有1、2或3个选自O、S、N的杂原子； In certain embodiments, R 1 , R 2 , R 3 , R 4 are each independently selected from H, F, Cl, Br, I, OH, cyano, methyl, ethyl, isopropyl, propyl , butyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, -(CH 2 ) m -C(=O)-NR 3a R 3b , -(CH 2 ) m -NR 3a R 3b , -(CH 2 ) m NR 3a C(=O)-R 3b , -(CH 2 ) m -cyclopropyl, -(CH 2 ) m -cyclobutyl, -( CH 2 ) m -cyclopentyl, -(CH 2 ) m -cyclohexyl, -(CH 2 ) m -azetidinyl, -(CH 2 ) m -oxetanyl, -(CH 2 ) m -pyrrolidinyl, -( CH2 ) m -tetrahydrofuranyl, -( CH2 ) m -piperidinyl, -( CH2 ) m -tetrahydropyranyl, -( CH2 ) m -morpholinyl , -(CH 2 ) m -piperazinyl or -(CH 2 ) m -azepanyl, said CH 2 , methyl, ethyl, isopropyl, propyl, butyl, methoxy , ethoxy, propoxy, cyclopropyl, vinyl, propenyl, ethynyl, propynyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrole Alkyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl or azepanyl optionally further selected by 0, 1, 2, 3 or 4 selected from H, halogen, CF 3 , =O, OH, cyano, COOH, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkane Oxygen, -C 1-4 alkylene-hydroxy, C 3-6 cycloalkyl or 3- to 8-membered heterocyclic group containing 1, 2 or 3 substituents selected from O , S, N heteroatoms;
在某些实施方案中，R 1、R 2、R 3各自独立的选自H、F、Cl、Br、I、OH、氰基、-(CH 2) m-C(＝O)-NR 3aR 3b、-(CH 2) m-NR 3aR 3b、-(CH 2) mNR 3aC(＝O)-R 3b、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基或丙氧基，所述的CH 2、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基或丙氧基任选进一步被0、1、2、3或4个选自H、F、CF 3、OH、氰基、 COOH、NH 2、-NHCH 3、-N(CH 3) 2、甲基、乙基、异丙基、丙基、乙炔基、甲氧基、乙氧基、丙氧基、-CH 2OH或-CH 2CH 2OH的取代基所取代； In certain embodiments, R 1 , R 2 , R 3 are each independently selected from H, F, Cl, Br, I, OH, cyano, -(CH 2 ) m -C(=O)-NR 3a R 3b , -(CH 2 ) m -NR 3a R 3b , -(CH 2 ) m NR 3a C(=O)-R 3b , methyl, ethyl, isopropyl, propyl, butyl, methoxy group, ethoxy or propoxy, the CH 2 , methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy are optionally further substituted by 0, 1 , 2, 3 or 4 selected from H, F, CF3 , OH, cyano, COOH, NH2 , -NHCH3, -N( CH3 )2 , methyl, ethyl, isopropyl, propyl , ethynyl, methoxy, ethoxy, propoxy, -CH 2 OH or -CH 2 CH 2 OH substituents;
在某些实施方案中，R 4选自H、F、Cl、Br、I、OH、氰基、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基、丙氧基、乙烯基、丙烯基、乙炔基、丙炔基、-(CH 2) m-C(＝O)-NR 3aR 3b、-(CH 2) m-NR 3aR 3b、-(CH 2) mNR 3aC(＝O)-R 3b、-(CH 2) m-环丙基、-(CH 2) m-环丁基、-(CH 2) m-环戊基、-(CH 2) m-环己基、-(CH 2) m-氮杂环丁基、-(CH 2) m-氧杂环丁基、-(CH 2) m-吡咯烷基、-(CH 2) m-四氢呋喃基、-(CH 2) m-哌啶基、-(CH 2) m-四氢吡喃基、-(CH 2) m-吗啉基、-(CH 2) m-哌嗪基或-(CH 2) m-氮杂环庚基，所述的CH 2、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基、丙氧基、环丙基、乙烯基、丙烯基、乙炔基、丙炔基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、四氢吡喃基、吗啉基、哌嗪基或氮杂环庚基任选进一步被0、1、2、3或4个选自H、F、＝O、OH、氰基、CF 3、COOH、NH 2、-NHCH 3、-N(CH 3) 2、甲基、乙基、异丙基、丙基、甲氧基、乙氧基、丙氧基、-CH 2OH、-CH 2CH 2OH、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、四氢吡喃基、吗啉基、哌嗪基或氮杂环庚基所取代； In certain embodiments, R4 is selected from H, F, Cl, Br, I, OH, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, Propoxy, vinyl, propenyl, ethynyl, propynyl, -(CH 2 ) m -C(=O)-NR 3a R 3b , -(CH 2 ) m -NR 3a R 3b , -(CH 2 ) m NR 3a C(=O)-R 3b , -(CH 2 ) m -cyclopropyl, -(CH 2 ) m -cyclobutyl, -(CH 2 ) m -cyclopentyl, -(CH 2 ) m -cyclohexyl, -(CH 2 ) m -azetidinyl, -(CH 2 ) m -oxetanyl, -(CH 2 ) m -pyrrolidinyl, -(CH 2 ) m -tetrahydrofuranyl, -( CH2 ) m -piperidinyl, -( CH2 ) m -tetrahydropyranyl, -( CH2 ) m -morpholinyl, -( CH2 ) m -piperazinyl or -(CH 2 ) m -azepanyl, said CH 2 , methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl , vinyl, propenyl, ethynyl, propynyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydro pyranyl, morpholinyl, piperazinyl or azepanyl optionally further selected from 0, 1, 2, 3 or 4 groups selected from H, F, =O, OH, cyano, CF3 , COOH, NH 2 , -NHCH 3 , -N(CH 3 ) 2 , methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, -CH 2 OH, -CH 2 CH 2 OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, substituted with piperazinyl or azepanyl;
在某些实施方案中，R 1、R 2各自独立的选自H、F、Cl、OH、CF 3、氰基、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基或丙氧基； In certain embodiments, 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;
在某些实施方案中，R 3选自H、F、Cl、OH、CF 3、-CN、-CH 2CN、-CH 2CH 2CN、NH 2、-N(CH 3) 2、-N(CH 2CH 3) 2、-C(O)NH 2、-CH 2C(O)NH 2、-C(O)NHCH 3、-NHC(O)CH 3、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基或丙氧基； In certain embodiments, 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;
在某些实施方案中，R 4选自H、F、OH、CF 3、NH 2、-CN、-CH 2CN、-CH 2CH 2CN、-NHCH 3、-N(CH 3) 2、-C(O)-NH 2、-CH 2C(O)-NH 2、-CH 2CH 2C(O)-NH 2、-C(O)NHCH 3、-C(O)N(CH 3) 2、-NHC(O)CH 3、甲基、乙基、异丙基、丙基、甲氧基、乙氧基、丙氧基、环丙基、-CH 2-环丙基、环丁基、-CH 2-环丁基、环戊基、-CH 2-环戊基、环己基、-CH 2-环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、四氢吡喃基、吗啉基或哌嗪基； In certain embodiments, 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, azetidine, oxetanyl, pyrrolidinyl, tetrahydrofuranyl , piperidinyl, tetrahydropyranyl, morpholinyl or piperazinyl;
在某些实施方案中，R 1选自H、F、Cl、氰基、CF 3、甲基、乙基或甲氧基； In certain embodiments, R 1 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl, or methoxy;
在某些实施方案中，R 2选自H、F、Cl、氰基、CF 3、甲基、乙基或甲氧基； In certain embodiments, R 2 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl, or methoxy;
在某些实施方案中，R 3选自H、F、Cl、氰基、CF 3、甲基、乙基或甲氧基； In certain embodiments, R3 is selected from H, F, Cl, cyano, CF3 , methyl, ethyl, or methoxy;
在某些实施方案中，R 4选自H、F、Cl、氰基、CF 3、甲基、乙基或甲氧基； In certain embodiments, R4 is selected from H, F, Cl, cyano, CF3 , methyl, ethyl, or methoxy;
在某些实施方案中，R a1、R a2、R 3a、R 3b各自独立的选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-12碳环基或3至12元杂环基，所述的烷基、烯基、炔基、烷氧基、碳环基或杂环基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、OH、氰基、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环基含有1、2或3个选自O、S、N的杂原子； In certain embodiments, 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;
在某些实施方案中，R a1、R a2、R 3a、R 3b各自独立的选自H、C 1-4烷基、C 3-6碳环基或3至6元杂环基，所述的烷基、碳环基或杂环基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、OH、氰基、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环基含有1、2或3个选自O、S、N的杂原子； In certain embodiments, 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;
在某些实施方案中，R a1、R a2、R 3a、R 3b各自独立的选自H、甲基、乙基、丙基、异丙基、丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基或哌啶基，所述的甲基、乙基、丙基、异丙基、丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基或哌啶基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、OH、氰基、COOH、C 1-4烷基或C 1-4烷氧基的取代基所取代； In certain embodiments, 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. Substituents of OH, cyano, COOH, C 1-4 alkyl or C 1-4 alkoxy are substituted;
在某些实施方案中，R 3a、R 3b各自独立的选自H、甲基、乙基、丙基、异丙基、丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基或哌啶基，所述的甲基、乙基、丙基、异丙基、丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基或哌啶基任选进一步被0、1、2、3或4个选自H、F、CF 3、OH、氰基、COOH、甲基、乙基、异丙基、丙基、甲氧基、乙氧基或丙氧基的取代基所取代； In certain embodiments, 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;
在某些实施方案中，R 5选自
Figure PCTCN2021117545-appb-000026
In certain embodiments, R 5 is selected from
Figure PCTCN2021117545-appb-000026
在某些实施方案中，R 5选自
Figure PCTCN2021117545-appb-000027
In certain embodiments, R 5 is selected from
Figure PCTCN2021117545-appb-000027
在某些实施方案中，R 5选自
Figure PCTCN2021117545-appb-000028
Figure PCTCN2021117545-appb-000029
In certain embodiments, R 5 is selected from
Figure PCTCN2021117545-appb-000028
Figure PCTCN2021117545-appb-000029
Figure PCTCN2021117545-appb-000030
Figure PCTCN2021117545-appb-000030
Figure PCTCN2021117545-appb-000031
Figure PCTCN2021117545-appb-000031
Figure PCTCN2021117545-appb-000032
Figure PCTCN2021117545-appb-000032
Figure PCTCN2021117545-appb-000033
Figure PCTCN2021117545-appb-000033
在某些实施方案中，R 5选自
Figure PCTCN2021117545-appb-000034
Figure PCTCN2021117545-appb-000035
In certain embodiments, R 5 is selected from
Figure PCTCN2021117545-appb-000034
Figure PCTCN2021117545-appb-000035
Figure PCTCN2021117545-appb-000036
Figure PCTCN2021117545-appb-000036
在某些实施方案中，R 5选自
Figure PCTCN2021117545-appb-000037
Figure PCTCN2021117545-appb-000038
In certain embodiments, R 5 is selected from
Figure PCTCN2021117545-appb-000037
Figure PCTCN2021117545-appb-000038
在某些实施方案中，R 5选自
Figure PCTCN2021117545-appb-000039
In certain embodiments, R 5 is selected from
Figure PCTCN2021117545-appb-000039
在某些实施方案中，R 5选自
Figure PCTCN2021117545-appb-000040
Figure PCTCN2021117545-appb-000041
In certain embodiments, R 5 is selected from
Figure PCTCN2021117545-appb-000040
Figure PCTCN2021117545-appb-000041
在某些实施方案中，R 5选自
Figure PCTCN2021117545-appb-000042
Figure PCTCN2021117545-appb-000043
In certain embodiments, R 5 is selected from
Figure PCTCN2021117545-appb-000042
Figure PCTCN2021117545-appb-000043
在某些实施方案中，R 5选自
Figure PCTCN2021117545-appb-000044
Figure PCTCN2021117545-appb-000045
In certain embodiments, R 5 is selected from
Figure PCTCN2021117545-appb-000044
Figure PCTCN2021117545-appb-000045
在某些实施方案中，R 5选自
Figure PCTCN2021117545-appb-000046
Figure PCTCN2021117545-appb-000047
In certain embodiments, R 5 is selected from
Figure PCTCN2021117545-appb-000046
Figure PCTCN2021117545-appb-000047
在某些实施方案中，R 5选自
Figure PCTCN2021117545-appb-000048
Figure PCTCN2021117545-appb-000049
In certain embodiments, R 5 is selected from
Figure PCTCN2021117545-appb-000048
Figure PCTCN2021117545-appb-000049
Figure PCTCN2021117545-appb-000050
Figure PCTCN2021117545-appb-000050
在某些实施方案中，R 5选自
Figure PCTCN2021117545-appb-000051
Figure PCTCN2021117545-appb-000052
In certain embodiments, R 5 is selected from
Figure PCTCN2021117545-appb-000051
Figure PCTCN2021117545-appb-000052
Figure PCTCN2021117545-appb-000053
Figure PCTCN2021117545-appb-000053
在某些实施方案中，R 5选自
Figure PCTCN2021117545-appb-000054
Figure PCTCN2021117545-appb-000055
In certain embodiments, R 5 is selected from
Figure PCTCN2021117545-appb-000054
Figure PCTCN2021117545-appb-000055
在某些实施方案中，R 5选自
Figure PCTCN2021117545-appb-000056
Figure PCTCN2021117545-appb-000057
In certain embodiments, R 5 is selected from
Figure PCTCN2021117545-appb-000056
Figure PCTCN2021117545-appb-000057
Figure PCTCN2021117545-appb-000058
Figure PCTCN2021117545-appb-000058
Figure PCTCN2021117545-appb-000059
Figure PCTCN2021117545-appb-000059
在某些实施方案中，R 5a、R 5b、R 5c各自独立的选自H、卤素、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8碳环基或3至10元杂环基，所述的烷基、烷氧基、碳环基或杂环基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3-6环烷基)、C 1-4烷基、C 1-4烷氧基或-SC 1-4烷基的取代基所取代，所述的杂环基含有1、2或3个选自O、S、N的杂原子； In certain embodiments, R 5a , R 5b , R 5c are each independently selected from H, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 carbocyclyl or 3- to 10-membered heterocyclic group, the alkyl, alkoxy, carbocyclic or heterocyclic group is optionally further selected by 0, 1, 2, 3 or 4 selected from H, halogen, CF 3 , =O , OH, cyano, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -NH(C 3-6 cycloalkyl), C 1-4 alkyl , C 1-4 alkoxy or -SC 1-4 alkyl substituent, the heterocyclic group contains 1, 2 or 3 heteroatoms selected from O, S, N;
在某些实施方案中，R 5b与R 5c可形成化学键； In certain embodiments, R 5b and R 5c can form a chemical bond;
在某些实施方案中，R 5d、R 5e各自独立的选自H、C 1-6烷基、C 3-8碳环基或3至10元杂环基，所述的烷基、碳环基或杂环基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3-6环烷基)、C 1-4烷基、C 1-4烷氧基或-SC 1-4烷基的取代基所取代，所述的杂环基含有1、2或3个选自O、S、N的杂原子； In certain embodiments, 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 radical or heterocyclyl is optionally further selected by 0, 1, 2, 3 or 4 selected from H, halogen, CF 3 , =O, OH, cyano, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -NH(C 3-6 cycloalkyl), C 1-4 alkyl, C 1-4 alkoxy or -SC 1-4 alkyl substituent Substituted, the heterocyclyl group contains 1, 2 or 3 heteroatoms selected from O, S, N;
在某些实施方案中，R 5d、R 5e与其直接相连的氮原子一起形成4至8元杂环基，所述杂环基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、C 1-4烷基、C 1-4烷氧基或-C 1-4亚烷基-C 1-4烷氧基的取代基取代，所述杂环基含有1、2或3个选自O、S、N的杂原子； In certain embodiments, R 5d , R 5e together with the nitrogen atom to which they are directly attached form a 4- to 8-membered heterocyclyl group optionally further selected from 0, 1, 2, 3, or 4 H atoms , halogen, CF 3 , =O, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy or -C 1-4 alkylene-C 1-4 alkoxy substituents, The heterocyclyl group contains 1, 2 or 3 heteroatoms selected from O, S, N;
在某些实施方案中，R 5a、R 5b、R 5c各自独立的选自H、卤素、氰基、C 1-4烷基、C 1-4烷氧基、3至6元碳环基或3至8元杂环基，所述的烷基、烷氧基、碳环基或杂环基任选进一步被0、1、2、3或4个选自H、卤素、＝O、OH、氰基、CF 3、C 1-4烷基、C 1-4烷氧基或-SC 1-4烷基的取代基所取代，所述的杂环基含有1、2或3个选自O、S、N的杂原子； In certain embodiments, R 5a , R 5b , R 5c are each independently selected from H, halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, 3- to 6-membered carbocyclyl, or 3- to 8-membered heterocyclyl, the alkyl, alkoxy, carbocyclyl or heterocyclyl is optionally further selected from 0, 1, 2, 3 or 4 groups selected from H, halogen, =O, OH, Substituents of cyano, CF 3 , C 1-4 alkyl, C 1-4 alkoxy or -SC 1-4 alkyl, and the heterocyclic group contains 1, 2 or 3 selected from O , S, N heteroatoms;
在某些实施方案中，R 5d、R 5e各自独立的选自H、C 1-4烷基、3至6元碳环或3至8元杂环，所述的烷基、碳环或杂环任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3-6环烷基)、C 1-4烷基、C 1-4 烷氧基或-SC 1-4烷基的取代基所取代，所述的杂环含有1、2或3个选自O、S、N的杂原子； In certain embodiments, 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 ring is optionally further 0, 1, 2, 3 or 4 selected from H, halogen, CF3 , =O, OH, cyano, NH2 , -NH( C1-4alkyl ), -N(C 1-4 alkyl) 2 , -NH(C 3-6 cycloalkyl), C 1-4 alkyl, C 1-4 alkoxy or -SC 1-4 alkyl substituent, the The heterocyclic ring contains 1, 2 or 3 heteroatoms selected from O, S, N;
在某些实施方案中，R 5d、R 5e与其直接相连的氮原子一起形成4至6元杂环，所述杂环任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、C 1-4烷基、C 1- 4烷氧基或-C 1-4亚烷基-C 1-4烷氧基的取代基取代，所述杂环含有1至3个选自O、S、N的杂原子； In certain embodiments, R 5d , R 5e are taken together with the nitrogen atom to which they are directly attached to form a 4- to 6-membered heterocycle optionally further substituted by 0, 1, 2, 3 or 4 selected from H, halogen , CF 3 , =O, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy or -C 1-4 alkylene-C 1-4 alkoxy substituents, the The heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
在某些实施方案中，R 5a、R 5b、R 5c各自独立的选自H、F、Cl、Br、I、氰基、甲基、乙基、丙基、异丙基、丁基、甲氧基、乙氧基、丙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基或哌啶基，所述的甲基、乙基、丙基、异丙基、丁基、甲氧基、乙氧基、丙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基或哌啶基任选进一步被0、1、2、3或4个选自H、卤素、＝O、OH、氰基、CF 3、C 1-4烷基、C 1-4烷氧基或-SC 1-4烷基的取代基所取代； In certain embodiments, R 5a , R 5b , R 5c are each independently selected from H, F, Cl, Br, I, cyano, methyl, ethyl, propyl, isopropyl, butyl, methyl Oxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl, the methyl , ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxa Cyclobutyl, pyrrolidinyl or piperidinyl is optionally further selected by 0, 1, 2, 3 or 4 from H, halogen, =O, OH, cyano, CF3 , C1-4alkyl , C 1-4 alkoxy or -SC 1-4 alkyl substituent;
在某些实施方案中，R 5d、R 5e各自独立的选自H、甲基、乙基、丙基、异丙基、丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基或吗啉基，所述的甲基、乙基、丙基、异丙基、丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基或吗啉基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3-6环烷基)、C 1-4烷基、C 1-4烷氧基或-SC 1-4烷基的取代基所取代，所述的杂环含有1、2或3个选自O、S、N的杂原子； In certain embodiments, R 5d , R 5e are each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Azetidine, oxetanyl, pyrrolidinyl, piperidinyl or morpholinyl, said methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl a , CF 3 , =O, OH, cyano, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -NH(C 3-6 cycloalkyl), C 1-4 alkyl, C 1-4 alkoxy or -SC 1-4 alkyl substituent, the heterocycle contains 1, 2 or 3 heteroatoms selected from O, S, N ;
在某些实施方案中，R 5d、R 5e与其直接相连的氮原子一起形成氮杂环丁基、吡咯基、吡咯烷基、哌嗪基、哌啶基、吗啉基或硫代吗啉基，所述氮杂环丁基、吡咯基、吡咯烷基、哌嗪基、哌啶基、吗啉基或硫代吗啉基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、C 1-4烷基、C 1-4烷氧基或-C 1-4亚烷基-C 1-4烷氧基的取代基取代； In certain embodiments, 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 azetidine, pyrrolyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl or thiomorpholinyl is optionally further selected from 0, 1, 2, 3 or 4 H , halogen, CF 3 , =O, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy or -C 1-4 alkylene-C 1-4 alkoxy substituent;
在某些实施方案中，R 5f选自H、C 1-6烷基、-C 0-4烷基-3至8元杂环基、-C 1-4烷基-C 3- 6环烷基、C 3-6环烷基，所述的烷基、环烷基或杂环基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、NH 2、-C(＝O)NH(C 1-4烷基)、-C(＝O)N(C 1-4烷基) 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3-6环烷基)、3至8元杂环基的取代基取代，所述杂环基含有1、2或3个选自O、S、N的杂原子； In certain embodiments, R 5f is selected from H, C 1-6 alkyl, -C 0-4 alkyl-3 to 8 membered heterocyclyl, -C 1-4 alkyl - C 3-6 cycloalkane group, C 3-6 cycloalkyl group, said alkyl group, cycloalkyl group or heterocyclyl group is optionally further selected by 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 , =O, OH , cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, NH 2 , -C(=O)NH(C 1-4 alkyl), -C(= O)N(C 1-4 alkyl) 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -NH(C 3-6 cycloalkyl), 3 to Substituent substitution of 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from O, S, N;
在某些实施方案中，R 5f选自H、C 1-4烷基、3至8元杂环基、-C 1-4烷基-3至8元杂环基、-C 1-4烷基-C 3-6环烷基或C 3-6环烷基，所述的烷基、环烷基或杂环基任选进一步被0、 1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、C 1-4烷基、C 1-4烷氧基、NH 2、-C(＝O)NH(C 1-4烷基)、-C(＝O)N(C 1-4烷基) 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3-6环烷基)、3至8元杂环基、C 3-6环烷基的取代基取代，所述杂环基含有1、2或3个选自O、S、N的杂原子； In certain embodiments, R 5f is selected from H, C 1-4 alkyl, 3 to 8 membered heterocyclyl, -C 1-4 alkyl-3 to 8 membered heterocyclyl, -C 1-4 alkyl base-C 3-6 cycloalkyl or C 3-6 cycloalkyl, the alkyl, cycloalkyl or heterocyclyl is optionally further selected by 0, 1, 2, 3 or 4 from H, halogen , CF 3 , =O, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy, NH 2 , -C(=O)NH(C 1-4 alkyl), -C(= O)N(C 1-4 alkyl) 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -NH(C 3-6 cycloalkyl), 3 to Substituent substitution of 8-membered heterocyclic group and C 3-6 cycloalkyl group, the heterocyclic group contains 1, 2 or 3 heteroatoms selected from O, S, N;
在某些实施方案中，R 5f选自H、C 1-4烷基、3至8元杂环基、-C 1-2烷基-3至8元杂环基、-C 1-2烷基-C 3-6环烷基或C 3-6环烷基，所述的烷基、环烷基或杂环基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、C 1-4烷基、C 1-4烷氧基、NH 2、-C(＝O)NH(C 1-4烷基)、-C(＝O)N(C 1-4烷基) 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3-6环烷基)、3至8元杂环基、C 3-6环烷基的取代基取代，所述杂环基含有1、2或3个选自O、S、N的杂原子； In certain embodiments, R 5f is selected from H, C 1-4 alkyl, 3 to 8 membered heterocyclyl, -C 1-2 alkyl-3 to 8 membered heterocyclyl, -C 1-2 alkane base-C 3-6 cycloalkyl or C 3-6 cycloalkyl, said alkyl, cycloalkyl or heterocyclyl is optionally further selected by 0, 1, 2, 3 or 4 from H, halogen , CF 3 , =O, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy, NH 2 , -C(=O)NH(C 1-4 alkyl), -C(= O)N(C 1-4 alkyl) 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -NH(C 3-6 cycloalkyl), 3 to Substituent substitution of 8-membered heterocyclic group and C 3-6 cycloalkyl group, the heterocyclic group contains 1, 2 or 3 heteroatoms selected from O, S, N;
在某些实施方案中，R 5f选自H或者取代的或者未取代的如下基团之一：甲基、乙基、丙基、丁基、异丙基、异丁基、氮杂环丁基、氮杂环戊基、氮杂环已基、哌嗪基、氧杂环丁基、氧杂环戊基、氧杂环已基、吗啉基、-CH 2-氮杂环丁基、-CH 2-氮杂环戊基、-CH 2-氮杂环已基、-CH 2-哌嗪、-CH 2-氧杂环丁基、-CH 2-氧杂环戊基、-CH 2-氧杂环已基、-CH 2-吗啉、-CH 2CH 2-氮杂环丁基、-CH 2CH 2-氮杂环戊基、-CH 2CH 2-氮杂环已基、-CH 2CH 2-哌嗪、-CH 2CH 2-氧杂环丁基、-CH 2CH 2-氧杂环戊基、-CH 2CH 2-氧杂环已基、-CH 2CH 2-吗啉、-CH 2-噻唑、-CH 2-噻吩、-CH 2-吡咯、-CH 2-吡唑、-CH 2-咪唑、-CH 2-呋喃、-CH 2-噁唑、-CH 2-吡咯、-CH 2-吡啶、
Figure PCTCN2021117545-appb-000060
当被取代时，任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、C 1-4烷基、C 1-4烷氧基、NH 2、-C(＝O)NH(C 1-4烷基)、-C(＝O)N(C 1-4烷基) 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3-6环烷基)、3至8元杂环基、C 3-6环烷基的取代基取代，所述杂环基含有1、2或3个选自O、S、N的杂原子； In certain embodiments, 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 -piperazine, -CH 2 CH 2 -oxetanyl, -CH 2 CH 2 -oxolane, -CH 2 CH 2 -oxane, -CH 2 CH 2 - Morpholine, -CH2 -thiazole, -CH2 -thiophene, -CH2 -pyrrole, -CH2 -pyrazole, -CH2 -imidazole, -CH2 -furan, -CH2 -oxazole, -CH2 -pyrrole, -CH 2 -pyridine,
Figure PCTCN2021117545-appb-000060
When substituted, optionally further by 0, 1, 2, 3 or 4 selected from H, halogen, CF 3 , =O, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy , NH 2 , -C(=O)NH(C 1-4 alkyl), -C(=O)N(C 1-4 alkyl) 2 , -NH(C 1-4 alkyl), -N (C 1-4 alkyl) 2 , -NH(C 3-6 cycloalkyl), 3- to 8-membered heterocyclic group, substituent substitution of C 3-6 cycloalkyl, the heterocyclic group contains 1, 2 or 3 heteroatoms selected from O, S, N;
在某些实施方案中，R 5f选自H或者取代的或者未取代的如下基团之一：甲基、乙基、丙基、丁基、异丙基、异丁基、氮杂环丁基、氮杂环戊基、氮杂环已基、哌嗪基、氧杂环丁基、氧杂环戊基、氧杂环已基、吗啉基、-CH 2-氮杂环丁基、-CH 2-氮杂环戊基、-CH 2-氮杂环已基、-CH 2-哌嗪、-CH 2-氧杂环丁基、-CH 2-氧杂环戊基、-CH 2-氧杂环已基、-CH 2-吗啉、-CH 2CH 2-氮杂环丁基、-CH 2CH 2-氮杂环戊基、-CH 2CH 2-氮杂环已基、-CH 2CH 2-哌嗪、-CH 2CH 2-氧杂环丁基、-CH 2CH 2-氧杂环戊基、-CH 2CH 2-氧杂环已基、-CH 2CH 2-吗啉、-CH 2-噻唑、-CH 2-噻吩、-CH 2-吡咯、-CH 2-吡唑、-CH 2-咪唑、-CH 2-呋喃、-CH 2-噁唑、-CH 2-吡咯、-CH 2-吡啶、
Figure PCTCN2021117545-appb-000061
当被取代时，任 选进一步被0、1、2、3或4个选自H、卤素(如F、Cl、Br)、CF 3、＝O、OH、氰基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、NH 2、-C(＝O)NH(CH 3)、C(＝O)N(CH 3) 2、-C(＝O)NH(CH 2CH 3)、-C(＝O)N(CH 2CH 3) 2、-NH(CH 3)、-NH(CH 2CH 3)、-N(CH 2CH 3) 2、-N(CH 3)(CH 2CH 3)、-NH(C 3-6环烷基)、氮杂环丁基、氮杂环戊基、氮杂环已基、哌嗪、氧杂环丁基、氧杂环戊基、氧杂环已基、吗啉基、环丙基、环丁基、环戊基、环己基、噻唑基、噻吩基、吡咯基、吡唑基、咪唑基、呋喃基、噁唑基、吡咯基、吡啶基的取代基取代； In certain embodiments, 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 -piperazine, -CH 2 CH 2 -oxetanyl, -CH 2 CH 2 -oxolane, -CH 2 CH 2 -oxane, -CH 2 CH 2 - Morpholine, -CH2 -thiazole, -CH2 -thiophene, -CH2 -pyrrole, -CH2 -pyrazole, -CH2 -imidazole, -CH2 -furan, -CH2 -oxazole, -CH2 -pyrrole, -CH 2 -pyridine,
Figure PCTCN2021117545-appb-000061
When substituted, optionally further 0, 1, 2, 3 or 4 selected from H, halogen (eg F, Cl, Br), CF3 , =O, OH, cyano, methyl, ethyl, Propyl, isopropyl, methoxy, ethoxy, propoxy, NH 2 , -C(=O)NH(CH 3 ), C(=O)N(CH 3 ) 2 , -C(= O)NH( CH2CH3 ), -C(=O)N( CH2CH3 ) 2 , -NH( CH3 ) , -NH( CH2CH3 ) , -N ( CH2CH3 ) 2 , -N(CH 3 )(CH 2 CH 3 ), -NH(C 3-6 cycloalkyl), azetidine, azacyclopentyl, azacyclohexyl, piperazine, oxane Butyl, oxolane, oxetyl, morpholinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, Substituent substitution of furyl, oxazolyl, pyrrolyl and pyridyl;
在某些实施方案中，R 5f选自H、C 1-6烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基取代； In certain embodiments, R 5f is selected from H, C 1-6 alkyl, or C 3-6 cycloalkyl, optionally further modified by 0, 1, 2, 3, or 4 substituted with a substituent selected from H, halogen, CF 3 , =O, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;
在某些实施方案中，R 5f选自H、C 1-4烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基取代； In certain embodiments, R 5f is selected from H, C 1-4 alkyl, or C 3-6 cycloalkyl, optionally further modified by 0, 1, 2, 3, or 4 substituted with a substituent selected from H, halogen, CF 3 , =O, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;
在某些实施方案中，R 5f选自H、甲基、乙基、
Figure PCTCN2021117545-appb-000062
In certain embodiments, R 5f is selected from H, methyl, ethyl,
Figure PCTCN2021117545-appb-000062
n、s选自0、1或2；n and s are selected from 0, 1 or 2;
m、p、q各自独立的选自0、1、2、3或4。m, p, q are each independently selected from 0, 1, 2, 3 or 4.
作为本发明的第一种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the first embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
Y 1、Y 2、Y 3各自独立的选自CH或N； Y 1 , Y 2 , and Y 3 are each independently selected from CH or N;
环A选自5至6元杂环或杂芳环，所述的杂环或杂芳环任选进一步被0、1、2或3个R a取代基所取代，所述的杂环或杂芳环含有1、2、3或4个选自O、S、N的杂原子； 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;
R a各自独立的选自H、＝O、卤素、氰基、C 1-6烷基、C 1-6烷氧基、-(CH 2) q-C(＝O)-NR a1R a2、-(CH 2) q-NR a1R a2、-(CH 2) qNR a1C(＝O)-R a2、-(CH 2) q-C 3-10碳环或-(CH 2) q-3至12元杂环，所述的CH 2、烷基、烷氧基、碳环或杂环任选进一步被0、1、2、3或4个选自H、卤素、CF 3、OH、氰基、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环含有1、2或3个选自O、S、N的杂原子； R a is each independently selected from H, =O, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, -(CH 2 ) q -C(=O)-NR a1 R a2 , -(CH 2 ) q -NR a1 R a2 , -(CH 2 ) q NR a1 C(=O)-R a2 , -(CH 2 ) q -C 3-10 carbocyclic or -(CH 2 ) q - 3- to 12-membered heterocycle, said CH 2 , alkyl, alkoxy, carbocycle or heterocycle is optionally further selected by 0, 1, 2, 3 or 4 from H, halogen, CF 3 , OH, substituted by substituents of cyano, COOH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy, and the heterocycle contains 1, 2 or 3 heteroatoms selected from O, S, N ;
环B选自C 3-10碳环，所述的碳环任选进一步被0、1、2、3或4个R b取代； Ring B is selected from C 3-10 carbocycles optionally further substituted by 0, 1, 2, 3 or 4 R b ;
R b各自独立的选自H、卤素、氰基、C 1-6烷基或C 1-6烷氧基，所述的烷基或烷氧基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、OH、氰基、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基或C 3-8环烷基的取代基所取代； 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选自键、-S(O) n-、-NR 1a-、-CR 1bR 1c-、-O(CR 1bR 1c) s-、-(CR 1bR 1c) sO-、-NR 1aCR 1bR 1c-、-NR 1aS(O) n-、-S(O) nNR 1a-、-NR 1aC(O)-、-C(O)NR 1a-、-SCR 1bR 1c-或-CR 1bR 1cS-； 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或R 1c各自独立的选自H、C 1-4烷基或-(CH 2) p-C 3-6碳环，所述的烷基或碳环任选进一步被0、1、2、3或4个选自H、卤素、OH、CF 3、氰基、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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;
作为选择，R 1b、R 1c与其直接相连的碳原子一起形成3元碳环； Alternatively, R 1b and R 1c together with the carbon atoms to which they are directly connected form a 3-membered carbocyclic ring;
环C选自5-6元杂芳基或苯基，所述的杂芳基或苯基任选进一步被0、1、2、3或4个R c取代； 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 c各自独立的选自H、卤素、OH、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、-(CH 2) m-C(＝O)-NR 3aR 3b、-(CH 2) m-NR 3aR 3b、-(CH 2) mNR 3aC(＝O)-R 3b、-(CH 2) m-C(＝O)R 3a、-(CH 2) m-C(＝O)OR 3a、-(CH 2) m-OC(＝O)R 3a、-(CH 2) m-3至12元杂环基或-(CH 2) m-C 3-10碳环基，所述的CH 2、烷基、烯基、炔基、烷氧基、碳环或杂环任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、-C 1-4亚烷基-羟基、C 3-6碳环基或3至8元杂环基的取代基所取代，所述的杂环基含有1、2或3个选自O、S、N的杂原子； R c is each independently selected from H, halogen, OH, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -(CH 2 ) m -C(=O)-NR 3a R 3b , -(CH 2 ) m -NR 3a R 3b , -(CH 2 ) m NR 3a C(=O)-R 3b , -(CH 2 ) m -C (=O)R 3a , -(CH 2 ) m -C(=O)OR 3a , -(CH 2 ) m -OC(=O)R 3a , -(CH 2 ) m -3- to 12-membered heterocycle or -(CH 2 ) m -C 3-10 carbocyclyl, said CH 2 , alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0, 1, 2 , 3 or 4 are selected from H, halogen, CF 3 , =O, OH, cyano, COOH, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , Substituents of C 1-4 alkyl, C 1-4 alkoxy, -C 1-4 alkylene-hydroxy, C 3-6 carbocyclyl or 3- to 8-membered heterocyclyl, the said Heterocyclyl contains 1, 2 or 3 heteroatoms selected from O, S, N;
R a1、R a2、R 3a、R 3b各自独立的选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-12碳环基或3至12元杂环基，所述的烷基、烯基、炔基、烷氧基、碳环基或杂环基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、OH、氰基、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环基含有1、2或3个选自O、S、N的杂原子； 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选自
Figure PCTCN2021117545-appb-000063
R 5 is selected from
Figure PCTCN2021117545-appb-000063
R 5a、R 5b、R 5c各自独立的选自H、卤素、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8碳环基或3至10元杂环基，所述的烷基、烷氧基、碳环基或杂环基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3-6环烷基)、C 1-4烷基、C 1-4烷氧基或-SC 1-4烷基的取代基所取代，所述的杂环基含有1、2或3个选自O、S、N的杂原子； R 5a , R 5b , R 5c are each independently selected from H, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 carbocyclyl or 3- to 10-membered heterocyclyl , the alkyl group, alkoxy group, carbocyclic group or heterocyclic group is optionally further selected from 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 , =O, OH, cyano, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -NH(C 3-6 cycloalkyl), C 1-4 alkyl, C 1-4 alkoxy substituted by the substituent of -SC 1-4 alkyl group, the heterocyclic group contains 1, 2 or 3 heteroatoms selected from O, S, N;
作为选择，R 5b与R 5c可形成化学键； Alternatively, R 5b and R 5c may form a chemical bond;
R 5d、R 5e各自独立的选自H、C 1-6烷基、C 3-8碳环基或3至10元杂环基，所述的烷基、碳环基或杂环基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、 NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3-6环烷基)、C 1-4烷基、C 1-4烷氧基或-SC 1-4烷基的取代基所取代，所述的杂环基含有1、2或3个选自O、S、N的杂原子； 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, and said alkyl, carbocyclyl or heterocyclyl are optional is further selected by 0, 1, 2, 3 or 4 from H, halogen, CF3 , =O, OH, cyano, NH2 , -NH( C1-4 alkyl), -N( C1-4 Alkyl) 2 , -NH(C 3-6 cycloalkyl), C 1-4 alkyl, C 1-4 alkoxy or -SC 1-4 alkyl substituents, the heterocycle group contains 1, 2 or 3 heteroatoms selected from O, S, N;
作为选择，R 5d、R 5e与其直接相连的氮原子一起形成4至8元杂环基，所述杂环基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、C 1-4烷基、C 1-4烷氧基或-C 1-4亚烷基-C 1-4烷氧基的取代基取代，所述杂环基含有1、2或3个选自O、S、N的杂原子； Alternatively, R 5d , R 5e together with the nitrogen atom to which they are directly attached form a 4- to 8-membered heterocyclyl group optionally further substituted by 0, 1, 2, 3 or 4 selected from H, halogen, CF 3 , substituted by a substituent of =O, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy or -C 1-4 alkylene-C 1-4 alkoxy, the heterocycle group contains 1, 2 or 3 heteroatoms selected from O, S, N;
R 5f选自H、C 1-6烷基、-C 0-4烷基-3至8元杂环基、-C 1-4烷基-C 3-6环烷基、C 3-6环烷基，所述的烷基、环烷基或杂环基任选进一步被0至4个选自H、卤素、CF 3、＝O、OH、氰基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、NH 2、-C(＝O)NH(C 1-4烷基)、-C(＝O)N(C 1-4烷基) 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3-6环烷基)、3至8元杂环基的取代基取代，所述杂环基含有1、2或3个选自O、S、N的杂原子； R 5f is selected from H, C 1-6 alkyl, -C 0-4 alkyl-3- to 8-membered heterocyclyl, -C 1-4 alkyl-C 3-6 cycloalkyl, C 3-6 ring Alkyl, said alkyl, cycloalkyl or heterocyclyl optionally further selected from 0 to 4 groups selected from H, halogen, CF 3 , =O, OH, cyano, C 1-4 alkyl, C 1 -4 alkoxy, C 3-6 cycloalkyl, NH 2 , -C(=O)NH(C 1-4 alkyl), -C(=O)N(C 1-4 alkyl) 2 , Substituents of -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -NH(C 3-6 cycloalkyl), 3- to 8-membered heterocyclic groups, the heterocyclic group The cyclic group contains 1, 2 or 3 heteroatoms selected from O, S, N;
n、s选自0、1或2；n and s are selected from 0, 1 or 2;
m、p、q各自独立的选自0、1、2、3或4。m, p, q are each independently selected from 0, 1, 2, 3 or 4.
作为本发明的第二种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the second embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
Figure PCTCN2021117545-appb-000064
选自
Figure PCTCN2021117545-appb-000065
Figure PCTCN2021117545-appb-000064
selected from
Figure PCTCN2021117545-appb-000065
右侧与L 1直接连接； The right side is directly connected to L 1 ;
Figure PCTCN2021117545-appb-000066
选自
Figure PCTCN2021117545-appb-000067
Figure PCTCN2021117545-appb-000066
selected from
Figure PCTCN2021117545-appb-000067
X 1选自N或CR a； X 1 is selected from N or CR a ;
R a选自H、卤素、氰基、C 1-4烷基、C 1-4烷氧基、-(CH 2) q-C(＝O)-NR a1R a2、-(CH 2) q-NR a1R a2、-(CH 2) qNR a1C(＝O)-R a2、-(CH 2) q-C 3-6碳环或-(CH 2) q-3至6元杂环，所述的CH 2、烷基、烷氧基、碳环或杂环任选进一步被0、1、2、3或4个选自H、卤素、CF 3、OH、氰基、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环含有1、2或3个选自O、S、N的杂原子； R a is selected from H, halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, -(CH 2 ) q -C(=O)-NR a1 R a2 , -(CH 2 ) q -NR a1 R a2 , -(CH 2 ) q NR a1 C(=O)-R a2 , -(CH 2 ) q -C 3-6 carbocycle or -(CH 2 ) q -3- to 6-membered heterocycle , the CH 2 , alkyl, alkoxy, carbocycle or heterocycle is optionally further 0, 1, 2, 3 or 4 selected from H, halogen, CF 3 , OH, cyano, COOH, NH 2. Substituents of C 1-4 alkyl or C 1-4 alkoxy are substituted, and the heterocycle contains 1, 2 or 3 heteroatoms selected from O, S, N;
环B选自C 3-6饱和或不饱和单环碳环、C 5-10饱和或不饱和螺环碳环、C 5-10饱和或不饱和并环碳环、C 5-10饱和或不饱和桥环碳环，所述碳环任选进一步被0、1、2、3或4个R b代； 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各自独立的选自H、卤素、氰基、C 1-4烷基或C 1-4烷氧基，所述的烷基或烷氧基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、OH、氰基、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基或C 3-8环烷基的取代基所取代； 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选自键、-O-、-S(O) n-、-NR 1a-、-CR 1bR 1c-、-OCR 1bR 1c-、-O(CR 1bR 1c) 2-、-CR 1bR 1cO-、-NR 1aCR 1bR 1c-、-SCR 1bR 1c-或-CR 1bR 1cS-； 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 1、R 2、R 3、R 4各自独立的选自H、卤素、OH、氰基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、-(CH 2) m-C(＝O)-NR 3aR 3b、-(CH 2) m-NR 3aR 3b、-(CH 2) mNR 3aC(＝O)-R 3b、-(CH 2) m-C(＝O)R 3a、-(CH 2) m-C(＝O)OR 3a、-(CH 2) m-OC(＝O)R 3a、-(CH 2) m-3至10元杂环或-(CH 2) m-C 3-8碳环，所述的CH 2、烷基、烯基、炔基、烷氧基、碳环或杂环任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、-C 1-4亚烷基-羟基、C 3-6环烷基或3至8元杂环基的取代基所取代，所述的杂环含有1、2或3个选自O、S、N的杂原子； R 1 , R 2 , R 3 , R 4 are each independently selected from H, halogen, OH, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 Alkoxy, -(CH 2 ) m -C(=O)-NR 3a R 3b , -(CH 2 ) m -NR 3a R 3b , -(CH 2 ) m NR 3a C(=O)-R 3b , -(CH 2 ) m -C(=O)R 3a , -(CH 2 ) m -C(=O)OR 3a , -(CH 2 ) m -OC(=O)R 3a , -(CH 2 ) m -3 to 10-membered heterocycle or -(CH 2 ) m -C 3-8 carbocycle, said CH 2 , alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle are optional is further selected from H, halogen, CF3 , =O, OH, cyano, COOH, NH2 , -NH( C1-4 alkyl), -N( C1 Substitution of -4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, -C 1-4 alkylene-hydroxy, C 3-6 cycloalkyl or 3- to 8-membered heterocyclyl substituted by a base, the heterocycle contains 1, 2 or 3 heteroatoms selected from O, S, N;
R a1、R a2、R 3a、R 3b各自独立的选自H、C 1-4烷基、C 3-6碳环基或3至6元杂环基，所述的烷基、碳环基或杂环基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、OH、氰基、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环基含有1、2或3个选自O、S、N的杂原子； 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 5a、R 5b、R 5c各自独立的选自H、卤素、氰基、C 1-4烷基、C 1-4烷氧基、3至6元碳环基或3至8元杂环基，所述的烷基、烷氧基、碳环基或杂环基任选进一步被0、1、2、3或4个选自H、卤素、＝O、OH、氰基、CF 3、C 1-4烷基、C 1-4烷氧基或-SC 1-4烷基的取代基所取代，所述的杂环基含有1、2或3个选自O、S、N的杂原子； R 5a , R 5b , R 5c are each independently selected from H, halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, 3- to 6-membered carbocyclyl or 3- to 8-membered heterocyclyl , the alkyl group, alkoxy group, carbocyclic group or heterocyclic group is optionally further selected from 0, 1, 2, 3 or 4 groups selected from H, halogen, =O, OH, cyano, CF 3 , C 1-4 alkyl, C 1-4 alkoxy or -SC 1-4 alkyl substituent, the heterocyclic group contains 1, 2 or 3 heteroatoms selected from O, S, N ;
作为选择，R 5b与R 5c可形成化学键； Alternatively, R 5b and R 5c may form a chemical bond;
R 5d、R 5e各自独立的选自H、C 1-4烷基、3至6元碳环或3至8元杂环，所述的烷基、碳环或杂环任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3-6环烷基)、C 1-4烷基、C 1-4烷氧基或-SC 1-4烷基的取代基所取代，所述的杂环含有1、2或3个选自O、S、N的杂原子； 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, and the alkyl, carbocycle or heterocycle is optionally further substituted by O, 1, 2, 3 or 4 are selected from H, halogen, CF3 , =O, OH, cyano, NH2 , -NH( C1-4alkyl ), -N( C1-4alkyl ) 2 , -NH(C 3-6 cycloalkyl), C 1-4 alkyl, C 1-4 alkoxy or -SC 1-4 alkyl substituent, the heterocycle contains 1, 2 or 3 heteroatoms selected from O, S, N;
作为选择，R 5d、R 5e与其直接相连的氮原子一起形成4至6元杂环，所述杂环任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、C 1-4烷基、C 1-4烷氧基 或-C 1-4亚烷基-C 1-4烷氧基的取代基取代，所述杂环含有1、2或3个选自O、S、N的杂原子； Alternatively, R 5d , R 5e together with the nitrogen atom to which they are directly attached form a 4- to 6-membered heterocyclic ring optionally further comprised of 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, the heterocycle contains 1 , 2 or 3 heteroatoms selected from O, S, N;
R 5f选自H、C 1-4烷基、3至8元杂环基、-C 1-4烷基-3至8元杂环基、-C 1-4烷基-C 3-6环烷基或C 3-6环烷基，所述的烷基、环烷基或杂环基任选进一步被0至4个选自H、卤素、CF 3、＝O、OH、氰基、C 1-4烷基、C 1-4烷氧基、NH 2、-C(＝O)NH(C 1-4烷基)、-C(＝O)N(C 1-4烷基) 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3-6环烷基)、3至8元杂环基、C 3-6环烷基的取代基取代，所述杂环基含有1、2或3个选自O、S、N的杂原子； R 5f is selected from H, C 1-4 alkyl, 3- to 8-membered heterocyclyl, -C 1-4 alkyl-3 to 8-membered heterocyclyl, -C 1-4 alkyl-C 3-6 ring Alkyl or C 3-6 cycloalkyl, said alkyl, cycloalkyl or heterocyclyl optionally further selected from 0 to 4 groups selected from H, halogen, CF 3 , =O, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy, NH 2 , -C(=O)NH(C 1-4 alkyl), -C(=O)N(C 1-4 alkyl) 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -NH(C 3-6 cycloalkyl), 3- to 8-membered heterocyclyl, C 3-6 cycloalkyl substituted by the substituent, the heterocyclic group contains 1, 2 or 3 heteroatoms selected from O, S, N;
其余基团的定义与第一种实施方案相同。The definitions of the remaining groups are the same as in the first embodiment.
作为本发明的第三种实施方案，前述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the third embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
L 1选自键、-O-、-S-、-NH-、-CH 2-、-S(O) 2-、-OCH 2-、-OCH(CH 3)-、-OC(CH 3) 2-、-OCH 2CH 2-、-CH 2O-、-NHCH 2-或-N(CH 3)-； 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 ) - ;
环B选自取代或者未取代的如下基团之一：环丙基、环丁基、环戊基、环己基、金刚烷基、双环[1.1.1]戊烷基、双环[2.2.1]庚烷基、立方烷基、双环[3.1.0]己烷基、双环[3.2.0]庚烷基、环戊基并环戊基、双环[4.2.0]辛烷基、双环[2.2.2]辛烷基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环己基，当被取代时，任选进一步被0、1、2、3或4个R b取代； 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. 2] Octyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclohexyl, when substituted, optionally further by 0, 1, 2 , 3 or 4 R b substitutions;
R b各自独立的选自H、F、Cl、Br、I、氰基、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基或丙氧基，所述的甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基或丙氧基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、OH、氰基、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基所取代； 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 a选自H、F、Cl、Br、I、氰基、甲基、乙基、异丙基、丙基、甲氧基、乙氧基、丙氧基、-(CH 2) q-C(＝O)-NR a1R a2、-(CH 2) q-NR a1R a2、-(CH 2) qNR a1C(＝O)-R a2、环丙基、环丁基、环戊基、环己基、-CH 2-环丙基、-CH 2-环丁基、-CH 2-环戊基或-CH 2-环己基，所述的CH 2、甲基、乙基、异丙基、丙基、甲氧基、乙氧基、丙氧基、环丙基、环丁基或环戊基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、OH、氰基、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； Ra is selected from H, F, Cl, Br, I, cyano, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, -( CH2 ) q -C (=O)-NR a1 R a2 , -(CH 2 ) q -NR a1 R a2 , -(CH 2 ) q NR a1 C(=O)-R a2 , cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl or -CH 2 -cyclohexyl, said CH 2 , methyl, ethyl, isopropyl , propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl or cyclopentyl are optionally further substituted by 0, 1, 2, 3 or 4 selected from H, halogen, CF 3 , substituted by the substituents of OH, cyano, COOH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy;
R 1、R 2、R 3、R 4各自独立的选自H、F、Cl、Br、I、OH、氰基、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基、丙氧基、乙烯基、丙烯基、乙炔基、丙炔基、-(CH 2) m-C(＝O)-NR 3aR 3b、-(CH 2) m-NR 3aR 3b、-(CH 2) mNR 3aC(＝O)-R 3b、-(CH 2) m-环丙基、-(CH 2) m-环丁基、-(CH 2) m-环戊基、-(CH 2) m-环己基、-(CH 2) m-氮杂环丁基、-(CH 2) m-氧杂环 丁基、-(CH 2) m-吡咯烷基、-(CH 2) m-四氢呋喃基、-(CH 2) m-哌啶基、-(CH 2) m-四氢吡喃基、-(CH 2) m-吗啉基、-(CH 2) m-哌嗪基或-(CH 2) m-氮杂环庚基，所述的CH 2、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基、丙氧基、环丙基、乙烯基、丙烯基、乙炔基、丙炔基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、四氢吡喃基、吗啉基、哌嗪基或氮杂环庚基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、-C 1-4亚烷基-羟基、C 3-6环烷基或3至8元杂环基的取代基所取代，所述的杂环基含有1、2或3个选自O、S、N的杂原子； R 1 , R 2 , R 3 , R 4 are each independently selected from H, F, Cl, Br, I, OH, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy , ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, -(CH 2 ) m -C(=O)-NR 3a R 3b , -(CH 2 ) m -NR 3a R 3b , -(CH 2 ) m NR 3a C(=O)-R 3b , -(CH 2 ) m -cyclopropyl, -(CH 2 ) m -cyclobutyl, -(CH 2 ) m -cyclopentane radical, -(CH 2 ) m -cyclohexyl, -(CH 2 ) m -azetidinyl, -(CH 2 ) m -oxetanyl, -(CH 2 ) m -pyrrolidinyl, - (CH 2 ) m -tetrahydrofuranyl, -(CH 2 ) m -piperidinyl, -(CH 2 ) m -tetrahydropyranyl, -(CH 2 ) m -morpholinyl, -(CH 2 ) m -piperazinyl or -( CH2 ) m -azepanyl, said CH2 , methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy radical, cyclopropyl, vinyl, propenyl, ethynyl, propynyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, pipette pyridinyl, tetrahydropyranyl, morpholinyl, piperazinyl or azepanyl is optionally further selected from 0, 1, 2, 3 or 4 by 0, 1, 2, 3 or 4 selected from H, halogen, CF3 , =O, OH, Cyano, COOH, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, -C 1- 4 alkylene-hydroxyl, C 3-6 cycloalkyl or 3- to 8-membered heterocyclic group containing 1, 2 or 3 heterocyclic groups selected from O, S, N atom;
R a1、R a2、R 3a、R 3b各自独立的选自H、甲基、乙基、丙基、异丙基、丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基或哌啶基，所述的甲基、乙基、丙基、异丙基、丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基或哌啶基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、OH、氰基、COOH、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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选自
Figure PCTCN2021117545-appb-000068
R 5 is selected from
Figure PCTCN2021117545-appb-000068
R 5a、R 5b、R 5c各自独立的选自H、F、Cl、Br、I、氰基、甲基、乙基、丙基、异丙基、丁基、甲氧基、乙氧基、丙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基或哌啶基，所述的甲基、乙基、丙基、异丙基、丁基、甲氧基、乙氧基、丙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基或哌啶基任选进一步被0、1、2、3或4个选自H、卤素、＝O、OH、氰基、CF 3、C 1-4烷基、C 1-4烷氧基或-SC 1-4烷基的取代基所取代； R 5a , R 5b , 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, the methyl, ethyl, propyl , isopropyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl is optionally further selected by 0, 1, 2, 3 or 4 selected from H, halogen, =O, OH, cyano, CF 3 , C 1-4 alkyl, C 1-4 alkoxy or -Substituted by substituents of -SC 1-4 alkyl;
作为选择，R 5b与R 5c可形成化学键； Alternatively, R 5b and R 5c may form a chemical bond;
R 5d、R 5e各自独立的选自H、甲基、乙基、丙基、异丙基、丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基或吗啉基，所述的甲基、乙基、丙基、异丙基、丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基或吗啉基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3-6环烷基)、C 1-4烷基、C 1-4烷氧基或-SC 1-4烷基的取代基所取代； R 5d and R 5e are each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, oxygen Heterocyclobutyl, pyrrolidinyl, piperidinyl or morpholinyl, said methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , azetidine, oxetanyl, pyrrolidinyl, piperidinyl or morpholinyl optionally further selected by 0, 1, 2, 3 or 4 selected from H, halogen, CF3 , =O, OH, cyano, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -NH(C 3-6 cycloalkyl), C 1-4 alkyl, C 1-4 alkoxy or -SC 1-4 alkyl substituent;
作为选择，R 5d、R 5e与其直接相连的氮原子一起形成氮杂环丁基、吡咯基、吡咯烷基、哌嗪基、哌啶基、吗啉基或硫代吗啉基，所述氮杂环丁基、吡咯基、吡咯烷基、哌嗪基、 哌啶基、吗啉基或硫代吗啉基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、C 1-4烷基、C 1-4烷氧基或-C 1-4亚烷基-C 1-4烷氧基的取代基取代； Alternatively, 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选自H或者取代的或者未取代的如下基团之一：甲基、乙基、丙基、丁基、异丙基、异丁基、氮杂环丁基、氮杂环戊基、氮杂环已基、哌嗪基、氧杂环丁基、氧杂环戊基、氧杂环已基、吗啉基、-CH 2-氮杂环丁基、-CH 2-氮杂环戊基、-CH 2-氮杂环已基、-CH 2-哌嗪、-CH 2-氧杂环丁基、-CH 2-氧杂环戊基、-CH 2-氧杂环已基、-CH 2-吗啉、-CH 2CH 2-氮杂环丁基、-CH 2CH 2-氮杂环戊基、-CH 2CH 2-氮杂环已基、-CH 2CH 2-哌嗪、-CH 2CH 2-氧杂环丁基、-CH 2CH 2-氧杂环戊基、-CH 2CH 2-氧杂环已基、-CH 2CH 2-吗啉、-CH 2-噻唑、-CH 2-噻吩、-CH 2-吡咯、-CH 2-吡唑、-CH 2-咪唑、-CH 2-呋喃、-CH 2-噁唑、-CH 2-吡咯、-CH 2-吡啶、
Figure PCTCN2021117545-appb-000069
当被取代时，任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、C 1-4烷基、C 1-4烷氧基、NH 2、-C(＝O)NH(C 1-4烷基)、-C(＝O)N(C 1-4烷基) 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3-6环烷基)、3至8元杂环基、C 3-6环烷基的取代基取代，所述杂环基含有1、2或3个选自O、S、N的杂原子； 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, -CH2CH2 - piperazine , -CH 2 CH 2 -oxetanyl, -CH 2 CH 2 -oxolane, -CH 2 CH 2 -oxane, -CH 2 CH 2 -morpholine, -CH 2 - Thiazole, -CH2 -thiophene, -CH2 -pyrrole, -CH2 -pyrazole, -CH2 -imidazole, -CH2 -furan, -CH2 -oxazole, -CH2 -pyrrole, -CH2- pyridine,
Figure PCTCN2021117545-appb-000069
When substituted, optionally further by 0, 1, 2, 3 or 4 selected from H, halogen, CF 3 , =O, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy , NH 2 , -C(=O)NH(C 1-4 alkyl), -C(=O)N(C 1-4 alkyl) 2 , -NH(C 1-4 alkyl), -N (C 1-4 alkyl) 2 , -NH(C 3-6 cycloalkyl), 3- to 8-membered heterocyclic group, substituent substitution of C 3-6 cycloalkyl, the heterocyclic group contains 1, 2 or 3 heteroatoms selected from O, S, N;
其余基团的定义与本发明第一或二种中任意一种实施方案一致。The definitions of the remaining groups are in accordance with any one of the first or second embodiments of the present invention.
作为本发明的第四种实施方案，前述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
环B选自取代的或者未取代的如下基团之一：
Figure PCTCN2021117545-appb-000070
Figure PCTCN2021117545-appb-000071
Figure PCTCN2021117545-appb-000072
当被取代时，任选进一步被0、1、2、3或4个R b取代，其左侧与L 1相连； Ring B is selected from one of the following groups, substituted or unsubstituted:
Figure PCTCN2021117545-appb-000070
Figure PCTCN2021117545-appb-000071
Figure PCTCN2021117545-appb-000072
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各自独立的选自H、F、Cl、Br、I、氰基、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基或丙氧基，所述的甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基或丙氧基任选进一步被0、1、2、3或4个选自H、F、CF 3、OH、氰基、NH 2、-NHCH 3、- N(CH 3) 2、-NHCH 2CH 3、-N(CH 2CH 3) 2、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基、丙氧基、环丙基、环丁基或环戊基的取代基所取代； 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;
R a选自H、F、Cl、氰基、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 2CH 3、-C(O)N(CH 2CH 3) 2、-C(O)NHCH 2CH 2OCH 3、-C(O)NH-环丙基、-C(O)NH-环丁基、-C(O)NH-环戊基、-C(O)NH-环已基、-NHC(O)CH 3、-NHC(O)CH 2CH 3、-NHC(O)-环丙基、-NHC(O)-环丁基、-NHC(O)-环戊基、-NHC(O)-环已基、环丙基、环丁基、环戊基、环己基、-CH 2-环丙基、-CH 2-环丁基、-CH 2-环戊基或-CH 2-环己基； 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)-cyclohexyl, cyclopropyl, cyclobutyl cyclopentyl, cyclopentyl, cyclohexyl, -CH2 -cyclopropyl, -CH2 -cyclobutyl, -CH2 -cyclopentyl or -CH2 -cyclohexyl;
R 1、R 2、R 3各自独立的选自H、F、Cl、Br、I、OH、氰基、-(CH 2) m-C(＝O)-NR 3aR 3b、-(CH 2) m-NR 3aR 3b、-(CH 2) mNR 3aC(＝O)-R 3b、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基或丙氧基，所述的CH 2、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基或丙氧基任选进一步被0、1、2、3或4个选自H、F、CF 3、OH、氰基、COOH、NH 2、-NHCH 3、-N(CH 3) 2、甲基、乙基、异丙基、丙基、甲氧基、乙氧基、丙氧基、-CH 2OH或-CH 2CH 2OH的取代基所取代； R 1 , R 2 , R 3 are each independently selected from H, F, Cl, Br, I, OH, cyano, -(CH 2 ) m -C(=O)-NR 3a R 3b , -(CH 2 ) m -NR 3a R 3b , -(CH 2 ) m NR 3a C(=O)-R 3b , methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propyl Oxygen, the CH 2 , methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy optionally further replaced by 0, 1, 2, 3 or 4 Selected from H, F, CF3 , OH, cyano, COOH, NH2 , -NHCH3, -N( CH3 )2 , methyl, ethyl, isopropyl, propyl, methoxy, ethoxy substituted with substituents of radical, propoxy, -CH 2 OH or -CH 2 CH 2 OH;
R 3a、R 3b各自独立的选自H、甲基、乙基、丙基、异丙基、丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基或哌啶基，所述的甲基、乙基、丙基、异丙基、丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基或哌啶基任选进一步被0、1、2、3或4个选自H、F、CF 3、OH、氰基、COOH、甲基、乙基、异丙基、丙基、甲氧基、乙氧基或丙氧基的取代基所取代； 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 4选自H、F、Cl、Br、I、OH、氰基、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基、丙氧基、乙烯基、丙烯基、乙炔基、丙炔基、-(CH 2) m-C(＝O)-NR 3aR 3b、-(CH 2) m-NR 3aR 3b、-(CH 2) mNR 3aC(＝O)-R 3b、-(CH 2) m-环丙基、-(CH 2) m-环丁基、-(CH 2) m-环戊基、-(CH 2) m-环己基、-(CH 2) m-氮杂环丁基、-(CH 2) m-氧杂环丁基、-(CH 2) m-吡咯烷基、-(CH 2) m-四氢呋喃基、-(CH 2) m-哌啶基、-(CH 2) m-四氢吡喃基、-(CH 2) m-吗啉基、-(CH 2) m-哌嗪基或-(CH 2) m-氮杂环庚基，所述的CH 2、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基、丙氧基、环丙基、乙烯基、丙烯基、乙炔基、丙炔基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、四氢吡喃基、吗啉基、哌嗪基或氮杂环庚基任选进一步被0、1、2、3或4个选自H、F、＝O、OH、氰基、CF 3、COOH、NH 2、-NHCH 3、-N(CH 3) 2、甲基、乙基、异丙基、丙基、甲氧基、乙氧基、丙氧基、-CH 2OH、-CH 2CH 2OH、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁 基、吡咯烷基、四氢呋喃基、哌啶基、四氢吡喃基、吗啉基、哌嗪基或氮杂环庚基所取代； R 4 is selected from H, F, Cl, Br, I, OH, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, -(CH 2 ) m -C(=O)-NR 3a R 3b , -(CH 2 ) m -NR 3a R 3b , -(CH 2 ) m NR 3a C( =O)-R 3b , -(CH 2 ) m -cyclopropyl, -(CH 2 ) m -cyclobutyl, -(CH 2 ) m -cyclopentyl, -(CH 2 ) m -cyclohexyl, -(CH 2 ) m -azetidine, -(CH 2 ) m -oxetanyl, -(CH 2 ) m -pyrrolidinyl, -(CH 2 ) m -tetrahydrofuranyl, -(CH 2 ) m -piperidinyl, -( CH2 ) m -tetrahydropyranyl, -( CH2 ) m -morpholinyl, -( CH2 ) m -piperazinyl or -( CH2 ) m- Azacycloheptyl, said CH 2 , methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, vinyl, propenyl, Ethynyl, propynyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl , piperazinyl or azepanyl optionally further selected from 0, 1, 2, 3 or 4 groups selected from H, F, =O, OH, cyano, CF3 , COOH, NH2 , -NHCH3 , -N( CH3 ) 2 , methyl, ethyl, isopropyl, propyl , methoxy, ethoxy, propoxy, -CH2OH , -CH2CH2OH , cyclopropyl, cyclo Butyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl or azacyclic substituted by heptyl;
R 5选自
Figure PCTCN2021117545-appb-000073
Figure PCTCN2021117545-appb-000074
R 5 is selected from
Figure PCTCN2021117545-appb-000073
Figure PCTCN2021117545-appb-000074
或者R 5选自
Figure PCTCN2021117545-appb-000075
Figure PCTCN2021117545-appb-000076
or R 5 is selected from
Figure PCTCN2021117545-appb-000075
Figure PCTCN2021117545-appb-000076
或者R 5选自
Figure PCTCN2021117545-appb-000077
Figure PCTCN2021117545-appb-000078
or R 5 is selected from
Figure PCTCN2021117545-appb-000077
Figure PCTCN2021117545-appb-000078
或者R 5选自
Figure PCTCN2021117545-appb-000079
Figure PCTCN2021117545-appb-000080
or R 5 is selected from
Figure PCTCN2021117545-appb-000079
Figure PCTCN2021117545-appb-000080
Figure PCTCN2021117545-appb-000081
Figure PCTCN2021117545-appb-000081
其余基团的定义与本发明第二或三种任意一种实施方案一致。The definitions of the remaining groups are in accordance with any of the second or third embodiments of the present invention.
作为本发明的第五种实施方案，前述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the fifth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
L 1选自-O-、-NH-、-OCH 2-、-OC(CH 3) 2-、-CH 2O-或-NHCH 2-； L 1 is selected from -O-, -NH-, -OCH 2 -, -OC(CH 3 ) 2 -, -CH 2 O- or -NHCH 2 -;
R b各自独立的选自H、F、Cl、氰基、甲基、乙基、异丙基、丙基、甲氧基或乙氧基，所述的甲基、乙基、异丙基、丙基、甲氧基或乙氧基任选进一步被0、1、2、3或4个选自H、F、CF 3、OH、氰基、NH 2、-N(CH 3) 2、-N(CH 2CH 3) 2、甲基、乙基、异丙基、丙基、环丙基或环丁基的取代基所取代； 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选自N或CH； X 1 is selected from N or CH;
R 1、R 2各自独立的选自H、F、Cl、OH、CF 3、氰基、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基或丙氧基； 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;
R 3选自H、F、Cl、OH、CF 3、-CN、-CH 2CN、-CH 2CH 2CN、NH 2、-N(CH 3) 2、-N(CH 2CH 3) 2、-C(O)NH 2、-CH 2C(O)NH 2、-C(O)NHCH 3、-NHC(O)CH 3、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基或丙氧基； 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;
R 4选自H、F、OH、CF 3、NH 2、-CN、-CH 2CN、-CH 2CH 2CN、-NHCH 3、-N(CH 3) 2、-C(O)-NH 2、-CH 2C(O)-NH 2、-CH 2CH 2C(O)-NH 2、-C(O)NHCH 3、-C(O)N(CH 3) 2、-NHC(O)CH 3、甲基、乙基、异丙基、丙基、甲氧基、乙氧基、丙氧基、环丙基、-CH 2-环丙基、环丁基、-CH 2-环丁基、环戊基、-CH 2-环戊基、环己基、-CH 2-环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、四氢吡喃基、吗啉基或哌嗪基； 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, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydro pyranyl, morpholinyl or piperazinyl;
R 5选自
Figure PCTCN2021117545-appb-000082
Figure PCTCN2021117545-appb-000083
R 5 is selected from
Figure PCTCN2021117545-appb-000082
Figure PCTCN2021117545-appb-000083
或者R 5选自
Figure PCTCN2021117545-appb-000084
Figure PCTCN2021117545-appb-000085
or R 5 is selected from
Figure PCTCN2021117545-appb-000084
Figure PCTCN2021117545-appb-000085
或者R 5选自
Figure PCTCN2021117545-appb-000086
Figure PCTCN2021117545-appb-000087
or R 5 is selected from
Figure PCTCN2021117545-appb-000086
Figure PCTCN2021117545-appb-000087
Figure PCTCN2021117545-appb-000088
Figure PCTCN2021117545-appb-000088
或者R 5选自
Figure PCTCN2021117545-appb-000089
Figure PCTCN2021117545-appb-000090
or R 5 is selected from
Figure PCTCN2021117545-appb-000089
Figure PCTCN2021117545-appb-000090
Figure PCTCN2021117545-appb-000091
Figure PCTCN2021117545-appb-000091
其余基团的定义与本发明第二、三或四种任意一种实施方案一致。The definitions of the remaining groups are in accordance with any one of the second, third or fourth embodiments of the present invention.
作为本发明的第六种实施方案，前述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the sixth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
L 1选自-O-、-OCH 2-、-OC(CH 3) 2-或-CH 2O-； L 1 is selected from -O-, -OCH 2 -, -OC(CH 3 ) 2 - or -CH 2 O-;
环B选自
Figure PCTCN2021117545-appb-000092
Figure PCTCN2021117545-appb-000093
其左侧与L 1相连； Ring B is selected from
Figure PCTCN2021117545-appb-000092
Figure PCTCN2021117545-appb-000093
Its left side is connected to L1 ;
Figure PCTCN2021117545-appb-000094
选自
Figure PCTCN2021117545-appb-000095
右侧与L 1直接连接；
Figure PCTCN2021117545-appb-000094
selected from
Figure PCTCN2021117545-appb-000095
The right side is directly connected to L 1 ;
R 5选自
Figure PCTCN2021117545-appb-000096
Figure PCTCN2021117545-appb-000097
R 5 is selected from
Figure PCTCN2021117545-appb-000096
Figure PCTCN2021117545-appb-000097
或者R 5选自
Figure PCTCN2021117545-appb-000098
Figure PCTCN2021117545-appb-000099
or R 5 is selected from
Figure PCTCN2021117545-appb-000098
Figure PCTCN2021117545-appb-000099
或者R 5选自
Figure PCTCN2021117545-appb-000100
Figure PCTCN2021117545-appb-000101
or R 5 is selected from
Figure PCTCN2021117545-appb-000100
Figure PCTCN2021117545-appb-000101
或者R 5选自
Figure PCTCN2021117545-appb-000102
Figure PCTCN2021117545-appb-000103
or R 5 is selected from
Figure PCTCN2021117545-appb-000102
Figure PCTCN2021117545-appb-000103
Figure PCTCN2021117545-appb-000104
Figure PCTCN2021117545-appb-000104
Figure PCTCN2021117545-appb-000105
Figure PCTCN2021117545-appb-000105
R 1选自H、F、Cl、氰基、CF 3、甲基、乙基或甲氧基； R 1 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy;
R 2选自H、F、Cl、氰基、CF 3、甲基、乙基或甲氧基； R 2 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy;
R 3选自H、F、Cl、氰基、CF 3、甲基、乙基或甲氧基； R3 is selected from H, F, Cl, cyano, CF3 , methyl, ethyl or methoxy;
R 4选自H、F、Cl、氰基、CF 3、甲基、乙基或甲氧基； R 4 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy;
其余基团的定义与本发明第二、三、四或五种任意一种实施方案一致。The definitions of the remaining groups are consistent with any one of the second, third, fourth or fifth embodiments of the present invention.
作为本发明的第七种实施方案，前述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the seventh embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
R 5选自
Figure PCTCN2021117545-appb-000106
Figure PCTCN2021117545-appb-000107
R 5 is selected from
Figure PCTCN2021117545-appb-000106
Figure PCTCN2021117545-appb-000107
R 5f选自H或者取代的或者未取代的如下基团之一：甲基、乙基、丙基、丁基、异丙基、异丁基、氮杂环丁基、氮杂环戊基、氮杂环已基、哌嗪基、氧杂环丁基、氧杂环戊基、氧杂环已基、吗啉基、-CH 2-氮杂环丁基、-CH 2-氮杂环戊基、-CH 2-氮杂环已基、-CH 2-哌嗪、-CH 2-氧杂环丁基、-CH 2-氧杂环戊基、-CH 2-氧杂环已基、-CH 2-吗啉、-CH 2CH 2-氮杂环丁基、-CH 2CH 2-氮杂环戊基、-CH 2CH 2-氮杂环已基、-CH 2CH 2-哌嗪、- CH 2CH 2-氧杂环丁基、-CH 2CH 2-氧杂环戊基、-CH 2CH 2-氧杂环已基、-CH 2CH 2-吗啉、-CH 2-噻唑、-CH 2-噻吩、-CH 2-吡咯、-CH 2-吡唑、-CH 2-咪唑、-CH 2-呋喃、-CH 2-噁唑、-CH 2-吡咯、-CH 2-吡啶、
Figure PCTCN2021117545-appb-000108
当被取代时，任选进一步被0、1、2、3或4个选自H、F、CF 3、＝O、OH、氰基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、NH 2、-C(＝O)NH(CH 3)、C(＝O)N(CH 3) 2、-C(＝O)NH(CH 2CH 3)、-C(＝O)N(CH 2CH 3) 2、-NH(CH 3)、-NH(CH 2CH 3)、-N(CH 2CH 3) 2、-N(CH 3)(CH 2CH 3)、-NH(C 3-6环烷基)、氮杂环丁基、氮杂环戊基、氮杂环已基、哌嗪基、氧杂环丁基、氧杂环戊基、氧杂环已基、吗啉基、环丙基、环丁基、环戊基、环己基、噻唑基、噻吩基、吡咯基、吡唑基、咪唑基、呋喃基、噁唑基、吡咯基、吡啶基的取代基取代； 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, -CH2CH2 - piperazine , -CH 2 CH 2 -oxetanyl, -CH 2 CH 2 -oxolane, -CH 2 CH 2 -oxane, -CH 2 CH 2 -morpholine, -CH 2 - Thiazole, -CH2 -thiophene, -CH2 -pyrrole, -CH2 -pyrazole, -CH2 -imidazole, -CH2 -furan, -CH2 -oxazole, -CH2 -pyrrole, -CH2- pyridine,
Figure PCTCN2021117545-appb-000108
When substituted, optionally further by 0, 1, 2, 3 or 4 selected from H, F, CF3 , =O, OH, cyano, methyl, ethyl, propyl, isopropyl, methyl Oxy, ethoxy, propoxy, NH 2 , -C(=O)NH(CH 3 ), C(=O)N(CH 3 ) 2 , -C(=O)NH(CH 2 CH 3 ), -C(=O)N(CH 2 CH 3 ) 2 , -NH(CH 3 ), -NH(CH 2 CH 3 ), -N(CH 2 CH 3 ) 2 , -N(CH 3 )( CH 2 CH 3 ), -NH(C 3-6 cycloalkyl), azetidine, azacyclopentyl, azacyclohexyl, piperazinyl, oxetanyl, oxolane base, oxetyl, morpholinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, Substituent substitution of pyrrolyl and pyridyl;
其余基团的定义与本发明第一、二、三种任意一种实施方案一致。The definitions of the remaining groups are consistent with any one of the first, second and third embodiments of the present invention.
作为本发明的第八种实施方案，前述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the eighth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
L 1选自-O-、-OCH 2-、-OC(CH 3) 2-或-CH 2O-； L 1 is selected from -O-, -OCH 2 -, -OC(CH 3 ) 2 - or -CH 2 O-;
环B选自
Figure PCTCN2021117545-appb-000109
Figure PCTCN2021117545-appb-000110
其左侧与L 1相连； Ring B is selected from
Figure PCTCN2021117545-appb-000109
Figure PCTCN2021117545-appb-000110
Its left side is connected to L1 ;
Figure PCTCN2021117545-appb-000111
选自
Figure PCTCN2021117545-appb-000112
右侧与L 1直接连接；
Figure PCTCN2021117545-appb-000111
selected from
Figure PCTCN2021117545-appb-000112
The right side is directly connected to L 1 ;
R 1选自H、F、Cl、氰基、CF 3、甲基、乙基或甲氧基； R 1 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy;
R 2选自H、F、Cl、氰基、CF 3、甲基、乙基或甲氧基； R 2 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy;
R 3选自H、F、Cl、氰基、CF 3、甲基、乙基或甲氧基； R3 is selected from H, F, Cl, cyano, CF3 , methyl, ethyl or methoxy;
R 4选自H、F、Cl、氰基、CF 3、甲基、乙基或甲氧基； R 4 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy;
其余基团的定义与本发明第七种实施方案一致。The definitions of the remaining groups are consistent with the seventh embodiment of the present invention.
作为本发明的第九种实施方案，下述通式(Ia)或(Ib)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the ninth embodiment of the present invention, the compound represented by the following general formula (Ia) or (Ib) or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic,
Figure PCTCN2021117545-appb-000113
Figure PCTCN2021117545-appb-000113
各个基团的定义与本发明第二、三、四、五、六、七或八种任意一种实施方案一致。The definition of each group is consistent with any one of the second, third, fourth, fifth, sixth, seventh or eighth embodiments of the present invention.
作为本发明的第十一种实施方案，下述通式(Ia)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the eleventh embodiment of the present invention, the compound represented by the following general formula (Ia) or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
L 1选自-O-、-OCH 2-、-OC(CH 3) 2-或-CH 2O-； L 1 is selected from -O-, -OCH 2 -, -OC(CH 3 ) 2 - or -CH 2 O-;
环B选自
Figure PCTCN2021117545-appb-000114
Figure PCTCN2021117545-appb-000115
其左侧与L 1相连； Ring B is selected from
Figure PCTCN2021117545-appb-000114
Figure PCTCN2021117545-appb-000115
Its left side is connected to L1 ;
Figure PCTCN2021117545-appb-000116
选自
Figure PCTCN2021117545-appb-000117
右侧与L 1直接连接；
Figure PCTCN2021117545-appb-000116
selected from
Figure PCTCN2021117545-appb-000117
The right side is directly connected to L 1 ;
R 1选自H、F、Cl、氰基、CF 3、甲基、乙基或甲氧基； R 1 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy;
R 2选自H、F、Cl、氰基、CF 3、甲基、乙基或甲氧基； R 2 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy;
R 3选自H、F、Cl、氰基、CF 3、甲基、乙基或甲氧基； R3 is selected from H, F, Cl, cyano, CF3 , methyl, ethyl or methoxy;
R 4选自H、F、Cl、氰基、CF 3、甲基、乙基或甲氧基； R 4 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy;
R 5选自
Figure PCTCN2021117545-appb-000118
Figure PCTCN2021117545-appb-000119
R 5 is selected from
Figure PCTCN2021117545-appb-000118
Figure PCTCN2021117545-appb-000119
Figure PCTCN2021117545-appb-000120
Figure PCTCN2021117545-appb-000120
作为本发明的第十二种实施方案，下述通式(Ia)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the twelfth embodiment of the present invention, the compound represented by the following general formula (Ia) or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
Y 1、Y 2选自CH，Y 3选自N或C； Y 1 and Y 2 are selected from CH, and Y 3 is selected from N or C;
Figure PCTCN2021117545-appb-000121
选自
Figure PCTCN2021117545-appb-000122
右侧与L 1直接连接；
Figure PCTCN2021117545-appb-000121
selected from
Figure PCTCN2021117545-appb-000122
The right side is directly connected to L 1 ;
L 1选自-O-、-OCH 2-； L 1 is selected from -O-, -OCH 2 -;
环B选自
Figure PCTCN2021117545-appb-000123
其左侧与L 1相连； Ring B is selected from
Figure PCTCN2021117545-appb-000123
Its left side is connected to L1 ;
R 1选自H、F、Cl、氰基、CF 3、甲基、乙基或甲氧基； R 1 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy;
R 2选自H、F、Cl、氰基、CF 3、甲基、乙基或甲氧基； R 2 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy;
R 3选自H、F、Cl、氰基、CF 3、甲基、乙基或甲氧基； R3 is selected from H, F, Cl, cyano, CF3 , methyl, ethyl or methoxy;
R 4选自H、F、Cl、氰基、CF 3、甲基、乙基或甲氧基； R 4 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy;
R 5与第十一种实施方案相同。 R 5 is the same as the eleventh embodiment.
本发明提供如下所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，The present invention provides the compounds shown below or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof,
Figure PCTCN2021117545-appb-000124
Figure PCTCN2021117545-appb-000124
Figure PCTCN2021117545-appb-000125
Figure PCTCN2021117545-appb-000125
Figure PCTCN2021117545-appb-000126
Figure PCTCN2021117545-appb-000126
Figure PCTCN2021117545-appb-000127
Figure PCTCN2021117545-appb-000127
Figure PCTCN2021117545-appb-000128
Figure PCTCN2021117545-appb-000128
Figure PCTCN2021117545-appb-000129
Figure PCTCN2021117545-appb-000129
Figure PCTCN2021117545-appb-000130
Figure PCTCN2021117545-appb-000130
Figure PCTCN2021117545-appb-000131
Figure PCTCN2021117545-appb-000131
Figure PCTCN2021117545-appb-000132
Figure PCTCN2021117545-appb-000132
Figure PCTCN2021117545-appb-000133
Figure PCTCN2021117545-appb-000133
Figure PCTCN2021117545-appb-000134
Figure PCTCN2021117545-appb-000134
Figure PCTCN2021117545-appb-000135
Figure PCTCN2021117545-appb-000135
Figure PCTCN2021117545-appb-000136
Figure PCTCN2021117545-appb-000136
Figure PCTCN2021117545-appb-000137
Figure PCTCN2021117545-appb-000137
Figure PCTCN2021117545-appb-000138
Figure PCTCN2021117545-appb-000138
Figure PCTCN2021117545-appb-000139
Figure PCTCN2021117545-appb-000139
Figure PCTCN2021117545-appb-000140
Figure PCTCN2021117545-appb-000140
Figure PCTCN2021117545-appb-000141
Figure PCTCN2021117545-appb-000141
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，Y 1、Y 2、Y 3各自独立的选自C、CH或N。 In some embodiments of the present invention relating to compounds represented by general formulae (I), (Ia) and (Ib), Y 1 , Y 2 and Y 3 are each independently selected from C, CH or N.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，Y 1、Y 2选自CH，Y 3选自N。 In some embodiments of the present invention relating to compounds represented by general formulae (I), (Ia) and (Ib), Y 1 and Y 2 are selected from CH, and Y 3 is selected from N.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，Y 1、Y 2、Y 3选自CH。 In some embodiments of the present invention relating to compounds represented by general formulae (I), (Ia) and (Ib), Y 1 , Y 2 and Y 3 are selected from CH.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，Y 1、Y 2选自CH，Y 3选自C。 In some embodiments of the present invention relating to compounds represented by general formulae (I), (Ia) and (Ib), Y 1 and Y 2 are selected from CH, and Y 3 is selected from C.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，Y 1、Y 2选自N，Y 3选自N。 In some embodiments of the present invention relating to compounds represented by general formulae (I), (Ia) and (Ib), Y 1 and Y 2 are selected from N, and Y 3 is selected from N.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，Y 1选自N，Y 2选自CH，Y 3选自C。 In some embodiments of the present invention relating to compounds represented by general formulae (I), (Ia) and (Ib), Y 1 is selected from N, Y 2 is selected from CH, and Y 3 is selected from C.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，Y 1选自CH，Y 2选自N，Y 3选自C。 In some embodiments of the present invention relating to compounds represented by general formulae (I), (Ia) and (Ib), Y 1 is selected from CH, Y 2 is selected from N, and Y 3 is selected from C.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，Y 1选自CH，Y 2选自N，Y 3选自N。 In some embodiments of the present invention relating to compounds represented by general formulae (I), (Ia) and (Ib), Y 1 is selected from CH, Y 2 is selected from N, and Y 3 is selected from N.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，环A选自5至6元杂环或杂芳环，所述的杂环或杂芳环任选进一步被0、1、2或3个R a取代基所取代，所述的杂环或杂芳环含有1至4个选自O、S、N的杂原子。 In some embodiments of the present invention relating to compounds represented by general formulae (I), (Ia) and (Ib), 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.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，
Figure PCTCN2021117545-appb-000142
选自
Figure PCTCN2021117545-appb-000143
Figure PCTCN2021117545-appb-000144
The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib),
Figure PCTCN2021117545-appb-000142
selected from
Figure PCTCN2021117545-appb-000143
Figure PCTCN2021117545-appb-000144
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，
Figure PCTCN2021117545-appb-000145
选自
Figure PCTCN2021117545-appb-000146
Figure PCTCN2021117545-appb-000147
X 1选自N或CR a。 The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib),
Figure PCTCN2021117545-appb-000145
selected from
Figure PCTCN2021117545-appb-000146
Figure PCTCN2021117545-appb-000147
X 1 is selected from N or CR a .
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，
Figure PCTCN2021117545-appb-000148
选自
Figure PCTCN2021117545-appb-000149
Figure PCTCN2021117545-appb-000150
The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib),
Figure PCTCN2021117545-appb-000148
selected from
Figure PCTCN2021117545-appb-000149
Figure PCTCN2021117545-appb-000150
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，
Figure PCTCN2021117545-appb-000151
选自
Figure PCTCN2021117545-appb-000152
Figure PCTCN2021117545-appb-000153
The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib),
Figure PCTCN2021117545-appb-000151
selected from
Figure PCTCN2021117545-appb-000152
Figure PCTCN2021117545-appb-000153
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R a各自独立的选自H、＝O、卤素、氰基、C 1-6烷基、C 1-6烷氧基、-(CH 2) q-C(＝O)-NR a1R a2、-(CH 2) q-NR a1R a2、-(CH 2) qNR a1C(＝O)-R a2、-(CH 2) q-C 3-10碳环或-(CH 2) q-3至12元杂环，所述的CH 2、烷基、烷氧基、碳环或杂环任选进一步被0、1、2、3或4个选自H、卤素、CF 3、OH、氰基、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环含有1、2或3个选自O、S、N的杂原子。 The present invention relates to some embodiments of the compounds represented by the general formulae (I), (Ia) and (Ib), R a is independently selected from H, =O, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, -(CH 2 ) q -C(=O)-NR a1 R a2 , -(CH 2 ) q -NR a1 R a2 , -(CH 2 ) q NR a1 C(=O) -R a2 , -(CH 2 ) q -C 3-10 carbocycle or -(CH 2 ) q -3- to 12-membered heterocycle, said CH 2 , alkyl, alkoxy, carbocycle or heterocycle optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, halogen, CF3 , OH, cyano, COOH, NH2 , C1-4alkyl or C1-4alkoxy Instead, the heterocycle contains 1, 2 or 3 heteroatoms selected from O, S, N.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R a选自H、卤素、氰基、C 1-4烷基、C 1-4烷氧基、-(CH 2) q-C(＝O)-NR a1R a2、-(CH 2) q-NR a1R a2、-(CH 2) qNR a1C(＝O)-R a2、-(CH 2) q-C 3-6碳环或-(CH 2) q-3至6元杂环，所述的CH 2、烷基、烷氧基、碳环或杂环任选进一步被0、1、2、3或4个选自H、卤素、CF 3、OH、氰基、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环含有1、2或3个选自O、S、N的杂原子。 The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R a is selected from H, halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy , -(CH 2 ) q -C(=O)-NR a1 R a2 , -(CH 2 ) q -NR a1 R a2 , -(CH 2 ) q NR a1 C(=O)-R a2 , -( CH 2 ) q -C 3-6 carbocyclic ring or -(CH 2 ) q -3- to 6-membered heterocyclic ring, said CH 2 , alkyl, alkoxy, carbocyclic or heterocyclic ring is optionally further substituted by O, 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 said Heterocycles contain 1, 2 or 3 heteroatoms selected from O, S, N.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R a选自H、F、Cl、Br、I、氰基、甲基、乙基、异丙基、丙基、甲氧基、乙氧基、丙氧基、-(CH 2) q-C(＝O)-NR a1R a2、-(CH 2) q-NR a1R a2、-(CH 2) qNR a1C(＝O)-R a2、环丙基、环丁基、环戊基、环己基、-CH 2-环丙基、-CH 2-环丁基、-CH 2-环戊基或-CH 2-环己基，所述的CH 2、甲基、乙基、异丙基、丙基、甲氧基、乙氧基、丙氧基、环丙基、环丁基或环戊基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、OH、氰基、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代。 The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R a is selected from H, F, Cl, Br, I, cyano, methyl, ethyl, isopropyl radical, propyl, methoxy, ethoxy, propoxy, -(CH 2 ) q -C(=O)-NR a1 R a2 , -(CH 2 ) q -NR a1 R a2 , -(CH 2 ) q NR a1 C(=O)-R a2 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclo Pentyl or -CH2 -cyclohexyl, said CH2 , methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl or cyclohexyl The pentyl group is optionally further replaced by 0, 1, 2, 3 or 4 groups selected from H, halogen, CF3 , OH, cyano, COOH, NH2 , C1-4alkyl or C1-4alkoxy Substituents are substituted.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R a选自H、F、Cl、氰基、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 2CH 3、-C(O)N(CH 2CH 3) 2、-C(O)NHCH 2CH 2OCH 3、-C(O)NH-环丙基、-C(O)NH-环丁基、-C(O)NH-环戊基、-C(O)NH-环已基、-NHC(O)CH 3、-NHC(O)CH 2CH 3、-NHC(O)-环丙基、-NHC(O)-环丁基、-NHC(O)-环戊基、-NHC(O)-环已基、环丙基、环丁基、环戊基、环己基、-CH 2-环丙基、-CH 2-环丁基、-CH 2-环戊基或-CH 2-环己基。 The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), 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)-cyclobutyl, - NHC(O)-cyclopentyl, -NHC(O)-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2 -cyclopropyl, -CH2 -cyclobutyl, -CH2 -cyclopentyl or -CH2 -cyclohexyl.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R a选自H。 In some embodiments of the present invention relating to compounds represented by general formulae (I), (Ia) and (Ib), R a is selected from H.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，环B选自C 3-10碳环，所述的碳环任选进一步被0、1、2、3或4个R b取代。 In some embodiments of the present invention relating to compounds represented by general formulae (I), (Ia) and (Ib), 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.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，环B选自C 3-6饱和或不饱和单环碳环、C 5-10饱和或不饱和螺环碳环、C 5-10饱和或不饱和并环碳环、C 5-10饱和或不饱和桥环碳环，所述碳环任选进一步被0、1、2、3或4个R b取代。 The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), 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.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，环B选自取代或者未取代的如下基团之一：环丙基、环丁基、环戊基、环己基、金刚烷基、双环[1.1.1]戊烷基、双环[2.2.1]庚烷基、立方烷基、双环[3.1.0]己烷基、双环[3.2.0]庚烷基、环戊基并环戊基、双环[4.2.0]辛烷基、双环[2.2.2]辛烷基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环己基，当被取代时，任选进一步被0、1、2、3或4个R b取代。 In some embodiments of the present invention relating to compounds represented by general formulae (I), (Ia) and (Ib), 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 substituted with 0, 1, 2, 3 or 4 R b .
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，环B选自取代的或者未取代的如下基团之一：
Figure PCTCN2021117545-appb-000154
Figure PCTCN2021117545-appb-000155
Figure PCTCN2021117545-appb-000156
当被取代时，任选进一步被0、1、2、3或4个R b取代，其左侧与L 1相连。 The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), ring B is selected from one of the following substituted or unsubstituted groups:
Figure PCTCN2021117545-appb-000154
Figure PCTCN2021117545-appb-000155
Figure PCTCN2021117545-appb-000156
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 .
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，环B选自
Figure PCTCN2021117545-appb-000157
Figure PCTCN2021117545-appb-000158
其左侧与L 1相连。 In some embodiments of the present invention relating to compounds represented by general formulae (I), (Ia) and (Ib), ring B is selected from
Figure PCTCN2021117545-appb-000157
Figure PCTCN2021117545-appb-000158
Its left side is connected to L1 .
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R b各自独立的选自H、卤素、氰基、C 1-6烷基或C 1-6烷氧基，所述的烷基或烷氧基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、OH、氰基、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基或C 3-8环烷基的取代基所取代。 In some embodiments of the present invention relating to compounds represented by general formulae (I), (Ia) and (Ib), 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.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R b各自独立的选自H、卤素、氰基、C 1-4烷基或C 1-4烷氧基，所述的烷基或烷氧基任选进一步被0、1、2、3或4 个选自H、卤素、CF 3、OH、氰基、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基或C 3-8环烷基的取代基所取代。 In some embodiments of the present invention relating to compounds represented by general formulae (I), (Ia) and (Ib), 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.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R b各自独立的选自H、F、Cl、Br、I、氰基、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基或丙氧基，所述的甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基或丙氧基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、OH、氰基、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基所取代。 In some embodiments of the present invention relating to compounds represented by general formulae (I), (Ia) and (Ib), 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.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R b各自独立的选自H、F、Cl、Br、I、氰基、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基或丙氧基，所述的甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基或丙氧基任选进一步被0、1、2、3或4个选自H、F、CF 3、OH、氰基、NH 2、-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 2CH 3) 2、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基、丙氧基、环丙基、环丁基或环戊基的取代基所取代。 In some embodiments of the present invention relating to compounds represented by general formulae (I), (Ia) and (Ib), 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 substituents of the base.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R b各自独立的选自H、F、Cl、氰基、甲基、乙基、异丙基、丙基、甲氧基或乙氧基，所述的甲基、乙基、异丙基、丙基、甲氧基或乙氧基任选进一步被0、1、2、3或4个选自H、F、CF 3、OH、氰基、NH 2、-N(CH 3) 2、-N(CH 2CH 3) 2、甲基、乙基、异丙基、丙基、环丙基或环丁基的取代基所取代。 In some embodiments of the present invention relating to compounds represented by general formulae (I), (Ia) and (Ib), 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.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，L 1选自键、-S(O) n-、-NR 1a-、-CR 1bR 1c-、-O(CR 1bR 1c) s-、-(CR 1bR 1c) sO-、-NR 1aCR 1bR 1c-、-NR 1aS(O) n-、-S(O) nNR 1a-、-NR 1aC(O)-、-C(O)NR 1a-、-SCR 1bR 1c-或-CR 1bR 1cS-。 The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), 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-.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，L 1选自键、-O-、-S(O) n-、-NR 1a-、-CR 1bR 1c-、-OCR 1bR 1c-、-O(CR 1bR 1c) 2-、-CR 1bR 1cO-、-NR 1aCR 1bR 1c-、-SCR 1bR 1c-或-CR 1bR 1cS-。 The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), 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-.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，L 1选自键、-O-、-S-、-NH-、-CH 2-、-S(O) 2-、-OCH 2-、-OCH(CH 3)-、-OC(CH 3) 2-、-OCH 2CH 2-、-CH 2O-、-NHCH 2-或-N(CH 3)-。 The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), 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 )-.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，L 1选自-O-、-NH-、-OCH 2-、-OC(CH 3) 2-、-CH 2O-或-NHCH 2-。 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 -.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，L 1选自-O-、-OCH 2-、-OC(CH 3) 2-或-CH 2O-。 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-.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 1a、R 1b或R 1c各自独立的选自H、C 1-4烷基或-(CH 2) p-C 3-6碳环，所述的烷基或碳环任选进一步被0、1、2、3或4个选自H、卤素、OH、CF 3、氰基、C 1-4烷基或C 1-4烷氧基的取代基所取代。 In some embodiments of the present invention relating to compounds represented by general formulae (I), (Ia) and (Ib), 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.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 1b、R 1c与其直接相连的碳原子一起形成3元碳环。 In some embodiments of the present invention relating to the compounds represented by the general formulae (I), (Ia) and (Ib), R 1b and R 1c together with the carbon atoms to which they are directly connected form a 3-membered carbocyclic ring.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，
Figure PCTCN2021117545-appb-000159
选自
Figure PCTCN2021117545-appb-000160
X 1选自N或CR a，右侧与L 1直接连接。 The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib),
Figure PCTCN2021117545-appb-000159
selected from
Figure PCTCN2021117545-appb-000160
X 1 is selected from N or CR a , and the right side is directly connected to L 1 .
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，
Figure PCTCN2021117545-appb-000161
选自
Figure PCTCN2021117545-appb-000162
X 1选自N或CH，右侧与L 1直接连接。 The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib),
Figure PCTCN2021117545-appb-000161
selected from
Figure PCTCN2021117545-appb-000162
X 1 is selected from N or CH, and the right side is directly connected to L 1 .
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，
Figure PCTCN2021117545-appb-000163
选自
Figure PCTCN2021117545-appb-000164
右侧与L 1直接连接 The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib),
Figure PCTCN2021117545-appb-000163
selected from
Figure PCTCN2021117545-appb-000164
The right side is directly connected to L 1
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，环C选自5-6元杂芳基或苯基，所述的杂芳基或苯基任选进一步被0、1、2、3或4个R c取代。 In some embodiments of the present invention relating to compounds represented by general formulae (I), (Ia) and (Ib), 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.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，环C选自吡啶，所述的吡啶任选进一步被0、1、2或3个R c取代。 In some embodiments of the present invention relating to compounds represented by general formulae (I), (Ia) and (Ib), ring C is selected from pyridine, and said pyridine is optionally further substituted by 0, 1, 2 or 3 R c .
本发明涉及通式(I)所示化合物的一些实施方案中，
Figure PCTCN2021117545-appb-000165
选自
Figure PCTCN2021117545-appb-000166
Figure PCTCN2021117545-appb-000167
The present invention relates to some embodiments of the compound represented by the general formula (I),
Figure PCTCN2021117545-appb-000165
selected from
Figure PCTCN2021117545-appb-000166
Figure PCTCN2021117545-appb-000167
本发明涉及通式(I)所示化合物的一些实施方案中，R c各自独立的选自H、卤素、OH、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、-(CH 2) m-C(＝O)-NR 3aR 3b、-(CH 2) m-NR 3aR 3b、-(CH 2) mNR 3aC(＝O)-R 3b、-(CH 2) m-C(＝O)R 3a、-(CH 2) m-C(＝O)OR 3a、-(CH 2) m-OC(＝O)R 3a、-(CH 2) m-3至12元杂环基或-(CH 2) m-C 3-10碳环基，所述的CH 2、烷基、烯基、炔基、烷氧基、碳环或杂环任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、-C 1-4亚烷基-羟基、C 3-6碳环基或3至8元杂环基的取代基所取代，所述的杂环基含有1、2或3个选自O、S、N的杂原子。 In some embodiments of the present invention relating to the compound represented by the general formula (I), R c is independently selected from H, halogen, OH, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 1-6 alkoxy, -(CH 2 ) m -C(=O)-NR 3a R 3b , -(CH 2 ) m -NR 3a R 3b , -(CH 2 ) m NR 3a C(=O)-R 3b , -(CH 2 ) m -C(=O)R 3a , -(CH 2 ) m -C(=O)OR 3a , -(CH 2 ) m -OC(=O ) R 3a , -(CH 2 ) m -3 to 12-membered heterocyclyl or -(CH 2 ) m -C 3-10 carbocyclyl, said CH 2 , alkyl, alkenyl, alkynyl, alkane Oxy, carbocycle or heterocycle is optionally further selected by 0, 1, 2, 3 or 4 from H, halogen, CF3 , =O, OH, cyano, COOH, NH2 , -NH( C1- 4 alkyl), -N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, -C 1-4 alkylene-hydroxy, C 3-6 carbocyclyl Or substituted with a 3- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from O, S, N.
本发明涉及通式(I)所示化合物的一些实施方案中，R c各自独立的选自R 1、R 2、R 3或R 4。 In some embodiments of the present invention relating to the compound represented by general formula (I), R c is each independently selected from R 1 , R 2 , R 3 or R 4 .
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 1、R 2、R 3、R 4各自独立的选自H、卤素、OH、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、-(CH 2) m-C(＝O)-NR 3aR 3b、-(CH 2) m-NR 3aR 3b、-(CH 2) mNR 3aC(＝O)-R 3b、-(CH 2) m-C(＝O)R 3a、-(CH 2) m-C(＝O)OR 3a、-(CH 2) m-OC(＝O)R 3a、-(CH 2) m-3至12元杂环基或-(CH 2) m-C 3-10碳环基，所述的CH 2、烷基、烯基、炔基、烷氧基、碳环或杂环任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、-C 1-4亚烷基-羟基、C 3-6碳环基或3至8元杂环基的取代基所取代，所述的杂环基含有1、2或3个选自O、S、N的杂原子。 The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 1 , R 2 , R 3 , R 4 are each independently selected from H, halogen, OH, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -(CH 2 ) m -C(=O)-NR 3a R 3b , -(CH 2 ) m -NR 3a R 3b , -(CH 2 ) m NR 3a C(=O)-R 3b , -(CH 2 ) m -C(=O)R 3a , -(CH 2 ) m -C( =O)OR 3a , -(CH 2 ) m -OC(=O)R 3a , -(CH 2 ) m -3- to 12-membered heterocyclyl or -(CH 2 ) m -C 3-10 carbocyclyl , the CH 2 , alkyl group, alkenyl group, alkynyl group, alkoxy group, carbocyclic ring or heterocyclic ring is optionally further selected by 0, 1, 2, 3 or 4 selected from H, halogen, CF 3 , =O , OH, cyano, COOH, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, - C 1-4 alkylene-hydroxyl group, C 3-6 carbocyclic group or 3- to 8-membered heterocyclic group substituents, the heterocyclic group contains 1, 2 or 3 selected from O, S, heteroatom of N.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 1、R 2、R 3、R 4各自独立的选自H、卤素、OH、氰基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、-(CH 2) m-C(＝O)-NR 3aR 3b、-(CH 2) m-NR 3aR 3b、-(CH 2) mNR 3aC(＝O)-R 3b、-(CH 2) m-C(＝O)R 3a、-(CH 2) m-C(＝O)OR 3a、-(CH 2) m-OC(＝O)R 3a、-(CH 2) m-3至10元杂环或-(CH 2) m-C 3-8碳环，所述的CH 2、烷基、烯基、炔基、烷氧基、碳环或杂环任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷 氧基、-C 1-4亚烷基-羟基、C 3-6环烷基或3至8元杂环基的取代基所取代，所述的杂环含有1、2或3个选自O、S、N的杂原子。 The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 1 , R 2 , R 3 , R 4 are each independently selected from H, halogen, OH, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -(CH 2 ) m -C(=O)-NR 3a R 3b , -(CH 2 ) m -NR 3a R 3b , -(CH 2 ) m NR 3a C(=O)-R 3b , -(CH 2 ) m -C(=O)R 3a , -(CH 2 ) m -C( =O)OR 3a , -(CH 2 ) m -OC(=O)R 3a , -(CH 2 ) m -3 to 10-membered heterocycle or -(CH 2 ) m -C 3-8 carbocycle, the Said CH 2 , alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle is optionally further selected by 0, 1, 2, 3 or 4 selected from H, halogen, CF 3 , =O, OH , cyano, COOH, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, -C 1 -4 alkylene-hydroxyl, C 3-6 cycloalkyl or 3- to 8-membered heterocyclic group substituents, the heterocyclic ring contains 1, 2 or 3 heterocyclic groups selected from O, S, N atom.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 1、R 2、R 3、R 4各自独立的选自H、F、Cl、Br、I、OH、氰基、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基、丙氧基、乙烯基、丙烯基、乙炔基、丙炔基、-(CH 2) m-C(＝O)-NR 3aR 3b、-(CH 2) m-NR 3aR 3b、-(CH 2) mNR 3aC(＝O)-R 3b、-(CH 2) m-环丙基、-(CH 2) m-环丁基、-(CH 2) m-环戊基、-(CH 2) m-环己基、-(CH 2) m-氮杂环丁基、-(CH 2) m-氧杂环丁基、-(CH 2) m-吡咯烷基、-(CH 2) m-四氢呋喃基、-(CH 2) m-哌啶基、-(CH 2) m-四氢吡喃基、-(CH 2) m-吗啉基、-(CH 2) m-哌嗪基或-(CH 2) m-氮杂环庚基，所述的CH 2、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基、丙氧基、环丙基、乙烯基、丙烯基、乙炔基、丙炔基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、四氢吡喃基、吗啉基、哌嗪基或氮杂环庚基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、-C 1-4亚烷基-羟基、C 3-6环烷基或3至8元杂环基的取代基所取代，所述的杂环含有1、2或3个选自O、S、N的杂原子。 The present invention relates to some embodiments of the compounds represented by general formula (I), (Ia), (Ib), R 1 , R 2 , R 3 , R 4 are each independently selected from H, F, Cl, Br, I , OH, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, -(CH 2 ) m -C(=O)-NR 3a R 3b , -(CH 2 ) m -NR 3a R 3b , -(CH 2 ) m NR 3a C(=O)-R 3b , -(CH 2 ) m -cyclopropyl, -( CH2 ) m -cyclobutyl, -( CH2 ) m -cyclopentyl, -( CH2 ) m -cyclohexyl, -( CH2 ) m -azetidinyl, -(CH 2 ) m -oxetanyl, -(CH 2 ) m -pyrrolidinyl, -(CH 2 ) m -tetrahydrofuranyl, -(CH 2 ) m -piperidinyl, -(CH 2 ) m -tetrahydropyranyl, -(CH 2 ) m -morpholinyl, -(CH 2 ) m -piperazinyl or -(CH 2 ) m -azepanyl, the CH 2 , methyl radical, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, vinyl, propenyl, ethynyl, propynyl, cyclobutyl, cyclopentyl radical, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl or azepanyl optionally further by 0, 1, 2, 3 or 4 selected from H, halogen, CF 3 , =O, OH, cyano, COOH, NH 2 , -NH(C 1-4 alkyl), -N(C 1- 4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, -C 1-4 alkylene-hydroxy, C 3-6 cycloalkyl or substituent of 3- to 8-membered heterocyclyl Instead, the heterocycle contains 1, 2 or 3 heteroatoms selected from O, S, N.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 1、R 2、R 3各自独立的选自H、F、Cl、Br、I、OH、氰基、-(CH 2) m-C(＝O)-NR 3aR 3b、-(CH 2) m-NR 3aR 3b、-(CH 2) mNR 3aC(＝O)-R 3b、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基或丙氧基，所述的CH 2、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基或丙氧基任选进一步被0、1、2、3或4个选自H、F、CF 3、OH、氰基、COOH、NH 2、-NHCH 3、-N(CH 3) 2、甲基、乙基、异丙基、丙基、乙炔基、甲氧基、乙氧基、丙氧基、-CH 2OH或-CH 2CH 2OH的取代基所取代。 The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 1 , R 2 , R 3 are each independently selected from H, F, Cl, Br, I, OH, cyano, -(CH 2 ) m -C(=O)-NR 3a R 3b , -(CH 2 ) m -NR 3a R 3b , -(CH 2 ) m NR 3a C(=O)-R 3b , Methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy, said CH 2 , methyl, ethyl, isopropyl, propyl, butyl, Methoxy, ethoxy or propoxy is optionally further 0, 1, 2, 3 or 4 selected from H, F, CF3 , OH, cyano, COOH, NH2 , -NHCH3 , -N (CH 3 ) 2 , methyl, ethyl, isopropyl, propyl, ethynyl, methoxy, ethoxy, propoxy, -CH 2 OH or -CH 2 CH 2 OH substituents .
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 4选自H、F、Cl、Br、I、OH、氰基、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基、丙氧基、乙烯基、丙烯基、乙炔基、丙炔基、-(CH 2) m-C(＝O)-NR 3aR 3b、-(CH 2) m-NR 3aR 3b、-(CH 2) mNR 3aC(＝O)-R 3b、-(CH 2) m-环丙基、-(CH 2) m-环丁基、-(CH 2) m-环戊基、-(CH 2) m-环己基、-(CH 2) m-氮杂环丁基、-(CH 2) m-氧杂环丁基、-(CH 2) m-吡咯烷基、-(CH 2) m-四氢呋喃基、-(CH 2) m-哌啶基、-(CH 2) m-四氢吡喃基、-(CH 2) m-吗啉基、-(CH 2) m-哌嗪基或-(CH 2) m-氮杂环庚基，所述的CH 2、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基、丙氧基、环丙基、乙烯基、丙烯基、乙炔基、丙炔基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、四氢吡喃基、吗啉基、哌嗪基或氮杂环庚基 任选进一步被0、1、2、3或4个选自H、F、＝O、OH、氰基、CF 3、COOH、NH 2、-NHCH 3、-N(CH 3) 2、甲基、乙基、异丙基、丙基、甲氧基、乙氧基、丙氧基、-CH 2OH、-CH 2CH 2OH、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、四氢吡喃基、吗啉基、哌嗪基或氮杂环庚基所取代。 The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 4 is selected from H, F, Cl, Br, I, OH, cyano, methyl, ethyl, Isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, -(CH 2 ) m -C(=O)-NR 3a R 3b , -(CH 2 ) m -NR 3a R 3b , -(CH 2 ) m NR 3a C(=O)-R 3b , -(CH 2 ) m -cyclopropyl, -(CH 2 ) m - cyclobutyl, -(CH 2 ) m -cyclopentyl, -(CH 2 ) m -cyclohexyl, -(CH 2 ) m -azetidinyl, -(CH 2 ) m -oxetanyl , -(CH 2 ) m -pyrrolidinyl, -(CH 2 ) m -tetrahydrofuranyl, -(CH 2 ) m -piperidinyl, -(CH 2 ) m -tetrahydropyranyl, -(CH 2 ) m -morpholinyl, -(CH 2 ) m -piperazinyl or -(CH 2 ) m -azepanyl, said CH 2 , methyl, ethyl, isopropyl, propyl, Butyl, methoxy, ethoxy, propoxy, cyclopropyl, vinyl, propenyl, ethynyl, propynyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, oxygen Heterocyclobutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl or azepanyl optionally further selected from 0, 1, 2, 3 or 4 From H, F, =O, OH, cyano, CF3 , COOH, NH2 , -NHCH3, -N( CH3 )2 , methyl, ethyl, isopropyl, propyl, methoxy, Ethoxy, propoxy, -CH 2 OH, -CH 2 CH 2 OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl , tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl or azepanyl.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 1、R 2各自独立的选自H、F、Cl、OH、CF 3、氰基、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基或丙氧基。 The present invention relates to some embodiments of compounds represented by general formulae (I), (Ia) and (Ib), 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.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 3选自H、F、Cl、OH、CF 3、-CN、-CH 2CN、-CH 2CH 2CN、NH 2、-N(CH 3) 2、-N(CH 2CH 3) 2、-C(O)NH 2、-CH 2C(O)NH 2、-C(O)NHCH 3、-NHC(O)CH 3、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基或丙氧基。 The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), 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.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 4选自H、F、OH、CF 3、NH 2、-CN、-CH 2CN、-CH 2CH 2CN、-NHCH 3、-N(CH 3) 2、-C(O)-NH 2、-CH 2C(O)-NH 2、-CH 2CH 2C(O)-NH 2、-C(O)NHCH 3、-C(O)N(CH 3) 2、-NHC(O)CH 3、甲基、乙基、异丙基、丙基、甲氧基、乙氧基、丙氧基、环丙基、-CH 2-环丙基、环丁基、-CH 2-环丁基、环戊基、-CH 2-环戊基、环己基、-CH 2-环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、四氢吡喃基、吗啉基或哌嗪基。 The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), 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, cyclohexyl, -CH2 -cyclohexyl, Azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl or piperazinyl.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 1选自H、F、Cl、氰基、CF 3、甲基、乙基或甲氧基。 In some embodiments of the present invention relating to compounds represented by general formulae (I), (Ia) and (Ib), R 1 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy .
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 2选自H、F、Cl、氰基、CF 3、甲基、乙基或甲氧基。 In some embodiments of the present invention relating to compounds represented by general formulae (I), (Ia) and (Ib), R 2 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy .
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 3选自H、F、Cl、氰基、CF 3、甲基、乙基或甲氧基。 In some embodiments of the present invention relating to compounds represented by general formula (I), (Ia), (Ib), R 3 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy .
本发明涉及通式(I)、(Ia)所示化合物的一些实施方案中，R 4选自H、F、Cl、氰基、CF 3、甲基、乙基或甲氧基。 In some embodiments of the present invention relating to compounds represented by general formula (I) and (Ia), R 4 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R a1、R a2、R 3a、R 3b各自独立的选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-12碳环基或3至12元杂环基，所述的烷基、烯基、炔基、烷氧基、碳环基或杂环基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、OH、氰基、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环基含有1至3个选自O、S、N的杂原子。 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.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R a1、R a2、R 3a、R 3b各自独立的选自H、C 1-4烷基、C 3-6碳环基或3至6元杂环基，所述的烷基、碳环基或杂环基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、OH、氰基、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环基含有1至3个选自O、S、N的杂原子。 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.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R a1、R a2、R 3a、R 3b各自独立的选自H、甲基、乙基、丙基、异丙基、丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基或哌啶基，所述的甲基、乙基、丙基、异丙基、丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基或哌啶基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、OH、氰基、COOH、C 1-4烷基或C 1-4烷氧基的取代基所取代。 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, cyano, COOH, C1-4alkyl or C1-4alkoxy .
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 3a、R 3b各自独立的选自H、甲基、乙基、丙基、异丙基、丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基或哌啶基，所述的甲基、乙基、丙基、异丙基、丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基或哌啶基任选进一步被0、1、2、3或4个选自H、F、CF 3、OH、氰基、COOH、甲基、乙基、异丙基、丙基、甲氧基、乙氧基或丙氧基的取代基所取代。 The present invention relates to some embodiments of the compounds represented by general formula (I), (Ia) and (Ib), 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, isopropyl, propyl, methoxy, ethoxy or propoxy .
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 5选自 The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 5 is selected from
Figure PCTCN2021117545-appb-000168
Figure PCTCN2021117545-appb-000168
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 5选自 The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 5 is selected from
Figure PCTCN2021117545-appb-000169
Figure PCTCN2021117545-appb-000169
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 5选自
Figure PCTCN2021117545-appb-000170
Figure PCTCN2021117545-appb-000171
The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 5 is selected from
Figure PCTCN2021117545-appb-000170
Figure PCTCN2021117545-appb-000171
Figure PCTCN2021117545-appb-000172
Figure PCTCN2021117545-appb-000172
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 5选自
Figure PCTCN2021117545-appb-000173
Figure PCTCN2021117545-appb-000174
The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 5 is selected from
Figure PCTCN2021117545-appb-000173
Figure PCTCN2021117545-appb-000174
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 5选自
Figure PCTCN2021117545-appb-000175
The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 5 is selected from
Figure PCTCN2021117545-appb-000175
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 5选自
Figure PCTCN2021117545-appb-000176
The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 5 is selected from
Figure PCTCN2021117545-appb-000176
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 5选自
Figure PCTCN2021117545-appb-000177
Figure PCTCN2021117545-appb-000178
The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 5 is selected from
Figure PCTCN2021117545-appb-000177
Figure PCTCN2021117545-appb-000178
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 5选自
Figure PCTCN2021117545-appb-000179
Figure PCTCN2021117545-appb-000180
The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 5 is selected from
Figure PCTCN2021117545-appb-000179
Figure PCTCN2021117545-appb-000180
Figure PCTCN2021117545-appb-000181
Figure PCTCN2021117545-appb-000181
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 5选自
Figure PCTCN2021117545-appb-000182
Figure PCTCN2021117545-appb-000183
The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 5 is selected from
Figure PCTCN2021117545-appb-000182
Figure PCTCN2021117545-appb-000183
Figure PCTCN2021117545-appb-000184
Figure PCTCN2021117545-appb-000184
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 5选自
Figure PCTCN2021117545-appb-000185
Figure PCTCN2021117545-appb-000186
The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 5 is selected from
Figure PCTCN2021117545-appb-000185
Figure PCTCN2021117545-appb-000186
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 5选自
Figure PCTCN2021117545-appb-000187
Figure PCTCN2021117545-appb-000188
The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 5 is selected from
Figure PCTCN2021117545-appb-000187
Figure PCTCN2021117545-appb-000188
Figure PCTCN2021117545-appb-000189
Figure PCTCN2021117545-appb-000189
Figure PCTCN2021117545-appb-000190
Figure PCTCN2021117545-appb-000190
Figure PCTCN2021117545-appb-000191
Figure PCTCN2021117545-appb-000191
Figure PCTCN2021117545-appb-000192
Figure PCTCN2021117545-appb-000192
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 5选自
Figure PCTCN2021117545-appb-000193
Figure PCTCN2021117545-appb-000194
The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 5 is selected from
Figure PCTCN2021117545-appb-000193
Figure PCTCN2021117545-appb-000194
Figure PCTCN2021117545-appb-000195
Figure PCTCN2021117545-appb-000195
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 5选自
Figure PCTCN2021117545-appb-000196
Figure PCTCN2021117545-appb-000197
The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 5 is selected from
Figure PCTCN2021117545-appb-000196
Figure PCTCN2021117545-appb-000197
Figure PCTCN2021117545-appb-000198
Figure PCTCN2021117545-appb-000198
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 5选自
Figure PCTCN2021117545-appb-000199
Figure PCTCN2021117545-appb-000200
The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 5 is selected from
Figure PCTCN2021117545-appb-000199
Figure PCTCN2021117545-appb-000200
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 5a、R 5b、R 5c各自独立的选自H、卤素、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8碳环基或3至10元杂环基，所述的烷基、烷氧基、碳环基或杂环基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3-6环烷基)、C 1-4烷基、C 1-4烷氧基或-SC 1-4烷基的取代基所取代，所述的杂环基含有1、2或3个选自O、S、N的杂原子。 The present invention relates to some embodiments of the compounds represented by general formula (I), (Ia), (Ib), R 5a , R 5b , R 5c are each independently selected from H, halogen, cyano, C 1-6 alkane group, C 1-6 alkoxy group, C 3-8 carbocyclic group or 3- to 10-membered heterocyclic group, the alkyl group, alkoxy group, carbocyclic group or heterocyclic group are optionally further replaced by 0, 1 , 2, 3 or 4 are selected from H, halogen, CF 3 , =O, OH, cyano, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -NH (C 3-6 cycloalkyl), C 1-4 alkyl, C 1-4 alkoxy or -SC 1-4 alkyl substituent, the heterocyclic group contains 1, 2 or 3 heteroatoms selected from O, S, N.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 5b与R 5c可形成化学键。 In some embodiments of the present invention relating to compounds represented by general formulae (I), (Ia) and (Ib), R 5b and R 5c can form a chemical bond.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 5d、R 5e各自独立的选自H、C 1-6烷基、C 3-8碳环基或3至10元杂环基，所述的烷基、碳环基或杂环基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3-6环烷基)、C 1-4烷基、C 1-4烷氧基或-SC 1-4烷基的取代基所取代，所述的杂环基含有1、2或3个选自O、S、N的杂原子。 The present invention relates to some embodiments of the compounds represented by the general formulae (I), (Ia) and (Ib), R 5d and R 5e are each independently selected from H, C 1-6 alkyl, C 3-8 carbocycle or a 3- to 10-membered heterocyclic group, the alkyl, carbocyclic or heterocyclic group is optionally further selected from 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 , =O, OH , cyano, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -NH(C 3-6 cycloalkyl), C 1-4 alkyl, C 1-4 alkoxy or -SC 1-4 alkyl substituent, the heterocyclic group contains 1, 2 or 3 heteroatoms selected from O, S, N.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 5d、R 5e与其直接相连的氮原子一起形成4至8元杂环基，所述杂环基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、C 1-4烷基、C 1-4烷氧基或-C 1-4亚烷基-C 1-4烷氧基的取代基取代，所述杂环基含有1、2或3个选自O、S、N的杂原子。 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 group is optionally further selected by 0, 1, 2, 3 or 4 groups selected from H, halogen, CF3 , =O, OH, cyano, C1-4alkyl , C1-4alkoxy or -C1 Substituent substitution of -4 alkylene-C 1-4 alkoxy, the heterocyclic group contains 1, 2 or 3 heteroatoms selected from O, S, N.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 5a、R 5b、R 5c各自独立的选自H、卤素、氰基、C 1-4烷基、C 1-4烷氧基、3至6元碳环基或3至8元杂环基，所述的烷基、烷氧基、碳环基或杂环基任选进一步被0、1、2、3或4个选自H、卤素、＝O、OH、氰基、CF 3、C 1-4烷基、C 1-4烷氧基或-SC 1-4烷基的取代基所取代，所述的杂环基含有1、2或3个选自O、S、N的杂原子。 The present invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib), R 5a , R 5b , R 5c are each independently selected from H, halogen, cyano, C 1-4 alkane base, C 1-4 alkoxy, 3- to 6-membered carbocyclic group or 3- to 8-membered heterocyclic group, the alkyl, alkoxy, carbocyclic or heterocyclic group is optionally further replaced by 0, 1 , 2, 3 or 4 substituents selected from H, halogen, =O, OH, cyano, CF 3 , C 1-4 alkyl, C 1-4 alkoxy or -SC 1-4 alkyl Alternatively, the heterocyclyl group contains 1, 2 or 3 heteroatoms selected from O, S and N.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 5d、R 5e各自独立的选自H、C 1-4烷基、3至6元碳环或3至8元杂环，所述的烷基、碳环或杂环任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3-6环烷基)、C 1-4烷基、C 1-4烷氧基或-SC 1-4烷基的取代基所取代，所述的杂环含有1、2或3个选自O、S、N的杂原子。 The present invention relates to some embodiments of the compounds represented by the general formulae (I), (Ia) and (Ib), R 5d and R 5e are each independently selected from H, C 1-4 alkyl, 3- to 6-membered carbocyclic rings or a 3- to 8-membered heterocycle, the alkyl, carbocycle or heterocycle is optionally further substituted by 0, 1, 2, 3 or 4 selected from H, halogen, CF 3 , =O, OH, cyano, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -NH(C 3-6 cycloalkyl), C 1-4 alkyl, C 1-4 alkane substituted by oxy or -SC 1-4 alkyl substituent, the heterocycle contains 1, 2 or 3 heteroatoms selected from O, S, N.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 5d、R 5e与其直接相连的氮原子一起形成4至6元杂环，所述杂环任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、C 1-4烷基、C 1-4烷氧基或-C 1-4亚烷基-C 1-4烷氧基的取代基取代，所述杂环含有1、2或3个选自O、S、N的杂原子； 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 the nitrogen atom directly connected to them form a 4- to 6-membered heterocyclic ring, and the heterocyclic ring can be any is further selected by 0, 1, 2, 3 or 4 selected from H, halogen, CF 3 , =O, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy or -C 1-4 Substituent substitution of alkylene-C 1-4 alkoxy, the heterocycle contains 1, 2 or 3 heteroatoms selected from O, S, N;
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 5a、R 5b、R 5c各自独立的选自H、F、Cl、Br、I、氰基、甲基、乙基、丙基、异丙基、丁基、甲氧基、乙氧基、丙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基或哌啶基，所述的甲基、乙基、丙基、异丙基、丁基、甲氧基、乙氧基、丙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基或哌啶基任选进一步被0、1、2、3或4个选自H、卤素、＝O、OH、氰基、CF 3、C 1-4烷基、C 1-4烷氧基或-SC 1-4烷基的取代基所取代。 The present invention relates to some embodiments of the compounds represented by the general formulae (I), (Ia) and (Ib), 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, 1, 2, 3 or 4 from H, halogen, = O, OH, cyano, CF 3 , C 1-4 alkyl, C 1-4 alkoxy or -SC 1-4 alkyl substituent.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 5d、R 5e各自独立的选自H、甲基、乙基、丙基、异丙基、丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基或吗啉基，所述的甲基、乙基、丙基、异丙基、丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基或吗啉基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、NH 2、- NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3-6环烷基)、C 1-4烷基、C 1-4烷氧基或-SC 1-4烷基的取代基所取代，所述的杂环含有1、2或3个选自O、S、N的杂原子。 The present invention relates to some embodiments of compounds represented by general formula (I), (Ia) and (Ib), R 5d and R 5e are each independently selected from H, methyl, ethyl, propyl, isopropyl, Butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, oxetanyl, pyrrolidinyl, piperidinyl or morpholinyl, the methyl, ethyl , propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl or morpholinyl selected further by 0, 1, 2, 3 or 4 selected from H, halogen, CF 3 , =O, OH, cyano, NH 2 , -NH(C 1-4 alkyl), -N(C 1- 4 alkyl) 2 , -NH(C 3-6 cycloalkyl), C 1-4 alkyl, C 1-4 alkoxy or -SC 1-4 alkyl substituent, the hetero The ring contains 1, 2 or 3 heteroatoms selected from O, S, N.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 5d、R 5e与其直接相连的氮原子一起形成氮杂环丁基、吡咯基、吡咯烷基、哌嗪基、哌啶基、吗啉基或硫代吗啉基，所述氮杂环丁基、吡咯基、吡咯烷基、哌嗪基、哌啶基、吗啉基或硫代吗啉基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、C 1-4烷基、C 1-4烷氧基或-C 1-4亚烷基-C 1-4烷氧基的取代基取代。 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 The group is optionally further selected by 0, 1, 2, 3 or 4 groups selected from H, halogen, CF3 , =O, OH, cyano, C1-4alkyl , C1-4alkoxy or -C1 Substituent substitution of -4 alkylene-C 1-4 alkoxy.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 5f选自H、C 1-6烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基取代。 In some embodiments of the present invention relating to compounds represented by general formulae (I), (Ia) and (Ib), R 5f is selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, the alkane The radical or cycloalkyl is optionally further selected by 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 , =O, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituent.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 5f选自H、C 1-6烷基、-C 0-4烷基-3至8元杂环基、-C 1-4烷基-C 3-6环烷基、C 3-6环烷基，所述的烷基、环烷基或杂环基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、-C(＝O)NH(C 1-4烷基)、-C(＝O)N(C 1-4烷基) 2、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3-6环烷基)、3至8元杂环基的取代基取代，所述杂环基含有1、2或3个选自O、S、N的杂原子。 The present invention relates to some embodiments of the compounds represented by general formula (I), (Ia), (Ib), R 5f is selected from H, C 1-6 alkyl, -C 0-4 alkyl-3- to 8-membered Heterocyclic group, -C 1-4 alkyl group-C 3-6 cycloalkyl group, C 3-6 cycloalkyl group, said alkyl group, cycloalkyl group or heterocyclic group are optionally further replaced by 0, 1, 2 , 3 or 4 are selected from H, halogen, CF 3 , =O, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, -C(=O )NH(C 1-4 alkyl), -C(=O)N(C 1-4 alkyl) 2 , NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkane base) 2 , -NH(C 3-6 cycloalkyl), substituents of 3- to 8-membered heterocyclic groups containing 1, 2 or 3 heteroatoms selected from O, S, N .
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 5f选自H、C 1-4烷基、3至8元杂环基、-C 1-4烷基-3至8元杂环基、-C 1-4烷基-C 3-6环烷基或C 3-6环烷基，所述的烷基、环烷基或杂环基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、C 1-4烷基、C 1-4烷氧基、NH 2、-C(＝O)NH(C 1-4烷基)、-C(＝O)N(C 1-4烷基) 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3-6环烷基)、3至8元杂环基、C 3-6环烷基的取代基取代，所述杂环基含有1、2或3个选自O、S、N的杂原子。 In some embodiments of the present invention relating to compounds represented by general formulae (I), (Ia) and (Ib), R 5f is selected from H, C 1-4 alkyl, 3- to 8-membered heterocyclyl, -C 1- 4 -alkyl-3- to 8-membered heterocyclic group, -C 1-4 alkyl-C 3-6 cycloalkyl or C 3-6 cycloalkyl, said alkyl, cycloalkyl or heterocyclic group is any selected further by 0, 1, 2, 3 or 4 selected from H, halogen, CF 3 , =O, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy, NH 2 , -C (=O)NH(C 1-4 alkyl), -C(=O)N(C 1-4 alkyl) 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkane base) 2 , -NH(C 3-6 cycloalkyl), 3- to 8-membered heterocyclic group, C 3-6 cycloalkyl substituent, the heterocyclic group contains 1, 2 or 3 selected from Heteroatoms of O, S, N.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 5f选自H、C 1-4烷基、3至8元杂环基、-C 1-2烷基-3至8元杂环基、-C 1-2烷基-C 3-6环烷基或C 3-6环烷基，所述的烷基、环烷基或杂环基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、C 1-4烷基、C 1-4烷氧基、NH 2、-C(＝O)NH(C 1-4烷基)、-C(＝O)N(C 1-4烷基) 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3-6环烷基)、3至8元杂环基、C 3-6环烷基的取代基取代，所述杂环基含有1、2或3个选自O、S、N的杂原子。 In some embodiments of the present invention relating to compounds represented by general formulae (I), (Ia) and (Ib), R 5f is selected from H, C 1-4 alkyl, 3- to 8-membered heterocyclyl, -C 1- 2 -alkyl-3- to 8-membered heterocyclic group, -C 1-2 alkyl-C 3-6 cycloalkyl or C 3-6 cycloalkyl, said alkyl, cycloalkyl or heterocyclic group is any selected further by 0, 1, 2, 3 or 4 selected from H, halogen, CF 3 , =O, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy, NH 2 , -C (=O)NH(C 1-4 alkyl), -C(=O)N(C 1-4 alkyl) 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkane base) 2 , -NH(C 3-6 cycloalkyl), 3- to 8-membered heterocyclic group, C 3-6 cycloalkyl substituent, the heterocyclic group contains 1, 2 or 3 selected from Heteroatoms of O, S, N.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 5f选自H或者取代的或者未取代的如下基团之一：甲基、乙基、丙基、丁基、异丙基、异丁基、氮杂环丁基、氮杂环戊基、氮杂环已基、哌嗪基、氧杂环丁基、氧杂环戊基、氧杂环已基、吗啉基、- CH 2-氮杂环丁基、-CH 2-氮杂环戊基、-CH 2-氮杂环已基、-CH 2-哌嗪、-CH 2-氧杂环丁基、-CH 2-氧杂环戊基、-CH 2-氧杂环已基、-CH 2-吗啉、-CH 2CH 2-氮杂环丁基、-CH 2CH 2-氮杂环戊基、-CH 2CH 2-氮杂环已基、-CH 2CH 2-哌嗪、-CH 2CH 2-氧杂环丁基、-CH 2CH 2-氧杂环戊基、-CH 2CH 2-氧杂环已基、-CH 2CH 2-吗啉、-CH 2-噻唑、-CH 2-噻吩、-CH 2-吡咯、-CH 2-吡唑、-CH 2-咪唑、-CH 2-呋喃、-CH 2-噁唑、-CH 2-吡咯、-CH 2-吡啶、
Figure PCTCN2021117545-appb-000201
Figure PCTCN2021117545-appb-000202
当被取代时，任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、C 1-4烷基、C 1-4烷氧基、NH 2、-C(＝O)NH(C 1-4烷基)、-C(＝O)N(C 1-4烷基) 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3-6环烷基)、3至8元杂环基、C 3-6环烷基的取代基取代，所述杂环基含有1、2或3个选自O、S、N的杂原子。 In some embodiments of the present invention relating to compounds represented by general formulae (I), (Ia) and (Ib), 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, -CH 2 CH 2 -nitrogen Heterocyclopentyl, -CH 2 CH 2 -azepinyl, -CH 2 CH 2 -piperazine, -CH 2 CH 2 -oxetanyl, -CH 2 CH 2 -oxolane, -CH2CH2-oxetyl, -CH2CH2-morpholine, -CH2 - thiazole, -CH2 - thiophene, -CH2 - pyrrole, -CH2 - pyrazole, -CH2- Imidazole, -CH2 -furan, -CH2 -oxazole, -CH2 -pyrrole, -CH2 -pyridine,
Figure PCTCN2021117545-appb-000201
Figure PCTCN2021117545-appb-000202
When substituted, optionally further by 0, 1, 2, 3 or 4 selected from H, halogen, CF 3 , =O, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy , NH 2 , -C(=O)NH(C 1-4 alkyl), -C(=O)N(C 1-4 alkyl) 2 , -NH(C 1-4 alkyl), -N (C 1-4 alkyl) 2 , -NH(C 3-6 cycloalkyl), 3- to 8-membered heterocyclic group, substituent substitution of C 3-6 cycloalkyl, the heterocyclic group contains 1, 2 or 3 heteroatoms selected from O, S, N.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 5f选自H、C 1-4烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0、1、2、3或4个选自H、卤素、CF 3、＝O、OH、氰基、C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基取代。 In some embodiments of the present invention relating to compounds represented by general formulae (I), (Ia) and (Ib), R 5f is selected from H, C 1-4 alkyl or C 3-6 cycloalkyl, the alkane The radical or cycloalkyl is optionally further selected by 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 , =O, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituent.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，R 5f选自H、甲基、乙基、
Figure PCTCN2021117545-appb-000203
In some embodiments of the present invention relating to compounds represented by general formula (I), (Ia) and (Ib), R 5f is selected from H, methyl, ethyl,
Figure PCTCN2021117545-appb-000203
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，n、s选自0、1或2。In some embodiments of the present invention relating to compounds represented by general formulae (I), (Ia) and (Ib), n and s are selected from 0, 1 or 2.
本发明涉及通式(I)、(Ia)、(Ib)所示化合物的一些实施方案中，m、p、q各自独立的选自0、1、2、3或4。In some embodiments of the present invention relating to compounds represented by general formulae (I), (Ia) and (Ib), m, p and q are each independently selected from 0, 1, 2, 3 or 4.
本发明涉及一种药物组合物，包括任意上述化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，以及药学上可接受的载体。The present invention relates to 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.
本发明涉及任意上述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶在用于制备药物的用途，所述药物用于预防或治疗与JAK3激酶活性或表达量相关疾病的药物中的。在某些实施方案中，所述疾病选自免疫系统相关疾病。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. In certain embodiments, the disease is selected from immune system related diseases.
在某些实施方案中，所述疾病选自类风湿性关节炎(RA)、炎症肠炎、克罗恩病。In certain embodiments, the disease is selected from rheumatoid arthritis (RA), inflammatory bowel disease, Crohn's disease.
在另一个方面，本发明提供了一种预防或治疗与JAK激酶活性或表达量相关疾病(例如上文所述的疾病)的方法，其包括下列步骤：将预防或治疗有效量的本发明的化合物或其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，或者上述药物组合物施用于对其有需求的个体。In another aspect, 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.
术语“个体”(或称受试者)是指人类或非人动物。The term "individual" (or subject) refers to a human or non-human animal.
本领域的参考书和专著，详细介绍了可用于制备本文所述化合物的反应物的合成，或提供了描述该制备方法的文章以供参考。这些参考书和专著包括：“Synthetic Organic Chemistry”,John Wiley&Sons,Inc.,New York；S.R.Sandler et al.,“Organic Functional Group Preparations,”2nd Ed.,Academic Press,New York,1983；H.O.House,“Modern Synthetic Reactions”,2nd Ed.,W.A.Benjamin,Inc.Menlo Park,Calif.1972；T.L.Gilchrist,“Heterocyclic Chemistry”,2nd Ed.,John Wiley&Sons,New York,1992；J.March,“Advanced Organic Chemistry:Reactions,Mechanisms and Structure”,4th Ed.,Wiley-Interscience,New York,1992；Fuhrhop,J.and Penzlin G.“Organic Synthesis:Concepts,Methods,Starting Materials”,Second,Revised and Enlarged Edition(1994)John Wiley&Sons ISBN:3-527-29074-5；Hoffman,R.V.“Organic Chemistry,An Intermediate Text”(1996)Oxford University Press,ISBN 0-19-509618-5；Larock,R.C.“Comprehensive Organic Transformations:A Guide to Functional Group Preparations”2nd Edition(1999)Wiley-VCH,ISBN:0-471-19031-4；March,J.“Advanced Organic Chemistry:Reactions,Mechanisms,and Structure”4th Edition(1992)John Wiley&Sons,ISBN:0-471-60180-2；Otera,J.(editor)“Modern Carbonyl Chemistry”(2000)Wiley-VCH,ISBN:3-527-29871-1；Patai,S.“Patai’s 1992 Guide to the Chemistry of Functional Groups”(1992)Interscience ISBN:0-471-93022-9；Solomons,T.W.G.“Organic Chemistry”7th Edition(2000)John Wiley&Sons,ISBN:0-471-19095-0；Stowell,J.C.,“Intermediate Organic Chemistry”2nd Edition(1993)Wiley-Interscience,ISBN:0-471-57456-2；“Industrial Organic Chemicals:Starting Materials and Intermediates:An Ullmann’s Encyclopedia”(1999)John Wiley&Sons,ISBN:3-527-29645-X,in 8volumes；“Organic Reactions”(1942-2000)John Wiley&Sons,in over 55 volumes；and“Chemistry of Functional Groups”John Wiley&Sons,in 73 volumes.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. March, "Advanced Organic Chemistry" : Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992; Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0 -471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemist ry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, TWG "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, JC, "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2 "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes ; and "Chemistry of Functional Groups" by John Wiley & Sons, in 73 volumes.
通过美国化学会化学文摘社制备的已知化学物质的索引，可以选择性地识别特定和类似的反应物，这些索引可在大多数公共图书馆和大学图书馆以及在线获得。已知但在目录中不可商购的化学品可选地由定制化学合成工厂制备，其中许多标准化学供应工厂(例如，上面列出的那些)提供定制合成服务。制备和选择本文所述化合物的药用盐的参考文献是P.H.Stahl&C.G.Wermuth“Handbook of Pharmaceutical Salts”,Verlag Helvetica Chimica Acta,Zurich,2002.Specific and similar reactants can be selectively identified through indexes of known chemicals prepared by the Chemical Abstracts Service of the American Chemical Society, available in most public and university libraries and online. Chemicals that are known but not commercially available in the catalog are optionally prepared by custom chemical synthesis facilities, many of which standard chemical supply facilities (eg, those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutically acceptable salts of the compounds described herein is P.H. Stahl & C.G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.
合成方法一：Synthesis method one:
Figure PCTCN2021117545-appb-000204
Figure PCTCN2021117545-appb-000204
R 10选自卤素或者OH； R 10 is selected from halogen or OH;
R 11选自卤素，优选自Br、Cl； R 11 is selected from halogen, preferably from Br, Cl;
R 12选自氨基保护基或者H； R 12 is selected from amino protecting group or H;
PG 1选自氨基保护基； PG 1 is selected from amino protecting groups;
其余基团定义与说明书一致；The definitions of other groups are consistent with the description;
通式(Ia-1)化合物通过亲核取代反应或者偶联反应得到通式(Ia-2)化合物；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);
通式(Ia-2)化合物通过偶联反应得到通式(Ia-3)化合物；或者通式(Ia-2)化合物先通过偶联反应、再通过脱去羟基保护基得到通式(Ia-3)化合物；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;
通式(Ia-3)化合物通过脱去氨基保护基得到通式(Ia-4)化合物；The compound of general formula (Ia-3) is obtained by removing the amino protecting group to obtain the compound of general formula (Ia-4);
通式(Ia-4)化合物通过缩合反应或者亲核取代反应得到通式(I)化合物。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).
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, terms used in the specification and claims have the following meanings.
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括 12C、 13C和 14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位素包括 16O、 17O和 18O，硫的同位素包括 32S、 33S、 34S和 36S，氮的同位素包括 14N和 15N，氟的同位素包括 17F和 19F，氯的同位素包括 35Cl和 37Cl，溴的同位素包括 79Br和 81Br。 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.
“卤素”是指F、Cl、Br或I。"Halogen" means F, Cl, Br or I.
“烷基”是指1至20个碳原子的直链或支链饱和脂肪族烃基，优选为1至8个碳原子的烷基，更优选为1至6个碳原子的烷基，进一步优选为1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体；所述的烷基可以任选进一步被0至6个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、烷基氨基、酰胺基、烯基、 炔基、C 1-6烷基、C 1-6羟基烷基、C 1-6烷氧基、3至8元碳环基、3至8元杂环基、3至8元碳环基氧基、3至8元杂环基氧基、羧基或者羧酸酯基的取代基所取代，本文中出现的烷基，其定义与本定义一致。 "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, and alkyl groups appearing herein, have the same definition as this definition.
“亚烷基”是指直链和支链的二价饱和烃基，包括-(CH 2) v-(v为1至10的整数)，亚烷基实施例包括但不限于亚甲基、亚乙基、亚丙基和亚丁基等；所述的亚烷基可以任选进一步被0至5个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、烷基氨基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。本文中出现的亚烷基，其定义与本定义一致。 "Alkylene" refers to linear and branched divalent saturated hydrocarbon groups, including -(CH 2 ) v - (v is an integer from 1 to 10). Examples of 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.
“环烷基”是指一价饱和的碳环烃基，通常有3至10个碳原子，非限制性实施例包括环丙基、环丁基、环戊基、环己基或环庚基等。所述的环烷基可以任选进一步被0至5个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、烷基氨基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。本文中出现的环烷基，其定义如上所述。"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.
“烯基”是指直链和支链的一价不饱和烃基，其具有至少1个，通常有1、2或3个碳碳双键，主链包括2至10个碳原子，进一步优选2至6个碳原子，更优选在主链上有2至4个碳原子，烯基实施例包括但不限于乙烯基、烯丙基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-甲基-1-丁烯基、2-甲基-1-丁烯基、2-甲基-3-丁烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、1-甲基-1-戊烯基、2-甲基-1-戊烯基、1-庚烯基、2-庚烯基、3-庚烯基、4-庚烯基、1-辛烯基、3-辛烯基、1-壬烯基、3-壬烯基、1-癸烯基、4-癸烯基、1,3-丁二烯、1,3-戊二烯、1,4-戊二烯和1,4-己二烯等；所述的烯基可以任选进一步被0至5个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、烷基氨基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。本文中出现的烯基，其定义与本定义一致。"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, examples of 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-heptenyl, 4-heptenyl, 1-octene base, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1, 4-pentadiene and 1,4-hexadiene, etc.; the alkenyl 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, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate substitution base substituted. Alkenyl groups appearing herein are defined in accordance with this definition.
“炔基”是指直链和支链的一价不饱和烃基，其具有至少1个，通常有1、2或3个碳碳三键，主链包括2至10个碳原子，进一步优选2至6个碳原子，更优选在主链上有2至4个碳原子，炔基实施例包括但不限于乙炔基、炔丙基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、1-戊炔基、2-戊炔基、3-戊炔基、4-戊炔基、1-甲基-1-丁炔基、2-甲基-1-丁炔基、2-甲基-3-丁炔基、1-己炔基、2-己炔基、3-己炔基、4-己炔基、5-己炔基、1-甲基-1-戊炔基、2-甲基-1-戊炔基、1-庚炔基、2-庚炔基、3-庚炔基、4-庚炔基、1-辛炔基、3-辛炔基、1-壬炔基、3-壬炔基、1-癸炔基、4-癸炔基等；所述的炔基可以任选 进一步被0至5个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、烷基氨基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。本文中出现的炔基，其定义与本定义一致。"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, examples of 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, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-heptynyl Octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, etc.; the alkynyl group can be optionally further selected from 0 to 5 From F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, Substituents of carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate. Alkynyl groups appearing herein are defined in accordance with this definition.
“烷氧基”是指-O-烷基。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。所述的烷氧基可以任选进一步被0至5个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、烷基氨基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。本文中出现的烷氧基，其定义与本定义一致。"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.
“碳环基”或“碳环”是指取代的或未取代的饱和或不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环体系，碳环基可以连接在芳香环上或者非芳香环上，芳香环或者非芳香环任选为单环、桥环或者螺环。非限制性实施例包括环丙烷、环丁烷、环戊烷、环己烷、环庚烷、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-2-烯基、1-环己基-3-烯基、环己烯基、苯环、萘环、
Figure PCTCN2021117545-appb-000205
所述的碳环可以任选进一步被0至5个选自F、Cl、Br、I、＝O、羟基、巯基、硝基、氰基、氨基、烷基氨基、酰胺基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。本文中出现的碳环或碳环基，其定义与本定义一致。 "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. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl Pentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring,
Figure PCTCN2021117545-appb-000205
Said carbocycle may optionally be further selected from 0 to 5 groups selected from F, Cl, Br, I, =O, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, amido, alkenyl, alkyne is substituted with a substituent of a radical, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate. Where carbocycle or carbocyclyl occurs herein, the definition is consistent with this definition.
“杂环基”或“杂环”是指取代的或未取代的饱和或不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环体系，且包含1至3个选自N、O或S的杂原子，优选3至8元杂环基，杂环基的环中选择性取代的N、S可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上，杂环基可以连接在芳香环上或者非芳香环上，杂环基可以连接有桥环或者螺环，非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、吡啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、吗啉基、硫代吗啉基、1,3-二噻基、二氢呋喃基、二氢吡喃基、二噻戊环基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、吡咯基、吡唑基、噻唑基、噁唑基、吡嗪基、吲唑基、苯并噻吩基、苯并呋喃基、苯并吡咯基、苯并咪唑 基、苯并噻唑基、苯并噁唑基、苯并吡啶基、苯并嘧啶基、苯并吡嗪基、哌嗪基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基、氧杂螺[3.3]庚烷基、
Figure PCTCN2021117545-appb-000206
Figure PCTCN2021117545-appb-000207
Figure PCTCN2021117545-appb-000208
所述的杂环基可以任选进一步被0至5个选自F、Cl、Br、I、＝O、羟基、巯基、硝基、氰基、氨基、烷基氨基、酰胺基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。本文中出现的杂环基，其定义与本定义一致。 "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, Tetrahydrofuranyl, Tetrahydropyrrolyl, Tetrahydroimidazolyl, Tetrahydrothiazolyl, Tetrahydropyran base, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl , benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azadi Cyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptyl alkyl,
Figure PCTCN2021117545-appb-000206
Figure PCTCN2021117545-appb-000207
Figure PCTCN2021117545-appb-000208
The heterocyclic group can be optionally further selected from 0 to 5 groups selected from F, Cl, Br, I, =O, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, amide, alkenyl, Substituents of alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate. Heterocyclyl groups appearing herein are defined in accordance with this definition.
“螺环”是指取代的或未取代的单环之间共用一个原子(称螺原子)的5至20元多环基团，其可以包含0至5个双键，且可以含有0至5个选自N、O或S(＝O) n的杂原子(其中n为0、1、2)。优选为6至14元，进一步优选为6至12元，更优选6至10元，其非限定性实例包括： "Spirocycle" refers to a 5- to 20-membered polycyclic group of substituted or unsubstituted monocyclic rings sharing one atom (called a spiro atom), which may contain 0 to 5 double bonds, and may contain 0 to 5 a heteroatom selected from N, O or S(=O) n (where n is 0, 1, 2). It is preferably 6 to 14 yuan, more preferably 6 to 12 yuan, more preferably 6 to 10 yuan, and non-limiting examples thereof include:
Figure PCTCN2021117545-appb-000209
Figure PCTCN2021117545-appb-000210
当被取代时，取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、甲酸酯、-(CH 2) m-C(＝O)-R a、-O-(CH 2) m-C(＝O)-R a、-(CH 2) m-C(＝O)-NR bR c、-(CH 2) mS(＝O) nR a、-(CH 2) m-烯基-R a、OR d或-(CH 2) m-炔基-R a(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NR bR c等基团，其中R b与R c独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，R b与R c可形成五或六元环烷基或杂环 基。R a与R d各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。本文中出现的螺环，其定义与本定义一致。
Figure PCTCN2021117545-appb-000209
Figure PCTCN2021117545-appb-000210
When substituted, the substituents may be 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano radical, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro, cyclo, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH 2 ) m -C(=O)-R a , -O-(CH 2 ) m -C(=O)-R a , -(CH 2 ) m -C(=O)-NR b R c , - (CH 2 ) m S(=O) n R a , -(CH 2 ) m -alkenyl-R a , OR d or -(CH 2 ) m -alkynyl-R a (wherein m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c and other groups, wherein R b and R c are independently selected from including H, hydroxyl, amino, carbonyl, alkyl, alkoxy , cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, alternatively, R b and R c may form a five- or six-membered cycloalkyl or heterocyclyl group. 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.
“并环”是指系统中的每个环与体系中的其他环共享毗邻的一对原子的多环基团，其中一个或多个环可以含有0个或多个双键，且可以是取代的或未取代，并环体系中的各个环可以含0至5个选自N、S(＝O) n或O的杂原子(其中n为0、1、2)。优选为5至20元，进一步优选为5至14元，更有选5至12元，再进一步优选5至10元。非限定性实例包括：
Figure PCTCN2021117545-appb-000211
Figure PCTCN2021117545-appb-000212
"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 Each ring in a substituted or unsubstituted ring system may contain 0 to 5 heteroatoms selected from N, S(=O) n or O (wherein n is 0, 1, 2). It is preferably 5 to 20 yuan, more preferably 5 to 14 yuan, more preferably 5 to 12 yuan, and still more preferably 5 to 10 yuan. Non-limiting examples include:
Figure PCTCN2021117545-appb-000211
Figure PCTCN2021117545-appb-000212
当被取代时，取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、甲酸酯、-(CH 2) m-C(＝O)-R a、-O-(CH 2) m-C(＝O)-R a、-(CH 2) m-C(＝O)-NR bR c、-(CH 2) mS(＝O) nR a、-(CH 2) m-烯基-R a、OR d或-(CH 2) m-炔基-R a(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NR bR c等基团，其中R b与R c独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，R b与R c可形成五或六元环烷基或杂环基。R a与R d各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。本文中出现的并环，其定义与本定义一致。 When substituted, the substituents may be 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano radical, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro, cyclo, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH 2 ) m -C(=O)-R a , -O-(CH 2 ) m -C(=O)-R a , -(CH 2 ) m -C(=O)-NR b R c , - (CH 2 ) m S(=O) n R a , -(CH 2 ) m -alkenyl-R a , OR d or -(CH 2 ) m -alkynyl-R a (wherein m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c and other groups, wherein R b and R c are independently selected from including H, hydroxyl, amino, carbonyl, alkyl, alkoxy , cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, alternatively, R b and R c may form a five- or six-membered cycloalkyl or heterocyclyl group. 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.
“桥环”是指任意两个不直接连接的原子的多环基团，可以含有0个或多个双键，且可以是取代的或未取代的，并环体系中的任意环可以含0至5个选自N、S(＝O)n或O杂原子或基团(其中n为0、1、2)。环原子包含5至20个原子，优选为5至14个原子，进一步优选5至12个，在进一步优选5至10个。非限定性实例包括
Figure PCTCN2021117545-appb-000213
Figure PCTCN2021117545-appb-000214
和金刚烷。当被取代时，取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、甲酸酯、-(CH 2) m-C(＝O)-R a、-O-(CH 2) m-C(＝O)-R a、-(CH 2) m-C(＝O)-NR bR c、-(CH 2) mS(＝O) nR a、-(CH 2) m-烯基-R a、OR d或-(CH 2) m-炔基-R a(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NR bR c等基团，其中R b与R c独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，R b与R c可形成五或六元环烷基或杂环基。R a与R d各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。本文中出现的桥环，其定义与本定义一致。 "Bridged ring" refers to a polycyclic group of any two atoms that are not directly connected, may contain zero or more double bonds, and may be substituted or unsubstituted, and any ring in the ring system may contain zero or more double bonds. to 5 heteroatoms or groups selected from N, S(=O)n or O (where n is 0, 1, 2). 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
Figure PCTCN2021117545-appb-000213
Figure PCTCN2021117545-appb-000214
and adamantane. When substituted, the substituents may be 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano radical, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro, cyclo, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH 2 ) m -C(=O)-R a , -O-(CH 2 ) m -C(=O)-R a , -(CH 2 ) m -C(=O)-NR b R c , - (CH 2 ) m S(=O) n R a , -(CH 2 ) m -alkenyl-R a , OR d or -(CH 2 ) m -alkynyl-R a (wherein m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c and other groups, wherein R b and R c are independently selected from including H, hydroxyl, amino, carbonyl, alkyl, alkoxy , cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, alternatively, R b and R c may form a five- or six-membered cycloalkyl or heterocyclyl group. 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.
“碳螺环”、“螺环碳环基”、“螺碳环基”或者“碳螺环基”是指环体系仅有碳原子组成的“螺环”。本文中出现的“碳螺环”、“螺环碳环基”、“螺碳环基”或者“碳螺环基”，其定义与本定义一致。“碳并环”、“并环碳环基”、“并碳环基”或者“碳并环基”是指环体系仅有碳原子组成的“并环”。本文中出现的“碳并环”、“并环碳环基”、“并碳环基”或者“碳并环基”，其定义与本定义一致。"Carbospiro", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spirocycle" in which the ring system consists of only carbon atoms. "Carbospiro", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" appearing herein are defined in accordance with this definition. "Carbocyclyl", "carbocyclyl", "carbocyclyl" or "carbocyclyl" refers to a "carbocyclyl" in which the ring system consists of only carbon atoms. The occurrences of "carbocyclyl", "carbocyclyl", "carbocyclyl" or "carbocyclyl" herein are defined in accordance with the present definitions.
“碳桥环”、“桥环碳环基”、“桥碳环基”或者“碳桥环基”是指环体系仅有碳原子组成的“桥环”。本文中出现的“碳桥环”、“桥环碳环基”、“桥碳环基”或者“碳桥环基”，其定义与本定义一致。"Carbon-bridged ring", "bridged-ring carbocyclyl", "bridged carbocyclyl" or "carbo-bridged cyclyl" 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.
“杂单环”、“单环杂环基”或“杂单环基”是指单环体系的“杂环基”或“杂环”，本文中出现的杂环基、“单环杂环基”或“杂单环基”，其定义与本定义一致。"Heterocyclyl", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a "heterocyclyl" or "heterocycle" of a monocyclic ring system, heterocyclyl, "monocyclic heterocyclyl" appearing herein group" or "heteromonocyclyl", as defined herein.
“杂并环”、“杂并环基”“并环杂环基”或“杂并环基”是指含有杂原子的“并环”。本文中出现的杂并环、“杂并环基”“并环杂环基”或“杂并环基”，其定义与本定义一致。"Heterocyclyl", "heterocyclyl", "heterocyclyl" or "heterocyclyl" refers to a "heterocyclyl" containing a heteroatom. As used herein, heterocyclyl, "heterocyclyl", "heterocyclyl" or "heterocyclyl" are defined in accordance with this definition.
“杂螺环”、“杂螺环基”、“螺环杂环基”或“杂螺环基”是指含有杂原子的“螺环”。本文中出现的杂螺环、“杂螺环基”、“螺环杂环基”或“杂螺环基”，其定义与本定义一致。"Heterospirocycle", "heterospirocyclyl", "spirocyclic heterocyclyl" or "heterospirocyclyl" refers to a "spirocycle" containing a heteroatom. As used herein, heterospirocycle, "heterospirocyclyl", "spirocyclic heterocyclyl" or "heterospirocyclyl" are defined in accordance with this definition.
“杂桥环”、“杂桥环基”、“桥环杂环基”或“杂桥环基”是指含有杂原子的“桥环”。本文中出现的杂桥环、“杂桥环基”、“桥环杂环基”或“杂桥环基”，其定义与本定义一致。"Heterobridged ring", "heterobridged cyclyl", "bridged heterocyclyl" or "heterobridged cyclyl" refers to a "bridged ring" containing a heteroatom. As used herein, a heterobridged ring, "heterobridged cyclyl", "bridged heterocyclyl" or "heterobridged cyclyl" is defined in accordance with this definition.
“芳基”或“芳环”是指具有单环或稠合环的一价芳香族烃基，通常有6至12个碳原子，且可以是取代的或未取代的。当被取代时，取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、甲酸酯、-(CH 2) m-C(＝O)-R a、-O-(CH 2) m-C(＝O)-R a、-(CH 2) m-C(＝O)-NR bR c、-(CH 2) mS(＝O) nR a、-(CH 2) m-烯基-R a、OR d或-(CH 2) m-炔基-R a(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NR bR c等基团，其中R b与R c独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，R b与R c可形成五或六元环烷基或杂环基。R a与R d各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。本文中出现的芳基或芳环，其定义与本定义一致。 "Aryl" or "aromatic ring" refers to a monovalent aromatic hydrocarbon group having a single or fused ring, usually 6 to 12 carbon atoms, and may be substituted or unsubstituted. When substituted, the substituents may be 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano radical, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro, cyclo, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH 2 ) m -C(=O)-R a , -O-(CH 2 ) m -C(=O)-R a , -(CH 2 ) m -C(=O)-NR b R c , - (CH 2 ) m S(=O) n R a , -(CH 2 ) m -alkenyl-R a , OR d or -(CH 2 ) m -alkynyl-R a (wherein m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c and other groups, wherein R b and R c are independently selected from including H, hydroxyl, amino, carbonyl, alkyl, alkoxy , cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, alternatively, R b and R c may form a five- or six-membered cycloalkyl or heterocyclyl group. 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.
“杂芳基”是指取代或未取代的5至15元芳香环，且含有1至5个选自N、O或S(＝O)n杂原子或基团(其中n为0、1、2)，优选5至10元杂芳香环，进一步优选5至6元。杂芳基的非限制性实施例包括但不限于吡啶基、呋喃基、噻吩基、吡啶基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、苯并吡唑、苯并咪唑、苯并吡啶、吡咯并吡啶等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，非限制性实施例包含
Figure PCTCN2021117545-appb-000215
当被取代时，取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、甲酸酯、-(CH 2) m-C(＝O)-R a、-O-(CH 2) m-C(＝O)-R a、-(CH 2) m-C(＝O)-NR bR c、-(CH 2) mS(＝O) nR a、-(CH 2) m-烯基-R a、OR d或-(CH 2) m-炔基-R a(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NR bR c等基团，其中R b与R c独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，R b与R c可形成五或六元环烷基或杂环基。R a与R d各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。本文中出现的杂芳基，其定义与本定义一致。 "Heteroaryl" refers to a substituted or unsubstituted 5- to 15-membered aromatic ring containing 1 to 5 heteroatoms or groups selected from N, O or S(=O)n (where n is 0, 1, 2), preferably a 5- to 10-membered heteroaromatic ring, more preferably a 5- to 6-membered ring. Non-limiting examples of 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
Figure PCTCN2021117545-appb-000215
When substituted, the substituents may be 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano radical, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro, cyclo, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH 2 ) m -C(=O)-R a , -O-(CH 2 ) m -C(=O)-R a , -(CH 2 ) m -C(=O)-NR b R c , - (CH 2 ) m S(=O) n R a , -(CH 2 ) m -alkenyl-R a , OR d or -(CH 2 ) m -alkynyl-R a (wherein m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c and other groups, wherein R b and R c are independently selected from including H, hydroxyl, amino, carbonyl, alkyl, alkoxy , cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, alternatively, R b and R c may form a five- or six-membered cycloalkyl or heterocyclyl group. 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.
“含有1至5个选自O、S、N的杂原子”是指含有1、2、3、4或5个选自O、S、N的杂原子。"Containing 1 to 5 heteroatoms selected from O, S, N" means containing 1, 2, 3, 4 or 5 heteroatoms selected from O, S, N.
“0至X个取代基所取代”是指被0、1、2、3….X个取代基所取代，X选自1至10之间的任意整数。如“0至4个取代基所取代”是指被0、1、2、3或4个取代基所取代。如“0至5个取代基所取代”是指被0、1、2、3、4或5个取代基所取代。如“杂桥环任选进一步被0至4个选自H或F的取代基所取代”是指杂桥环任选进一步被0、1、2、3或4个选自H或F的取代基所取代。"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. As in "substituted with 0 to 4 substituents" means substituted with 0, 1, 2, 3 or 4 substituents. As in "substituted with 0 to 5 substituents" means substituted with 0, 1, 2, 3, 4 or 5 substituents. Such as "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.
X-Y元的环(X选自小于Y大于等于3的整数，Y选自4至12之间的任意整数)包括了X+1、X+2、X+3、X+4….Y元的环。环包括了杂环、碳环、芳环、芳基、杂芳基、环烷基、杂单环、杂并环、杂螺环或杂桥环。如“4-7元杂单环”是指4元、5元、6元或7元的杂单环，“5-10元杂并环”是指5元、6元、7元、8元、9元或10元的杂并环。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. For example, "4-7 membered heteromonocycle" refers to a 4-membered, 5-membered, 6-membered or 7-membered heteromonocycle, and "5-10 membered heterocyclic ring" refers to 5-membered, 6-membered, 7-membered, 8-membered , 9- or 10-membered heterocyclic ring.
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生，该说明包括该事件或环境发生或不发生的场合。如：“任选被F取代的烷基”指烷基可以但不必须被F取代，说明包括烷基被F取代的情形和烷基不被F取代的情形。"Optional" or "optionally" means that the subsequently described event or circumstance can, but need not, occur, and that the description includes instances where the event or circumstance does or does not occur. For example, "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.
“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性，且所述的游离酸通过与无毒的无机碱或者有机碱，所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。"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.
“药物组合物”是指一种或多种本发明所述化合物、其药学上可接受的盐或前药和其它化学组分形成的混合物，其中，“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。"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.
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。"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.
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。"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.
“前药”是指可经体内代谢转化为具有生物活性的本发明化合物。本发明的前药通过修饰本发明化合物中的氨基或者羧基来制备，该修饰可以通过常规的操作或者在体内被除去，而得到母体化合物。当本发明的前药被施予哺乳动物个体时，前药被割裂形成游离的氨基或者羧基。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. When the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.
“共晶”是指活性药物成分(API)和共晶形成物(CCF)在氢键或其他非共价键的作用下结合而成的晶体，其中API和CCF的纯态在室温下均为固体，并且各组分间存在固定的化 学计量比。共晶是一种多组分晶体，既包含两种中性固体之间形成的二元共晶，也包含中性固体与盐或溶剂化物形成的多元共晶。"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.
“动物”是指包括哺乳动物，例如人、陪伴动物、动物园动物和家畜，优选人、马或者犬。"Animal" is meant to include mammals such as humans, companion animals, zoo animals and domestic animals, preferably humans, horses or dogs.
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和构象异构体。"Stereoisomers" refer to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
具体实施方式detailed description
以下实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited thereto.
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)； The structures of the compounds were determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10<" 6 > (ppm). NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instruments, and the solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) ), the internal standard is tetramethylsilane (TMS);
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))；For MS determination (Agilent 6120B (ESI) and Agilent 6120B (APCI));
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm,3.5μM)；The determination of HPLC uses an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM);
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm；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;
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体；Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;
本发明的己知起始原料可以采用或按照本领域已知的方法来合成，或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司；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;
SEM:
Figure PCTCN2021117545-appb-000216
THP:
Figure PCTCN2021117545-appb-000217
Boc：叔丁氧基羰基；Ms：
Figure PCTCN2021117545-appb-000218
TBS:
Figure PCTCN2021117545-appb-000219
MTBE:甲基叔丁基醚；Bn:
Figure PCTCN2021117545-appb-000220
SEM:
Figure PCTCN2021117545-appb-000216
THP:
Figure PCTCN2021117545-appb-000217
Boc: tert-butoxycarbonyl; Ms:
Figure PCTCN2021117545-appb-000218
TBS:
Figure PCTCN2021117545-appb-000219
MTBE: methyl tert-butyl ether; Bn:
Figure PCTCN2021117545-appb-000220
中间体I：6-溴-1-四氢吡喃-2-基-吲唑-4-醇Intermediate I: 6-Bromo-1-tetrahydropyran-2-yl-indazol-4-ol
6-bromo-1-tetrahydropyran-2-yl-indazol-4-ol6-bromo-1-tetrahydropyran-2-yl-indazol-4-ol
Figure PCTCN2021117545-appb-000221
Figure PCTCN2021117545-appb-000221
第一步：6-溴-4-氟-1H-吲唑(1b)Step 1: 6-Bromo-4-fluoro-1H-indazole (1b)
6-bromo-4-fluoro-1H-indazole6-bromo-4-fluoro-1H-indazole
在1000mL反应瓶中，依次加入1a(84g，380mmol)、80％水合肼(170mL)，1,4-二氧六环(400mL)，加完后在100℃下搅拌7h。冷却至室温，加入水(500mL)，搅拌析晶30min，过滤，滤饼加入二氯甲烷(160mL)，石油醚(800mL)，搅拌打浆1小时，抽滤，滤饼石油醚(100mL)洗涤一次，45℃减压干燥约18小时，得到1b，白色固体(76g，收率：92.9％)。In a 1000 mL reaction flask, 1a (84 g, 380 mmol), 80% hydrazine hydrate (170 mL), and 1,4-dioxane (400 mL) were sequentially added, and the mixture was stirred at 100° C. for 7 h after the addition. Cool to room temperature, add water (500mL), stir and crystallize for 30min, filter, add dichloromethane (160mL) and petroleum ether (800mL) to the filter cake, stir and beat for 1 hour, filter with suction, and wash the filter cake with petroleum ether (100mL) once , and dried under reduced pressure at 45°C for about 18 hours to obtain 1b as a white solid (76 g, yield: 92.9%).
LCMS m/z＝215.0/217.0[M+H] + LCMS m/z=215.0/217.0[M+H] +
第二步：6-溴-4-氟-1-四氢吡喃-2-基-吲唑(1c)Step 2: 6-Bromo-4-fluoro-1-tetrahydropyran-2-yl-indazole (1c)
6-bromo-4-fluoro-1-tetrahydropyran-2-yl-indazole6-bromo-4-fluoro-1-tetrahydropyran-2-yl-indazole
将1b(21.4g，99.55mmol)、二氯甲烷(220mL)和一水合对甲苯磺酸(1.89g，9.95mmol)加入到反应瓶中，水浴冷却下加入3,4-二氢-2H-吡喃(16.75g，199.10mmol)，加完室温搅拌反应4小时，TLC监控反应完全，加入饱和碳酸氢钠溶液(300mL×1)洗涤，有机层无水硫酸钠干燥，过滤，40℃减压浓缩干，加入甲醇50ml，冰水冷却下搅拌析晶1小时，过滤，滤饼40℃减压浓缩干得1c，土黄色固体(13g，收率：43.6％)。1b (21.4g, 99.55mmol), dichloromethane (220mL) and p-toluenesulfonic acid monohydrate (1.89g, 9.95mmol) were added to the reaction flask, and 3,4-dihydro-2H-pyridine was added under water bath cooling 16.75 g, 199.10 mmol) was added and stirred at room temperature for 4 hours. TLC monitored the reaction to complete the reaction. Saturated sodium bicarbonate solution (300 mL×1) was added for washing, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 40°C. Dry, add methanol 50ml, stir and crystallize under ice-water cooling for 1 hour, filter, and concentrate the filter cake under reduced pressure at 40°C to dryness to obtain 1c, a khaki solid (13g, yield: 43.6%).
1H NMR(400MHz,CDCl 3)δ8.03(s,1H),7.59(s,1H),6.97(dd,1H),5.65(dd,1H),4.06–3.95(m,1H),3.80–3.68(m,1H),2.60–2.40(m,1H),2.21–2.03(m,2H),1.82–1.61(m,3H). 1 H NMR (400MHz, CDCl 3 )δ8.03(s,1H), 7.59(s,1H), 6.97(dd,1H), 5.65(dd,1H), 4.06–3.95(m,1H), 3.80– 3.68 (m, 1H), 2.60–2.40 (m, 1H), 2.21–2.03 (m, 2H), 1.82–1.61 (m, 3H).
第三步：6-溴-4-甲氧基-1-四氢吡喃-2-基-吲唑(1d)The third step: 6-bromo-4-methoxy-1-tetrahydropyran-2-yl-indazole (1d)
6-bromo-4-methoxy-1-tetrahydropyran-2-yl-indazole6-bromo-4-methoxy-1-tetrahydropyran-2-yl-indazole
在50mL反应瓶中，依次加入甲醇(0.48g，15mmol)、NaH(0.8g，20mmol，60wt％)和N,N-二甲基甲酰胺(20mL)，加完后在0℃下搅拌20分钟，加入1c(2.99g，10mmol)并在室温下搅拌反应3h。反应液中加入乙酸乙酯(100mL)和水(100mL)，分液，有机相用水(100mL×2)洗涤，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(PE/EA＝10/1)得到1d，白色固体(1.76g，产率57％)。In a 50 mL reaction flask, methanol (0.48 g, 15 mmol), NaH (0.8 g, 20 mmol, 60 wt %) and N,N-dimethylformamide (20 mL) were sequentially added, and stirred at 0 °C for 20 minutes after the addition was complete. , 1c (2.99 g, 10 mmol) was added and the reaction was stirred at room temperature for 3 h. Ethyl acetate (100 mL) and water (100 mL) were added to the reaction solution, the layers were separated, the organic phase was washed with water (100 mL×2), the organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was passed through the column layer Segregation and purification (PE/EA=10/1) gave 1d as a white solid (1.76 g, yield 57%).
LCMS m/z＝311.0/313.0[M+H] + LCMS m/z=311.0/313.0[M+H] +
第四步：6-溴-1H-吲唑-4-醇(1e)Step 4: 6-Bromo-1H-indazol-4-ol (1e)
6-bromo-1H-indazol-4-ol6-bromo-1H-indazol-4-ol
在100mL反应瓶中，依次加入1d(1.76g，5.7mmol)和氢溴酸(30mL)，加完后在140℃下搅拌4h。反应液冷却至室温后用饱和碳酸氢钠溶液调节pH为8，然后用二氯甲烷(100mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(PE/EA＝5/1)得到1e，淡黄色固体(0.448g，产率37％).In a 100 mL reaction flask, 1d (1.76 g, 5.7 mmol) and hydrobromic acid (30 mL) were sequentially added, and the mixture was stirred at 140° C. for 4 h after the addition. The reaction solution was cooled to room temperature and adjusted to pH 8 with saturated sodium bicarbonate solution, then extracted with dichloromethane (100 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 passed through a column Chromatographic separation and purification (PE/EA=5/1) gave 1e as a pale yellow solid (0.448 g, yield 37%).
LCMS m/z＝213.0/215.1[M+H] + LCMS m/z=213.0/215.1[M+H] +
第五步：(6-溴-1H-吲唑-4-基)氧基-叔丁基-二甲基-硅烷(1f)Step 5: (6-Bromo-1H-indazol-4-yl)oxy-tert-butyl-dimethyl-silane (1f)
(6-bromo-1H-indazol-4-yl)oxy-tert-butyl-dimethyl-silane(6-bromo-1H-indazol-4-yl)oxy-tert-butyl-dimethyl-silane
在50mL反应瓶中，依次加入1e(0.44g，2.07mmol)、咪唑(0.42g，6.2mmol)和N,N-二甲基甲酰胺(20mL)，加完后加入叔丁基二甲基氯硅烷(0.62g，4.13mmol)，加完后在室温下搅拌10分钟。反应液中加入乙酸乙酯(50mL)，然后用饱和碳酸氢钠溶液(50mL×3)洗，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过快速柱层析分离纯化(PE/EA＝40/1)得到1f粗品，淡黄色油状物，直接用于下一步反应。In a 50 mL reaction flask, 1e (0.44 g, 2.07 mmol), imidazole (0.42 g, 6.2 mmol) and N,N-dimethylformamide (20 mL) were added in sequence, and tert-butyldimethyl chloride was added after the addition. Silane (0.62 g, 4.13 mmol) was added and stirred at room temperature for 10 minutes. Ethyl acetate (50 mL) was added to the reaction solution, then washed with saturated sodium bicarbonate solution (50 mL×3), the organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by flash column chromatography (PE/EA=40/1) to obtain 1f crude product as pale yellow oil, which was directly used in the next reaction.
第六步：(6-溴-1-四氢吡喃-2-基-吲唑-4-基)氧基-叔丁基-二甲基-硅烷(1g)The sixth step: (6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxy-tert-butyl-dimethyl-silane (1g)
(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxy-tert-butyl-dimethyl-silane(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxy-tert-butyl-dimethyl-silane
在50mL反应瓶中，依次加入1f粗品、一水合对甲苯磺酸(0.038g，0.2mmol)和二氯甲烷(20mL)，加完后加入3,4-二氢-2H-吡喃(0.52g，6.2mmol)，加完后在室温下搅拌20分钟。反应液中加入乙酸乙酯(50mL)，然后用饱和碳酸氢钠溶液(50mL×3)洗，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(PE/EA＝20/1)得到1g，淡黄色油状物(0.75g，两步产率88％)。In a 50mL reaction flask, 1f crude product, p-toluenesulfonic acid monohydrate (0.038g, 0.2mmol) and dichloromethane (20mL) were sequentially added, and 3,4-dihydro-2H-pyran (0.52g) was added after the addition. , 6.2 mmol), and stirred at room temperature for 20 minutes after the addition. Ethyl acetate (50 mL) was added to the reaction solution, then washed with saturated sodium bicarbonate solution (50 mL×3), the organic layer was 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=20/1) gave 1 g, pale yellow oil (0.75 g, 88% yield for two steps).
第七步：6-溴-1-四氢吡喃-2-基-吲唑-4-醇(中间体I)The seventh step: 6-bromo-1-tetrahydropyran-2-yl-indazol-4-ol (intermediate I)
6-bromo-1-tetrahydropyran-2-yl-indazol-4-ol6-bromo-1-tetrahydropyran-2-yl-indazol-4-ol
在50mL反应瓶中，依次加入1g(0.54g，1.32mmol)四氢呋喃(20mL)，加完后加入氢氧化钾(0.22g，3.96mmol)，加完后在室温下搅拌4小时。反应液中加入饱和氯化铵(40mL)，然后用乙酸乙酯(40mL×2)萃取，合并有机相用无水硫酸钠干燥，抽滤，滤液减压浓缩干，残留物通过柱层析分离纯化(PE/EA＝10/1到PE/EA＝1/1)得到中间体I，白色泡沫状固体(0.36g，产率92％)。In a 50 mL reaction flask, 1 g (0.54 g, 1.32 mmol) of tetrahydrofuran (20 mL) was successively added, potassium hydroxide (0.22 g, 3.96 mmol) was added after the addition, and the mixture was stirred at room temperature for 4 hours. Saturated ammonium chloride (40 mL) was added to the reaction solution, then extracted with ethyl acetate (40 mL×2), the combined organic phases were dried over anhydrous sodium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and the residue was separated by column chromatography Purification (PE/EA=10/1 to PE/EA=1/1) afforded Intermediate I as a white foamy solid (0.36 g, 92% yield).
LCMS m/z＝297.0/299.0[M+H] +； LCMS m/z=297.0/299.0[M+H] + ;
1H NMR(400MHz,CD 3OD)δ8.01(d,1H),7.40–7.24(m,1H),6.62(d,1H),5.68(dd,1H),4.04–3.93(m,1H),3.85–3.72(m,1H),2.51-2.36(m,1H),2.16-2.05(m,1H),2.03-1.95(m,1H),1.88–1.57(m,3H). 1 H NMR (400MHz, CD 3 OD) δ 8.01 (d, 1H), 7.40–7.24 (m, 1H), 6.62 (d, 1H), 5.68 (dd, 1H), 4.04–3.93 (m, 1H) ,3.85-3.72(m,1H),2.51-2.36(m,1H),2.16-2.05(m,1H),2.03-1.95(m,1H),1.88-1.57(m,3H).
实施例1：反式-(E)-4-(二甲基胺基)-N-[3-[[6-(4-羟基苯基)-1H-吲唑-4-基]氧基]环丁基]丁-2-烯酰胺(化合物1)Example 1: trans-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy] Cyclobutyl]but-2-enamide (Compound 1)
trans-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclobutyl]but-2-enamidetrans-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclobutyl]but-2-enamide
Figure PCTCN2021117545-appb-000222
Figure PCTCN2021117545-appb-000222
第一步：顺式-[3-(叔丁氧基羰基氨基)环丁基]甲磺酸酯(1B)The first step: cis-[3-(tert-butoxycarbonylamino)cyclobutyl]methanesulfonate (1B)
cis-[3-(tert-butoxycarbonylamino)cyclobutyl]methanesulfonatecis-[3-(tert-butoxycarbonylamino)cyclobutyl]methanesulfonate
在50mL反应瓶中，依次加入顺式-3-Boc氨基环丁醇(0.47g，2.5mmol)、三乙胺(0.51g，5mmol)和二氯甲烷(20mL)，加完后在0℃下搅拌20分钟，缓慢滴加甲基磺酰氯(0.37g，3.25mmol)并在室温下搅拌反应1h。反应液依次用水(30mL×1)、饱和食盐水(30mL×1)洗涤，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩得到1B粗品，淡黄色固体(0.647g)，直接用于下一步反应。In a 50 mL reaction flask, add cis-3-Boc aminocyclobutanol (0.47 g, 2.5 mmol), triethylamine (0.51 g, 5 mmol) and dichloromethane (20 mL) in sequence, and after adding, at 0 °C After stirring for 20 minutes, methylsulfonyl chloride (0.37 g, 3.25 mmol) was slowly added dropwise and the reaction was stirred at room temperature for 1 h. The 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.
第二步：反式-N-[3-(6-溴-1-四氢吡喃-2-基-吲唑-4-基)氧基环丁基]氨基甲酸叔丁酯(1C)The second step: tert-butyl trans-N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]carbamate (1C)
trans-tert-butyl N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]carbamatetrans-tert-butyl N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]carbamate
在50mL反应瓶中，依次加入6-溴-1-四氢吡喃-2-基-吲唑-4-醇(中间体I)(0.288g，0.97mmol)、1B粗品(0.33g)、碳酸铯(1.26g，3.87mmol)和N,N-二甲基甲酰胺(40mL)，加完后在90℃下搅拌反应5小时，反应液中加入乙酸乙酯(50mL)，然后用水(50mL×3)洗，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩得到1C，淡黄色油状物(0.38g，产率84％)。In a 50 mL reaction flask, 6-bromo-1-tetrahydropyran-2-yl-indazol-4-ol (Intermediate I) (0.288 g, 0.97 mmol), 1B crude product (0.33 g), carbonic acid were added in sequence Cesium (1.26g, 3.87mmol) and N,N-dimethylformamide (40mL) were added, and the reaction was stirred at 90°C for 5 hours. Ethyl acetate (50mL) was added to the reaction solution, followed by water (50mL× 3) Washed, the organic layer was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1C, a pale yellow oil (0.38 g, yield 84%).
LCMS m/z＝466.1/468.0[M+H] + LCMS m/z=466.1/468.0[M+H] +
第三步：反式-N-[3-[6-(4-羟基苯基)-1-四氢吡喃-2-基-吲唑-4-基]氧环丁基]氨基甲酸叔丁酯(1D)The third step: tert-butyl trans-N-[3-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclobutyl]carbamate Esters (1D)
trans-tert-butyl N-[3-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclobutyl]carbamatetrans-tert-butyl N-[3-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclobutyl]carbamate
在50mL反应瓶中，依次加入1C(0.38g，0.82mmol)、4-羟基苯硼酸(0.136g，0.98mmol)、七水合磷酸钾(0.83g，2.46mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(67mg，0.082mmol)和二氧六环/水(v/v＝4/1，10mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(PE/EA＝3/1)得到1D，淡黄色固体(0.28g，产率71％)。In a 50mL reaction flask, 1C (0.38g, 0.82mmol), 4-hydroxyphenylboronic acid (0.136g, 0.98mmol), potassium phosphate heptahydrate (0.83g, 2.46mmol), [1,1'-bis( Diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (67mg, 0.082mmol) and dioxane/water (v/v=4/1, 10mL), after nitrogen replacement three times, in The reaction was stirred at 90°C for 2 hours. 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 ID as a pale yellow solid (0.28 g, 71% yield).
第四步：反式-(E)-4-(二甲基氨基)-N-[3-[[6-(4-羟基苯基)-1H-吲唑-4-基]氧基]环丁基]丁-2-烯酰胺(化合物1)The fourth step: trans-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy] ring Butyl]but-2-enamide (Compound 1)
trans-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclobutyl]but-2-enamidetrans-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclobutyl]but-2-enamide
在50mL反应瓶中，加入1D(0.27g，0.56mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用MTBE(10mL×3)洗，然后减压浓缩干。所得残留物中依次加入反式-4-二甲基胺基巴豆酸盐酸盐(0.093g，0.56mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.216g，1.13mmol)、1-羟基苯并三唑(0.098g，0.73mmol)和N,N-二甲基甲酰胺(40mL)，加完后在室温下搅拌10分钟，加入N,N-二异丙基乙胺(0.45g，3.48mmol)，加完后在室温下搅拌50分钟。反应液中加入饱和碳酸氢钠(50mL)，然后用二氯甲烷/甲醇(v/v＝10/1)(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过制备液相(仪器：waters 2767制备液相；色谱柱:SunFire@Prep C18(19mm×150mm)；流动相组成：流动相A：乙腈流动相B：水(含5mM乙酸铵))分离纯化得到化合物1(76mg，产率33％)。In a 50 mL reaction flask, 1D (0.27 g, 0.56 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with MTBE (10 mL×3), and then concentrated to dryness under reduced pressure. To the obtained residue were added 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) and N,N-dimethylformamide (40 mL), stir at room temperature for 10 min after addition, add N , N-diisopropylethylamine (0.45 g, 3.48 mmol) was added and stirred at room temperature for 50 minutes. Saturated sodium bicarbonate (50 mL) was added to the reaction solution, then extracted with dichloromethane/methanol (v/v=10/1) (50 mL×2), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced in pressure Concentrated, the residue was passed through preparative liquid phase (instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm×150mm); mobile phase composition: mobile phase A: acetonitrile Mobile phase B: water (containing 5mM ammonium acetate) ) was isolated and purified to obtain compound 1 (76 mg, yield 33%).
LCMS m/z＝407.1[M+H] +； LCMS m/z=407.1[M+H] + ;
1H NMR(400MHz,CD 3OD)δ8.03(s,1H),7.51–7.43(m,2H),7.20(s,1H),6.91–6.83(m,2H),6.81-6.70(m,1H),6.50(s,1H),6.22–6.14(m,1H),5.19–5.09(m,1H),4.63–4.51(m,1H),3.36(dd,2H),2.76-2.65(m,2H),2.64-2.54(m,2H),2.45(s,6H). 1 H NMR (400MHz, CD 3 OD) δ8.03(s, 1H), 7.51-7.43(m, 2H), 7.20(s, 1H), 6.91-6.83(m, 2H), 6.81-6.70(m, 1H), 6.50 (s, 1H), 6.22–6.14 (m, 1H), 5.19–5.09 (m, 1H), 4.63–4.51 (m, 1H), 3.36 (dd, 2H), 2.76–2.65 (m, 2H), 2.64-2.54(m, 2H), 2.45(s, 6H).
实施例2：顺式-(E)-4-(二甲基氨基)-N-[3-[[6-(4-羟基苯基)-1H-吲唑-4-基]氧基]环丁基]丁-2-烯酰胺(化合物2)Example 2: cis-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]ring Butyl]but-2-enamide (compound 2)
cis-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclobutyl]but-2-enamidecis-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclobutyl]but-2-enamide
Figure PCTCN2021117545-appb-000223
Figure PCTCN2021117545-appb-000223
第一步：反式-[3-(叔丁氧基羰基氨基)环丁基]甲磺酸酯(2B)The first step: trans-[3-(tert-butoxycarbonylamino)cyclobutyl]methanesulfonate (2B)
trans-[3-(tert-butoxycarbonylamino)cyclobutyl]methanesulfonatetrans-[3-(tert-butoxycarbonylamino)cyclobutyl]methanesulfonate
在50mL反应瓶中，依次加入反式-3-Boc氨基环丁醇(0.5g，2.6mmol)、三乙胺(0.51g，5mmol)和二氯甲烷(10mL)，加完后在0℃下搅拌20分钟，缓慢滴加甲基磺酰氯(0.37g，3.25mmol)并在室温下搅拌反应1h。反应液依次用水(30mL×1)、饱和食盐水(30mL×1)洗涤，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩得到2B，粗品，淡黄色固体(0.67g)，直接用于下一步反应。In a 50 mL reaction flask, add trans-3-Boc aminocyclobutanol (0.5 g, 2.6 mmol), triethylamine (0.51 g, 5 mmol) and dichloromethane (10 mL) in sequence. After stirring for 20 minutes, methylsulfonyl chloride (0.37 g, 3.25 mmol) was slowly added dropwise and the reaction was stirred at room temperature for 1 h. The 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.
第二步：顺式-N-[3-(6-溴-1-四氢吡喃-2-基-吲唑-4-基)氧基环丁基]氨基甲酸叔丁酯(2C)The second step: cis-N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]carbamic acid tert-butyl ester (2C)
cis-tert-butyl N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]carbamatecis-tert-butyl N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]carbamate
在50mL反应瓶中，依次加入6-溴-1-四氢吡喃-2-基-吲唑-4-醇(中间体I)(0.57g，1.96mmol)、2B粗品(0.67g)、碳酸铯(2.52g，7.6mmol)和N,N-二甲基甲酰胺(40mL)，加完后在90℃下搅拌反应5小时，反应液中加入乙酸乙酯(50mL)，然后用水(50mL×3)洗，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩得到2C，淡黄色油状物(0.71g，产率82％)。In a 50 mL reaction flask, 6-bromo-1-tetrahydropyran-2-yl-indazol-4-ol (intermediate I) (0.57 g, 1.96 mmol), 2B crude product (0.67 g), carbonic acid were added in sequence Cesium (2.52g, 7.6mmol) and N,N-dimethylformamide (40mL) were added, and the reaction was stirred at 90°C for 5 hours. Ethyl acetate (50mL) was added to the reaction solution, followed by water (50mL× 3) Washed, the organic layer was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 2C, a pale yellow oil (0.71 g, yield 82%).
第三步：顺式-N-[3-[6-(4-羟基苯基)-1-四氢吡喃-2-基-吲唑-4-基]氧环丁基]氨基甲酸叔丁酯(2D)The third step: cis-N-[3-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclobutyl]carbamic acid tert-butyl Esters (2D)
cis-tert-butyl N-[3-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclobutyl]carbamatecis-tert-butyl N-[3-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclobutyl]carbamate
在50mL反应瓶中，依次加入2C(0.36g，0.81mmol)、4-羟基苯硼酸(0.136g，0.98mmol)、七水合磷酸钾(0.83g，2.46mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(67mg，0.082mmol)和二氧六环/水(v/v＝4/1，10mL)，氮气置换三次后，在90℃ 下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(PE/EA＝3/1)得到2D，淡黄色固体(0.31g，产率80％)。In a 50mL reaction flask, 2C (0.36g, 0.81mmol), 4-hydroxyphenylboronic acid (0.136g, 0.98mmol), potassium phosphate heptahydrate (0.83g, 2.46mmol), [1,1'-bis( Diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (67mg, 0.082mmol) and dioxane/water (v/v=4/1, 10mL), after nitrogen replacement three times, in The reaction was stirred at 90°C for 2 hours. 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 2D as a pale yellow solid (0.31 g, 80% yield).
LCMS m/z＝480.2[M+H] + LCMS m/z=480.2[M+H] +
第四步：顺式-(E)-4-(二甲基氨基)-N-[3-[[6-(4-羟基苯基)-1H-吲唑-4-基]氧基]环丁基]丁-2-烯酰胺(化合物2)The fourth step: cis-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy] ring Butyl]but-2-enamide (compound 2)
cis-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclobutyl]but-2-enamidecis-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclobutyl]but-2-enamide
在50mL反应瓶中，加入2D(0.31g，0.59mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用MTBE(10mL×3)洗，然后减压浓缩干。所得残留物中依次加入反式-4-二甲基胺基巴豆酸盐酸盐(0.093g，0.56mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.216g，1.13mmol)、1-羟基苯并三唑(0.098g，0.73mmol)和N,N-二甲基甲酰胺(40mL)，加完后在室温下搅拌10分钟，加入N,N-二异丙基乙胺(0.45g，3.48mmol)，加完后在室温下搅拌50分钟。反应液中加入饱和碳酸氢钠(50mL)，然后用二氯甲烷/甲醇(v/v＝10/1，50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过硅胶柱层析(二氯甲烷/甲醇(v/v＝20/1-10/1))纯化得到化合物2(26mg，产率11％)。In a 50 mL reaction flask, 2D (0.31 g, 0.59 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with MTBE (10 mL×3), and then concentrated to dryness under reduced pressure. To the obtained residue were added 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) and N,N-dimethylformamide (40 mL), stir at room temperature for 10 min after addition, add N , N-diisopropylethylamine (0.45 g, 3.48 mmol) was added and stirred at room temperature for 50 minutes. Saturated sodium bicarbonate (50 mL) was added to the reaction solution, then extracted with dichloromethane/methanol (v/v=10/1, 50 mL×2), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure , the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v=20/1-10/1)) to obtain compound 2 (26 mg, yield 11%).
LCMS m/z＝407.2[M+H] +； LCMS m/z=407.2[M+H] + ;
1H NMR(400MHz,DMSO-d 6)δ12.99(s,1H),9.52(s,1H),8.33(d,1H),7.97(s,1H),7.59–7.46(m,2H),7.17(s,1H),6.90–6.80(m,2H),6.63–6.50(m,2H),6.06–5.89(m,1H),4.87–4.63(m,1H),4.23–3.94(m,1H),3.03-2.88(m,4H),2.19–2.05(m,8H). 1 H NMR (400MHz, DMSO-d 6 )δ12.99(s,1H), 9.52(s,1H), 8.33(d,1H), 7.97(s,1H), 7.59-7.46(m,2H), 7.17(s,1H), 6.90–6.80(m,2H), 6.63–6.50(m,2H), 6.06–5.89(m,1H), 4.87–4.63(m,1H), 4.23–3.94(m,1H) ), 3.03-2.88(m, 4H), 2.19-2.05(m, 8H).
实施例3：反式-(E)-4-(二甲基胺基)-N-[3-[[6-(4-羟基苯基)-1H-吲唑-4-基]氧甲基]环丁基]丁-2-烯酰胺(化合物3)Example 3: trans-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxymethyl ]cyclobutyl]but-2-enamide (compound 3)
trans-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxymethyl]cyclobutyl]but-2-enamidetrans-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxymethyl]cyclobutyl]but-2-enamide
Figure PCTCN2021117545-appb-000224
Figure PCTCN2021117545-appb-000224
Figure PCTCN2021117545-appb-000225
Figure PCTCN2021117545-appb-000225
第一步：反式-[3-(叔丁氧基羰基氨基)环丁基]甲磺酸甲酯(3B)The first step: trans-[3-(tert-butoxycarbonylamino) cyclobutyl] methyl methanesulfonate (3B)
trans-[3-(tert-butoxycarbonylamino)cyclobutyl]methyl methanesulfonatetrans-[3-(tert-butoxycarbonylamino)cyclobutyl]methyl methanesulfonate
在50mL反应瓶中，依次加入反式-3-羟甲基环丁基氨基甲酸叔丁酯(0.4g，2.0mmol)、三乙胺(0.404g，4mmol)和二氯甲烷(10mL)，加完后在0℃下搅拌20分钟，缓慢滴加甲基磺酰氯(0.30g，2.6mmol)并在室温下搅拌反应1h。反应液依次用水(30mL×1)、饱和食盐水(30mL×1)洗涤，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩得到3B，粗品，淡黄色固体(0.51g)，直接用于下一步反应。In a 50 mL reaction flask, tert-butyl trans-3-hydroxymethylcyclobutylcarbamate (0.4 g, 2.0 mmol), triethylamine (0.404 g, 4 mmol) and dichloromethane (10 mL) were added in sequence, After stirring at 0°C for 20 minutes, methylsulfonyl chloride (0.30 g, 2.6 mmol) was slowly added dropwise and the reaction was stirred at room temperature for 1 h. The 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.
第二步：反式-N-[3-[(6-溴-1-四氢吡喃-2-基-吲唑-4-基)氧甲基]环丁基]氨基甲酸叔丁酯(3C)The second step: tert-butyl trans-N-[3-[(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxymethyl]cyclobutyl]carbamate ( 3C)
trans-tert-butyl N-[3-[(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxymethyl]cyclobutyl]carbamatetrans-tert-butyl N-[3-[(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxymethyl]cyclobutyl]carbamate
在100mL反应瓶中，依次加入6-溴-1-四氢吡喃-2-基-吲唑-4-醇(中间体I)(0.5g，1.69mmol)、3B粗品(0.51g)、碳酸铯(1.66g，5.07mmol)和N,N-二甲基甲酰胺(10mL)，加完后在75℃下搅拌反应2小时，反应液中加入乙酸乙酯(100mL)，然后用水(100mL×3)洗，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩得到3C，淡黄色泡沫状固体(0.712g，产率86％)。In a 100 mL reaction flask, 6-bromo-1-tetrahydropyran-2-yl-indazol-4-ol (intermediate I) (0.5 g, 1.69 mmol), 3B crude product (0.51 g), carbonic acid were added in sequence Cesium (1.66g, 5.07mmol) and N,N-dimethylformamide (10mL) were added, and the reaction was stirred at 75°C for 2 hours. Ethyl acetate (100mL) was added to the reaction solution, followed by water (100mL× 3) Washed, the organic layer was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 3C, a pale yellow foamy solid (0.712 g, yield 86%).
第三步：反式-N-[3-[[6-(4-羟基苯基)-1-四氢吡喃-2-基-吲唑-4-基]氧甲基]环丁基]氨基甲酸叔丁酯(3D)The third step: trans-N-[3-[[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxymethyl]cyclobutyl] tert-Butyl Carbamate (3D)
trans-tert-butyl N-[3-[[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxymethyl]cyclobutyl]carbamatetrans-tert-butyl N-[3-[[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxymethyl]cyclobutyl]carbamate
在100mL反应瓶中，依次加入3C(0.7g，1.46mmol)、4-羟基苯硼酸(0.25g，1.78mmol)、七水合磷酸钾(1.04，3.07mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(119mg，0.146mmol)和二氧六环/水(v/v＝4/1，10mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(PE/EA＝3/1)得到3D，淡黄色固体(0.66g，产率92％)。In a 100 mL reaction flask, 3C (0.7 g, 1.46 mmol), 4-hydroxyphenylboronic acid (0.25 g, 1.78 mmol), potassium phosphate heptahydrate (1.04, 3.07 mmol), [1,1'-bis(bis(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(bis(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di)-))”) however were added to the 100 mL reaction flask. Phenylphosphine)ferrocene]dichloropalladium dichloromethane complex (119mg, 0.146mmol) and dioxane/water (v/v=4/1, 10mL), after nitrogen replacement three times, at 90 The reaction was stirred at °C for 2 hours. 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).
LCMS m/z＝494.2[M+H] + LCMS m/z=494.2[M+H] +
第四步：反式-(E)-4-(二甲基氨基)-N-[3-[[6-(4-羟基苯基)-1H-吲唑-4-基]氧甲基]环丁基]丁-2-烯酰胺(化合物3)The fourth step: trans-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxymethyl] Cyclobutyl]but-2-enamide (Compound 3)
trans-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxymethyl]cyclobutyl]but-2-enamidetrans-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxymethyl]cyclobutyl]but-2-enamide
在50mL反应瓶中，加入3D(0.3g，0.61mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用MTBE(10mL×3)洗，然后减压浓缩干。所得残留物中依次加入反式-4-二甲基胺基巴豆酸盐酸盐(0.131g，0.79mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.232g，1.22mmol)、1-羟基苯并三唑(0.109g，0.81mmol)和N,N-二甲基甲酰胺(20mL)，加完后在室温下搅拌10分钟，加入N,N-二异丙基乙胺(0.47g，3.65mmol)，加完后在室温下搅拌50分钟。反应液中加入饱和碳酸氢钠(50mL)，然后用二氯甲烷/甲醇(v/v＝10/1，50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过制备液相(仪器：waters 2767制备液相；色谱柱:SunFire@Prep C18(19mm×150mm)；流动相组成：流动相A：乙腈流动相B：水(含5mM乙酸铵))分离纯化得到化合物3(81mg，产率32％)。In a 50 mL reaction flask, 3D (0.3 g, 0.61 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with MTBE (10 mL×3), and then concentrated to dryness under reduced pressure. To the obtained residue were added 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) and 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. Saturated sodium bicarbonate (50 mL) was added to the reaction solution, then extracted with dichloromethane/methanol (v/v=10/1, 50 mL×2), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure , the residue was passed through preparative liquid phase (instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm×150mm); mobile phase composition: mobile phase A: acetonitrile Mobile phase B: water (containing 5mM ammonium acetate)) Isolation and purification gave compound 3 (81 mg, yield 32%).
LCMS m/z＝421.2[M+H] +； LCMS m/z=421.2[M+H] + ;
1H NMR(400MHz,DMSO-d 6)δ8.32(d,1H),7.98(d,1H),7.61–7.50(m,2H),7.18(s,1H),6.91–6.82(m,2H),6.77(d,1H),6.66–6.45(m,1H),6.11–5.94(m,1H),4.57–4.46(m,1H),4.29(d,2H),2.98(dd,2H),2.74–2.64(m,1H),2.28–2.11(m,4H),1.88(s,6H). 1 H NMR (400MHz, DMSO-d 6 )δ8.32(d,1H),7.98(d,1H),7.61-7.50(m,2H),7.18(s,1H),6.91-6.82(m,2H) ),6.77(d,1H),6.66–6.45(m,1H),6.11–5.94(m,1H),4.57–4.46(m,1H),4.29(d,2H),2.98(dd,2H), 2.74–2.64 (m, 1H), 2.28–2.11 (m, 4H), 1.88 (s, 6H).
实施例4：顺式-(E)-4-(二甲基胺基)-N-[3-[[6-(4-羟基苯基)-1H-吲唑-4-基]氧甲基]环丁基]丁-2-烯酰胺(化合物4)Example 4: cis-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxymethyl ]cyclobutyl]but-2-enamide (compound 4)
cis-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxymethyl]cyclobutyl]but-2-enamidecis-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxymethyl]cyclobutyl]but-2-enamide
Figure PCTCN2021117545-appb-000226
Figure PCTCN2021117545-appb-000226
第一步：顺式-[3-(叔丁氧基羰基氨基)环丁基]甲磺酸甲酯(4B)The first step: cis-[3-(tert-butoxycarbonylamino) cyclobutyl] methyl methanesulfonate (4B)
cis-[3-(tert-butoxycarbonylamino)cyclobutyl]methyl methanesulfonatecis-[3-(tert-butoxycarbonylamino)cyclobutyl]methyl methanesulfonate
在50mL反应瓶中，依次加入顺式-3-羟甲基环丁基氨基甲酸叔丁酯(0.403g，2.0mmol)、三乙胺(0.404g，4mmol)和二氯甲烷(20mL)，加完后在0℃下搅拌20分钟，缓慢滴加甲基磺酰氯(0.30g，2.6mmol)并在室温下搅拌反应1h。反应液依次用水(30mL×1)、饱和食盐水(30mL×1)洗涤，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩得到4B粗品，淡黄色固体(0.677g)，直接用于下一步反应。In a 50 mL reaction flask, add tert-butyl cis-3-hydroxymethylcyclobutylcarbamate (0.403 g, 2.0 mmol), triethylamine (0.404 g, 4 mmol) and dichloromethane (20 mL) in turn, add After stirring at 0°C for 20 minutes, methylsulfonyl chloride (0.30 g, 2.6 mmol) was slowly added dropwise and the reaction was stirred at room temperature for 1 h. The 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.
LCMS m/z＝302.1[M+Na] + LCMS m/z=302.1[M+Na] +
第二步：顺式-N-[3-[(6-溴-1-四氢吡喃-2-基-吲唑-4-基)氧甲基]环丁基]氨基甲酸叔丁酯(4C)The second step: cis-N-[3-[(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxymethyl]cyclobutyl]carbamic acid tert-butyl ester ( 4C)
cis-tert-butyl N-[3-[(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxymethyl]cyclobutyl]carbamatecis-tert-butyl N-[3-[(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxymethyl]cyclobutyl]carbamate
在100mL反应瓶中，依次加入6-溴-1-四氢吡喃-2-基-吲唑-4-醇(中间体I)(0.6g，2.0mmol)、4B粗品(0.6g)、碳酸铯(2.6g，8.0mmol)和N,N-二甲基甲酰胺(40mL)，加完后在90℃下搅拌反应5小时，反应液中加入乙酸乙酯(100mL)，然后用水(100mL×3)洗，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩得到4C，淡黄色泡沫状固体(0.86g，产率90％)。In a 100 mL reaction flask, 6-bromo-1-tetrahydropyran-2-yl-indazol-4-ol (intermediate I) (0.6 g, 2.0 mmol), 4B crude product (0.6 g), carbonic acid were sequentially added Cesium (2.6g, 8.0mmol) and N,N-dimethylformamide (40mL) were added, and the reaction was stirred at 90°C for 5 hours. Ethyl acetate (100mL) was added to the reaction solution, followed by water (100mL× 3) Washed, the organic layer was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 4C, a pale yellow foamy solid (0.86 g, yield 90%).
LCMS m/z＝480.1/482.0[M+H] + LCMS m/z=480.1/482.0[M+H] +
第三步：顺式-N-[3-[[6-(4-羟基苯基)-1-四氢吡喃-2-基-吲唑-4-基]氧甲基]环丁基]氨基甲酸叔丁酯(4D)The third step: cis-N-[3-[[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxymethyl]cyclobutyl] tert-Butyl carbamate (4D)
cis-tert-butylN-[3-[[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxymethyl]cyclobutyl]carbamatecis-tert-butylN-[3-[[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxymethyl]cyclobutyl]carbamate
在100mL反应瓶中，依次加入4C(0.74g，1.54mmol)、4-羟基苯硼酸(0.26g，1.88mmol)、七水合磷酸钾(1.04，3.07mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(126mg，0.154mmol)和二氧六环/水(v/v＝4/1，10mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(PE/EA＝3/1)得到4D，淡黄色固体(0.75g，产率98％)。In a 100 mL reaction flask, 4C (0.74 g, 1.54 mmol), 4-hydroxyphenylboronic acid (0.26 g, 1.88 mmol), potassium phosphate heptahydrate (1.04, 3.07 mmol), [1,1'-bis(di(bis(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di))) however, were added to a 100 mL reaction flask. Phenylphosphine)ferrocene]dichloropalladium dichloromethane complex (126mg, 0.154mmol) and dioxane/water (v/v=4/1, 10mL), after nitrogen replacement three times, at 90 The reaction was stirred at °C for 2 hours. 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).
LCMS m/z＝494.2[M+H] + LCMS m/z=494.2[M+H] +
第四步：顺式-(E)-4-(二甲基胺基)-N-[3-[[6-(4-羟基苯基)-1H-吲唑-4-基]氧甲基]环丁基]丁-2-烯酰胺(化合物4)The fourth step: cis-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxymethyl ]cyclobutyl]but-2-enamide (compound 4)
cis-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxymethyl]cyclobutyl]but-2-enamidecis-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxymethyl]cyclobutyl]but-2-enamide
在50mL反应瓶中，加入4D(0.37g，0.75mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用MTBE(10mL×3)洗，然后减压浓缩干。所得残留物中依次加入反式-4-二甲基胺基巴豆酸盐酸盐(0.161g，0.97mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.288g，1.5mmol)、1-羟基苯并三唑(0.132g，1.0mmol)和N,N-二甲基甲酰胺(40mL)，加完后在室温下搅拌10分钟，加入N,N-二异丙基乙胺(0.58g，4.5mmol)，加完后在室温下搅拌50分钟。反应液中加入饱和碳酸氢钠(50mL)，然后用二氯甲烷/甲醇(v/v＝10/1，50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过制备液相(仪器：waters 2767制备液相；色谱柱:XBridge@Prep C18(30mm×150mm)；流动相组成：流动相A：乙腈，流动相B：水(含0.05％氨水))分离纯化得到化合物4(97mg，产率31％)。In a 50 mL reaction flask, 4D (0.37 g, 0.75 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with MTBE (10 mL×3), and then concentrated to dryness under reduced pressure. To the obtained residue were added 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) and N,N-dimethylformamide (40 mL), stir at room temperature for 10 minutes after addition, add N , N-diisopropylethylamine (0.58 g, 4.5 mmol) was added and stirred at room temperature for 50 minutes. Saturated sodium bicarbonate (50 mL) was added to the reaction solution, then extracted with dichloromethane/methanol (v/v=10/1, 50 mL×2), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure , the residue was passed through preparative liquid phase (instrument: waters 2767 preparative liquid phase; chromatographic column: XBridge@Prep C18 (30mm×150mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.05% ammonia water) ) was isolated and purified to give compound 4 (97 mg, yield 31%).
LCMS m/z＝421.3[M+H] +； LCMS m/z=421.3[M+H] + ;
1H NMR(400MHz,CD 3OD)δ8.05(d,1H),7.55–7.45(m,2H),7.20(s,1H),6.90–6.83(m,2H),6.81–6.67(m,2H),6.07(dt,1H),4.40-4.26(m,1H),4.18(d,2H),3.11(dd,2H),2.68–2.50(m,3H),2.26(s,6H),2.08–1.91(m,2H). 1 H NMR (400MHz, CD 3 OD) δ8.05(d, 1H), 7.55–7.45 (m, 2H), 7.20 (s, 1H), 6.90–6.83 (m, 2H), 6.81–6.67 (m, 2H), 6.07(dt, 1H), 4.40-4.26(m, 1H), 4.18(d, 2H), 3.11(dd, 2H), 2.68-2.50(m, 3H), 2.26(s, 6H), 2.08 –1.91(m,2H).
实施例5：(E)-4-(二甲基胺基)-N-[1-[[6-(4-羟基苯基)-1H-吲唑-4-基]氧甲基]-3-双环[1.1.1]戊基]丁基-2-烯酰胺(化合物5)Example 5: (E)-4-(dimethylamino)-N-[1-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxymethyl]-3 - Bicyclo[1.1.1]pentyl]butyl-2-enamide (compound 5)
(E)-4-(dimethylamino)-N-[1-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxymethyl]-3-bicyclo[1.1.1]pentanyl]but-2-enamide(E)-4-(dimethylamino)-N-[1-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxymethyl]-3-bicyclo[1.1.1]pentanyl]but-2- enamide
Figure PCTCN2021117545-appb-000227
Figure PCTCN2021117545-appb-000227
第一步：[3-(叔丁氧基羰基氨基)-1-双环[1.1.1]戊基]甲磺酸甲酯(5B)The first step: methyl [3-(tert-butoxycarbonylamino)-1-bicyclo[1.1.1]pentyl]methanesulfonate (5B)
[3-(tert-butoxycarbonylamino)-1-bicyclo[1.1.1]pentanyl]methylmethanesulfonate[3-(tert-butoxycarbonylamino)-1-bicyclo[1.1.1]pentanyl]methylmethanesulfonate
在50mL反应瓶中，依次加入(3-(羟甲基)双环[1.1.1]戊-1-基)氨基甲酸叔丁酯(5A)(0.626g，2.73mmol)、三乙胺(0.58g，5.7mmol)和二氯甲烷(20mL)，加完后在0℃下搅拌20分钟，缓慢滴加甲基磺酰氯(0.336g，2.93mmol)并在室温下搅拌反应1h。反应液依次用水(30mL×1)、饱和食盐水(30mL×1)洗涤，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩得到5B粗品，淡黄色固体(0.72g)，直接用于下一步反应。Into a 50mL reaction flask, add (3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)carbamate tert-butyl ester (5A) (0.626g, 2.73mmol), triethylamine (0.58g) in turn , 5.7 mmol) and dichloromethane (20 mL), stir at 0 °C for 20 minutes after the addition, slowly dropwise add methylsulfonyl chloride (0.336 g, 2.93 mmol) and stir the reaction at room temperature for 1 h. The 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.
第二步：N-[1-[(6-溴-1-四氢吡喃-2-基-吲唑-4-基)氧基甲基]-3-双环[1.1.1]戊基]氨基甲酸叔丁酯(5C)Step 2: N-[1-[(6-Bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxymethyl]-3-bicyclo[1.1.1]pentyl] tert-Butyl carbamate (5C)
tert-butyl N-[1-[(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxymethyl]-3-bicyclo[1.1.1]pentanyl]carbamatetert-butyl N-[1-[(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxymethyl]-3-bicyclo[1.1.1]pentanyl]carbamate
在100mL反应瓶中，依次加入6-溴-1-四氢吡喃-2-基-吲唑-4-醇(中间体I)(0.23g，0.774mmol)、5B粗品(0.6g)、碳酸铯(1.0g，3.06mmol)和N,N-二甲基甲酰胺(40mL)，加完后在90℃下搅拌反应5小时，反应液中加入乙酸乙酯(100mL)，然后用水(100mL×3)洗，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩得到5C，淡黄色泡沫状固体(0.343g，产率90％)。In a 100 mL reaction flask, 6-bromo-1-tetrahydropyran-2-yl-indazol-4-ol (intermediate I) (0.23 g, 0.774 mmol), 5B crude product (0.6 g), carbonic acid were added in sequence Cesium (1.0g, 3.06mmol) and N,N-dimethylformamide (40mL) were added, and the reaction was stirred at 90°C for 5 hours. Ethyl acetate (100mL) was added to the reaction solution, followed by water (100mL× 3) Washed, the organic layer was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 5C, a pale yellow foamy solid (0.343 g, yield 90%).
LCMS m/z＝492.1/494.1[M+H] + LCMS m/z=492.1/494.1[M+H] +
第三步：N-[1-[[[6-(4-羟基苯基)-1-四氢吡喃-2-基-吲唑-4-基]氧甲基]-3-双环[1.1.1]戊基]氨基甲酸叔丁酯(5D)The third step: N-[1-[[[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxymethyl]-3-bicyclo[1.1 .1] Amyl] tert-butyl carbamate (5D)
tert-butyl N-[1-[[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxymethyl]-3-bicyclo[1.1.1]pentanyl]carbamatetert-butyl N-[1-[[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxymethyl]-3-bicyclo[1.1.1]pentanyl]carbamate
在100mL反应瓶中，依次加入5C(0.318g，0.646mmol)、4-羟基苯硼酸(0.107g，0.775mmol)、七水合磷酸钾(0.656g，1.938mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(53mg，0.065mmol)和二氧六环/水(v/v＝4/1，10mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(PE/EA＝3/1)得到5D，淡黄色固体(0.30g，产率92％)。In a 100mL reaction flask, 5C (0.318g, 0.646mmol), 4-hydroxyphenylboronic acid (0.107g, 0.775mmol), potassium phosphate heptahydrate (0.656g, 1.938mmol), [1,1'-bis( Diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (53mg, 0.065mmol) and dioxane/water (v/v=4/1, 10mL), after nitrogen replacement three times, in The reaction was stirred at 90°C for 2 hours. 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 5D as a pale yellow solid (0.30 g, 92% yield).
LCMS m/z＝506.2[M+H] + LCMS m/z=506.2[M+H] +
第四步：(E)-4-(二甲基胺基)-N-[1-[[6-(4-羟基苯基)-1H-吲唑-4-基]氧甲基]-3-双环[1.1.1]戊基]丁基-2-烯酰胺(化合物5)The fourth step: (E)-4-(dimethylamino)-N-[1-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxymethyl]-3 - Bicyclo[1.1.1]pentyl]butyl-2-enamide (compound 5)
(E)-4-(dimethylamino)-N-[1-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxymethyl]-3-bicyclo[1.1.1]pentanyl]but-2-enamide(E)-4-(dimethylamino)-N-[1-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxymethyl]-3-bicyclo[1.1.1]pentanyl]but-2- enamide
在50mL反应瓶中，加入5D(0.11g，0.218mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用MTBE(10mL×3) 洗，然后减压浓缩干。所得残留物中依次加入反式-4-二甲基胺基巴豆酸盐酸盐(0.047g，0.283mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.084g，0.438mmol)、1-羟基苯并三唑(0.038g，0.283mmol)和N,N-二甲基甲酰胺(40mL)，加完后在室温下搅拌10分钟，加入N,N-二异丙基乙胺(0.58g，4.5mmol)，加完后在室温下搅拌50分钟。反应液中加入饱和碳酸氢钠(50mL)，然后用二氯甲烷/甲醇(v/v＝10/1，50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过硅胶柱层析(二氯甲烷/甲醇(v/v＝20/1-10/1))分离纯化得到化合物5(27mg，产率29％)。In a 50 mL reaction flask, 5D (0.11 g, 0.218 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with MTBE (10 mL×3), and then concentrated to dryness under reduced pressure. To the obtained residue were added 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. Saturated sodium bicarbonate (50 mL) was added to the reaction solution, then extracted with dichloromethane/methanol (v/v=10/1, 50 mL×2), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure , the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v=20/1-10/1)) to obtain compound 5 (27 mg, yield 29%).
LCMS m/z＝433.2[M+H] +； LCMS m/z=433.2[M+H] + ;
1H NMR(400MHz,CD 3OD)δ8.00(d,1H),7.54–7.47(m,2H),7.19(s,1H),6.91–6.83(m,2H),6.78–6.68(m,2H),6.05(d,1H),4.35(s,2H),3.21(dd,2H),2.34(s,6H),2.19(s,6H). 1 H NMR (400MHz, CD 3 OD) δ 8.00 (d, 1H), 7.54–7.47 (m, 2H), 7.19 (s, 1H), 6.91–6.83 (m, 2H), 6.78–6.68 (m, 2H), 6.05(d, 1H), 4.35(s, 2H), 3.21(dd, 2H), 2.34(s, 6H), 2.19(s, 6H).
实施例6：反式-(E)-4-(二甲基氨基)-N-3-((6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)丁-2-烯酰胺(化合物6)Example 6: trans-(E)-4-(dimethylamino)-N-3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazole- 4-yl)oxy)cyclobutyl)but-2-enamide (compound 6)
trans-(E)-4-(dimethylamino)-N-(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)but-2-enamidetrans-(E)-4-(dimethylamino)-N-(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)but-2 -enamide
Figure PCTCN2021117545-appb-000228
Figure PCTCN2021117545-appb-000228
第一步：反式-叔丁基(3-((6-(4-(苄氧基)-2-乙基-5-氟苯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基)环丁基)氨基甲酸酯(6A)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)
trans-tert-butyl(3-((6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)carbamatetrans-tert-butyl(3-((6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl) oxy)cyclobutyl)carbamate
氮气保护，将2-(4-(苄氧基)-2-乙基-5-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(480.9mg，1.35mmol)，七水磷酸钾(913mg，2.7mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(73.5mg，0.09mmol)，分别加入至反式-N-[3-(6-溴-1-四氢吡喃-2-基-吲唑-4-基)氧基环丁基]氨基甲酸叔丁酯(1C)(420mg，0.9mmol)的1,4-二氧六环(40mL)和水(10mL)的溶液中，110℃搅拌1h，饱和碳酸氢钠溶液(30mL)淬灭，乙酸乙酯(30mL*3)萃取，合并有机层用无水硫酸钠干燥，抽滤，滤液减压浓缩后硅胶柱层析(石油醚/乙酸乙酯(v/v)＝2:1)，得到6A，灰色固体(480mg，产率86.5％)。Under nitrogen protection, 2-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (480.9 mg, 1.35 mmol), potassium phosphate heptahydrate (913 mg, 2.7 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (73.5 mg, 0.09mmol), were added to tert-butyl trans-N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]carbamate ( 1C) (420 mg, 0.9 mmol) in a solution of 1,4-dioxane (40 mL) and water (10 mL), stirred at 110 °C for 1 h, quenched with saturated sodium bicarbonate solution (30 mL), ethyl acetate (30 mL) *3) Extraction, the combined organic layers were dried with anhydrous sodium sulfate, filtered with suction, the filtrate was concentrated under reduced pressure, and then subjected to silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2:1) to obtain 6A, a gray solid (480 mg, 86.5% yield).
第二步：反式-叔丁基(3-((6-(2-乙基-5-氟-4-羟基苯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-乙氧基)环丁基氨基甲酸酯(6B)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)
trans-tert-butyl(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)carbamatetrans-tert-butyl(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy) cyclobutyl)carbamate
将6A(480mg,0.78mmol)。加入反应瓶中，加入钯碳(48mg，10wt％)和甲醇溶液(30mL)，氢气换气三次；室温搅拌反应6h。反应液通过硅藻土过滤，乙酸乙酯洗脱。减压浓缩干，得6B粗品，灰色固体(410mg)，直接用于下一步反应。6A (480 mg, 0.78 mmol). It was put into a reaction flask, palladium carbon (48 mg, 10 wt %) and methanol solution (30 mL) were added, and hydrogen was exchanged three times; the reaction was stirred at room temperature for 6 h. The reaction solution was filtered through celite and eluted with ethyl acetate. Concentrated to dryness under reduced pressure to obtain crude 6B as a gray solid (410 mg), which was directly used in the next reaction.
LCMS m/z＝526.2[M+1] + LCMS m/z=526.2[M+1] +
第三步：反式-4-(4-((3-氨基环丁氧基)-1H-吲唑-6-基)-5-乙基-2-氟苯酚(6C)的三氟乙酸盐The third step: trifluoroacetic acid of trans-4-(4-((3-aminocyclobutoxy)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (6C) Salt
trans-4-(4-(3-aminocyclobutoxy)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol；trifluoroaceticacidtrans-4-(4-(3-aminocyclobutoxy)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol; trifluoroacetic acid
将6B粗品(410mg)溶于二氯甲烷(10mL)溶液中并加入三氟乙酸(8mL)，室温反应3小时。将反应液直接浓缩，得到6C的三氟乙酸盐粗品，黄色油状物(355mg)。Crude 6B (410 mg) was dissolved in dichloromethane (10 mL) solution, trifluoroacetic acid (8 mL) was added, and the reaction was carried out at room temperature for 3 hours. The reaction solution was directly concentrated to give crude 6C trifluoroacetate as a yellow oil (355 mg).
第四步：反式-(E)-4-(二甲基氨基)-N-(3-((6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)丁-2-烯酰胺(化合物6)The fourth step: trans-(E)-4-(dimethylamino)-N-(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazole -4-yl)oxy)cyclobutyl)but-2-enamide (compound 6)
trans-(E)-4-(dimethylamino)-N-(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)but-2-enamidetrans-(E)-4-(dimethylamino)-N-(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)but-2 -enamide
氮气保护，50mL三口瓶中，将6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯(62mg,0.15mmol)加入到反式4-二甲基胺基巴豆酸盐酸盐(24.8mg,0.15mmol)的N,N-二甲基甲酰胺(2mL)溶液中，室温反应10min，0℃下，再将6C的三氟乙酸盐(59mg)溶于1 mL N,N-二甲基甲酰胺中滴加到上述反应液中，0℃搅拌1min后，再将N,N-二异丙基乙胺(101mg,0.78mmol)溶于1mL N,N-二甲基甲酰胺中滴加到上述反应液中，0℃搅拌3h，饱和碳酸氢钠溶液(5mL)淬灭，乙酸乙酯(20*3mL)萃取，减压浓缩，残留物通过制备液相(仪器：waters 2767制备液相；色谱柱:SunFire@Prep C18(19mm×150mm)；流动相组成：流动相A：乙腈流动相B：水(含5mM乙酸铵))分离纯化得到化合物6(7mg，产率12％)Under nitrogen protection, in a 50mL three-necked flask, add 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate (62mg, 0.15mmol) to trans-4-dimethylamine In a solution of crotonic acid hydrochloride (24.8 mg, 0.15 mmol) in N,N-dimethylformamide (2 mL), the reaction was carried out at room temperature for 10 min, and at 0 °C, 6C trifluoroacetate (59 mg) was dissolved in In 1 mL of N,N-dimethylformamide, it was added dropwise to the above reaction solution, and after stirring at 0°C for 1 min, N,N-diisopropylethylamine (101 mg, 0.78 mmol) was dissolved in 1 mL of N, N-dimethylformamide was added dropwise to the above reaction solution, stirred at 0 °C for 3 h, quenched with saturated sodium bicarbonate solution (5 mL), extracted with ethyl acetate (20*3 mL), concentrated under reduced pressure, and the residue was prepared by Liquid phase (instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm×150mm); mobile phase composition: mobile phase A: acetonitrile Mobile phase B: water (containing 5mM ammonium acetate)) separation and purification to obtain compound 6 (7 mg, 12% yield)
LCMS m/z＝453.3[M+1] + LCMS m/z=453.3[M+1] +
1H NMR(400MHz,CD 3OD)δ8.07(d,1H),6.99–6.84(m,3H),6.81-6.71(m,1H),6.21(d,1H),6.13-6.05(m,1H),5.10–4.98(m,1H),4.60-4.51(m,1H),3.16(d,2H),2.71-2.61(m,2H),2.59–2.43(m,4H),2.30(s,6H),1.06(t,3H). 1H NMR (400MHz, CD 3 OD) δ8.07(d,1H), 6.99-6.84(m,3H), 6.81-6.71(m,1H), 6.21(d,1H), 6.13-6.05(m,1H) ), 5.10-4.98(m, 1H), 4.60-4.51(m, 1H), 3.16(d, 2H), 2.71-2.61(m, 2H), 2.59-2.43(m, 4H), 2.30(s, 6H ),1.06(t,3H).
实施例7：反式-(E)-4-(二甲基胺基)-N-[3-[[6-(4-羟基苯基)-1H-吲唑-4-基]氧基]环丁基]-N-甲基丁-2-烯酰胺(化合物7)Example 7: trans-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy] Cyclobutyl]-N-methylbut-2-enamide (Compound 7)
trans-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclobutyl]-N-methyl-but-2-enamidetrans-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclobutyl]-N-methyl-but-2-enamide
Figure PCTCN2021117545-appb-000229
Figure PCTCN2021117545-appb-000229
第一步：反式-N-[3-(6-溴-1-四氢吡喃-2-基-吲唑-4-基)氧基环丁基]-N-甲基-氨基甲酸叔丁酯(7A)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-tert-butyl N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]-N-methyl-carbamatetrans-tert-butyl N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]-N-methyl-carbamate
在50mL反应瓶中，依次加入1C(0.22g，0.47mmol)、四氢呋喃(15mL)和氢化钠(0.28g，7.05mmol，60wt％)，加完后在25℃下搅拌30分钟，缓慢滴加碘甲烷(1.33g，9.4mmol)并在室温下搅拌反应1.2h。反应液中加入乙酸乙酯(50mL)，然后依次用水(30mL×1)、饱和食盐水(30mL×1)洗涤，有机层用无水硫酸钠干燥，过滤，滤液减 压浓缩，残留物通过柱层析分离纯化(PE/EA＝9/1)得到7A粗品，淡黄色油状物(0.12g)，直接用于下一步反应。In a 50 mL reaction flask, 1C (0.22 g, 0.47 mmol), tetrahydrofuran (15 mL) and sodium hydride (0.28 g, 7.05 mmol, 60 wt %) were sequentially added, and after the addition, the mixture was stirred at 25° C. for 30 minutes, and iodine was slowly added dropwise. Methane (1.33 g, 9.4 mmol) and the reaction was stirred at room temperature for 1.2 h. Ethyl acetate (50 mL) was added to the reaction solution, then washed with water (30 mL×1) and saturated brine (30 mL×1) successively, the organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was passed through a column Chromatographic separation and purification (PE/EA=9/1) gave crude 7A as a pale yellow oil (0.12 g), which was directly used in the next reaction.
第二步：反式-N-[3-[6-(4-羟基苯基)-1-四氢吡喃-2-基-吲唑-4-基]氧环丁基]-N-甲基-氨基甲酸叔丁酯(7B)The second step: trans-N-[3-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxocyclobutyl]-N-methane tert-Butyl-carbamate (7B)
trans-tert-butyl N-[3-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclobutyl]-N-methyl-carbamatetrans-tert-butyl N-[3-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclobutyl]-N-methyl-carbamate
在50mL反应瓶中，依次加入7A粗品(0.12g)、4-羟基苯硼酸(0.040g，0.287mmol)、七水合磷酸钾(0.243g，0.720mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(20mg，0.024mmol)和二氧六环/水(v/v＝4/1，10mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(PE/EA＝3/1)得到7B，淡黄色固体(0.075g，两步产率32％)。In a 50mL reaction flask, add 7A crude product (0.12g), 4-hydroxyphenylboronic acid (0.040g, 0.287mmol), potassium phosphate heptahydrate (0.243g, 0.720mmol), [1,1'-bis(diphenyl) phosphine)ferrocene]dichloropalladium dichloromethane complex (20mg, 0.024mmol) and dioxane/water (v/v=4/1, 10mL), after nitrogen replacement three times, at 90°C The reaction was stirred for 2 hours. 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 7B as a pale yellow solid (0.075 g, 32% yield for two steps).
LCMS m/z＝494.2[M+H] +； LCMS m/z=494.2[M+H] + ;
第三步：反式-(E)-4-(二甲基胺基)-N-[3-[[6-(4-羟基苯基)-1H-吲唑-4-基]氧基]环丁基]-N-甲基丁-2-烯酰胺(化合物7)The third step: trans-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy] Cyclobutyl]-N-methylbut-2-enamide (Compound 7)
trans-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclobutyl]-N-methyl-but-2-enamidetrans-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclobutyl]-N-methyl-but-2-enamide
在50mL反应瓶中，加入7B(0.071g，0.132mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用MTBE(10mL×3)洗，然后减压浓缩干。In a 50 mL reaction flask, 7B (0.071 g, 0.132 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with MTBE (10 mL×3), and then concentrated to dryness under reduced pressure.
在50mL反应瓶中，加入反式-4-二甲基胺基巴豆酸盐酸盐(0.024g，0.145mmol)、6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯(0.071g，0.172mmol)和DMF(10mL)，加完后在室温下搅拌30分钟，然后加入上步所得残留物的DMF(5mL)溶液，加完后在室温下搅拌10分钟，加入N,N-二异丙基乙胺(0.102g，0.79mmol)，加完后在室温下搅拌50分钟。反应液中加入饱和碳酸氢钠(50mL)，然后用二氯甲烷/甲醇(v/v＝10/1)(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过硅胶制备板分离纯化(二氯甲烷/甲醇＝5/1)得到化合物7(18mg，产率32％)。In a 50mL reaction flask, add 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. Saturated sodium bicarbonate (50 mL) was added to the reaction solution, then extracted with dichloromethane/methanol (v/v=10/1) (50 mL×2), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced in pressure After concentration, the residue was separated and purified by silica gel preparation plate (dichloromethane/methanol=5/1) to obtain compound 7 (18 mg, yield 32%).
LCMS m/z＝421.2[M+H] +； LCMS m/z=421.2[M+H] + ;
1H NMR(400MHz,DMSO-d 6)δ13.01(s,1H),9.54(s,1H),8.02(s,1H),7.56–7.47(m,2H),7.19(s,1H),6.91–6.82(m,2H),6.65–6.45(m,3H),5.38–4.69(m,2H),3.15–2.90(m,5H),2.89–2.67(m,2H),2.60–2.35(m,2H),2.14(s,6H). 1 H NMR (400MHz, DMSO-d 6 )δ13.01(s,1H), 9.54(s,1H), 8.02(s,1H), 7.56–7.47(m,2H), 7.19(s,1H), 6.91–6.82 (m, 2H), 6.65–6.45 (m, 3H), 5.38–4.69 (m, 2H), 3.15–2.90 (m, 5H), 2.89–2.67 (m, 2H), 2.60–2.35 (m ,2H),2.14(s,6H).
实施例8：反式-(E)-4-(二甲基氨基)-N-[4-[[6-(4-羟基苯基)-1H-吲唑-4-基]氧基]环己基]丁-2-烯酰胺(化合物8)Example 8: trans-(E)-4-(dimethylamino)-N-[4-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]ring Hexyl]but-2-enamide (Compound 8)
trans-(E)-4-(dimethylamino)-N-[4-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclohexyl]but-2-enamidetrans-(E)-4-(dimethylamino)-N-[4-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclohexyl]but-2-enamide
Figure PCTCN2021117545-appb-000230
Figure PCTCN2021117545-appb-000230
第一步：顺式-[4-(叔丁氧基羰基氨基)环己基]甲磺酸酯(8B)The first step: cis-[4-(tert-butoxycarbonylamino)cyclohexyl]methanesulfonate (8B)
cis-[4-(tert-butoxycarbonylamino)cyclohexyl]methanesulfonatecis-[4-(tert-butoxycarbonylamino)cyclohexyl]methanesulfonate
在50mL反应瓶中，依次加入顺式-4-Boc氨基环己醇(1.08g，5.0mmol)、三乙胺(1.01g，10.0mmol)和二氯甲烷(20mL)，加完后在0℃下搅拌20分钟，缓慢滴加甲基磺酰氯(0.75g，6.5mmol)并在室温下搅拌反应1h。反应液依次用水(30mL×1)、饱和食盐水(30mL×1)洗涤，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩得到8B粗品，淡黄色固体(1.17g)，直接用于下一步反应。In a 50 mL reaction flask, cis-4-Boc aminocyclohexanol (1.08 g, 5.0 mmol), triethylamine (1.01 g, 10.0 mmol) and dichloromethane (20 mL) were added in sequence, and the temperature was kept at 0 °C after the addition. After stirring for 20 minutes, methylsulfonyl chloride (0.75 g, 6.5 mmol) was slowly added dropwise and the reaction was stirred at room temperature for 1 h. The 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.
第二步：反式-N-[4-(6-溴-1-四氢吡喃-2-基-吲唑-4-基)氧基环己基]氨基甲酸叔丁酯(8C)The second step: tert-butyl trans-N-[4-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclohexyl]carbamate (8C)
trans-tert-butyl N-[4-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclohexyl]carbamatetrans-tert-butyl N-[4-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclohexyl]carbamate
在50mL反应瓶中，依次加入6-溴-1-四氢吡喃-2-基-吲唑-4-醇(中间体I)(0.297g，1.0mmol)、8B粗品(0.38g)、碳酸铯(1.26g，3.87mmol)和N,N-二甲基甲酰胺(40mL)，加完后在90℃下搅拌反应过夜，反应液中加入乙酸乙酯(50mL)，然后用水(50mL×3)洗，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩得到8C，淡黄色油状物(0.43g，产率87％)。In a 50 mL reaction flask, 6-bromo-1-tetrahydropyran-2-yl-indazol-4-ol (intermediate I) (0.297 g, 1.0 mmol), 8B crude product (0.38 g), carbonic acid were added in sequence Cesium (1.26g, 3.87mmol) and N,N-dimethylformamide (40mL) were added, and the reaction was stirred at 90°C overnight. Ethyl acetate (50mL) was added to the reaction solution, followed by water (50mL×3 ), the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 8C, a pale yellow oil (0.43 g, 87% yield).
第三步：反式-N-[4-[6-(4-羟基苯基)-1-四氢吡喃-2-基-吲唑-4-基]氧环己基]氨基甲酸叔丁酯(8D)The third step: tert-butyl trans-N-[4-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclohexyl]carbamate (8D)
trans-tert-butyl N-[4-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclohexyl]carbamatetrans-tert-butyl N-[4-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclohexyl]carbamate
在50mL反应瓶中，依次加入8C(0.43g，0.87mmol)、4-羟基苯硼酸(0.144g，1.04mmol)、七水合磷酸钾(0.883g，2.61mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(71mg，0.087mmol)和二氧六环/水(v/v＝4/1，10mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(PE/EA＝3/1)得到8D，淡黄色固体(0.224g，产率51％)。In a 50mL reaction flask, 8C (0.43g, 0.87mmol), 4-hydroxyphenylboronic acid (0.144g, 1.04mmol), potassium phosphate heptahydrate (0.883g, 2.61mmol), [1,1'-bis( Diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (71mg, 0.087mmol) and dioxane/water (v/v=4/1, 10mL), after nitrogen replacement three times, in The reaction was stirred at 90°C for 2 hours. 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 8D as a pale yellow solid (0.224 g, 51% yield).
LCMS m/z＝508.3[M+H] + LCMS m/z=508.3[M+H] +
第四步：反式-(E)-4-(二甲基氨基)-N-[4-[[6-(4-羟基苯基)-1H-吲唑-4-基]氧基]环己基]丁-2-烯酰胺(化合物8)The fourth step: trans-(E)-4-(dimethylamino)-N-[4-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy] ring Hexyl]but-2-enamide (Compound 8)
trans-(E)-4-(dimethylamino)-N-[4-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclohexyl]but-2-enamidetrans-(E)-4-(dimethylamino)-N-[4-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclohexyl]but-2-enamide
在50mL反应瓶中，加入8D(0.22g，0.42mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用MTBE(10mL×3)洗，然后减压浓缩干。In a 50 mL reaction flask, 8D (0.22 g, 0.42 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with MTBE (10 mL×3), and then concentrated to dryness under reduced pressure.
在50mL反应瓶中，加入反式-4-二甲基胺基巴豆酸盐酸盐(0.066g，0.397mmol)、6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯(0.194g，0.172mmol)和DMF(10mL)，加完后在室温下搅拌30分钟，然后加入上步所得残留物的DMF(5mL)溶液，加完后在室温下搅拌10分钟，加入N,N-二异丙基乙胺(0.28g，2.17mmol)，加完后在室温下搅拌50分钟。反应液中加入饱和碳酸氢钠(50mL)，然后用二氯甲烷/甲醇(v/v＝10/1)(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过硅胶制备板分离纯化(二氯甲烷/甲醇＝5/1)得到化合物8(15mg，产率8％)。In a 50mL reaction flask, add trans-4-dimethylaminocrotonate hydrochloride (0.066g, 0.397mmol), 6-chlorobenzotriazole-1,1,3,3-tetramethyl Urea hexafluorophosphate (0.194 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 (0.28 g, 2.17 mmol) was added, and the mixture was stirred at room temperature for 50 minutes after the addition. Saturated sodium bicarbonate (50 mL) was added to the reaction solution, then extracted with dichloromethane/methanol (v/v=10/1) (50 mL×2), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced in pressure After concentration, the residue was separated and purified by silica gel preparative plate (dichloromethane/methanol=5/1) to obtain compound 8 (15 mg, yield 8%).
LCMS m/z＝435.2[M+H] +； LCMS m/z=435.2[M+H] + ;
1H NMR(400MHz,CD 3OD)δ7.99(d,1H),7.53–7.45(m,2H),7.18(s,1H),6.91–6.84(m,2H),6.78–6.66(m,2H),6.40-6.30(m,1H),4.66-4.54(m,1H),3.92–3.78(m,3H),2.82(s,6H),2.35-2.25(m,2H),2.12–1.99(m,2H),1.77-1.63(m,2H),1.59-1.46(m,2H). 1 H NMR (400MHz, CD 3 OD) δ 7.99(d, 1H), 7.53–7.45 (m, 2H), 7.18 (s, 1H), 6.91–6.84 (m, 2H), 6.78–6.66 (m, 2H), 6.40-6.30(m, 1H), 4.66-4.54(m, 1H), 3.92-3.78(m, 3H), 2.82(s, 6H), 2.35-2.25(m, 2H), 2.12-1.99( m,2H),1.77-1.63(m,2H),1.59-1.46(m,2H).
实施例9：顺式-(E)-4-(二甲基氨基)-N-[4-[[6-(4-羟基苯基)-1H-吲唑-4-基]氧基]环己基]丁-2-烯酰胺(化合物9)Example 9: cis-(E)-4-(dimethylamino)-N-[4-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]ring Hexyl]but-2-enamide (Compound 9)
cis-(E)-4-(dimethylamino)-N-[4-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclohexyl]but-2-enamidecis-(E)-4-(dimethylamino)-N-[4-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclohexyl]but-2-enamide
Figure PCTCN2021117545-appb-000231
Figure PCTCN2021117545-appb-000231
第一步：反式-[4-(叔丁氧基羰基氨基)环己基]甲磺酸酯(9B)The first step: trans-[4-(tert-butoxycarbonylamino)cyclohexyl]methanesulfonate (9B)
trans-[4-(tert-butoxycarbonylamino)cyclohexyl]methanesulfonatetrans-[4-(tert-butoxycarbonylamino)cyclohexyl]methanesulfonate
在50mL反应瓶中，依次加入反式-4-Boc氨基环己醇(0.75g，3.48mmol)、三乙胺(0.88g，8.7mmol)和二氯甲烷(30mL)，加完后在0℃下搅拌20分钟，缓慢滴加甲基磺酰氯(0.6g，5.22mmol)并在室温下搅拌反应1h。反应液依次用水(30mL×1)、饱和食盐水(30mL×1)洗涤，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩得到9B粗品，淡黄色固体(1g)，直接用于下一步反应。In a 50 mL reaction flask, add trans-4-Boc aminocyclohexanol (0.75 g, 3.48 mmol), triethylamine (0.88 g, 8.7 mmol) and dichloromethane (30 mL) in sequence. After stirring for 20 minutes, methylsulfonyl chloride (0.6 g, 5.22 mmol) was slowly added dropwise and the reaction was stirred at room temperature for 1 h. The 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.
第二步：顺式-N-[4-(6-溴-1-四氢吡喃-2-基-吲唑-4-基)氧基环己基]氨基甲酸叔丁酯(9C)The second step: cis-N-[4-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclohexyl]carbamic acid tert-butyl ester (9C)
cis-tert-butylN-[4-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclohexyl]carbamatecis-tert-butylN-[4-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclohexyl]carbamate
在50mL反应瓶中，依次加入6-溴-1-四氢吡喃-2-基-吲唑-4-醇(中间体I)(0.6g，2.02mmol)、9B粗品(0.89g)、碳酸铯(1.97g，6.06mmol)和N,N-二甲基甲酰胺(40mL)，加完后在90℃下搅拌反应过夜，反应液中加入乙酸乙酯(50mL)，然后用水(50mL×3)洗，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩得粗品，粗品通过硅胶制备板分离纯化得到9C，淡黄色油状物(0.215g，产率22％)。In a 50 mL reaction flask, 6-bromo-1-tetrahydropyran-2-yl-indazol-4-ol (intermediate I) (0.6 g, 2.02 mmol), 9B crude product (0.89 g), carbonic acid were added in sequence Cesium (1.97g, 6.06mmol) and N,N-dimethylformamide (40mL) were added, and the reaction was stirred at 90°C overnight. Ethyl acetate (50mL) was added to the reaction solution, followed by water (50mL×3 ), the organic layer was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by a silica gel preparative plate to obtain 9C as a pale yellow oil (0.215 g, 22% yield).
第三步：顺式-N-[4-[6-(4-羟基苯基)-1-四氢吡喃-2-基-吲唑-4-基]氧环己基]氨基甲酸叔丁酯(9D)The third step: cis-N-[4-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclohexyl]carbamic acid tert-butyl ester (9D)
cis-tert-butyl N-[4-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclohexyl]carbamatecis-tert-butyl N-[4-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclohexyl]carbamate
在50mL反应瓶中，依次加入9C(0.215g，0.43mmol)、4-羟基苯硼酸(0.077g，0.56mmol)、七水合磷酸钾(0.73g，2.15mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(35mg，0.043mmol)和二氧六环/水(v/v＝4/1，20mL)，氮气置换三次后，在110℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(80mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(PE/EA＝3/1)得到9D，淡黄色固体(0.199g，产率91％)。In a 50mL reaction flask, 9C (0.215g, 0.43mmol), 4-hydroxyphenylboronic acid (0.077g, 0.56mmol), potassium phosphate heptahydrate (0.73g, 2.15mmol), [1,1'-bis( Diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (35mg, 0.043mmol) and dioxane/water (v/v=4/1, 20mL), after nitrogen replacement three times, in The reaction was stirred at 110°C for 2 hours. Water (50 mL) was added to the reaction solution, then extracted with ethyl acetate (80 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 9D as a pale yellow solid (0.199 g, 91% yield).
LCMS m/z＝508.3[M+H] + LCMS m/z=508.3[M+H] +
第四步：顺式-(E)-4-(二甲基氨基)-N-[4-[[6-(4-羟基苯基)-1H-吲唑-4-基]氧基]环己基]丁-2-烯酰胺(化合物9)The fourth step: cis-(E)-4-(dimethylamino)-N-[4-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy] ring Hexyl]but-2-enamide (Compound 9)
cis-(E)-4-(dimethylamino)-N-[4-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclohexyl]but-2-enamidecis-(E)-4-(dimethylamino)-N-[4-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclohexyl]but-2-enamide
在50mL反应瓶中，加入9D(0.199g，0.39mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用MTBE(10mL×3)洗，然后减压浓缩干。In a 50 mL reaction flask, 9D (0.199 g, 0.39 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with MTBE (10 mL×3), and then concentrated to dryness under reduced pressure.
在50mL反应瓶中，加入反式-4-二甲基胺基巴豆酸盐酸盐(0.05g，0.38mmol)、6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯(0.194g，0.172mmol)和DMF(10mL)，加完后在室温下搅拌30分钟，然后加入上步所得残留物的DMF(5mL)溶液，加完后在室温下搅拌10分钟，加入N,N-二异丙基乙胺(0.28g，2.17mmol)，加完后在室温下搅拌50分钟。反应液中加入饱和碳酸氢钠(50mL)，然后用二氯甲烷/甲醇(v/v＝10/1)(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过硅胶制备板分离纯化(二氯甲烷/甲醇＝5/1)得到化合物9(14mg，产率10％)。In a 50mL reaction flask, add trans-4-dimethylaminocrotonate hydrochloride (0.05g, 0.38mmol), 6-chlorobenzotriazole-1,1,3,3-tetramethyl Urea hexafluorophosphate (0.194 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 (0.28 g, 2.17 mmol) was added, and the mixture was stirred at room temperature for 50 minutes after the addition. Saturated sodium bicarbonate (50 mL) was added to the reaction solution, then extracted with dichloromethane/methanol (v/v=10/1) (50 mL×2), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced in pressure After concentration, the residue was separated and purified by silica gel preparation plate (dichloromethane/methanol=5/1) to obtain compound 9 (14 mg, yield 10%).
LCMS m/z＝435.2[M+H] +； LCMS m/z=435.2[M+H] + ;
1H NMR(400MHz,CD 3OD)δ8.04(d,1H),7.52–7.43(m,2H),7.19(s,1H),6.90–6.83(m,2H),6.81–6.69(m,2H),6.26–6.15(m,1H),4.92–4.84(m,1H),3.97–3.83(m,1H),3.38(dd,2H),2.47(s,6H),2.27–2.11(m,2H),1.88–1.66(m,6H). 1 H NMR (400MHz, CD 3 OD) δ8.04(d, 1H), 7.52–7.43 (m, 2H), 7.19 (s, 1H), 6.90–6.83 (m, 2H), 6.81–6.69 (m, 2H), 6.26–6.15 (m, 1H), 4.92–4.84 (m, 1H), 3.97–3.83 (m, 1H), 3.38 (dd, 2H), 2.47 (s, 6H), 2.27–2.11 (m, 2H), 1.88–1.66 (m, 6H).
实施例10：(E)-4-(二甲基氨基)-N-[(1S，3S)-3-[[6-(4-羟苯基)-1H-吲唑-4-基]氧基]环戊基]丁-2-烯酰胺(化合物10)Example 10: (E)-4-(Dimethylamino)-N-[(1S,3S)-3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy yl]cyclopentyl]but-2-enamide (Compound 10)
(E)-4-(dimethylamino)-N-[(1S,3S)-3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclopentyl]but-2-enamide(E)-4-(dimethylamino)-N-[(1S,3S)-3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclopentyl]but-2-enamide
Figure PCTCN2021117545-appb-000232
Figure PCTCN2021117545-appb-000232
第一步：[(1R，3S)-3-(叔丁氧基羰基氨基)环戊基]甲磺酸盐酯(10B)The first step: [(1R,3S)-3-(tert-butoxycarbonylamino)cyclopentyl]methanesulfonate ester (10B)
[(1R,3S)-3-(tert-butoxycarbonylamino)cyclopentyl]methanesulfonate[(1R,3S)-3-(tert-butoxycarbonylamino)cyclopentyl]methanesulfonate
在50mL反应瓶中，依次加入[(1S,3R)-3-羟基环戊基]氨基甲酸叔丁酯(0.50g，2.5mmol)、三乙胺(0.51g，5.0mmol)和二氯甲烷(20mL)，加完后在0℃下搅拌20分钟，缓慢滴加甲基磺酰氯(0.37g，3.25mmol)并在室温下搅拌反应1h。反应液依次用水(30mL×1)、饱和食盐水(30mL×1)洗涤，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩得到10B粗品，淡黄色固体(0.67g)，直接用于下一步反应。In a 50 mL reaction flask, add [(1S,3R)-3-hydroxycyclopentyl]carbamate tert-butyl ester (0.50 g, 2.5 mmol), triethylamine (0.51 g, 5.0 mmol) and dichloromethane ( 20 mL), stirred at 0 °C for 20 minutes after the addition, slowly added methanesulfonyl chloride (0.37 g, 3.25 mmol) dropwise and stirred at room temperature for 1 h. The 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.
第二步：N-[(1S，3S)-3-(6-溴-1-四氢吡喃-2-基-吲唑-4-基)氧基环戊基]氨基甲酸叔丁酯(10C)The second step: tert-butyl N-[(1S,3S)-3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclopentyl]carbamate ( 10C)
tert-butyl N-[(1S,3S)-3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclopentyl]carbamatetert-butyl N-[(1S,3S)-3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclopentyl]carbamate
在50mL反应瓶中，依次加入6-溴-1-四氢吡喃-2-基-吲唑-4-醇(中间体I)(0.585g，1.97mmol)、10B粗品(0.66g)、碳酸铯(2.57g，7.88mmol)和N,N-二甲基甲酰胺(40mL)，加完后在90℃下搅拌反应过夜，反应液中加入乙酸乙酯(50mL)，然后用水(50mL×3)洗，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(PE/EA＝4/1)得到10C，白色固体(0.9g，产率95％)。In a 50 mL reaction flask, 6-bromo-1-tetrahydropyran-2-yl-indazol-4-ol (intermediate I) (0.585 g, 1.97 mmol), 10B crude product (0.66 g), carbonic acid were added in sequence Cesium (2.57g, 7.88mmol) and N,N-dimethylformamide (40mL) were added, and the reaction was stirred at 90°C overnight. Ethyl acetate (50mL) was added to the reaction solution, followed by water (50mL×3 ), the organic layer was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (PE/EA=4/1) to obtain 10C as a white solid (0.9 g, yield 95%) .
第三步：N-[(1S,3S)-3-[6-(4-羟苯基)-1-四氢吡喃-2-基-吲唑-4-基]氧环戊基]氨基甲酸叔丁酯(10D)The third step: N-[(1S,3S)-3-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclopentyl]amino tert-Butyl formate (10D)
tert-butyl N-[(1S,3S)-3-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclopentyl]carbamatetert-butyl N-[(1S,3S)-3-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclopentyl]carbamate
在50mL反应瓶中，依次加入10C(0.40g，0.83mmol)、4-羟基苯硼酸(0.14g，0.99mmol)、七水合磷酸钾(0.84g，2.49mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷 络合物(69mg，0.083mmol)和二氧六环/水(v/v＝4/1，10mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(PE/EA＝3/1)得到10D，淡黄色固体(0.37g，产率91％)。In a 50 mL reaction flask, 10C (0.40 g, 0.83 mmol), 4-hydroxyphenylboronic acid (0.14 g, 0.99 mmol), potassium phosphate heptahydrate (0.84 g, 2.49 mmol), [1,1'-bis( Diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (69mg, 0.083mmol) and dioxane/water (v/v=4/1, 10mL), after nitrogen replacement three times, in The reaction was stirred at 90°C for 2 hours. 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 10D as a pale yellow solid (0.37 g, 91% yield).
LCMS m/z＝494.3[M+H] + LCMS m/z=494.3[M+H] +
第四步：(E)-4-(二甲基氨基)-N-[(1S，3S)-3-[[6-(4-羟苯基)-1H-吲唑-4-基]氧基]环戊基]丁-2-烯酰胺(化合物10)The fourth step: (E)-4-(dimethylamino)-N-[(1S,3S)-3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxygen yl]cyclopentyl]but-2-enamide (Compound 10)
(E)-4-(dimethylamino)-N-[(1S,3S)-3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclopentyl]but-2-enamide(E)-4-(dimethylamino)-N-[(1S,3S)-3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclopentyl]but-2-enamide
在50mL反应瓶中，加入10D(0.37g，0.75mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用MTBE(10mL×3)洗，然后减压浓缩干。所得残留物中依次加入反式-4-二甲基胺基巴豆酸盐酸盐(0.146g，0.88mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.335g，1.74mmol)、1-羟基苯并三唑(0.116g，0.86mmol)和N,N-二甲基甲酰胺(40mL)，加完后在室温下搅拌10分钟，加入N,N-二异丙基乙胺(0.43g，3.33mmol)，加完后在室温下搅拌50分钟。反应液中加入饱和碳酸氢钠(50mL)，然后用二氯甲烷/甲醇(v/v＝10/1，50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析(二氯甲烷/甲醇(v/v)＝20/1至10/1)分离纯化得到化合物10(140mg，产率44％)。In a 50 mL reaction flask, 10D (0.37 g, 0.75 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with MTBE (10 mL×3), and then concentrated to dryness under reduced pressure. To the obtained residue were added 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) and N,N-dimethylformamide (40 mL) were added and stirred at room temperature for 10 min. N , N-diisopropylethylamine (0.43 g, 3.33 mmol) was added and stirred at room temperature for 50 minutes. Saturated sodium bicarbonate (50 mL) was added to the reaction solution, then extracted with dichloromethane/methanol (v/v=10/1, 50 mL×2), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure , the residue was separated and purified by column chromatography (dichloromethane/methanol (v/v)=20/1 to 10/1) to obtain compound 10 (140 mg, yield 44%).
LCMS m/z＝421.2[M+H] +； LCMS m/z=421.2[M+H] + ;
1H NMR(400MHz,DMSO-d 6)δ12.98(s,1H),9.53(s,1H),8.07(d,1H),7.97(s,1H),7.52(d,2H),7.16(s,1H),6.86(d,2H),6.66(s,1H),6.60-6.50(m,1H),6.02(d,1H),5.24-5.13(m,1H),4.41-4.27(m,1H),2.98(d,2H),2.34–2.04(m,9H),2.01–1.79(m,2H),1.61–1.46(m,1H). 1 H NMR (400MHz, DMSO-d 6 )δ12.98(s,1H), 9.53(s,1H), 8.07(d,1H), 7.97(s,1H), 7.52(d,2H), 7.16( s,1H),6.86(d,2H),6.66(s,1H),6.60-6.50(m,1H),6.02(d,1H),5.24-5.13(m,1H),4.41-4.27(m, 1H), 2.98 (d, 2H), 2.34–2.04 (m, 9H), 2.01–1.79 (m, 2H), 1.61–1.46 (m, 1H).
实施例11：(E)-4-(二甲基氨基)-N-[(1S，3S)-3-[[6-(2-乙基-5-氟-4-羟基-苯基)-1H-吲唑-4-基]氧基]环戊基]丁-2-烯酰胺(化合物11)Example 11: (E)-4-(Dimethylamino)-N-[(1S,3S)-3-[[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)- 1H-Indazol-4-yl]oxy]cyclopentyl]but-2-enamide (Compound 11)
(E)-4-(dimethylamino)-N-[(1S,3S)-3-[[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-1H-indazol-4-yl]oxy]cyclopentyl]but-2-enamide(E)-4-(dimethylamino)-N-[(1S,3S)-3-[[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-1H-indazol-4-yl]oxy ]cyclopentyl]but-2-enamide
Figure PCTCN2021117545-appb-000233
Figure PCTCN2021117545-appb-000233
Figure PCTCN2021117545-appb-000234
Figure PCTCN2021117545-appb-000234
第一步：N-[(1S，3S)-3-[6-(4-苄氧基-2-乙基-5-氟-苯基)-1-四氢吡喃-2基-吲唑-4-基]氧环戊基]氨基甲酸叔丁酯(11A)The first step: N-[(1S,3S)-3-[6-(4-benzyloxy-2-ethyl-5-fluoro-phenyl)-1-tetrahydropyran-2yl-indazole -4-yl]oxycyclopentyl]carbamate tert-butyl ester (11A)
tert-butyl N-[(1S,3S)-3-[6-(4-benzyloxy-2-ethyl-5-fluoro-phenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclopentyl]carbamatetert-butyl N-[(1S,3S)-3-[6-(4-benzyloxy-2-ethyl-5-fluoro-phenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclopentyl]carbamate
在50mL反应瓶中，依次加入10C(0.49g，1.04mmol)、2-(4-(苄氧基)-2-乙基-5-氟苯基)-4,4,5,5-四甲基-1,3,2-二噁硼戊环(0.44g，1.24mmol)、七水合磷酸钾(1.06g，3.12mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(85mg，0.106mmol)和二氧六环/水(v/v＝4/1，10mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(PE/EA＝3/1)得到11A，淡黄色固体(0.624g，产率96％)。In a 50 mL reaction flask, add 10C (0.49 g, 1.04 mmol), 2-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-4,4,5,5-tetramethyl in turn yl-1,3,2-dioxaborolane (0.44g, 1.24mmol), potassium phosphate heptahydrate (1.06g, 3.12mmol), [1,1'-bis(diphenylphosphino)ferrocene] Palladium dichloride dichloromethane complex (85 mg, 0.106 mmol) and dioxane/water (v/v=4/1, 10 mL) were replaced with nitrogen three times, and the reaction was stirred at 90° C. for 2 hours. 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 11A as a pale yellow solid (0.624 g, 96% yield).
第二步：N-[(1S，3S)-3-[6-(2-乙基-5-氟-4-羟基-苯基)-1-四氢吡喃-2-基-吲唑-4-基]氧环戊基]氨基甲酸叔丁酯(11B)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)
tert-butylN-[(1S,3S)-3-[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclopentyl]carbamatetert-butylN-[(1S,3S)-3-[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclopentyl]carbamate
在50mL反应瓶中，加入11A(0.618g，0.98mmol)、钯/碳(0.12g，60wt％)和甲醇(50mL)，氢气置换三次后在室温下搅拌反应3小时。反应液用硅藻土抽滤，滤液减压浓缩干得到11B粗品，白色固体(0.524g)，直接用于下一步反应。In a 50 mL reaction flask, 11A (0.618 g, 0.98 mmol), palladium/carbon (0.12 g, 60 wt%) and methanol (50 mL) were added, and the reaction was stirred at room temperature for 3 hours after hydrogen replacement for three times. The reaction solution was filtered with celite, and the filtrate was concentrated to dryness under reduced pressure to obtain crude 11B as a white solid (0.524 g), which was directly used in the next reaction.
LCMS m/z＝540.3[M+H] + LCMS m/z=540.3[M+H] +
第三步：(E)-4-(二甲基氨基)-N-[(1S，3S)-3-[[6-(2-乙基-5-氟-4-羟基-苯基)-1H-吲唑-4-基]氧基]环戊基]丁-2-烯酰胺(化合物11)The third step: (E)-4-(dimethylamino)-N-[(1S,3S)-3-[[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)- 1H-Indazol-4-yl]oxy]cyclopentyl]but-2-enamide (Compound 11)
(E)-4-(dimethylamino)-N-[(1S,3S)-3-[[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-1H-indazol-4-yl]oxy]cyclopentyl]but-2-enamide(E)-4-(dimethylamino)-N-[(1S,3S)-3-[[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-1H-indazol-4-yl]oxy ]cyclopentyl]but-2-enamide
在50mL反应瓶中，加入11B粗品(0.524g)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用MTBE(10mL×3)洗，然后减压浓缩干。所得残留物中依次加入反式-4-二甲基胺基巴豆酸盐酸盐(0.19g，1.15mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.604g，3.15mmol)、1-羟基苯并三唑(0.212g，1.57mmol)和N,N-二甲基甲酰胺(40mL)，加完后在室温下搅拌10分钟，加 入N,N-二异丙基乙胺(0.814g，6.3mmol)，加完后在室温下搅拌50分钟。反应液中加入饱和碳酸氢钠(50mL)，然后用二氯甲烷/甲醇(v/v＝10/1，50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析(二氯甲烷/甲醇(v/v)＝20/1至10/1)分离纯化得到化合物11(210mg，产率46％)。In a 50 mL reaction flask, crude 11B (0.524 g) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with MTBE (10 mL×3), and then concentrated to dryness under reduced pressure. To the obtained residue were added 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. Saturated sodium bicarbonate (50 mL) was added to the reaction solution, then extracted with dichloromethane/methanol (v/v=10/1, 50 mL×2), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure , the residue was separated and purified by column chromatography (dichloromethane/methanol (v/v)=20/1 to 10/1) to obtain compound 11 (210 mg, yield 46%).
LCMS m/z＝467.2[M+H] +； LCMS m/z=467.2[M+H] + ;
1H NMR(400MHz,DMSO-d 6)δ13.01(s,1H),9.60(s,1H),8.13–7.94(m,2H),7.03–6.86(m,3H),6.60-6.48(m,1H),6.35(s,1H),6.00(dt,1H),5.13–5.04(m,1H),4.42-4.26(m,1H),2.97(dd,2H),2.54-2.43(m,2H),2.30–2.03(m,9H),1.93-1.77(m,2H),1.56–1.44(m,1H),1.03(t,3H). 1 H NMR (400MHz, DMSO-d 6 )δ13.01(s,1H),9.60(s,1H),8.13-7.94(m,2H),7.03-6.86(m,3H),6.60-6.48(m ,1H),6.35(s,1H),6.00(dt,1H),5.13-5.04(m,1H),4.42-4.26(m,1H),2.97(dd,2H),2.54-2.43(m,2H) ), 2.30–2.03 (m, 9H), 1.93–1.77 (m, 2H), 1.56–1.44 (m, 1H), 1.03 (t, 3H).
实施例12：反式-(2E)-4-(二甲氨基)-N-[3-[(6-(3-氯-4-羟基苯基)-1H-吲唑-4-基)氧基]环丁基]丁-2-烯胺(化合物12)Example 12: trans-(2E)-4-(dimethylamino)-N-[3-[(6-(3-chloro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy yl]cyclobutyl]but-2-enamine (Compound 12)
trans-(2E)-4-(dimethylamino)-N-[3-[(6-(3-chloro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamidetrans-(2E)-4-(dimethylamino)-N-[3-[(6-(3-chloro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamide
Figure PCTCN2021117545-appb-000235
Figure PCTCN2021117545-appb-000235
第一步：反式-N-[3-(6-溴-1-四氢吡喃-2-基-吲唑-4-基)氧基环丁基]氨基甲酸叔丁酯(12B)The first step: tert-butyl trans-N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]carbamate (12B)
trans-tert-butyl N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]carbamatetrans-tert-butyl N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]carbamate
在50mL反应瓶中，加入反式-N-[3-羟基环丁基]氨基甲酸叔丁酯(1.41g，7.51mmol)和N,N-二甲基甲酰胺(20mL)，冰水冷却下分批加入NaH(0.4g，9.92mmol，60wt％)，加完后在0℃下搅拌20分钟，加入6-溴-4-氟-1-四氢吡喃-2-基-吲唑(1c)(1.5g，5mmol)并在室温下搅拌反应2h。反应液中加入饱和氯化铵溶液(200mL)和水(200mL)，反应 液用乙酸乙酯(300mL×2)提取，有机层合并，有机相用饱和氯化钠溶液(300mL×2)洗涤，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(PE/EA＝5/1)得到12B，白色固体(0.90g，产率38.5％)。In a 50 mL reaction flask, add tert-butyl trans-N-[3-hydroxycyclobutyl]carbamate (1.41 g, 7.51 mmol) and N,N-dimethylformamide (20 mL), under ice-water cooling NaH (0.4 g, 9.92 mmol, 60 wt%) was added in portions, stirred at 0 °C for 20 minutes after the addition, and 6-bromo-4-fluoro-1-tetrahydropyran-2-yl-indazole (1c ) (1.5 g, 5 mmol) and the reaction was stirred at room temperature for 2 h. Saturated ammonium chloride solution (200 mL) and water (200 mL) were added to the reaction solution, the reaction solution was extracted with ethyl acetate (300 mL×2), the organic layers were combined, and the organic phase was washed with saturated sodium chloride solution (300 mL×2), The organic layer was 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=5/1) to give 12B as a white solid (0.90 g, yield 38.5%).
第二步：反式-(3-(((6-(3-氯-4-羟基苯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基)环丁基)氨基甲酸叔丁酯(12C)The second step: trans-(3-(((6-(3-chloro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4- tert-butyl)oxy)cyclobutyl)carbamate (12C)
trans-tert-butyl(3-((6-(3-chloro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)carbamatetrans-tert-butyl(3-((6-(3-chloro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)carbamate
在100mL反应瓶中，依次加入12B(0.8g，1.72mmol)、3-氯-4-羟基苯硼酸(0.44g，2.58mmol)、七水合磷酸钾(1.75g，5.16mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(210mg，0.26mmol)和二氧六环/水(v/v＝4/1，20mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(PE/EA＝3/1)得到12C，淡黄色固体(0.80g，产率90.4％)。In a 100mL reaction flask, 12B (0.8g, 1.72mmol), 3-chloro-4-hydroxyphenylboronic acid (0.44g, 2.58mmol), potassium phosphate heptahydrate (1.75g, 5.16mmol), [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (210 mg, 0.26 mmol) and dioxane/water (v/v=4/1, 20 mL), nitrogen replacement After three times, the reaction was stirred at 90°C for 2 hours. 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 12C as a pale yellow solid (0.80 g, 90.4% yield).
LCMS m/z＝514.2[M+H] + LCMS m/z=514.2[M+H] +
第三步：反式-(2E)-4-(二甲氨基)-N-[3-[(6-(3-氯-4-羟基苯基)-1H-吲唑-4-基)氧基]环丁基]丁-2-烯胺(化合物12)The third step: trans-(2E)-4-(dimethylamino)-N-[3-[(6-(3-chloro-4-hydroxyphenyl)-1H-indazol-4-yl)oxygen yl]cyclobutyl]but-2-enamine (Compound 12)
trans-(2E)-4-(dimethylamino)-N-[3-[(6-(3-chloro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamidetrans-(2E)-4-(dimethylamino)-N-[3-[(6-(3-chloro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamide
在50mL反应瓶中，加入12C(0.4g，0.78mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，8mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干。所得残留物中依次加入反式-4-二甲基胺基巴豆酸盐酸盐(0.15g，1.17mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.30g，1.56mmol)、1-羟基苯并三唑(0.16g，1.17mmol)和N,N-二甲基甲酰胺(10mL)，加完后在室温下搅拌10分钟，加入N,N-二异丙基乙胺(0.6g，4.68mmol)，加完后在室温下搅拌50分钟。反应液中加入饱和碳酸氢钠(50mL)，然后用二氯甲烷/甲醇(v/v＝10/1，50mL×4)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过制备液相(仪器：waters 2767制备液相；色谱柱:XBridge@Prep C18(30mm×150mm)；流动相组成：流动相A：乙腈，流动相B：水(含0.05％氨水))分离纯化得到化合物12(180mg，产率52.3％)。In a 50 mL reaction flask, 12C (0.4 g, 0.78 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 8 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure. To the obtained residue were added 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) and 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. Saturated sodium bicarbonate (50 mL) was added to the reaction solution, then extracted with dichloromethane/methanol (v/v=10/1, 50 mL×4), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure , the residue was passed through preparative liquid phase (instrument: waters 2767 preparative liquid phase; chromatographic column: XBridge@Prep C18 (30mm×150mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.05% ammonia water) ) was isolated and purified to obtain compound 12 (180 mg, yield 52.3%).
LCMS m/z＝441.2[M+H] + LCMS m/z=441.2[M+H] +
1H NMR(400MHz,CD 3OD)δ8.05(d,1H),7.56(d,1H),7.41(dd,1H),7.21(s,1H),7.00(d,1H),6.84–6.71(m,1H),6.47(d,1H),6.25–6.15(m,1H),5.21-5.08(m,1H),4.63-4.50(m,1H),3.37(dd,2H),2.75–2.53(m,4H),2.46(s,6H). 1 H NMR (400MHz, CD 3 OD) δ 8.05(d,1H), 7.56(d,1H), 7.41(dd,1H), 7.21(s,1H), 7.00(d,1H), 6.84–6.71 (m, 1H), 6.47 (d, 1H), 6.25–6.15 (m, 1H), 5.21–5.08 (m, 1H), 4.63–4.50 (m, 1H), 3.37 (dd, 2H), 2.75–2.53 (m,4H),2.46(s,6H).
实施例13：反式-N-(3-((6-(2-乙基-5-氟-4-羟基苯基)咪唑并[1,5-a]吡啶-8-基)氧基)环丁基)丙烯酰胺(化合物13)Example 13: trans-N-(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy) Cyclobutyl)acrylamide (Compound 13)
trans-N-(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)acrylamidetrans-N-(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)acrylamide
Figure PCTCN2021117545-appb-000236
Figure PCTCN2021117545-appb-000236
第一步：((5-溴-3-氟吡啶-2-基)甲基)氨基甲酸叔丁酯(13B)The first step: ((5-bromo-3-fluoropyridin-2-yl)methyl) tert-butyl carbamate (13B)
tert-butyl((5-bromo-3-fluoropyridin-2-yl)methyl)carbamatetert-butyl((5-bromo-3-fluoropyridin-2-yl)methyl)carbamate
50mL反应瓶中，依次加入5-溴-3-氟-2-吡啶甲腈(13A)(2.0g，10mmol)、雷尼镍(2g)，甲醇(20mL)，BOC酸酐(4.36g，20mmol)，室温搅拌48h，硅藻土过滤，减压浓缩，硅胶柱纯化(石油醚/乙酸乙酯(v/v)＝10:1)，得到13B，黄色油状物(0.92g，产率30％)In a 50mL reaction flask, 5-bromo-3-fluoro-2-pyridinecarbonitrile (13A) (2.0g, 10mmol), Raney nickel (2g), methanol (20mL), BOC anhydride (4.36g, 20mmol) were sequentially added , stirred at room temperature for 48 h, filtered through celite, concentrated under reduced pressure, and purified by silica gel column (petroleum ether/ethyl acetate (v/v)=10:1) to obtain 13B as a yellow oil (0.92 g, yield 30%)
LCMS m/z＝249.0/251.0[M-55] + LCMS m/z=249.0/251.0[M-55] +
第二步：(5-溴-3-氟吡啶-2-基)甲胺(13C)的三氟乙酸盐Step 2: Trifluoroacetate salt of (5-bromo-3-fluoropyridin-2-yl)methanamine (13C)
(5-bromo-3-fluoropyridin-2-yl)methanamine；2,2,2-trifluoroacetic acid(5-bromo-3-fluoropyridin-2-yl)methanamine; 2,2,2-trifluoroacetic acid
将13B(0.92g，3mmol)溶于二氯甲烷(10mL)溶液中并加入三氟乙酸(3mL)，室温反应1小时。将反应液直接浓缩，得到13C的三氟乙酸盐粗品，黄色油状物(962mg)，直接用于下一步反应。13B (0.92 g, 3 mmol) was dissolved in dichloromethane (10 mL) solution and trifluoroacetic acid (3 mL) was added, and the reaction was carried out at room temperature for 1 hour. The reaction solution was directly concentrated to obtain crude 13C trifluoroacetate as a yellow oil (962 mg), which was directly used in the next reaction.
第三步：N-((5-溴-3-氟吡啶-2-基)甲基)甲酰胺(13D)Step 3: N-((5-Bromo-3-fluoropyridin-2-yl)methyl)formamide (13D)
N-((5-bromo-3-fluoropyridin-2-yl)methyl)formamideN-((5-bromo-3-fluoropyridin-2-yl)methyl)formamide
氮气保护，在50mL反应瓶中，依次加入上一步的(5-溴-3-氟吡啶-2-基)甲胺(13C)的三氟乙酸盐粗品(962mg)、无水甲酸(20mL)，100℃下搅拌1h后，加入醋酸酐(4mL)，100℃搅拌48h,减压浓缩，得到13D粗品，黑色油状物(700mg)，直接用于下一步反应。Under nitrogen protection, in a 50mL reaction flask, add the crude trifluoroacetate salt (962mg) of the previous step (5-bromo-3-fluoropyridin-2-yl)methanamine (13C) and anhydrous formic acid (20mL) in turn. , after stirring at 100 °C for 1 h, acetic anhydride (4 mL) was added, stirred at 100 °C for 48 h, and concentrated under reduced pressure to obtain crude 13D as a black oil (700 mg), which was directly used in the next reaction.
第四步：6-溴-8-氟咪唑并[1,5-a]吡啶(13E)Step 4: 6-Bromo-8-fluoroimidazo[1,5-a]pyridine (13E)
6-bromo-8-fluoroimidazo[1,5-a]pyridine6-bromo-8-fluoroimidazo[1,5-a]pyridine
氮气保护，在50mL反应瓶中，依次加入13D粗品(700mg)、三氯氧磷(1mL)，甲苯(10mL)，加完后在80℃下搅拌2h。减压浓缩，饱和碳酸氢钠溶液(50mL)淬灭，二氯甲烷(30mL*3)萃取，合并有机层，用无水硫酸钠干燥，过滤，滤液减压浓缩，得到13E，灰色固体(291mg，三步产率45％)。Under nitrogen protection, in a 50 mL reaction flask, add 13D crude product (700 mg), phosphorus oxychloride (1 mL), and toluene (10 mL) in sequence, and stir at 80 °C for 2 h after the addition. Concentrated under reduced pressure, quenched with saturated sodium bicarbonate solution (50 mL), extracted with dichloromethane (30 mL*3), combined the organic layers, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 13E, a gray solid (291 mg , the three-step yield is 45%).
LCMS m/z＝215.0/217.0[M+1] + LCMS m/z=215.0/217.0[M+1] +
1H NMR(400MHz,CDCl 3)δ8.32(s,1H),8.01(s,1H),7.62(s,1H),6.58(d,1H). 1 H NMR (400MHz, CDCl 3 ) δ 8.32(s,1H), 8.01(s,1H), 7.62(s,1H), 6.58(d,1H).
第五步:反式-叔丁基(3-(6-溴咪唑并[1,5-a]吡啶-8-基)氧基)环丁基)氨基甲酸酯(13F)Step 5: trans-tert-butyl (3-(6-bromoimidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)carbamate (13F)
trans-tert-butyl(3-((6-bromoimidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)carbamatetrans-tert-butyl(3-((6-bromoimidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)carbamate
氮气保护下加入反式-(3-羟基环丁基)氨基甲酸叔丁酯(224.5mg，1.2mmol)和DMF(5mL)到反应瓶中，冰水冷却下加入钠氢(48mg，60wt％，1.6mmol)，加完室温搅拌反应30分钟；冰水冷却，滴入13E(215mg，1mmol)的DMF溶液(5mL)，加完室温搅拌反应3小时。TLC监控反应完全，加入乙酸乙酯(100mL)和水(100mL)，分层，水层用乙酸乙酯(100mL×1)提取一次，有机层合并，饱和氯化钠溶液(100mL×2)洗涤，无水硫酸钠干燥，过滤，40℃减压浓缩干，残余物硅胶柱层析纯化(洗脱剂PE/EA＝5/1)得13F，白色固体(340mg，产率89％)。Under nitrogen protection, tert-butyl trans-(3-hydroxycyclobutyl)carbamate (224.5 mg, 1.2 mmol) and DMF (5 mL) were added to the reaction flask, and 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 aqueous layer was extracted once with ethyl acetate (100 mL×1), the organic layers were combined, and washed with saturated sodium chloride solution (100 mL×2). , dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure at 40°C, and the residue was purified by silica gel column chromatography (eluent PE/EA=5/1) to obtain 13F as a white solid (340 mg, yield 89%).
第六步：反式-叔丁基(3-((6-(4-(苄氧基)-2-乙基-5-氟苯基)咪唑并[1,5-a]吡啶-8-基)氧基)环丁基)氨基甲酸酯(13G)The sixth step: trans-tert-butyl(3-((6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)imidazo[1,5-a]pyridine-8- yl)oxy)cyclobutyl)carbamate (13G)
trans-tert-butyl(3-((6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)carbamatetrans-tert-butyl(3-((6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)carbamate
氮气保护，将2-(4-(苄氧基)-2-乙基-5-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(480.9mg，1.35mmol)，七水磷酸钾(913mg，2.7mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化 钯二氯甲烷络合物(73.5mg，0.09mmol)，分别加入至13F(340mg，0.89mmol)的1,4-二氧六环(20mL)和水(5mL)的溶液中，110℃搅拌1h，饱和碳酸氢钠溶液(20mL)淬灭，乙酸乙酯(20mL*3)萃取，合并有机层用无水硫酸钠干燥，抽滤，滤液减压浓缩，残余物硅胶柱层析纯化(石油醚/乙酸乙酯(v/v)＝2:1)，得到13G，灰色固体(413mg，产率87.3％)。Under nitrogen protection, 2-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (480.9 mg, 1.35 mmol), potassium phosphate heptahydrate (913 mg, 2.7 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (73.5 mg, 0.09 mmol), were added to a solution of 13F (340 mg, 0.89 mmol) in 1,4-dioxane (20 mL) and water (5 mL) respectively, stirred at 110 °C for 1 h, and quenched with saturated sodium bicarbonate solution (20 mL) , extracted with ethyl acetate (20 mL*3), the combined organic layers were dried over anhydrous sodium sulfate, filtered with suction, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2 : 1) to give 13G as a grey solid (413 mg, 87.3% yield).
LCMS m/z＝532.3[M+1] + LCMS m/z=532.3[M+1] +
第七步：反式-叔丁基(3-((6-(2-乙基-5-氟-4-羟基苯基)咪唑并[1,5-a]吡啶-8-基)氧基)环丁基)氨基甲酸酯(13H)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)
trans-tert-butyl(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)carbamatetrans-tert-butyl(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)carbamate
将13G(413mg，0.78mmol)加入反应瓶中，加入钯碳(41mg)和甲醇溶液(30mL)，氢气换气三次，室温搅拌反应6h。反应液通过硅藻土过滤，乙酸乙酯洗脱。减压浓缩干，得13H粗品(343mg)，直接用于下一步反应。13G (413 mg, 0.78 mmol) was added to the reaction flask, palladium carbon (41 mg) and methanol solution (30 mL) were added, the hydrogen was purged three times, and the reaction was stirred at room temperature for 6 h. The reaction solution was filtered through celite and eluted with ethyl acetate. Concentrated to dryness under reduced pressure to obtain crude 13H (343 mg), which was directly used in the next reaction.
第八步:反式-4-(8-((3-氨基环丁氧基)咪唑并[1,5-a]吡啶-6-基)-5-乙基-2-氟苯酚(13I)的三氟乙酸盐The eighth step: trans-4-(8-((3-aminocyclobutoxy)imidazo[1,5-a]pyridin-6-yl)-5-ethyl-2-fluorophenol (13I) Trifluoroacetate
trans-4-(8-(3-aminocyclobutoxy)imidazo[1,5-a]pyridin-6-yl)-5-ethyl-2-fluorophenol；trifluoroacetic acidtrans-4-(8-(3-aminocyclobutoxy)imidazo[1,5-a]pyridin-6-yl)-5-ethyl-2-fluorophenol; trifluoroacetic acid
将13H粗品(343mg)溶于二氯甲烷(10mL)溶液中并加入三氟乙酸(3mL)，室温反应1小时。将反应液直接浓缩，得到13I的三氟乙酸盐粗品，白色固体(355mg)，直接用于下一步反应。The crude 13H (343 mg) was dissolved in dichloromethane (10 mL) solution and trifluoroacetic acid (3 mL) was added, and the reaction was performed at room temperature for 1 hour. The reaction solution was directly concentrated to obtain crude trifluoroacetate salt of 13I as a white solid (355 mg), which was directly used in the next reaction.
第九步:反式-N-(3-((6-(2-乙基-5-氟-4-羟基苯基)咪唑并[1,5-a]吡啶-8-基)氧基)环丁基)丙烯酰胺(化合物13)Step 9: Trans-N-(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy) Cyclobutyl)acrylamide (Compound 13)
trans-N-(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)acrylamidetrans-N-(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)acrylamide
氮气保护，50mL三口瓶中，将6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯(62mg,0.15mmol)加入到丙烯酸(10.8mg,0.15mmol)的N,N-二甲基甲酰胺(2mL)溶液中，室温反应10min，0℃下，再将13I的三氟乙酸盐粗品(59mg)溶于1mL N,N-二甲基甲酰胺中滴加到上述反应液中，0℃搅拌1min后，再将N,N-二异丙基乙胺(101mg,0.78mmol)溶于1mL N,N-二甲基甲酰胺中滴加到上述反应液中，0℃搅拌3h，饱和碳酸氢钠溶液(5mL)淬灭，乙酸乙酯(20*3mL)萃取，减压浓缩，残留物通过制备液相(仪器：waters 2767制备液相；色谱柱:SunFire@Prep C18(19mm×150mm)；流动相组成：流动相A：乙腈流动相B：水(含5mM乙酸铵))分离纯化得到化合物13(6.8mg，产率13.3％)。Under nitrogen protection, in a 50mL three-necked flask, add 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate (62mg, 0.15mmol) to acrylic acid (10.8mg, 0.15mmol) In the N,N-dimethylformamide (2 mL) solution of 13I, react at room temperature for 10 min, and at 0 °C, the crude trifluoroacetate salt of 13I (59 mg) was dissolved in 1 mL of N,N-dimethylformamide. Add dropwise to the above reaction solution, after stirring for 1min at 0°C, 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%).
LCMS m/z＝396.1[M+1] + LCMS m/z=396.1[M+1] +
1H NMR(400MHz,CD 3OD)δ8.32(s,1H),7.79(s,1H),7.47(s,1H),6.96(d,1H),6.88(d,1H),6.25–6.19(m,2H),5.87(s,1H),5.65(dd,1H),5.09–4.98(m,1H),4.62–4.50(m,1H),2.75–2.61(m,2H),2.60–2.47(m,4H),1.11(t,3H). 1 H NMR (400MHz, CD 3 OD) δ 8.32(s, 1H), 7.79(s, 1H), 7.47(s, 1H), 6.96(d, 1H), 6.88(d, 1H), 6.25–6.19 (m, 2H), 5.87 (s, 1H), 5.65 (dd, 1H), 5.09–4.98 (m, 1H), 4.62–4.50 (m, 1H), 2.75–2.61 (m, 2H), 2.60–2.47 (m,4H),1.11(t,3H).
实施例14:反式-2-氟-N-((3-((6-(4-羟基苯基)咪唑并[1,5-a]吡啶-8-基)氧基)环丁基)丙烯酰胺(化合物14)的三氟乙酸盐Example 14: trans-2-fluoro-N-((3-((6-(4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl) Trifluoroacetate salt of acrylamide (compound 14)
trans-2-fluoro-N-(3-((6-(4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)acrylamide；trifluoroacetic acidtrans-2-fluoro-N-(3-((6-(4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)acrylamide; trifluoroacetic acid
Figure PCTCN2021117545-appb-000237
Figure PCTCN2021117545-appb-000237
第一步：反式-叔丁基(3-((6-(4-羟基苯基)咪唑并[1,5-a]吡啶-8-基)氧基)环丁基)氨基甲酸酯(14A)The first step: trans-tert-butyl (3-((6-(4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)carbamate (14A)
trans-tert-butyl(3-((6-(4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)carbamatetrans-tert-butyl(3-((6-(4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)carbamate
氮气保护，将4-羟基苯硼酸(186mg，1.35mmol)，七水磷酸钾(913mg，2.7mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(73.5mg，0.09mmol)，分别加入至13F(344mg，0.9mmol)的1,4-二氧六环(20mL)和水(5mL)的溶液中，110℃搅拌1h，饱和碳酸氢钠溶液(20mL)淬灭，乙酸乙酯(20mL*3)萃取，合并有机层用无水硫酸钠干燥，抽滤，滤液减压浓缩，残留物硅胶柱层析(石油醚/乙酸乙酯(v/v)＝2:1)，得到14A，黄色固体(312mg，产率87.7％)。Under nitrogen protection, 4-hydroxyphenylboronic acid (186mg, 1.35mmol), potassium phosphate heptahydrate (913mg, 2.7mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloride Methane complex (73.5 mg, 0.09 mmol) was added to a solution of 13F (344 mg, 0.9 mmol) in 1,4-dioxane (20 mL) and water (5 mL) respectively, stirred at 110 °C for 1 h, saturated carbonic acid Sodium hydrogen solution (20 mL) was quenched, extracted with ethyl acetate (20 mL*3), the combined organic layers were dried over anhydrous sodium sulfate, filtered with suction, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate) (v/v)=2:1) to give 14A as a yellow solid (312 mg, 87.7% yield).
第二步：反式-4-(8-((3-氨基环丁氧基)咪唑并[1,5-a]吡啶-6-基)苯酚(14B)的三氟乙酸盐Step 2: Trifluoroacetate salt of trans-4-(8-((3-aminocyclobutoxy)imidazo[1,5-a]pyridin-6-yl)phenol (14B)
trans-4-(8-(3-aminocyclobutoxy)imidazo[1,5-a]pyridin-6-yl)phenol；trifluoroacetic acidtrans-4-(8-(3-aminocyclobutoxy)imidazo[1,5-a]pyridin-6-yl)phenol; trifluoroacetic acid
将反式-叔丁基(3-((6-(4-羟基苯基)咪唑并[1,5-a]吡啶-8-基)氧基)环丁基)氨基甲酸酯(14A)(312mg，0.79mmol)溶于二氯甲烷(10mL)溶液中并加入三氟乙酸(3mL)，室温反应1小时。将反应液直接浓缩，得到14B的三氟乙酸盐粗品，黄色油状物(323.4mg)。Trans-tert-butyl(3-((6-(4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)carbamate (14A) (312 mg, 0.79 mmol) was dissolved in dichloromethane (10 mL) solution and trifluoroacetic acid (3 mL) was added to react at room temperature for 1 hour. The reaction solution was directly concentrated to give crude trifluoroacetate of 14B as a yellow oil (323.4 mg).
第三步：反式-2-氟-N-((3-((6-(4-羟基苯基)咪唑并[1,5-a]吡啶-8-基)氧基)环丁基)丙烯酰胺(化合物14)的三氟乙酸盐The third step: trans-2-fluoro-N-((3-((6-(4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl) Trifluoroacetate salt of acrylamide (compound 14)
trans-2-fluoro-N-(3-((6-(4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)acrylamide；trifluoroacetic acidtrans-2-fluoro-N-(3-((6-(4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)acrylamide; trifluoroacetic acid
氮气保护，50mL三口瓶中，将1-羟基苯并三氮唑(20.3mg，0.15mmol)，1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(28.8mg,0.15mmol)，加入到2-氟丙烯酸(9mg,0.1mmol)的N,N-二甲基甲酰胺(2mL)溶液中，室温反应1min，0℃下，再将14B的三氟乙酸盐粗品(32.7mg)溶于1mL N,N-二甲基甲酰胺中滴加到上述反应液中，再将N,N-二异丙基乙胺(56mg,0.39mmol)溶于1mL N,N-二甲基甲酰胺中滴加到上述反应液中，0℃搅拌3h，饱和碳酸氢钠溶液(5mL)淬灭，乙酸乙酯(20*3mL)萃取，减压浓缩，残留物通过制备液相(仪器：waters 2767制备液相；色谱柱:SunFire@Prep C18(19mm×150mm)；流动相组成：流动相A：乙腈，流动相B：水(含0.1％三氟乙酸))分离纯化得到化合物14的三氟乙酸盐(5.8mg，产率15％)Under nitrogen protection, in a 50 mL three-necked flask, 1-hydroxybenzotriazole (20.3 mg, 0.15 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (28.8 mg, 0.15 mmol), was added to a solution of 2-fluoroacrylic acid (9 mg, 0.1 mmol) in N, N-dimethylformamide (2 mL), and reacted at room temperature for 1 min. At 0 °C, the trifluoroacetic acid of 14B was added. The crude salt product (32.7mg) was dissolved in 1mL N,N-dimethylformamide and added dropwise to the above reaction solution, and then N,N-diisopropylethylamine (56mg, 0.39mmol) was dissolved in 1mL N, N-dimethylformamide was added dropwise to the above reaction solution, stirred at 0 °C for 3 h, quenched with saturated sodium bicarbonate solution (5 mL), extracted with ethyl acetate (20*3 mL), concentrated under reduced pressure, and the residue was prepared by Liquid phase (instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm×150mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid)) separation and purification Trifluoroacetate salt of compound 14 was obtained (5.8 mg, 15% yield)
LCMS m/z＝368.2[M+1] + LCMS m/z=368.2[M+1] +
1H NMR(400MHz,CD 3OD)δ9.27(s,1H),8.25(s,1H),8.01(s,1H),7.55–7.45(m,2H),6.98–6.88(m,2H),6.54(s,1H),5.6(dd,1H),5.26-5.16(m,2H),4.69-4.60(m,1H),2.71(dd,4H). 1H NMR (400MHz, CD 3 OD) δ9.27(s,1H), 8.25(s,1H), 8.01(s,1H), 7.55–7.45(m,2H), 6.98–6.88(m,2H), 6.54(s, 1H), 5.6(dd, 1H), 5.26-5.16(m, 2H), 4.69-4.60(m, 1H), 2.71(dd, 4H).
实施例15：反式-(E)-4-(二甲基氨基)-N-((3-((6-(2-乙基-5-氟-4-羟苯基)咪唑并[1,5-a]吡啶-8-乙氧基)环丁基)丁-2-烯酰胺(化合物15)Example 15: trans-(E)-4-(dimethylamino)-N-((3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1 ,5-a]pyridine-8-ethoxy)cyclobutyl)but-2-enamide (Compound 15)
trans-(E)-4-(dimethylamino)-N-(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)but-2-enamidetrans-(E)-4-(dimethylamino)-N-(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy) cyclobutyl)but-2-enamide
Figure PCTCN2021117545-appb-000238
Figure PCTCN2021117545-appb-000238
氮气保护，50mL三口瓶中，将6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯(62mg,0.15mmol)加入到反式4-二甲基胺基巴豆酸盐酸盐(24.8mg,0.15mmol)的N,N-二甲基甲酰胺(2mL)溶液中，室温反应10min，0℃下，再将13I的三氟乙酸盐粗品(59mg)溶于1mL N,N-二甲基甲酰胺中滴加到上述反应液中，0℃搅拌1min后，再将N,N-二异丙基乙胺(101mg,0.78mmol)溶于1mL N,N-二甲基甲酰胺中滴加到上述反应液中，0℃搅拌3h，饱和碳酸氢钠溶液(5mL)淬灭，乙酸乙酯(20*3mL)萃取，减压浓缩，残留物通过制备液相(仪器：waters 2767制备液相；色谱柱:SunFire@Prep C18(19mm×150mm)；流动相组成：流动相A：乙腈流动相B：水(含5mM乙酸铵))分离纯化得到化合物15(10.8mg，产率18.4％)Under nitrogen protection, in a 50mL three-necked flask, add 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate (62mg, 0.15mmol) to trans-4-dimethylamine In a solution of N,N-dimethylformamide (2mL) of crotonic acid hydrochloride (24.8mg, 0.15mmol), the reaction was carried out at room temperature for 10min at 0°C, and then crude trifluoroacetate (59mg) of 13I was added. It was dissolved in 1 mL of N,N-dimethylformamide and added dropwise to the above reaction solution. After stirring at 0°C for 1 min, N,N-diisopropylethylamine (101 mg, 0.78 mmol) was dissolved in 1 mL of N, N-dimethylformamide was added dropwise to the above reaction solution, stirred at 0 °C for 3 h, quenched with saturated sodium bicarbonate solution (5 mL), extracted with ethyl acetate (20*3 mL), concentrated under reduced pressure, and the residue was prepared by Liquid phase (instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm×150mm); mobile phase composition: mobile phase A: acetonitrile Mobile phase B: water (containing 5mM ammonium acetate)) separation and purification to obtain compound 15 (10.8 mg, 18.4% yield)
LCMS m/z＝453.2[M+1] + LCMS m/z=453.2[M+1] +
1H NMR(400MHz,CD 3OD)δ9.25(s,1H),8.01(d,2H),6.96(dd,2H),6.77–6.65(m,1H),6.37(d,1H),6.21(s,1H),5.17–5.05(m,1H),4.66–4.53(m,1H),3.93(d,2H),2.74(s,6H),2.76-2.66(m,2H),2.65–2.48(m,4H),1.12(t,3H). 1H NMR (400MHz, CD 3 OD) δ 9.25(s, 1H), 8.01(d, 2H), 6.96(dd, 2H), 6.77–6.65(m, 1H), 6.37(d, 1H), 6.21( s, 1H), 5.17–5.05 (m, 1H), 4.66–4.53 (m, 1H), 3.93 (d, 2H), 2.74 (s, 6H), 2.76–2.66 (m, 2H), 2.65–2.48 ( m,4H),1.12(t,3H).
实施例16：顺式-(E)-4-(二甲基胺基)-N-[3-[[6-(4-羟基苯基)-1H-吲唑-4-基]氧基]环丁基]-N-甲基丁-2-烯酰胺(化合物16)Example 16: cis-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy] Cyclobutyl]-N-methylbut-2-enamide (Compound 16)
cis-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclobutyl]-N-methyl-but-2-enamidecis-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclobutyl]-N-methyl-but-2-enamide
Figure PCTCN2021117545-appb-000239
Figure PCTCN2021117545-appb-000239
Figure PCTCN2021117545-appb-000240
Figure PCTCN2021117545-appb-000240
第一步：顺式-N-[3-(6-溴-1-四氢吡喃-2-基-吲唑-4-基)氧基环丁基]-N-甲基-氨基甲酸叔丁酯(16A)The first step: cis-N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]-N-methyl-carbamic acid tertiary Butyl ester (16A)
cis-tert-butyl N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]-N-methyl-carbamatecis-tert-butyl N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]-N-methyl-carbamate
在50mL反应瓶中，依次加入顺式-N-[3-(6-溴-1-四氢吡喃-2-基-吲唑-4-基)氧基环丁基]氨基甲酸叔丁酯(2C)(0.7g，1.50mmol)、四氢呋喃(15mL)和氢化钠(1.2g，30mmol，60wt％)，加完后在25℃下搅拌30分钟，缓慢滴加碘甲烷(4.2g，30mmol)并在室温下搅拌反应1.2h。反应液中加入乙酸乙酯(50mL)，然后依次用水(30mL×1)、饱和食盐水(30mL×1)洗涤，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(PE/EA＝9/1)得到16A，白色固体(0.6g，产率：83％)。In a 50mL reaction flask, add cis-N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]carbamic acid tert-butyl ester in turn (2C) (0.7 g, 1.50 mmol), tetrahydrofuran (15 mL) and sodium hydride (1.2 g, 30 mmol, 60 wt%), after the addition was completed, the mixture was stirred at 25°C for 30 minutes, and iodomethane (4.2 g, 30 mmol) was slowly added dropwise. And the reaction was stirred at room temperature for 1.2 h. Ethyl acetate (50 mL) was added to the reaction solution, then washed with water (30 mL×1) and saturated brine (30 mL×1) successively, the organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was passed through a column Purification by chromatography (PE/EA=9/1) gave 16A as a white solid (0.6 g, yield: 83%).
1H NMR(400MHz,CDCl 3)δ8.02(s,1H),7.36(s,1H),6.47(d,1H),5.65-5.56(m,1H),4.52-4.44(m,1H),4.28(brs,1H),4.06–3.97(m,1H),3.78-3.65(m,1H),2.91–2.77(m,5H),2.57–2.44(m,1H),2.41-2.29(m,2H),2.19-2.09(m,1H),2.09-2.01(m,1H),1.79–1.68(m,3H),1.47(s,9H). 1 H NMR (400MHz, CDCl 3 )δ8.02(s,1H), 7.36(s,1H), 6.47(d,1H), 5.65-5.56(m,1H), 4.52-4.44(m,1H), 4.28(brs,1H),4.06-3.97(m,1H),3.78-3.65(m,1H),2.91-2.77(m,5H),2.57-2.44(m,1H),2.41-2.29(m,2H) ), 2.19-2.09(m, 1H), 2.09-2.01(m, 1H), 1.79-1.68(m, 3H), 1.47(s, 9H).
第二步：顺式-N-[3-[6-(4-羟基苯基)-1-四氢吡喃-2-基-吲唑-4-基]氧环丁基]-N-甲基-氨基甲酸叔丁酯(16B)The second step: cis-N-[3-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxocyclobutyl]-N-methane tert-Butyl-carbamate (16B)
cis-tert-butylN-[3-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclobutyl]-N-methyl-carbamatecis-tert-butylN-[3-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclobutyl]-N-methyl-carbamate
在50mL反应瓶中，依次16A(0.6g，1.25mmol)、4-羟基苯硼酸(0.26g，1.88mmol)、七水合磷酸钾(1.69g，5mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(102mg，0.125mmol)和二氧六环/水(v/v＝4/1，10mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(PE/EA＝3/1)得到16B，淡黄色固体(0.6g，产率97％)。In a 50mL reaction flask, sequentially 16A (0.6g, 1.25mmol), 4-hydroxyphenylboronic acid (0.26g, 1.88mmol), potassium phosphate heptahydrate (1.69g, 5mmol), [1,1'-bis(diphenyl) phosphine)ferrocene]dichloropalladium dichloromethane complex (102mg, 0.125mmol) and dioxane/water (v/v=4/1, 10mL), after nitrogen replacement three times, at 90°C The reaction was stirred for 2 hours. 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 16B as a pale yellow solid (0.6 g, 97% yield).
LCMS m/z＝494.2[M+H] +； LCMS m/z=494.2[M+H] + ;
第三步：顺式-(E)-4-(二甲基胺基)-N-[3-[[6-(4-羟基苯基)-1H-吲唑-4-基]氧基]环丁基]-N-甲基丁-2-烯酰胺(化合物16)The third step: cis-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy] Cyclobutyl]-N-methylbut-2-enamide (Compound 16)
cis-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclobutyl]-N-methyl-but-2-enamidecis-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclobutyl]-N-methyl-but-2-enamide
在50mL反应瓶中，加入16B(0.3g，0.61mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用MTBE(10mL×3)洗，然后减压浓缩干。In a 50 mL reaction flask, 16B (0.3 g, 0.61 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with MTBE (10 mL×3), and then concentrated to dryness under reduced pressure.
在50mL反应瓶中，加入反式-4-二甲基胺基巴豆酸盐酸盐(0.15g，0.915mmol)、6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯(0.378g，0.915mmol)和DMF(10mL)，加完后在室温下搅拌30分钟，然后加入上步所得残留物的DMF(5mL)溶液，加完后在室温下搅拌10分钟，加入N,N-二异丙基乙胺(0.79g，6.1mmol)，加完后在室温下搅拌过夜。反应液中加入饱和碳酸氢钠(50mL)，然后用二氯甲烷/甲醇(v/v＝10/1)(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物制备HPLC(仪器：waters 2767制备液相；色谱柱:XBridge@Prep C18(30mm×150mm)；流动相组成：流动相A：乙腈，流动相B：水(含0.05％氨水))纯化得到化合物16(60mg，产率24％)。In a 50mL reaction flask, add trans-4-dimethylaminocrotonate hydrochloride (0.15g, 0.915mmol), 6-chlorobenzotriazole-1,1,3,3-tetramethyl Urea hexafluorophosphate (0.378 g, 0.915 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 (0.79 g, 6.1 mmol) was added, and after the addition was complete, the mixture was stirred at room temperature overnight. Saturated sodium bicarbonate (50 mL) was added to the reaction solution, then extracted with dichloromethane/methanol (v/v=10/1) (50 mL×2), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced in pressure Concentrated, the residue was prepared by HPLC (instrument: waters 2767 preparative liquid phase; chromatographic column: XBridge@Prep C18 (30mm×150mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.05% ammonia water)) Purification gave compound 16 (60 mg, 24% yield).
LCMS m/z＝421.2[M+H] +； LCMS m/z=421.2[M+H] + ;
1H NMR(400MHz,CD 3OD)δ8.02(s,1H),7.54–7.44(m,2H),7.21(s,1H),6.97–6.83(m,2H),6.82–6.67(m,1H),6.65–6.47(m,2H),4.81–4.62(m,2H),3.17(d,2H),3.07(d,3H),3.00–2.82(m,2H),2.64–2.35(m,2H),2.28(s,6H). 1 H NMR (400MHz, CD 3 OD) δ 8.02 (s, 1H), 7.54–7.44 (m, 2H), 7.21 (s, 1H), 6.97–6.83 (m, 2H), 6.82–6.67 (m, 1H), 6.65–6.47 (m, 2H), 4.81–4.62 (m, 2H), 3.17 (d, 2H), 3.07 (d, 3H), 3.00–2.82 (m, 2H), 2.64–2.35 (m, 2H), 2.28(s, 6H).
实施例17：反式(E)-4-(二甲氨基)-N-(3-((6-(3-氟-4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)丁-2-烯酰胺(化合物17)Example 17: trans(E)-4-(dimethylamino)-N-(3-((6-(3-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy ) cyclobutyl)but-2-enamide (compound 17)
trans-(E)-4-(dimethylamino)-N-(3-((6-(3-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)but-2-enamidetrans-(E)-4-(dimethylamino)-N-(3-((6-(3-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)but-2-enamide
Figure PCTCN2021117545-appb-000241
Figure PCTCN2021117545-appb-000241
第一步：反式-叔丁基-3-((6-(3-氟-4-羟基苯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基)环丁基)氨基甲酸氨基酯(17A)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-tert-butyl-3-((6-(3-fluoro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)carbamatetrans-tert-butyl-3-((6-(3-fluoro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)carbamate
在100mL反应瓶中，依次加入反式-N-[3-(6-溴-1-四氢吡喃-2-基-吲唑-4-基)氧基环丁基]氨基甲酸叔丁酯(1C)(0.8g，1.72mmol)、3-氟-4-羟基苯硼酸(0.40g，2.56mmol)、七水合磷酸钾(1.75g，5.16mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(210mg，0.26mmol)和二氧六环/水(v/v＝4/1，20mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(PE/EA＝3/1)得到17A，淡黄色固体(0.78g，产率92％)。In a 100mL reaction flask, add trans-N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]carbamic acid tert-butyl ester in turn (1C) (0.8 g, 1.72 mmol), 3-fluoro-4-hydroxyphenylboronic acid (0.40 g, 2.56 mmol), potassium phosphate heptahydrate (1.75 g, 5.16 mmol), [1,1'-bis(diphenyl) phosphine)ferrocene]dichloropalladium dichloromethane complex (210mg, 0.26mmol) and dioxane/water (v/v=4/1, 20mL), after nitrogen replacement three times, at 90°C The reaction was stirred for 2 hours. 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 17A as a pale yellow solid (0.78 g, 92% yield).
第二步：反式-(E)-4-(二甲氨基)-N-(3-((6-(3-氟-4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)丁-2-烯酰胺(化合物17)The second step: trans-(E)-4-(dimethylamino)-N-(3-((6-(3-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl)oxygen yl)cyclobutyl)but-2-enamide (Compound 17)
trans-(E)-4-(dimethylamino)-N-(3-((6-(3-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)but-2-enamidetrans-(E)-4-(dimethylamino)-N-(3-((6-(3-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)but-2-enamide
在50mL反应瓶中，加入17A(0.039g，0.078mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，8mL)，然后在室温下搅拌反应5小时，反应液减压浓缩干。所得残留物中依次加入反式-4-二甲基胺基巴豆酸盐酸盐(0.015g，0.117mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐 酸盐(0.030g，0.156mmol)、1-羟基苯并三唑(0.016g，0.117mmol)和N,N-二甲基甲酰胺(10mL)，加完后在室温下搅拌10分钟，加入N,N-二异丙基乙胺(0.06g，0.468mmol)，加完后在室温下搅拌50分钟。反应液中加入饱和碳酸氢钠水溶液(50mL)，然后用二氯甲烷/甲醇(v/v＝10/1，50mL×4)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过制备液相(仪器：waters 2767制备液相；色谱柱:XBridge@Prep C18(30mm×150mm)；流动相组成：流动相A：乙腈，流动相B：水(含0.05％氨水))分离纯化得到化合物17(17mg，产率51.5％)。In a 50 mL reaction flask, 17A (0.039 g, 0.078 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 8 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure to dryness. . To the obtained residue were added 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) was added and stirred at room temperature for 50 minutes. Saturated aqueous sodium bicarbonate solution (50 mL) was added to the reaction solution, then extracted with dichloromethane/methanol (v/v=10/1, 50 mL×4), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed Concentrated, the residue was passed through preparative liquid phase (instrument: waters 2767 preparative liquid phase; chromatographic column: XBridge@Prep C18 (30mm×150mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.05% ammonia water) )) was isolated and purified to obtain compound 17 (17 mg, yield 51.5%).
LCMS m/z＝425.2[M+1] + LCMS m/z=425.2[M+1] +
1H NMR(400MHz,CD 3OD)δ8.04(s,1H),7.34(dd,1H),7.28(dd,1H),7.22(s,1H),7.05–6.94(m,1H),6.84-6.72(m,1H),6.49(s,1H),6.17-6.02(m,1H),5.18-5.08(m,1H),4.64–4.49(m,1H),3.18-3.06(m,2H),2.73–2.50(m,4H),2.27(s,6H). 1H NMR (400MHz, CD 3 OD) δ 8.04(s, 1H), 7.34(dd, 1H), 7.28(dd, 1H), 7.22(s, 1H), 7.05–6.94(m, 1H), 6.84- 6.72(m, 1H), 6.49(s, 1H), 6.17-6.02(m, 1H), 5.18-5.08(m, 1H), 4.64-4.49(m, 1H), 3.18-3.06(m, 2H), 2.73–2.50(m, 4H), 2.27(s, 6H).
实施例18：反式-(2E)-4-(二甲基氨基)-N-[3-[(6-(2-氟-4-羟基苯基)-1H-吲唑-4-基)氧基]环丁基]丁-2-烯酰胺(化合物18)Example 18: trans-(2E)-4-(dimethylamino)-N-[3-[(6-(2-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl) Oxy]cyclobutyl]but-2-enamide (Compound 18)
trans-(2E)-4-(dimethylamino)-N-[3-[(6-(2-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamidetrans-(2E)-4-(dimethylamino)-N-[3-[(6-(2-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamide
Figure PCTCN2021117545-appb-000242
Figure PCTCN2021117545-appb-000242
第一步：反式-N-[3-[(6-(2-氟-4-羟基苯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基]环丁基]氨基甲酸酯(18A)The first step: trans-N-[3-[(6-(2-fluoro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4 -yl)oxy]cyclobutyl]carbamate (18A)
trans-tert-butyl(3-((6-(2-fluoro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)carbamatetrans-tert-butyl(3-((6-(2-fluoro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)carbamate
在50mL反应瓶中，依次加入反式-N-[3-(6-溴-1-四氢吡喃-2-基-吲唑-4-基)氧基环丁基]氨基甲酸叔丁酯(1C)(0.297g，0.64mmol)、2-氟-4-羟基苯硼酸(0.119g，0.76mmol)、 七水合磷酸钾(0.645g，1.91mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(53mg，0.065mmol)和二氧六环/水(v/v＝4/1，10mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(PE/EA＝3/1)得到18A，白色固体(0.289g，产率91％)。In a 50mL reaction flask, add trans-N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]carbamic acid tert-butyl ester in turn (1C) (0.297 g, 0.64 mmol), 2-fluoro-4-hydroxyphenylboronic acid (0.119 g, 0.76 mmol), potassium phosphate heptahydrate (0.645 g, 1.91 mmol), [1,1'-bis(diphenylene) phosphine)ferrocene]dichloropalladium dichloromethane complex (53 mg, 0.065 mmol) and dioxane/water (v/v=4/1, 10 mL), after nitrogen replacement three times, at 90°C The reaction was stirred for 2 hours. 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 18A as a white solid (0.289 g, 91% yield).
LCMS m/z＝498.3[M+H] +； LCMS m/z=498.3[M+H] + ;
第二步：反式-(2E)-4-(二甲基氨基)-N-[3-[(6-(2-氟-4-羟基苯基)-1H-吲唑-4-基)氧基]环丁基]丁-2-烯酰胺(化合物18)The second step: trans-(2E)-4-(dimethylamino)-N-[3-[(6-(2-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl) Oxy]cyclobutyl]but-2-enamide (Compound 18)
trans-(2E)-4-(dimethylamino)-N-[3-[(6-(2-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamidetrans-(2E)-4-(dimethylamino)-N-[3-[(6-(2-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamide
在50mL反应瓶中，加入18A(0.14g，0.28mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用MTBE(10mL×3)洗，然后减压浓缩干。所得残留物中依次加入反式-4-二甲基胺基巴豆酸盐酸盐(0.062g，0.37mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.165g，0.858mmol)、1-羟基苯并三唑(0.058g，0.429mmol)和N,N-二甲基甲酰胺(20mL)，加完后在室温下搅拌10分钟，加入N,N-二异丙基乙胺(0.222g，1.76mmol)，加完后在室温下搅拌50分钟。反应液中加入饱和碳酸氢钠(50mL)，然后用二氯甲烷/甲醇(v/v＝10/1)(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过制备液相(仪器：waters 2767制备液相；色谱柱:SunFire@Prep C18(19mm×150mm)；流动相组成：流动相A：乙腈流动相B：水(含5mM乙酸铵))分离纯化得到化合物18(48mg，产率40％)。In a 50 mL reaction flask, 18A (0.14 g, 0.28 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with MTBE (10 mL×3), and then concentrated to dryness under reduced pressure. To the obtained residue were added 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) and N,N-dimethylformamide (20 mL), stir at room temperature for 10 min after addition, add N , N-diisopropylethylamine (0.222 g, 1.76 mmol) was added and stirred at room temperature for 50 minutes. Saturated sodium bicarbonate (50 mL) was added to the reaction solution, then extracted with dichloromethane/methanol (v/v=10/1) (50 mL×2), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced in pressure Concentrated, the residue was passed through preparative liquid phase (instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm×150mm); mobile phase composition: mobile phase A: acetonitrile Mobile phase B: water (containing 5mM ammonium acetate) ) was isolated and purified to obtain compound 18 (48 mg, yield 40%).
LCMS m/z＝425.2[M+H] +； LCMS m/z=425.2[M+H] + ;
1H NMR(400MHz,CD 3OD)δ8.05(d,1H),7.33(t,1H),7.17(d,1H),6.81–6.64(m,2H),6.61(dd,1H),6.44(s,1H),6.21-6.13(d,1H),5.14–5.03(m,1H),4.62–4.51(m,1H),3.34(dd,2H),2.74–2.62(m,2H),2.62–2.50(m,2H),2.44(s,6H). 1 H NMR (400 MHz, CD 3 OD) δ 8.05 (d, 1H), 7.33 (t, 1H), 7.17 (d, 1H), 6.81–6.64 (m, 2H), 6.61 (dd, 1H), 6.44 (s,1H), 6.21-6.13(d,1H), 5.14-5.03(m,1H), 4.62-4.51(m,1H), 3.34(dd,2H), 2.74-2.62(m,2H), 2.62 –2.50(m, 2H), 2.44(s, 6H).
实施例19：反式-(2E)-4-(二甲基氨基)-N-[3-[[6-(4-羟基-2-甲基苯基)-1H-吲唑-4-基)氧基]环丁基]丁-2-烯酰胺(化合物19)Example 19: trans-(2E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxy-2-methylphenyl)-1H-indazol-4-yl )oxy]cyclobutyl]but-2-enamide (Compound 19)
trans-(2E)-4-(dimethylamino)-N-[3-[(6-(4-hydroxy-2-methylphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamidetrans-(2E)-4-(dimethylamino)-N-[3-[(6-(4-hydroxy-2-methylphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamide
Figure PCTCN2021117545-appb-000243
Figure PCTCN2021117545-appb-000243
第一步：反式-叔丁基(3-(((6-(4-羟基-2-甲基苯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基)环丁基)氨基甲酸酯(19A)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-tert-butyl(3-((6-(4-hydroxy-2-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)carbamatetrans-tert-butyl(3-((6-(4-hydroxy-2-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)carbamate
在50mL反应瓶中，依次加入反式-N-[3-(6-溴-1-四氢吡喃-2-基-吲唑-4-基)氧基环丁基]氨基甲酸叔丁酯(1C)(0.297g，0.64mmol)、4-羟基-2-甲基苯硼酸(0.116g，0.76mmol)、七水合磷酸钾(0.645g，1.91mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(53mg，0.065mmol)和二氧六环/水(v/v＝4/1，10mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(PE/EA＝3/1)得到19A，白色固体(0.287g，产率91％)。In a 50mL reaction flask, add trans-N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]carbamic acid tert-butyl ester in turn (1C) (0.297 g, 0.64 mmol), 4-hydroxy-2-methylphenylboronic acid (0.116 g, 0.76 mmol), potassium phosphate heptahydrate (0.645 g, 1.91 mmol), [1,1'-bis(bis(bis) Phenylphosphine)ferrocene]dichloropalladium dichloromethane complex (53 mg, 0.065 mmol) and dioxane/water (v/v=4/1, 10 mL), after nitrogen replacement three times, at 90 The reaction was stirred at °C for 2 hours. 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 19A as a white solid (0.287 g, 91% yield).
LCMS m/z＝494.3[M+H] +； LCMS m/z=494.3[M+H] + ;
第二步：反式-(2E)-4-(二甲基氨基)-N-[3-[[6-(4-羟基-2-甲基苯基)-1H-吲唑-4-基)氧基]环丁基]丁-2-烯酰胺(化合物19)The second step: trans-(2E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxy-2-methylphenyl)-1H-indazol-4-yl )oxy]cyclobutyl]but-2-enamide (Compound 19)
trans-(2E)-4-(dimethylamino)-N-[3-[(6-(4-hydroxy-2-methylphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamidetrans-(2E)-4-(dimethylamino)-N-[3-[(6-(4-hydroxy-2-methylphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamide
在50mL反应瓶中，加入19A(0.22g，0.45mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用MTBE(10mL×3)洗，然后减压浓缩干。所得残留物中依次加入反式-4-二甲基胺基巴豆酸盐酸盐(0.096g，0.58mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.222g，1.156mmol)、1-羟基苯 并三唑(0.102g，0.75mmol)和N,N-二甲基甲酰胺(20mL)，加完后在室温下搅拌10分钟，加入N,N-二异丙基乙胺(0.448g，3.468mmol)，加完后在室温下搅拌50分钟。反应液中加入饱和碳酸氢钠(50mL)，然后用二氯甲烷/甲醇(v/v＝10/1)(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过制备液相(仪器：waters 2767制备液相；色谱柱:SunFire@Prep C18(19mm×150mm)；.流动相组成：流动相A：乙腈流动相B：水(含5mM乙酸铵))分离纯化得到化合物19，白色固体(60mg，产率32％)。In a 50 mL reaction flask, 19A (0.22 g, 0.45 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with MTBE (10 mL×3), and then concentrated to dryness under reduced pressure. To the obtained residue were added 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) and N,N-dimethylformamide (20 mL), stir at room temperature for 10 min after addition, add N , N-diisopropylethylamine (0.448 g, 3.468 mmol) was added and stirred at room temperature for 50 minutes. Saturated sodium bicarbonate (50 mL) was added to the reaction solution, then extracted with dichloromethane/methanol (v/v=10/1) (50 mL×2), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced in pressure Concentrated, the residue was passed through preparative liquid phase (instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm×150mm); mobile phase composition: mobile phase A: acetonitrile Mobile phase B: water (containing 5mM ammonium acetate) )) was isolated and purified to give compound 19 as a white solid (60 mg, yield 32%).
LCMS m/z＝421.1[M+H] +； LCMS m/z=421.1[M+H] + ;
1H NMR(400MHz,CD 3OD)δ8.05(d,1H),7.05(d,1H),6.93(s,1H),6.80–6.60(m,3H),6.25–6.10(m,2H),5.10–5.00(m,1H),4.62–4.50(m,1H),3.34(dd,2H),2.72-2.61(m,2H),2.58-2.47(m,2H),2.43(s,6H),2.19(s,3H). 1 H NMR (400MHz, CD 3 OD) δ8.05(d,1H), 7.05(d,1H), 6.93(s,1H), 6.80-6.60(m,3H), 6.25-6.10(m,2H) ,5.10–5.00(m,1H),4.62–4.50(m,1H),3.34(dd,2H),2.72-2.61(m,2H),2.58-2.47(m,2H),2.43(s,6H) ,2.19(s,3H).
实施例20：反式-(E)-N-(3-((6-(2-氯-4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)-4-(二甲基氨基)丁-2-烯酰胺(化合物20)Example 20: trans-(E)-N-(3-((6-(2-chloro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-4 -(Dimethylamino)but-2-enamide (Compound 20)
trans-(E)-N-(3-((6-(2-chloro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-4-(dimethylamino)but-2-enamidetrans-(E)-N-(3-((6-(2-chloro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-4-(dimethylamino)but-2-enamide
Figure PCTCN2021117545-appb-000244
Figure PCTCN2021117545-appb-000244
第一步：反式-叔丁基-3-((6-(2-氯-4-羟基苯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基)环丁基)氨基甲酸氨基酯(20A)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-tert-butyl-3-((6-(2-chloro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)carbamatetrans-tert-butyl-3-((6-(2-chloro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)carbamate
在100mL反应瓶中，依次加入反式-N-[3-(6-溴-1-四氢吡喃-2-基-吲唑-4-基)氧基环丁基]氨基甲酸叔丁酯(1C)(0.8g，1.72mmol)、2-氯-4-羟基苯硼酸(0.44g，2.58mmol)、七水合磷酸钾(1.75g，5.16mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(210mg，0.26mmol)和二氧六环/水(v/v＝4/1，20mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(PE/EA＝3/1)得到20A，淡黄色固体(0.80g，产率90.4％)。In a 100mL reaction flask, add trans-N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]carbamic acid tert-butyl ester in turn (1C) (0.8 g, 1.72 mmol), 2-chloro-4-hydroxyphenylboronic acid (0.44 g, 2.58 mmol), potassium phosphate heptahydrate (1.75 g, 5.16 mmol), [1,1'-bis(diphenyl) phosphine)ferrocene]dichloropalladium dichloromethane complex (210mg, 0.26mmol) and dioxane/water (v/v=4/1, 20mL), after nitrogen replacement three times, at 90°C The reaction was stirred for 2 hours. 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 20A as a pale yellow solid (0.80 g, 90.4% yield).
第二步：反式-(E)-N-(3-((6-(2-氯-4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)-4-(二甲基氨基)丁-2-烯酰胺(化合物20)The second step: trans-(E)-N-(3-((6-(2-chloro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-4 -(Dimethylamino)but-2-enamide (Compound 20)
trans-(E)-N-(3-((6-(2-chloro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-4-(dimethylamino)but-2-enamidetrans-(E)-N-(3-((6-(2-chloro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-4-(dimethylamino)but-2-enamide
在50mL反应瓶中，加入20A(0.04g，0.078mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，8mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干。所得残留物中依次加入反式-4-二甲基胺基巴豆酸盐酸盐(0.015g，0.117mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.030g，0.156mmol)、1-羟基苯并三唑(0.016g，0.117mmol)和N,N-二甲基甲酰胺(10mL)，加完后在室温下搅拌10分钟，加入N,N-二异丙基乙胺(0.06g，0.468mmol)，加完后在室温下搅拌50分钟。反应液中加入饱和碳酸氢钠(50mL)，然后用二氯甲烷/甲醇(v/v＝10/1，50mL×4)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过制备液相(仪器：waters 2767制备液相；色谱柱:XBridge@Prep C18(30mm×150mm)；流动相组成：流动相A：乙腈，流动相B：水(含0.05％氨水))分离纯化得到化合物20(18mg，产率52.3％)。In a 50 mL reaction flask, 20A (0.04 g, 0.078 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 8 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure. To the obtained residue were added 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) was added and stirred at room temperature for 50 minutes. Saturated sodium bicarbonate (50 mL) was added to the reaction solution, then extracted with dichloromethane/methanol (v/v=10/1, 50 mL×4), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure , the residue was passed through preparative liquid phase (instrument: waters 2767 preparative liquid phase; chromatographic column: XBridge@Prep C18 (30mm×150mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.05% ammonia water) ) was isolated and purified to obtain compound 20 (18 mg, yield 52.3%).
LCMS m/z＝441.2[M+1] + LCMS m/z=441.2[M+1] +
1H NMR(400MHz,MeOD)δ8.07(d,1H),7.23(d,1H),7.05(s,1H),6.93(d,1H),6.84–6.71(m,2H),6.33(d,1H),6.13-6.04(m,1H),5.10–4.98(m,1H),4.62–4.46(m,1H),3.18–3.06(m,2H),2.73-2.63(m,2H),2.60-2.49(m,2H),2.27(s,6H).1H NMR (400MHz, MeOD) δ8.07(d,1H), 7.23(d,1H), 7.05(s,1H), 6.93(d,1H), 6.84–6.71(m,2H), 6.33(d, 1H),6.13-6.04(m,1H),5.10-4.98(m,1H),4.62-4.46(m,1H),3.18-3.06(m,2H),2.73-2.63(m,2H),2.60- 2.49(m, 2H), 2.27(s, 6H).
实施例21：顺式-(2E)-4-(二甲基氨基)-N-乙基-N-[3-[(6-(4-羟基苯基)-1H-吲唑-4-基)氧基]环丁基]丁-2-烯酰胺(化合物21)Example 21: cis-(2E)-4-(dimethylamino)-N-ethyl-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl )oxy]cyclobutyl]but-2-enamide (Compound 21)
cis-(2E)-4-(dimethylamino)-N-ethyl-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamidecis-(2E)-4-(dimethylamino)-N-ethyl-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamide
Figure PCTCN2021117545-appb-000245
Figure PCTCN2021117545-appb-000245
第一步：顺式-叔丁基(-3-((6-溴-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基)环丁基)(乙基)氨基甲酸酯(21A)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)
cis-tert-butyl(3-((6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)(ethyl)carbamatecis-tert-butyl(3-((6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)(ethyl)carbamate
在50mL反应瓶中，依次加入顺式-N-[3-(6-溴-1-四氢吡喃-2-基-吲唑-4-基)氧基环丁基]氨基甲酸叔丁酯(2C)(0.558g，1.20mmol)、四氢呋喃(15mL)和氢化钠(1.06g，26.4mmol，60wt％)，加完后在25℃下搅拌30分钟，缓慢滴加碘乙烷(2.81g，18mmol)并在室温下搅拌反应2h。反应液中加入乙酸乙酯(50mL)，然后依次用水(30mL×1)、饱和食盐水(30mL×1)洗涤，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(PE/EA＝7/1)得到21A，白色固体(0.4g，产率：68％)。In a 50mL reaction flask, add cis-N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]carbamic acid tert-butyl ester in turn (2C) (0.558 g, 1.20 mmol), tetrahydrofuran (15 mL) and sodium hydride (1.06 g, 26.4 mmol, 60 wt %), stir at 25 °C for 30 minutes after the addition, and slowly add iodoethane (2.81 g, 18 mmol) and the reaction was stirred at room temperature for 2 h. Ethyl acetate (50 mL) was added to the reaction solution, then washed with water (30 mL×1) and saturated brine (30 mL×1) successively, the organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was passed through a column Purification by chromatography (PE/EA=7/1) gave 21A as a white solid (0.4 g, yield: 68%).
LCMS m/z＝438.1/440.0[M-55] +； LCMS m/z=438.1/440.0[M-55] + ;
第二步：顺式-N-乙基-N-[3-[(6-(4-羟基苯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基]环丁基]氨基甲酸叔丁酯(21B)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)
cis-tert-butyl N-ethyl-N-[3-[(6-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy]cyclobutyl]carbamatecis-tert-butyl N-ethyl-N-[3-[(6-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy]cyclobutyl] carbamate
在50mL反应瓶中，依次加入顺式-叔丁基(-3-((6-溴-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基)环丁基)(乙基)氨基甲酸酯(21A)(0.4g，0.8mmol)、4-羟基苯硼酸(0.13g，0.96mmol)、七水合磷酸钾(0.81g，2.4mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(65mg，0.08mmol)和二氧六环/水(v/v＝4/1，10mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50 mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(PE/EA＝3/1)得到21B，淡黄色固体(0.32g，产率79％)。In a 50mL reaction flask, add cis-tert-butyl(-3-((6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy yl)cyclobutyl)(ethyl)carbamate (21A) (0.4g, 0.8mmol), 4-hydroxyphenylboronic acid (0.13g, 0.96mmol), potassium phosphate heptahydrate (0.81g, 2.4mmol), [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (65 mg, 0.08 mmol) and dioxane/water (v/v=4/1, 10 mL) ), and after nitrogen replacement three times, the reaction was stirred at 90 °C for 2 hours. 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 21B as a pale yellow solid (0.32 g, 79% yield).
LCMS m/z＝508.2[M+H] + LCMS m/z=508.2[M+H] +
第三步：顺式-(2E)-4-(二甲基氨基)-N-乙基-N-[3-[(6-(4-羟基苯基)-1H-吲唑-4-基)氧基]环丁基]丁-2-烯酰胺(化合物21)The third step: cis-(2E)-4-(dimethylamino)-N-ethyl-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl )oxy]cyclobutyl]but-2-enamide (Compound 21)
cis-(2E)-4-(dimethylamino)-N-ethyl-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamidecis-(2E)-4-(dimethylamino)-N-ethyl-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamide
在50mL反应瓶中，加入顺式-N-乙基-N-[3-[(6-(4-羟基苯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基]环丁基]氨基甲酸叔丁酯(21B)(0.31g，0.61mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用MTBE(10mL×3)洗，然后减压浓缩干。In a 50 mL reaction flask, add cis-N-ethyl-N-[3-[(6-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H- Indazol-4-yl)oxy]cyclobutyl]carbamate tert-butyl ester (21B) (0.31 g, 0.61 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL), then The reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with MTBE (10 mL×3), and then concentrated to dryness under reduced pressure.
在50mL反应瓶中，加入反式-4-二甲基胺基巴豆酸盐酸盐(0.162g，0.98mmol)、DMF(5mL一次性塑料滴管滴入1滴)和二氯甲烷(3mL)，加完后在室温下搅拌5分钟，然后滴加草酰氯(0.25g，1.97mmol)，然后加入上步所得残留物的二氯甲烷(5mL)和N,N-二异丙基乙胺(0.79g，6.1mmol)溶液，加完后在室温下搅拌10分钟。反应液中加入饱和碳酸氢钠(50mL)，然后用二氯甲烷/甲醇(v/v＝10/1)(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物制备HPLC(仪器：waters 2767制备液相；色谱柱:XBridge@Prep C18(30mm×150mm)；流动相组成：流动相A：乙腈，流动相B：水(含0.05％氨水))纯化得到化合物21(6mg，产率2％)。In a 50mL reaction flask, add trans-4-dimethylaminocrotonate hydrochloride (0.162g, 0.98mmol), DMF (1 drop in a 5mL disposable plastic dropper) and dichloromethane (3mL) , after the addition, stir at room temperature for 5 minutes, then add dropwise oxalyl chloride (0.25 g, 1.97 mmol), then add the residue obtained in the previous step in dichloromethane (5 mL) and N,N-diisopropylethylamine ( 0.79 g, 6.1 mmol) solution and stirred at room temperature for 10 minutes after the addition was complete. Saturated sodium bicarbonate (50 mL) was added to the reaction solution, then extracted with dichloromethane/methanol (v/v=10/1) (50 mL×2), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed Concentrated, the residue was prepared by HPLC (instrument: waters 2767 preparative liquid phase; chromatographic column: XBridge@Prep C18 (30mm×150mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.05% ammonia water)) Purification gave compound 21 (6 mg, 2% yield).
LCMS m/z＝435.3[M+H] +； LCMS m/z=435.3[M+H] + ;
1H NMR(400MHz,CD 3OD)δ8.02(s,1H),7.54–7.46(m,2H),7.22(s,1H),6.91–6.85(m,2H),6.84-6.56(m,3H),4.82-4.71(m,1H),4.61-4.28(m,1H),3.66(d,2H),3.63-3.54(m,2H),3.10-2.95(m,2H),2.68(s,6H),2.55-2.30(m,2H),1.26-1.11(t,3H). 1 H NMR (400MHz, CD 3 OD) δ 8.02(s, 1H), 7.54-7.46(m, 2H), 7.22(s, 1H), 6.91-6.85(m, 2H), 6.84-6.56(m, 3H), 4.82-4.71(m, 1H), 4.61-4.28(m, 1H), 3.66(d, 2H), 3.63-3.54(m, 2H), 3.10-2.95(m, 2H), 2.68(s, 6H), 2.55-2.30(m, 2H), 1.26-1.11(t, 3H).
实施例22：顺式-(2E)-N-(环丙基甲基)-4-(二甲基氨基)-N-[3-[(6-(4-羟基苯基)-1H-吲唑-4-基)氧基]环丁基]丁-2-烯酰胺(化合物22)Example 22: cis-(2E)-N-(cyclopropylmethyl)-4-(dimethylamino)-N-[3-[(6-(4-hydroxyphenyl)-1H-indone Azol-4-yl)oxy]cyclobutyl]but-2-enamide (Compound 22)
cis-(2E)-N-(cyclopropylmethyl)-4-(dimethylamino)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamidecis-(2E)-N-(cyclopropylmethyl)-4-(dimethylamino)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamide
Figure PCTCN2021117545-appb-000246
Figure PCTCN2021117545-appb-000246
Figure PCTCN2021117545-appb-000247
Figure PCTCN2021117545-appb-000247
第一步：顺式-N-[3-[[6-溴-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基]环丁基]-N-(环丙基甲基)氨基甲酸酯叔丁基(22A)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)
cis-tert-butyl N-[3-[(6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy]cyclobutyl]-N-(cyclopropylmethyl)carbamatecis-tert-butyl N-[3-[(6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy]cyclobutyl]-N-(cyclopropylmethyl)carbamate
在50mL反应瓶中，依次加入顺式-N-[3-(6-溴-1-四氢吡喃-2-基-吲唑-4-基)氧基环丁基]氨基甲酸叔丁酯(2C)(0.466g，1.0mmol)、碘化钠(450mg,3.0mmol)、DMF(15mL)和氢化钠(0.8g，20mmol，60wt％)，加完后在25℃下搅拌30分钟，缓慢滴加溴甲基环丙烷(2.81g，18mmol)并在45℃下搅拌反应2h。反应液中加入乙酸乙酯(50mL)，然后依次用水(30mL×1)、饱和食盐水(30mL×1)洗涤，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(PE/EA＝7/1)得到22A，粗品，白色固体(0.57g，产率：100％)。In a 50mL reaction flask, add cis-N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]carbamic acid tert-butyl ester in turn (2C) (0.466 g, 1.0 mmol), sodium iodide (450 mg, 3.0 mmol), DMF (15 mL) and sodium hydride (0.8 g, 20 mmol, 60 wt%), after the addition was completed, stir at 25 °C for 30 minutes, slowly Bromomethylcyclopropane (2.81 g, 18 mmol) was added dropwise and the reaction was stirred at 45 °C for 2 h. Ethyl acetate (50 mL) was added to the reaction solution, then washed with water (30 mL×1) and saturated brine (30 mL×1) successively, the organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was passed through a column Purification by chromatography (PE/EA=7/1) gave 22A as a crude product as a white solid (0.57 g, yield: 100%).
LCMS m/z＝464.1/466.2[M-55] +； LCMS m/z=464.1/466.2[M-55] + ;
第二步：顺式-N-(环丙基甲基)-N-[3-[(6-(4-羟基苯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基]氧基]环丁基]氨基甲酸叔丁酯(22B)The second step: cis-N-(cyclopropylmethyl)-N-[3-[(6-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)- 1H-Indazol-4-yl]oxy]cyclobutyl]carbamate tert-butyl ester (22B)
cis-tert-butyl N-(cyclopropylmethyl)-N-[3-[(6-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy]cyclobutyl]carbamatecis-tert-butyl N-(cyclopropylmethyl)-N-[3-[(6-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy] cyclobutyl]carbamate
在50mL反应瓶中，依次加入顺式-N-[3-[[6-溴-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基]环丁基]-N-(环丙基甲基)氨基甲酸酯叔丁基(22A)(0.57g，1.1mmol)、4-羟基苯硼酸(0.18g，1.31mmol)、七水合磷酸钾(1.11g，3.29mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(90mg，0.11mmol)和二氧六环/水(v/v＝4/1，10mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(PE/EA＝3/1)得到22B，淡黄色固体(0.48g，产率82％)。In a 50mL reaction flask, add cis-N-[3-[[6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy] Cyclobutyl]-N-(cyclopropylmethyl)carbamate tert-butyl (22A) (0.57 g, 1.1 mmol), 4-hydroxyphenylboronic acid (0.18 g, 1.31 mmol), potassium phosphate heptahydrate ( 1.11 g, 3.29 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (90 mg, 0.11 mmol) and dioxane/water (v/ v=4/1, 10 mL), after three nitrogen replacements, the reaction was stirred at 90° C. for 2 hours. 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 22B as a pale yellow solid (0.48 g, 82% yield).
1H NMR(400MHz,CD 3OD)δ8.01(s,1H),7.55–7.47(m,2H),7.31(s,1H),6.91–6.85(m,2H),6.65(d,1H),5.79(dd,1H),4.74-4.64(m,1H),4.06–3.95(m,2H),3.87-3.77(m,1H), 3.19(d,2H),3.00-2.87(m,2H),2.50-2.36(m,3H),2.18–2.06(m,1H),2.05–1.98(m,1H),1.91–1.58(m,3H),1.44(s,9H),1.04–0.90(m,1H),0.54–0.44(m,2H),0.30-0.22(m,2H). 1 H NMR (400MHz, CD 3 OD) δ 8.01(s, 1H), 7.55-7.47(m, 2H), 7.31(s, 1H), 6.91-6.85(m, 2H), 6.65(d, 1H) ,5.79(dd,1H),4.74-4.64(m,1H),4.06-3.95(m,2H),3.87-3.77(m,1H), 3.19(d,2H),3.00-2.87(m,2H) ,2.50-2.36(m,3H),2.18-2.06(m,1H),2.05-1.98(m,1H),1.91-1.58(m,3H),1.44(s,9H),1.04-0.90(m, 1H),0.54-0.44(m,2H),0.30-0.22(m,2H).
第三步：顺式-(2E)-N-(环丙基甲基)-4-(二甲基氨基)-N-[3-[(6-(4-羟基苯基)-1H-吲唑-4-基)氧基]环丁基]丁-2-烯酰胺(化合物22)The third step: cis-(2E)-N-(cyclopropylmethyl)-4-(dimethylamino)-N-[3-[(6-(4-hydroxyphenyl)-1H-indium Azol-4-yl)oxy]cyclobutyl]but-2-enamide (Compound 22)
cis-(2E)-N-(cyclopropylmethyl)-4-(dimethylamino)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamidecis-(2E)-N-(cyclopropylmethyl)-4-(dimethylamino)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamide
在50mL反应瓶中，加入22B(0.395g，0.74mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用MTBE(10mL×3)洗，然后减压浓缩干，加入二氯甲烷(5mL)和N,N-二异丙基乙胺(0.574g，4.44mmol)搅拌10分钟为反应待用溶液I。In a 50 mL reaction flask, 22B (0.395 g, 0.74 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and the reaction was stirred at room temperature for 5 hours. 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.
将反式-4-二甲基胺基巴豆酸盐酸盐(0.331g，2.0mmol)和二异丙基乙胺(775mg，6.0mmol，1.0mL)溶于二氯甲烷(9.0mL)和乙腈(1.0mL)的混合溶液中，加入三吡咯烷基溴化鏻六氟磷酸盐(0.932g，2mmol)，室温搅拌20min得到反应中间体溶液II。Trans-4-dimethylaminocrotonate hydrochloride (0.331 g, 2.0 mmol) and diisopropylethylamine (775 mg, 6.0 mmol, 1.0 mL) were dissolved in dichloromethane (9.0 mL) and acetonitrile (1.0 mL) of the mixed solution, tripyrrolidinophosphonium bromide hexafluorophosphate (0.932 g, 2 mmol) was added, and the mixture was stirred at room temperature for 20 min to obtain a reaction intermediate solution II.
将反应中间体溶液II(4.88mL)缓慢滴加到上述反应待用溶液I中，加完后在室温下搅拌60分钟。反应液中加入饱和碳酸氢钠(50mL)，然后用二氯甲烷/甲醇(v/v＝10/1)(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(二氯甲烷/甲醇＝(v/v)30/1-25/1)得到化合物22(90mg，产率26％)。The 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. Saturated sodium bicarbonate (50 mL) was added to the reaction solution, then extracted with dichloromethane/methanol (v/v=10/1) (50 mL×2), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced in pressure After concentration, the residue was separated and purified by column chromatography (dichloromethane/methanol=(v/v) 30/1-25/1) to obtain compound 22 (90 mg, yield 26%).
LCMS m/z＝461.2[M+H] +； LCMS m/z=461.2[M+H] + ;
1H NMR(400MHz,CD 3OD)δ8.01(s,1H),7.55–7.46(m,2H),7.21(s,1H),6.92–6.84(m,2H),6.84-6.69(m,1H),6.65-6.56(m,2H),4.81-4.71(m,1H),4.39–4.28(m,1H),3.44(d,2H),3.17(d,2H),3.11–2.98(m,2H),2.56-2.34(m,2H),2.28(s,6H),1.08–0.90(m,1H),0.63–0.44(m,2H),0.38-0.22(m,2H). 1 H NMR (400MHz, CD 3 OD) δ 8.01 (s, 1H), 7.55–7.46 (m, 2H), 7.21 (s, 1H), 6.92–6.84 (m, 2H), 6.84–6.69 (m, 1H), 6.65-6.56(m, 2H), 4.81-4.71(m, 1H), 4.39-4.28(m, 1H), 3.44(d, 2H), 3.17(d, 2H), 3.11-2.98(m, 2H), 2.56-2.34(m, 2H), 2.28(s, 6H), 1.08-0.90(m, 1H), 0.63-0.44(m, 2H), 0.38-0.22(m, 2H).
实施例23：反式-(2E)-N-(2-(二甲基氨基)乙基)-N-[3-[(6-(4-羟苯基)-1H-吲唑-4-基)氧基]环丁基]丁-2-烯酰胺(化合物23)Example 23: trans-(2E)-N-(2-(dimethylamino)ethyl)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazole-4- yl)oxy]cyclobutyl]but-2-enamide (Compound 23)
trans-(2E)-N-(2-(dimethylamino)ethyl)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamidetrans-(2E)-N-(2-(dimethylamino)ethyl)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamide
Figure PCTCN2021117545-appb-000248
Figure PCTCN2021117545-appb-000248
Figure PCTCN2021117545-appb-000249
Figure PCTCN2021117545-appb-000249
第一步：反式-叔丁基(3-((6-溴-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基)环丁基)(2-(二甲基氨基)乙基)氨基甲酸酯(23A)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)
trans-tert-butyl(3-((6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)(2-(dimethylamino)ethyl)carbamatetrans-tert-butyl(3-((6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)(2-(dimethylamino)ethyl)carbamate
在50mL反应瓶中，依次加入反式-N-[3-(6-溴-1-四氢吡喃-2-基-吲唑-4-基)氧基环丁基]氨基甲酸叔丁酯(1C)(0.72g，1.54mmol)、N,N-二甲基甲酰胺(15mL)，碘化钠(0.12g,0.77mmol)和氢化钠(1.23g，30.8mmol，60wt％)，加完后在25℃下搅拌10分钟，加入2-氯乙基二甲胺(0.66g，6.16mmol)，升温至50℃搅拌反应5h。冷却至室温，用1mL水淬灭反应，反应液中加入乙酸乙酯(50mL)，然后依次用水(30mL×1)、饱和食盐水(30mL×1)洗涤，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(DCM/MeOH(V/V)＝100/0-100/5)得到23A，白色固体(0.48g，收率：58％)。In a 50mL reaction flask, add trans-N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]carbamic acid tert-butyl ester in turn (1C) (0.72 g, 1.54 mmol), N,N-dimethylformamide (15 mL), sodium iodide (0.12 g, 0.77 mmol) and sodium hydride (1.23 g, 30.8 mmol, 60 wt %), complete addition After stirring at 25° C. for 10 minutes, 2-chloroethyldimethylamine (0.66 g, 6.16 mmol) was added, and the temperature was raised to 50° C. and stirred for 5 h. Cool to room temperature, quench the reaction with 1 mL of water, add ethyl acetate (50 mL) to the reaction solution, then wash with water (30 mL×1) and saturated brine (30 mL×1) successively, and dry the organic layer with anhydrous sodium sulfate, Filtration, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (DCM/MeOH (V/V)=100/0-100/5) to obtain 23A as a white solid (0.48 g, yield: 58%).
LCMS m/z＝537.1/539.1[M+H] + LCMS m/z=537.1/539.1[M+H] +
第二步：反式-叔丁基N-(2-(二甲基氨基)乙基)-N-[3-[[6-(4-羟基苯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基]环丁基]氨基甲酸酯(23B)The second step: trans-tert-butyl N-(2-(dimethylamino)ethyl)-N-[3-[[6-(4-hydroxyphenyl)-1-(tetrahydro-2H- Pyran-2-yl)-1H-indazol-4-yl)oxy]cyclobutyl]carbamate (23B)
trans-tert-butyl N-(2-(dimethylamino)ethyl)-N-[3-[(6-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy]cyclobutyl]carbamatetrans-tert-butyl N-(2-(dimethylamino)ethyl)-N-[3-[(6-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4 -yl)oxy]cyclobutyl]carbamate
在50mL反应瓶中，依次加入上一步的反式-叔丁基(3-((6-溴-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基)环丁基)(2-(二甲基氨基)乙基)氨基甲酸酯(23A)(0.48g,0.89mmol)、4-羟基苯硼酸(0.18g，1.33mmol)、七水合磷酸钾(0.9g，2.67mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(73mg，0.089mmol)和二氧六环/水(v/v＝4/1，10mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(DCM/MeOH(V/V)＝100/0-100/5)得到23B，淡黄色固体(0.49g，产率98％)。In a 50mL reaction flask, add the trans-tert-butyl(3-((6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl )oxy)cyclobutyl)(2-(dimethylamino)ethyl)carbamate (23A) (0.48g, 0.89mmol), 4-hydroxyphenylboronic acid (0.18g, 1.33mmol), heptahydrate Potassium phosphate (0.9 g, 2.67 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (73 mg, 0.089 mmol) and dioxane/water (v/v=4/1, 10 mL), after nitrogen replacement three times, the reaction was stirred at 90° C. for 2 hours. 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 (DCM/MeOH (V/V)=100/0-100/5) to give 23B as a pale yellow solid (0.49 g, 98% yield).
LCMS m/z＝551.4[M+H] + LCMS m/z=551.4[M+H] +
第三步：反式-(2E)-N-(2-(二甲基氨基)乙基)-N-[3-[(6-(4-羟苯基)-1H-吲唑-4-基)氧基]环丁基]丁-2-烯酰胺(化合物23)The third step: trans-(2E)-N-(2-(dimethylamino)ethyl)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazole-4- yl)oxy]cyclobutyl]but-2-enamide (Compound 23)
trans-(2E)-N-(2-(dimethylamino)ethyl)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamidetrans-(2E)-N-(2-(dimethylamino)ethyl)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamide
在50mL反应瓶中，加入化合物23B(0.14g，0.25mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用甲基叔丁基醚(10mL×3)洗，然后减压浓缩干，加入5mL乙腈溶解，加入二异丙基乙胺(0.35g，2.7mmol)搅拌10min，待用。In a 50 mL reaction flask, compound 23B (0.14 g, 0.25 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with methyl tert-butyl ether (10 mL×3), then concentrated to dryness under reduced pressure, dissolved in 5 mL of acetonitrile, added with diisopropylethylamine (0.35 g, 2.7 mmol) and stirred for 10 min ,stand-by.
将巴豆酸(0.028g，0.32mmol)和二异丙基乙胺(83mg，0.64mmol)溶于二氯甲烷(5mL)和乙腈(5mL)的混合溶液中，加入三吡咯烷基溴化鏻六氟磷酸盐(0.15g，0.32mmol)，室温搅拌20分钟。将此反应液缓慢滴加到上述待用的乙腈溶液中，继续搅拌1h。加入10mL饱和碳酸氢钠水溶液碱化，分液后，有机层用无水硫酸钠干燥后，减压浓缩，残留物柱层析纯化(DCM/MeOH/NH 3H 2O(V/V/V)＝50/1/0.5-25/1/0.25)，得到化合物23(60mg,收率：50％)。 Crotonic acid (0.028 g, 0.32 mmol) and diisopropylethylamine (83 mg, 0.64 mmol) were dissolved in a mixed solution of dichloromethane (5 mL) and acetonitrile (5 mL), and 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. Add 10 mL of saturated aqueous sodium bicarbonate solution to basify, after separation, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM/MeOH/NH 3 H 2 O (V/V/V )=50/1/0.5-25/1/0.25) to obtain compound 23 (60 mg, yield: 50%).
LCMS m/z＝435.3[M+H] + LCMS m/z=435.3[M+H] +
1H NMR(400MHz,CD 3OD)δ8.06(s,1H),7.54–7.44(m,2H),7.21(s,1H),6.93–6.69(m,3H),6.50(s,1H),6.45-6.24(m,1H),5.13-5.02(m,1H),4.98–4.85(m,1H),3.70-3.52(m,2H),2.85–2.73(m,2H),2.72-2.58(m,2H),2.55–2.43(m,2H),2.33(s,6H),1.89(d,3H). 1 H NMR (400MHz, CD 3 OD) δ8.06(s,1H), 7.54-7.44(m,2H), 7.21(s,1H), 6.93-6.69(m,3H), 6.50(s,1H) ,6.45-6.24(m,1H),5.13-5.02(m,1H),4.98-4.85(m,1H),3.70-3.52(m,2H),2.85-2.73(m,2H),2.72-2.58( m, 2H), 2.55–2.43 (m, 2H), 2.33 (s, 6H), 1.89 (d, 3H).
实施例24：反式-N-(2-(二甲基氨基)乙基)-2-氟-N-(3-((6-(4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)丙烯酰胺(化合物24)Example 24: trans-N-(2-(dimethylamino)ethyl)-2-fluoro-N-(3-((6-(4-hydroxyphenyl)-1H-indazole-4- yl)oxy)cyclobutyl)acrylamide (Compound 24)
trans-N-(2-(dimethylamino)ethyl)-2-fluoro-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)acrylamidetrans-N-(2-(dimethylamino)ethyl)-2-fluoro-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)acrylamide
Figure PCTCN2021117545-appb-000250
Figure PCTCN2021117545-appb-000250
在50mL反应瓶中，加入化合物23B(0.14g，0.25mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用甲基叔丁基醚(10mL×3)洗，然后减压浓缩干，加入5mL乙腈溶解，加入二异丙基乙胺(0.35g，2.7mmol)搅拌10min，待用。In a 50 mL reaction flask, compound 23B (0.14 g, 0.25 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with methyl tert-butyl ether (10 mL×3), then concentrated to dryness under reduced pressure, dissolved in 5 mL of acetonitrile, added with diisopropylethylamine (0.35 g, 2.7 mmol) and stirred for 10 min ,stand-by.
将2-氟丙烯酸(0.029g，0.32mmol)和二异丙基乙胺(83mg，0.64mmol)溶于二氯甲烷(5mL)和乙腈(5mL)的混合溶液中，加入三吡咯烷基溴化鏻六氟磷酸盐(0.15g，0.32mmol)，室温搅拌20min。将此反应液缓慢滴加到上述待用的乙腈溶液中，继续搅拌1h。加入10mL饱和碳酸氢钠水溶液，分液后，有机层用无水硫酸钠干燥后，减压浓缩，残留物柱层析纯化(DCM/MeOH/NH 3H 2O(V/V/V)＝50/1/0.5-25/1/0.25)，得到化合物24(58mg,收率：57％)。 2-Fluoroacrylic acid (0.029 g, 0.32 mmol) and diisopropylethylamine (83 mg, 0.64 mmol) were dissolved in a mixed solution of dichloromethane (5 mL) and acetonitrile (5 mL), and tripyrrolidinyl bromide was added. Phosphonium hexafluorophosphate (0.15 g, 0.32 mmol), stirred at room temperature for 20 min. The reaction solution was slowly added dropwise to the above-mentioned acetonitrile solution to be used, and stirring was continued for 1 h. 10 mL of saturated aqueous sodium bicarbonate solution was added, and after separation, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM/MeOH/NH 3 H 2 O (V/V/V)= 50/1/0.5-25/1/0.25) to obtain compound 24 (58 mg, yield: 57%).
LCMS m/z＝439.1[M+H] + LCMS m/z=439.1[M+H] +
实施例25：反式-(2E)-3-[(2R)-1-甲基吡咯烷-2-基]-N-[3-[(6-(4-羟基苯基)-1H-吲唑-4-基)氧基]环丁基]丙-2-烯酰胺(化合物25)Example 25: trans-(2E)-3-[(2R)-1-methylpyrrolidin-2-yl]-N-[3-[(6-(4-hydroxyphenyl)-1H-indium Azol-4-yl)oxy]cyclobutyl]prop-2-enamide (Compound 25)
trans-(2E)-3-[(2R)-1-methylpyrrolidin-2-yl]-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]prop-2-enamidetrans-(2E)-3-[(2R)-1-methylpyrrolidin-2-yl]-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]prop -2-enamide
Figure PCTCN2021117545-appb-000251
Figure PCTCN2021117545-appb-000251
第一步：(2R)-2-[((1E)-3-乙氧基-3-氧代丙-1-烯-1-基]吡咯烷-1-羧酸叔丁酯(25A)The first step: (2R)-2-[((1E)-3-ethoxy-3-oxoprop-1-en-1-yl]pyrrolidine-1-carboxylate tert-butyl ester (25A)
tert-butyl(2R)-2-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]pyrrolidine-1-carboxylatetert-butyl(2R)-2-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]pyrrolidine-1-carboxylate
将化合物磷酰基乙酸三乙酯(1.24g，5.52mmol)溶于二氯甲烷(10ml)中，冰浴下加入氢化钠(60％，0.4g，10.04mmol)，加毕，自然升温至室温，搅拌20min，冷却至0℃，加入BOC-D-脯氨醛(1g，5.02mmol)，加毕，自然升温至室温搅拌1h。缓慢滴加10mL饱和氯化铵水溶液淬灭反应，分液后，有机层减压浓缩，柱层析纯化(乙酸乙酯/石油醚(V/V)＝1/50-1/5)得到25A，浅黄色油状物(0.62g，产率：46％)。The compound triethyl phosphoryl acetate (1.24 g, 5.52 mmol) was dissolved in dichloromethane (10 ml), sodium hydride (60%, 0.4 g, 10.04 mmol) was added under ice bath, the addition was completed, and the temperature was naturally raised to room temperature, Stir for 20 min, cool to 0° C., add BOC-D-prolinaldehyde (1 g, 5.02 mmol), and after the addition is completed, the temperature is naturally raised to room temperature and stirred for 1 h. 10 mL of saturated aqueous ammonium chloride solution was slowly added dropwise to quench the reaction, after separation, the organic layer was concentrated under reduced pressure, and purified by column chromatography (ethyl acetate/petroleum ether (V/V)=1/50-1/5) to obtain 25A , pale yellow oil (0.62 g, yield: 46%).
1H NMR(400MHz,CDCl 3)δ6.82(dd,1H),5.82(d,1H),4.56-4.30(m,1H),4.25–4.13(m,2H),3.49-3.33(m,2H),2.13-2.00(m,1H),1.90–1.73(m,3H),1.44(s,9H),1.28(t,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 6.82 (dd, 1H), 5.82 (d, 1H), 4.56-4.30 (m, 1H), 4.25-4.13 (m, 2H), 3.49-3.33 (m, 2H) ), 2.13-2.00(m, 1H), 1.90-1.73(m, 3H), 1.44(s, 9H), 1.28(t, 3H).
第二步：(2E)-3-[((2R)-1-甲基吡咯烷-2-基]丙-2-烯酸酯(25B)The second step: (2E)-3-[((2R)-1-methylpyrrolidin-2-yl]prop-2-enoate (25B)
ethyl(2E)-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enoateethyl(2E)-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enoate
将化合物25A(0.62g，2.30mmol)和多聚甲醛(0.35g，11.5mmol)溶于无水甲酸(8mL)中，加热至90℃搅拌2h。冷却至室温，减压出去溶剂，加入10ml 1N的盐酸，用10mL乙酸乙酯萃取，弃去有机层，用6N的氢氧化钠水溶液调节pH>7，加入20mL乙酸乙酯萃取，有机层减压浓缩得到25B粗品，黄色油状物(0.39g)，直接用于下一步。Compound 25A (0.62 g, 2.30 mmol) and paraformaldehyde (0.35 g, 11.5 mmol) were dissolved in anhydrous formic acid (8 mL), heated to 90 °C and stirred for 2 h. Cool to room temperature, remove the solvent under reduced pressure, add 10 mL of 1N hydrochloric acid, extract with 10 mL of ethyl acetate, discard the organic layer, adjust pH>7 with 6N aqueous sodium hydroxide solution, add 20 mL of ethyl acetate for extraction, and the organic layer is decompressed. Concentration gave crude 25B as a yellow oil (0.39 g), which was used directly in the next step.
LCMS m/z＝184.2[M+H] + LCMS m/z=184.2[M+H] +
第三步：(2E)-3-[((2R)-1-甲基吡咯烷-2-基]丙-2-烯酸(25C)的盐酸盐The third step: hydrochloride of (2E)-3-[((2R)-1-methylpyrrolidin-2-yl]prop-2-enoic acid (25C)
(2E)-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enoic acid；hydrochloric acid(2E)-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enoic acid; hydrochloric acid
将化合物25B(0.39g，2.13mmol)溶于甲醇(5mL)和水(2mL)的混合溶剂中，加入氢氧化钾(0.24g，4.26mmol)搅拌2h，用1N的稀盐酸调节pH＝5-6。减压浓缩除去溶剂，加入20mL DCM/MeOH(V/V＝10/1)混合溶剂搅拌10min，过滤除去有机盐，滤液加入2mL 3N的氯化氢/乙酸乙酯溶液，减压浓缩，残留物用5mL乙腈打浆，过滤，减压干燥滤饼得25C的盐酸盐，黄色固体(0.12g，收率：29％)，直接用于下一步反应。Compound 25B (0.39 g, 2.13 mmol) was dissolved in a mixed solvent of methanol (5 mL) and water (2 mL), potassium hydroxide (0.24 g, 4.26 mmol) was added and stirred for 2 h, and 1 N dilute hydrochloric acid was used to adjust pH=5- 6. Concentrate under reduced pressure to remove the solvent, add 20 mL of DCM/MeOH (V/V=10/1) mixed solvent and stir for 10 min, filter to remove organic salts, add 2 mL of 3N hydrogen chloride/ethyl acetate solution to the filtrate, concentrate under reduced pressure, and use 5 mL of the residue for the filtrate. Acetonitrile was slurried, filtered, and the filter cake was dried under reduced pressure to obtain 25C hydrochloride as a yellow solid (0.12 g, yield: 29%), which was directly used in the next reaction.
第四步：反式-(2E)-3-[(2R)-1-甲基吡咯烷-2-基]-N-[3-[(6-(4-羟基苯基)-1H-吲唑-4-基)氧基]环丁基]丙-2-烯酰胺(化合物25)The fourth step: trans-(2E)-3-[(2R)-1-methylpyrrolidin-2-yl]-N-[3-[(6-(4-hydroxyphenyl)-1H-indium Azol-4-yl)oxy]cyclobutyl]prop-2-enamide (Compound 25)
trans-(2E)-3-[(2R)-1-methylpyrrolidin-2-yl]-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]prop-2-enamidetrans-(2E)-3-[(2R)-1-methylpyrrolidin-2-yl]-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]prop -2-enamide
在50mL反应瓶中，加入反式-N-[3-[6-(4-羟基苯基)-1-四氢吡喃-2-基-吲唑-4-基]氧环丁基]氨基甲酸叔丁酯(1D)(0.2g，0.42mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用MTBE(10mL×3)洗，然后减压浓缩干。所得残留物中依次加入化合物25C的盐酸盐(0.107g)，6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯(231mg,0.56mmol)和N,N-二甲基甲酰胺(10mL)，加完后在室温下搅拌10分钟，缓慢加入N,N-二异丙基乙胺(0.45g，3.48mmol)，加完后在室温下搅拌50分钟。反应液中加入饱和碳酸氢钠(50mL)，然后用二氯甲烷/甲醇(v/v＝10/1)(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过制备液相(仪器：waters 2767制备液相；色谱柱:SunFire@Prep C18(19mm×150mm)；流动相组成：流动相A：乙腈流动相B：水(含5mM乙酸铵))分离纯化得到化合物25(50mg，产率23％)。In a 50 mL reaction flask, add trans-N-[3-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclobutyl]amino tert-Butyl formate (1D) (0.2 g, 0.42 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL), then the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with MTBE (10 mL×3), and then concentrated to dryness under reduced pressure. To the obtained residue were added compound 25C hydrochloride (0.107 g), 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate (231 mg, 0.56 mmol) and N , N-dimethylformamide (10 mL), stirred at room temperature for 10 minutes after the addition, slowly added N,N-diisopropylethylamine (0.45 g, 3.48 mmol), and stirred at room temperature for 50 minutes after the addition was complete minute. Saturated sodium bicarbonate (50 mL) was added to the reaction solution, then extracted with dichloromethane/methanol (v/v=10/1) (50 mL×2), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced in pressure Concentrated, the residue was passed through preparative liquid phase (instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm×150mm); mobile phase composition: mobile phase A: acetonitrile Mobile phase B: water (containing 5mM ammonium acetate) ) was isolated and purified to obtain compound 25 (50 mg, yield 23%).
LCMS m/z＝433.2[M+H] +； LCMS m/z=433.2[M+H] + ;
1H NMR(400MHz,CD 3OD)δ8.03(s,1H),7.50–7.44(m,2H),7.20(s,1H),6.89–6.84(m,2H),6.65(dd,1H),6.50(s,1H),6.09(d,1H),5.17–5.10(m,1H),4.61–4.51(m,1H),3.16–3.07(m,1H),2.88-2.78(m,1H),2.74-2.64(m,2H),2.64–2.52(m,2H),2.36–2.27(m,4H),2.12–2.00(m,1H),1.92-1.80(m,2H),1.75–1.62(m,1H). 1 H NMR (400MHz, CD 3 OD) δ 8.03 (s, 1H), 7.50–7.44 (m, 2H), 7.20 (s, 1H), 6.89–6.84 (m, 2H), 6.65 (dd, 1H) ,6.50(s,1H),6.09(d,1H),5.17-5.10(m,1H),4.61-4.51(m,1H),3.16-3.07(m,1H),2.88-2.78(m,1H) ,2.74-2.64(m,2H),2.64-2.52(m,2H),2.36-2.27(m,4H),2.12-2.00(m,1H),1.92-1.80(m,2H),1.75-1.62( m,1H).
实施例26：反式-(2E)-3-[(2S)-1-甲基吡咯烷-2-基]-N-[3-[(6-(4-羟基苯基)-1H-吲唑-4-基)氧基]环丁基]丙-2-烯酰胺(化合物26)Example 26: trans-(2E)-3-[(2S)-1-methylpyrrolidin-2-yl]-N-[3-[(6-(4-hydroxyphenyl)-1H-indone Azol-4-yl)oxy]cyclobutyl]prop-2-enamide (Compound 26)
trans-(2E)-3-[(2S)-1-methylpyrrolidin-2-yl]-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]prop-2-enamidetrans-(2E)-3-[(2S)-1-methylpyrrolidin-2-yl]-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]prop -2-enamide
Figure PCTCN2021117545-appb-000252
Figure PCTCN2021117545-appb-000252
第一步：(2S)-2-[((1E)-3-乙氧基-3-氧代丙-1-烯-1-基]吡咯烷-1-羧酸叔丁酯(26A)The first step: (2S)-2-[((1E)-3-ethoxy-3-oxoprop-1-en-1-yl]pyrrolidine-1-carboxylate tert-butyl ester (26A)
tert-butyl(2S)-2-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]pyrrolidine-1-carboxylatetert-butyl(2S)-2-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]pyrrolidine-1-carboxylate
将化合物磷酰基乙酸三乙酯(3.71g，16.57mmol)溶于二氯甲烷(30ml)中，冰浴下加入氢化钠(60％，1.2g，30.12mmol)，加毕，自然升温至室温，搅拌20min，冷却至0℃，加入BOC-L-脯氨醛(3g，15.06mmol)，加毕，自然升温至室温搅拌1h。缓慢滴加20mL饱和氯化铵水溶液淬灭反应，分液后，有机层减压浓缩，柱层析纯化(乙酸乙酯/石油醚(V/V)＝1/50-1/5)得到26A，浅黄色油状物(1.9g，产率：47％)。The compound triethyl phosphoryl acetate (3.71 g, 16.57 mmol) was dissolved in dichloromethane (30 ml), sodium hydride (60%, 1.2 g, 30.12 mmol) was added under ice bath, the addition was completed, and the temperature was naturally raised to room temperature, Stir for 20 min, cool to 0° C., add BOC-L-prolinaldehyde (3 g, 15.06 mmol), and after the addition is completed, the temperature is naturally raised to room temperature and stirred for 1 h. 20 mL of saturated aqueous ammonium chloride solution was slowly added dropwise to quench the reaction, after separation, the organic layer was concentrated under reduced pressure, and purified by column chromatography (ethyl acetate/petroleum ether (V/V)=1/50-1/5) to obtain 26A , pale yellow oil (1.9 g, yield: 47%).
第二步：(2E)-3-[((2S)-1-甲基吡咯烷-2-基]丙-2-烯酸酯(26B)The second step: (2E)-3-[((2S)-1-methylpyrrolidin-2-yl]prop-2-enoate (26B)
ethyl(2E)-3-[(2S)-1-methylpyrrolidin-2-yl]prop-2-enoateethyl(2E)-3-[(2S)-1-methylpyrrolidin-2-yl]prop-2-enoate
将化合物26A(1.9g，7.05mmol)和多聚甲醛(1.06g，35.25mmol)溶于无水甲酸(15ml)中，加热至90℃搅拌2h。冷却至室温，减压浓缩除去溶剂，加入20ml 1N的盐酸， 用10mL乙酸乙酯萃取，弃去有机层，用6N的氢氧化钠水溶液调节pH>7，加入30mL乙酸乙酯萃取，有机层减压浓缩得到26B，黄色油状物(1.1g，收率：85％)，直接用于下一步。Compound 26A (1.9 g, 7.05 mmol) and paraformaldehyde (1.06 g, 35.25 mmol) were dissolved in anhydrous formic acid (15 ml), heated to 90° C. and stirred for 2 h. Cooled to room temperature, concentrated under reduced pressure to remove the solvent, added 20 mL of 1N hydrochloric acid, extracted with 10 mL of ethyl acetate, discarded the organic layer, adjusted pH>7 with 6N aqueous sodium hydroxide solution, added 30 mL of ethyl acetate for extraction, the organic layer was reduced Concentration under pressure gave 26B as a yellow oil (1.1 g, yield: 85%), which was used directly in the next step.
LCMS m/z＝184.2[M+H] + LCMS m/z=184.2[M+H] +
第三步：(2E)-3-[((2S)-1-甲基吡咯烷-2-基]丙-2-烯酸(26C)的盐酸盐The third step: hydrochloride of (2E)-3-[((2S)-1-methylpyrrolidin-2-yl]prop-2-enoic acid (26C)
(2E)-3-[(2S)-1-methylpyrrolidin-2-yl]prop-2-enoic acid；chlorohydrogen(2E)-3-[(2S)-1-methylpyrrolidin-2-yl]prop-2-enoic acid; chlorohydrogen
将化合物26B(1.1g，6.00mmol)溶于甲醇(10ml)和水(4ml)的混合溶剂中，加入氢氧化钾(0.67g，12mmol)搅拌2h，用1N的稀盐酸调节pH＝5-6。减压浓缩除去溶剂，加入20mL DCM/MeOH(V/V＝10/1)混合溶剂搅拌10min，过滤除去有机盐，滤液加入4mL3N的氯化氢/乙酸乙酯溶液，减压浓缩，残留物用10mL乙腈打浆，过滤，减压干燥滤饼得26C的盐酸盐，灰色固体(0.4g，收率：35％)。Compound 26B (1.1 g, 6.00 mmol) was dissolved in a mixed solvent of methanol (10 ml) and water (4 ml), potassium hydroxide (0.67 g, 12 mmol) was added, stirred for 2 h, and pH=5-6 was adjusted with 1N dilute hydrochloric acid . Concentrate under reduced pressure to remove the solvent, add 20 mL of DCM/MeOH (V/V=10/1) mixed solvent and stir for 10 min, filter to remove organic salts, add 4 mL of 3N hydrogen chloride/ethyl acetate solution to the filtrate, concentrate under reduced pressure, and use 10 mL of acetonitrile for the residue. Beating, filtering, and drying the filter cake under reduced pressure gave 26C hydrochloride as a gray solid (0.4 g, yield: 35%).
1H NMR(400MHz,DMSO-d 6)δ12.18(brs,2H),6.89(dd,1H),6.16(d,1H),3.95-3.80(m,1H),3.54-3.43(m,1H),3.06-2.92(m,1H),2.61(s,3H),2.27-2.14(m,1H),2.06-1.92(m,2H),1.92-1.79(m,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 12.18 (brs, 2H), 6.89 (dd, 1H), 6.16 (d, 1H), 3.95-3.80 (m, 1H), 3.54-3.43 (m, 1H) ),3.06-2.92(m,1H),2.61(s,3H),2.27-2.14(m,1H),2.06-1.92(m,2H),1.92-1.79(m,1H).
第四步：反式-(2E)-3-[(2S)-1-甲基吡咯烷-2-基]-N-[3-[(6-(4-羟基苯基)-1H-吲唑-4-基)氧基]环丁基]丙-2-烯酰胺(化合物26)The fourth step: trans-(2E)-3-[(2S)-1-methylpyrrolidin-2-yl]-N-[3-[(6-(4-hydroxyphenyl)-1H-indium Azol-4-yl)oxy]cyclobutyl]prop-2-enamide (Compound 26)
Trans-(2E)-3-[(2S)-1-methylpyrrolidin-2-yl]-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]prop-2-enamide.Trans-(2E)-3-[(2S)-1-methylpyrrolidin-2-yl]-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]prop -2-enamide.
在50mL反应瓶中，加入反式-N-[3-[6-(4-羟基苯基)-1-四氢吡喃-2-基-吲唑-4-基]氧环丁基]氨基甲酸叔丁酯(1D)(0.2g，0.42mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用MTBE(10mL×3)洗，然后减压浓缩干。所得残留物中依次加入26C的盐酸盐(0.107g)，6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯(231mg,0.56mmol)和N,N-二甲基甲酰胺(10mL)，加完后在室温下搅拌10分钟，缓慢加入N,N-二异丙基乙胺(0.45g，3.48mmol)，加完后在室温下搅拌50分钟。反应液中加入饱和碳酸氢钠(50mL)，然后用二氯甲烷/甲醇(v/v＝10/1)(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过制备液相(仪器：waters 2767制备液相；色谱柱:SunFire@Prep C18(19mm×150mm)；流动相组成：流动相A：乙腈流动相B：水(含5mM乙酸铵))分离纯化得到化合物26(50mg，产率23％)。In a 50 mL reaction flask, add trans-N-[3-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclobutyl]amino tert-Butyl formate (1D) (0.2 g, 0.42 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL), then the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with MTBE (10 mL×3), and then concentrated to dryness under reduced pressure. To the obtained residue was added 26C hydrochloride (0.107g), 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate (231mg, 0.56mmol) and N, N-dimethylformamide (10 mL) was added and stirred at room temperature for 10 minutes, N,N-diisopropylethylamine (0.45 g, 3.48 mmol) was slowly added, and the addition was completed and stirred at room temperature for 50 minutes . Saturated sodium bicarbonate (50 mL) was added to the reaction solution, then extracted with dichloromethane/methanol (v/v=10/1) (50 mL×2), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced in pressure Concentrated, the residue was passed through preparative liquid phase (instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm×150mm); mobile phase composition: mobile phase A: acetonitrile Mobile phase B: water (containing 5mM ammonium acetate) ) was isolated and purified to obtain compound 26 (50 mg, yield 23%).
LCMS m/z＝433.2[M+H] + LCMS m/z=433.2[M+H] +
1H NMR(400MHz,CD 3OD)δ8.03(s,1H),7.50–7.44(m,2H),7.20(s,1H),6.89–6.84(m,2H),6.65(dd,1H),6.50(d,1H),6.08(d,1H),5.17–5.10(m,1H),4.61–4.51(m,1H),3.15 –3.06(m,1H),2.84-2.75(m,1H),2.73-2.64(m,2H),2.63–2.53(m,2H),2.34–2.22(m,4H),2.11–2.00(m,1H),1.91-1.80(m,2H),1.74–1.61(m,1H). 1 H NMR (400MHz, CD 3 OD) δ 8.03 (s, 1H), 7.50–7.44 (m, 2H), 7.20 (s, 1H), 6.89–6.84 (m, 2H), 6.65 (dd, 1H) ,6.50(d,1H),6.08(d,1H),5.17-5.10(m,1H),4.61-4.51(m,1H),3.15-3.06(m,1H),2.84-2.75(m,1H) ,2.73-2.64(m,2H),2.63-2.53(m,2H),2.34-2.22(m,4H),2.11-2.00(m,1H),1.91-1.80(m,2H),1.74-1.61( m,1H).
实施例27：反式-(E)-4-(双(2-甲氧基乙基)氨基)-N-(3-((6-(4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)-2-烯酰胺(化合物27)Example 27: trans-(E)-4-(bis(2-methoxyethyl)amino)-N-(3-((6-(4-hydroxyphenyl)-1H-indazole-4 -yl)oxy)cyclobutyl)-2-enamide (compound 27)
trans-(E)-4-(bis(2-methoxyethyl)amino)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)but-2-enamidetrans-(E)-4-(bis(2-methoxyethyl)amino)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)but-2-enamide
Figure PCTCN2021117545-appb-000253
Figure PCTCN2021117545-appb-000253
第一步：(E)-4-(双(2-甲氧基乙基)氨基)丁-2-烯酸酯(27B)The first step: (E)-4-(bis(2-methoxyethyl)amino)but-2-enoate (27B)
methyl(E)-4-(bis(2-methoxyethyl)amino)but-2-enoatemethyl(E)-4-(bis(2-methoxyethyl)amino)but-2-enoate
在100mL反应瓶中，将(E)-4-溴丁-2-烯酸甲酯(1.33g，10mmol)滴至双(2-甲氧基乙基)胺(27A)(1.79g，10mmol)和三乙胺(2.02g，20mmol)的四氢呋喃溶液中(60mL)，室温下搅拌反应12小时，反应液中加入乙酸乙酯(100mL)，然后用水(100mL×3)洗，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩得到27B，淡黄色油状物(2.31g，产率100％)。In a 100 mL reaction flask, add (E)-methyl 4-bromobut-2-enoate (1.33 g, 10 mmol) dropwise to bis(2-methoxyethyl)amine (27A) (1.79 g, 10 mmol) and triethylamine (2.02 g, 20 mmol) in tetrahydrofuran solution (60 mL), the reaction was stirred at room temperature for 12 hours, ethyl acetate (100 mL) was added to the reaction solution, then washed with water (100 mL×3), and the organic layer was washed with anhydrous Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to give 27B as a pale yellow oil (2.31 g, 100% yield).
第二步：(E)-4-(双(2-甲氧基乙基)氨基)丁-2-烯酸(27C)的盐酸盐The second step: hydrochloride of (E)-4-(bis(2-methoxyethyl)amino)but-2-enoic acid (27C)
(E)-4-(bis(2-methoxyethyl)amino)but-2-enoic acid(E)-4-(bis(2-methoxyethyl)amino)but-2-enoic acid
在100mL反应瓶中，依次加入(E)-4-(双(2-甲氧基乙基)氨基)丁-2-烯酸酯(27B)(2.31g，10mmol)，氢氧化钾(1.12g，20mmol),水(1mL)和甲醇(20mL)， 室温下搅拌反应2小时，反应液中加入10％稀盐酸(8mL)减压浓缩得到27C的盐酸盐，白色固体(2.17g)，直接用于下一步反应。In a 100 mL reaction flask, add (E)-4-(bis(2-methoxyethyl)amino)but-2-enoate (27B) (2.31g, 10mmol), potassium hydroxide (1.12g) in turn , 20 mmol), water (1 mL) and methanol (20 mL), the reaction was stirred at room temperature for 2 hours, 10% dilute hydrochloric acid (8 mL) was added to the reaction solution and concentrated under reduced pressure to obtain 27C of hydrochloride, a white solid (2.17 g), which was directly used for the next reaction.
第三步：反式-(E)-4-(双(2-甲氧基乙基)氨基)-N-(3-((6-(4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)-2-烯酰胺(化合物27)The third step: trans-(E)-4-(bis(2-methoxyethyl)amino)-N-(3-((6-(4-hydroxyphenyl)-1H-indazole-4 -yl)oxy)cyclobutyl)-2-enamide (compound 27)
trans-(E)-4-(bis(2-methoxyethyl)amino)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)but-2-enamidetrans-(E)-4-(bis(2-methoxyethyl)amino)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)but-2-enamide
在50mL反应瓶中，加入反式-N-[3-[6-(4-羟基苯基)-1-四氢吡喃-2-基-吲唑-4-基]氧环丁基]氨基甲酸叔丁酯(1D)(0.037g，0.077mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，8mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干。所得残留物中依次加入27C的盐酸盐(0.025g)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.030g，0.156mmol)、1-羟基苯并三唑(0.016g，0.117mmol)和N,N-二甲基甲酰胺(10mL)，加完后在室温下搅拌10分钟，加入N,N-二异丙基乙胺(0.06g，0.468mmol)，加完后在室温下搅拌50分钟。反应液中加入饱和碳酸氢钠(50mL)，然后用二氯甲烷/甲醇(v/v＝10/1，50mL×4)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过制备液相(仪器：waters 2767制备液相；色谱柱:XBridge@Prep C18(30mm×150mm)；流动相组成：流动相A：乙腈，流动相B：水(含0.05％氨水))分离纯化得到化合物27(14mg，产率36.8％)。In a 50 mL reaction flask, add trans-N-[3-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclobutyl]amino tert-Butyl formate (1D) (0.037 g, 0.077 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 8 mL), then the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure. To the obtained residue were added 27C hydrochloride (0.025g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.030g, 0.156mmol), 1-hydroxyl Benzotriazole (0.016g, 0.117mmol) and N,N-dimethylformamide (10mL) were added and stirred at room temperature for 10 minutes, and N,N-diisopropylethylamine (0.06g, 0.468 mmol) and stirred at room temperature for 50 minutes after the addition was complete. Saturated sodium bicarbonate (50 mL) was added to the reaction solution, then extracted with dichloromethane/methanol (v/v=10/1, 50 mL×4), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure , the residue was passed through preparative liquid phase (instrument: waters 2767 preparative liquid phase; chromatographic column: XBridge@Prep C18 (30mm×150mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.05% ammonia water) ) was isolated and purified to obtain compound 27 (14 mg, yield 36.8%).
LCMS m/z＝495.4[M+1] + LCMS m/z=495.4[M+1] +
1H NMR(400MHz,CD 3OD)δ8.03(d,1H),7.55–7.45(m,2H),7.20(s,1H),6.90–6.76(m,3H),6.51(d,1H),6.11(d,1H),5.19-5.11(s,1H),4.60-4.52(m,1H),3.50(t,4H),3.37(dd,2H),3.32(d,6H),2.74(t,4H),2.68-2.65(m,2H),2.63–2.53(m,2H). 1 H NMR (400MHz, CD 3 OD) δ 8.03(d, 1H), 7.55–7.45 (m, 2H), 7.20 (s, 1H), 6.90–6.76 (m, 3H), 6.51 (d, 1H) ,6.11(d,1H),5.19-5.11(s,1H),4.60-4.52(m,1H),3.50(t,4H),3.37(dd,2H),3.32(d,6H),2.74(t ,4H),2.68-2.65(m,2H),2.63-2.53(m,2H).
实施例28：反式-(E)-N-((3-((6-(4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)-4-(吡咯烷-1-基)丁-2-烯酰胺；乙酸盐(化合物28)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)
trans-(E)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-4-(pyrrolidin-1-yl)but-2-enamide；acetic acidtrans-(E)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-4-(pyrrolidin-1-yl)but-2-enamide;acetic acid
Figure PCTCN2021117545-appb-000254
Figure PCTCN2021117545-appb-000254
Figure PCTCN2021117545-appb-000255
Figure PCTCN2021117545-appb-000255
第一步：(E)-4-(吡咯烷基-1-基)丁-2-烯酸(28A)的盐酸盐The first step: hydrochloride of (E)-4-(pyrrolidin-1-yl)but-2-enoic acid (28A)
(E)-4-(pyrrolidin-1-yl)but-2-enoic acid(E)-4-(pyrrolidin-1-yl)but-2-enoic acid
称取4-溴-2-丁烯酸甲酯(1.79g,10.0mmol),用30mL四氢呋喃溶解于100mL单口圆底烧瓶中，用冰水浴降温至0-5℃，缓慢滴加四氢吡咯(1.42g,20mmol),滴加完毕，缓慢升温至室温反应1小时，加入水淬灭，用40mL乙醚萃取，有机相用30mL饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩得黄色油状残留物。将残留物加入至250mL单口圆底烧瓶中，加入40mL 3N HCl，加热至100℃回流反应2小时，减压浓缩得残余物，向残余物中加入异丙醇与乙醚混合物，白色固体析出，抽滤，得28A的盐酸盐，白色固体(0.708g,产率：46％)。Weigh methyl 4-bromo-2-butenoate (1.79 g, 10.0 mmol), dissolve it in a 100 mL single-neck round-bottomed flask with 30 mL of tetrahydrofuran, cool it to 0-5 ℃ with an ice-water bath, and slowly dropwise add tetrahydropyrrole ( 1.42 g, 20 mmol), added dropwise, slowly warmed to room temperature for 1 hour, quenched by adding water, extracted with 40 mL of ether, the organic phase was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow oily residue thing. The residue was added to a 250mL single-neck round-bottomed flask, 40mL of 3N HCl was added, heated to 100°C for reflux reaction for 2 hours, concentrated under reduced pressure to obtain a residue, a mixture of isopropanol and ether was added to the residue, a white solid was precipitated, and the mixture was extracted. Filtration gave the hydrochloride salt of 28A as a white solid (0.708 g, yield: 46%).
LCMS m/z＝156.2[M+H] + LCMS m/z=156.2[M+H] +
第二步：反式-4-(4-((3-氨基环丁氧基)-1H-吲唑-6-基)苯酚(28B)的三氟乙酸盐Step 2: Trifluoroacetate salt of trans-4-(4-((3-aminocyclobutoxy)-1H-indazol-6-yl)phenol (28B)
trans-4-(4-(3-aminocyclobutoxy)-1H-indazol-6-yl)phenoltrans-4-(4-(3-aminocyclobutoxy)-1H-indazol-6-yl)phenol
将反式-N-[3-[6-(4-羟基苯基)-1-四氢吡喃-2-基-吲唑-4-基]氧环丁基]氨基甲酸叔丁酯(1D)(0.4g,0.84mmol)用20mL二氯甲烷溶解于50mL单口圆底烧瓶中，加入10mL三氟乙酸，加热至35℃搅拌2小时。减压浓缩得28B的三氟乙酸盐，黄褐色固体(0.246g)，直接用于下一步反应。Trans-N-[3-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclobutyl]carbamic acid tert-butyl ester (1D ) (0.4 g, 0.84 mmol) was dissolved in a 50 mL single-neck round-bottomed flask with 20 mL of dichloromethane, 10 mL of trifluoroacetic acid was added, and the mixture was heated to 35° C. and stirred for 2 hours. Concentration under reduced pressure gave the trifluoroacetate salt of 28B as a tan solid (0.246 g), which was directly used in the next reaction.
LCMS m/z＝296.1[M+H] + LCMS m/z=296.1[M+H] +
第三步：反式-(E)-N-((3-((6-(4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)-4-(吡咯烷-1-基)丁-2-烯酰胺；乙酸盐(化合物28)The third step: 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)
trans-(E)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-4-(pyrrolidin-1-yl)but-2-enamide；acetic acidtrans-(E)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-4-(pyrrolidin-1-yl)but-2-enamide;acetic acid
称取(E)-4-(吡咯烷基-1-基)丁-2-烯酸(28A)盐酸盐(78mg)，用5mL DMF溶解于50mL单口圆底烧瓶中，加入6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯(210mg,0.5mmol),室温搅拌十五分钟。将搅拌好的混合物滴加入到28B三氟乙酸盐(123mg)的 5mL DMF溶液中，用冰水浴降温至0-5℃，滴加N,N-二异丙基乙胺(270mg,2.1mmol),滴加完毕，回至室温反应2小时。加入30mL水淬灭，加入30mL x 2混合溶剂二氯甲烷/甲醇(v/v＝10/1)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得粗品，粗品通过制备液相(仪器：waters 2767制备液相；色谱柱:SunFire@Prep C18(19mm×150mm)；.流动相组成：流动相A：乙腈流动相B：水(含5mM乙酸铵))分离纯化得到化合物28(20mg,产率：9.67％)。Weigh (E)-4-(pyrrolidin-1-yl)but-2-enoic acid (28A) hydrochloride (78mg), dissolve it in a 50mL single-neck round bottom flask with 5mL DMF, add 6-chlorobenzene Triazole-1,1,3,3-tetramethylurea hexafluorophosphate (210 mg, 0.5 mmol) was stirred at room temperature for 15 minutes. The stirred mixture was added dropwise to a solution of 28B trifluoroacetate (123 mg) in 5 mL of DMF, cooled to 0-5° C. with an ice-water bath, and N,N-diisopropylethylamine (270 mg, 2.1 mmol) was added dropwise. ), the dropwise addition was completed, and the reaction was returned to room temperature for 2 hours. Add 30 mL of water to quench, add 30 mL x 2 mixed solvent dichloromethane/methanol (v/v=10/1) for extraction, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product, which is passed through the preparation solution. Phase (instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm×150mm); mobile phase composition: mobile phase A: acetonitrile Mobile phase B: water (containing 5mM ammonium acetate)) separation and purification to obtain compound 28 (20 mg, yield: 9.67%).
LCMS m/z＝433.3[M-CH 3COOH+H] + LCMS m/z=433.3[M- CH3COOH +H] +
1H NMR(400MHz,CD 3OD)δ8.03(d,1H),7.52–7.44(m,2H),7.20(s,1H),6.91–6.84(m,2H),6.84-6.72(m,1H),6.50(s,1H),6.22(d,1H),5.18–5.08(m,1H),4.64–4.52(m,1H),3.59(dd,2H),3.00-2.89(m,4H),2.75-2.64(m,2H),2.64-2.53(m,2H),1.98–1.91(m,7H). 1 H NMR (400MHz, CD 3 OD) δ 8.03(d, 1H), 7.52-7.44(m, 2H), 7.20(s, 1H), 6.91-6.84(m, 2H), 6.84-6.72(m, 1H), 6.50(s, 1H), 6.22(d, 1H), 5.18-5.08(m, 1H), 4.64-4.52(m, 1H), 3.59(dd, 2H), 3.00-2.89(m, 4H) ,2.75-2.64(m,2H),2.64-2.53(m,2H),1.98-1.91(m,7H).
实施例29：反式-(E)-4-(氮杂环丁烷-1-基)-N-((3-((6-(4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)丁-2-烯酰胺(化合物29)Example 29: trans-(E)-4-(azetidin-1-yl)-N-((3-((6-(4-hydroxyphenyl)-1H-indazole-4- yl)oxy)cyclobutyl)but-2-enamide (compound 29)
trans-(E)-4-(azetidin-1-yl)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)but-2-enamidetrans-(E)-4-(azetidin-1-yl)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)but-2-enamide
Figure PCTCN2021117545-appb-000256
Figure PCTCN2021117545-appb-000256
第一步：(E)-4-(氮杂环丁烷-1-基)丁-2-烯酸(29A)盐酸盐The first step: (E)-4-(azetidin-1-yl)but-2-enoic acid (29A) hydrochloride
(E)-4-(azetidin-1-yl)but-2-enoic acid(E)-4-(azetidin-1-yl)but-2-enoic acid
称取4-溴-2-丁烯酸甲酯(1.79g,10.0mmol),用30mL四氢呋喃溶解于100mL单口圆底烧瓶中，冰水浴降温至0-5℃，缓慢滴加杂氮环丁烷(1.71g,30.0mmol),滴加完毕，缓慢升温至室温反应1小时，加入水淬灭，用40mL乙醚萃取，有机相用30mL饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩得淡黄色油状残留物。将残留物加入至250mL单口圆底烧瓶中，加入40mL 3N HCl，加热至100℃回流反应2小时，减压浓缩得残余物，向残余物中加入异丙醇与乙醚混合物，白色固体析出，抽滤，得29A盐酸盐，白色固体(0.168g,产率：12％)。Weigh methyl 4-bromo-2-butenoate (1.79 g, 10.0 mmol), dissolve it in a 100 mL single-neck round-bottomed flask with 30 mL of tetrahydrofuran, cool it down to 0-5 °C in an ice-water bath, and slowly add azetidine dropwise. (1.71 g, 30.0 mmol), added dropwise, slowly warmed to room temperature for 1 hour, quenched by adding water, extracted with 40 mL of diethyl ether, the organic phase was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain light Yellow oily residue. The residue was added to a 250mL single-neck round-bottomed flask, 40mL of 3N HCl was added, heated to 100°C for reflux reaction for 2 hours, concentrated under reduced pressure to obtain a residue, a mixture of isopropanol and ether was added to the residue, a white solid was precipitated, and the mixture was extracted. Filtration gave 29A hydrochloride as a white solid (0.168 g, yield: 12%).
LCMS m/z＝142.2[M+H] + LCMS m/z=142.2[M+H] +
第二步：反式-(E)-4-(氮杂环丁烷-1-基)-N-((3-((6-(4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)丁-2-烯酰胺(化合物29)The second step: trans-(E)-4-(azetidin-1-yl)-N-((3-((6-(4-hydroxyphenyl)-1H-indazole-4- yl)oxy)cyclobutyl)but-2-enamide (compound 29)
trans-(E)-4-(azetidin-1-yl)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)but-2-enamidetrans-(E)-4-(azetidin-1-yl)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)but-2-enamide
称取29A(71mg,0.5mmol)，用5mL DMF溶解于50mL单口圆底烧瓶中，加入6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯(210mg,0.5mmol),在室温搅拌十五分钟。将搅拌好的(E)-4-(吡咯烷基-1-基)丁-2-烯酸与6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯混合物滴加入反式-4-(4-((3-氨基环丁氧基)-1H-吲唑-6-基)苯酚(28B)盐酸盐(123mg)的5mL DMF溶液中，用冰水浴降温至0-5℃，滴加N,N-二异丙基乙胺(270mg,2.1mmol),滴加完毕，回至室温反应2小时。加入30mL水淬灭，加入30mL x 2混合溶剂二氯甲烷/甲醇(v/v＝10/1)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得粗品，粗品通过制备液相(仪器：waters 2767制备液相；色谱柱:SunFire@Prep C18(19mm×150mm)；.流动相组成：流动相A：乙腈流动相B：水(含5mM乙酸铵))分离纯化得到化合物29(15mg,产率：8.53％)。Weigh 29A (71mg, 0.5mmol), dissolve it in a 50mL single-neck round bottom flask with 5mL DMF, add 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate (210mg , 0.5 mmol), and stirred for fifteen minutes at room temperature. Mix the stirred (E)-4-(pyrrolidin-1-yl)but-2-enoic acid with 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphoric acid The ester mixture was added dropwise to a solution of trans-4-(4-((3-aminocyclobutoxy)-1H-indazol-6-yl)phenol (28B) hydrochloride (123 mg) in 5 mL of DMF over ice. The water bath is cooled to 0-5 ℃, and N,N-diisopropylethylamine (270mg, 2.1mmol) is added dropwise, and the dropwise addition is completed, and the reaction is returned to room temperature for 2 hours. Add 30mL of water to quench, add 30mL × 2 mixed solvent Extraction with dichloromethane/methanol (v/v=10/1), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was passed through the preparative liquid phase (instrument: waters 2767; : 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 29 (15 mg, yield: 8.53%).
LCMS m/z＝419.1[M+H] + LCMS m/z=419.1[M+H] +
实施例30:反式-(2E)-4-(二乙氨基)-N-[3-[(6-(4-羟苯基)-1H-吲唑-4-基)氧基]环丁基]丁-2-烯酰胺(化合物30)Example 30: trans-(2E)-4-(diethylamino)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutane yl]but-2-enamide (compound 30)
trans-(2E)-4-(diethylamino)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamidetrans-(2E)-4-(diethylamino)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamide
Figure PCTCN2021117545-appb-000257
Figure PCTCN2021117545-appb-000257
第一步：(2E)-4-(二乙氨基)丁-2-烯酸甲酯(30A)The first step: (2E)-4-(diethylamino)but-2-enoic acid methyl ester (30A)
methyl(2E)-4-(diethylamino)but-2-enoatemethyl(2E)-4-(diethylamino)but-2-enoate
将E-4-溴-2-丁烯酸甲酯(2g，11.17mmol)溶于四氢呋喃(10ml)中，室温下缓慢滴加二乙胺(3.27g，44.68mmol)，加毕，室温搅拌2h。加入20mL水和20mL乙酸乙 酯萃取，有机层用饱和食盐水20mL洗涤一次，无水硫酸钠干燥，减压浓缩得到30A粗品，黄色液体(2g)，直接用于下一步。Methyl E-4-bromo-2-butenoate (2 g, 11.17 mmol) was dissolved in tetrahydrofuran (10 ml), and diethylamine (3.27 g, 44.68 mmol) was slowly added dropwise at room temperature. After the addition was completed, the mixture was stirred at room temperature for 2 h . 20 mL of water and 20 mL of ethyl acetate were added for extraction, and the organic layer was washed once with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude 30A, a yellow liquid (2 g), which was directly used in the next step.
LCMS m/z＝172.1[M+H] + LCMS m/z=172.1[M+H] +
第二步：(2E)-4-(二乙氨基)丁-2-烯酸(30B)盐酸盐The second step: (2E)-4-(diethylamino)but-2-enoic acid (30B) hydrochloride
(2E)-4-(diethylamino)but-2-enoic acid；hydrochloric acid(2E)-4-(diethylamino)but-2-enoic acid; hydrochloric acid
将化合物30A(2g)溶于甲醇(9mL)和水(3mL)的混合溶剂中，加入固体氢氧化钾(1.31g，23.36mmol)，室温搅拌2h。用浓盐酸调节pH＝5-6，减压浓缩，加入二氯甲烷/甲醇(V/V＝10/1，20mL)溶解残留物，过滤，向滤液中加入3N的氯化氢/乙酸乙酯溶液5mL，减压浓缩滤液，残留物加入乙酸乙酯/乙腈(20mL，V/V＝1/1)打浆，过滤，滤饼减压干燥得30B盐酸盐，白色固体(1.1g，产率：49％)。Compound 30A (2 g) was dissolved in a mixed solvent of methanol (9 mL) and water (3 mL), solid potassium hydroxide (1.31 g, 23.36 mmol) was added, and the mixture was stirred at room temperature for 2 h. Adjust pH=5-6 with concentrated hydrochloric acid, concentrate under reduced pressure, add dichloromethane/methanol (V/V=10/1, 20 mL) to dissolve the residue, filter, add 5 mL of 3N hydrogen chloride/ethyl acetate solution to the filtrate , the filtrate was concentrated under reduced pressure, ethyl acetate/acetonitrile (20 mL, V/V=1/1) was added to the residue to make a slurry, filtered, and the filter cake was dried under reduced pressure to obtain 30B hydrochloride, a white solid (1.1 g, yield: 49 %).
1H NMR(400MHz,DMSO-d 6)δ12.68(brs,1H),11.34(brs,1H),6.97–6.83(m,1H),6.24(d,1H),3.89(d,2H),3.06(q,4H),1.22(t,6H). 1 H NMR (400MHz, DMSO-d 6 )δ12.68(brs,1H), 11.34(brs,1H), 6.97-6.83(m,1H), 6.24(d,1H), 3.89(d,2H), 3.06(q, 4H), 1.22(t, 6H).
第三步：反式-(2E)-4-(二乙氨基)-N-[3-[(6-(4-羟苯基)-1H-吲唑-4-基)氧基]环丁基]丁-2-烯酰胺(化合物30)The third step: trans-(2E)-4-(diethylamino)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutane yl]but-2-enamide (compound 30)
trans-(2E)-4-(diethylamino)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamidetrans-(2E)-4-(diethylamino)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamide
在50mL反应瓶中，加入反式-N-[3-[6-(4-羟基苯基)-1-四氢吡喃-2-基-吲唑-4-基]氧环丁基]氨基甲酸叔丁酯(1D)(0.2g，0.42mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用MTBE(10mL×3)洗，然后减压浓缩干。所得残留物中依次加入化合物30B盐酸盐(0.11g)，6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯(231mg,0.56mmol)和N,N-二甲基甲酰胺(10mL)，加完后在室温下搅拌10分钟，缓慢加入N,N-二异丙基乙胺(0.45g，3.48mmol)，加完后在室温下搅拌50分钟。反应液中加入饱和碳酸氢钠(50mL)，然后用二氯甲烷/甲醇(v/v＝10/1)(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过制备液相(仪器：waters 2767制备液相；色谱柱:SunFire@Prep C18(19mm×150mm)；.流动相组成：流动相A：乙腈流动相B：水(含5mM乙酸铵))分离纯化得到化合物30(100mg，产率45％)。In a 50 mL reaction flask, add trans-N-[3-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclobutyl]amino tert-Butyl formate (1D) (0.2 g, 0.42 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL), then the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with MTBE (10 mL×3), and then concentrated to dryness under reduced pressure. Compound 30B hydrochloride (0.11g), 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate (231mg, 0.56mmol) and N, 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate (231mg, 0.56mmol) and N, N-dimethylformamide (10 mL) was added and stirred at room temperature for 10 minutes, N,N-diisopropylethylamine (0.45 g, 3.48 mmol) was slowly added, and the addition was completed and stirred at room temperature for 50 minutes . Saturated sodium bicarbonate (50 mL) was added to the reaction solution, then extracted with dichloromethane/methanol (v/v=10/1) (50 mL×2), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced in pressure Concentrated, the residue was passed through preparative liquid phase (instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm×150mm); mobile phase composition: mobile phase A: acetonitrile Mobile phase B: water (containing 5mM ammonium acetate) )) was isolated and purified to obtain compound 30 (100 mg, yield 45%).
LCMS m/z＝435.1[M+H] +； LCMS m/z=435.1[M+H] + ;
1H NMR(400MHz,CD 3OD)δ8.03(s,1H),7.51–7.44(m,2H),7.20(s,1H),6.90–6.76(m,3H),6.50(d,1H),6.15-6.08(m,1H),5.18–5.08(m,1H),4.61–4.51(m,1H),3.28(dd,2H),2.73-2.64(m,2H),2.62-2.53(m,6H),1.07(t,6H). 1 H NMR (400MHz, CD 3 OD) δ 8.03 (s, 1H), 7.51–7.44 (m, 2H), 7.20 (s, 1H), 6.90–6.76 (m, 3H), 6.50 (d, 1H) ,6.15-6.08(m,1H),5.18-5.08(m,1H),4.61-4.51(m,1H),3.28(dd,2H),2.73-2.64(m,2H),2.62-2.53(m, 6H),1.07(t,6H).
实施例31：反式-N-(3-((6-(4-羟基苯基)咪唑并[1,5-a]吡啶-8-基)氧基)环丁基)丙烯酰胺(化合物31)Example 31: trans-N-(3-((6-(4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)acrylamide (Compound 31 )
trans-N-(3-((6-(4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)acrylamidetrans-N-(3-((6-(4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)acrylamide
Figure PCTCN2021117545-appb-000258
Figure PCTCN2021117545-appb-000258
氮气保护，50mL三口瓶中，将6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯(62mg,0.15mmol)加入到丙烯酸(10.8mg,0.15mmol)的N,N-二甲基甲酰胺(2mL)溶液中，室温反应10min，0℃下，再将反式-4-(8-((3-氨基环丁氧基)咪唑并[1,5-a]吡啶-6-基)苯酚(14B)的三氟乙酸盐(61.4mg,0.15mmol)溶于1mL N,N-二甲基甲酰胺中滴加到上述反应液中，0℃搅拌1min后，再将N,N-二异丙基乙胺(101mg,0.78mmol)溶于1mLN,N-二甲基甲酰胺中滴加到上述反应液中，0℃搅拌3h，饱和碳酸氢钠溶液(5mL)淬灭，乙酸乙酯(20*3mL)萃取，减压浓缩，残留物通过制备液相(仪器：waters 2767制备液相；色谱柱:SunFire@Prep C18(19mm×150mm)；流动相组成：流动相A：乙腈流动相B：水(含5mM乙酸铵))分离纯化得到化合物31(8.5mg，产率16％)。Under nitrogen protection, in a 50mL three-necked flask, add 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate (62mg, 0.15mmol) to acrylic acid (10.8mg, 0.15mmol) in N,N-dimethylformamide (2 mL) solution, react at room temperature for 10 min, at 0 °C, and then trans-4-(8-((3-aminocyclobutoxy)imidazo[1,5] -a] Pyridin-6-yl) phenol (14B) trifluoroacetate (61.4 mg, 0.15 mmol) was dissolved in 1 mL of N,N-dimethylformamide and added dropwise to the above reaction solution, stirred at 0°C After 1min, N,N-diisopropylethylamine (101mg, 0.78mmol) was dissolved in 1mL N,N-dimethylformamide and added dropwise to the above reaction solution, stirred at 0°C for 3h, saturated sodium bicarbonate The solution (5mL) was quenched, extracted with ethyl acetate (20*3mL), concentrated under reduced pressure, and the residue was passed through a preparative liquid phase (apparatus: waters 2767; chromatographic column: SunFire@Prep C18 (19mm×150mm); flow Phase composition: Mobile phase A: acetonitrile Mobile phase B: water (containing 5 mM ammonium acetate)) was isolated and purified to obtain compound 31 (8.5 mg, yield 16%).
LCMS m/z＝350.1[M+1] + LCMS m/z=350.1[M+1] +
实施例32：顺式-N-(3-((6-(2-乙基-5-氟-4-羟基苯基)咪唑并[1,5-a]吡啶-8-基)氧基)环丁基)丙烯酰胺(化合物32)Example 32: cis-N-(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy) Cyclobutyl)acrylamide (Compound 32)
cis-N-(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)acrylamidecis-N-(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)acrylamide
Figure PCTCN2021117545-appb-000259
Figure PCTCN2021117545-appb-000259
第一步:顺式-叔丁基(3-((6-溴咪唑并[1,5-a]吡啶-8-基)氧基)环丁基)氨基甲酸酯(32A)The first step: cis-tert-butyl (3-((6-bromoimidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)carbamate (32A)
cis-tert-butyl(3-((6-bromoimidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)carbamatecis-tert-butyl(3-((6-bromoimidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)carbamate
氮气保护下加入顺式-(3-羟基环丁基)氨基甲酸叔丁酯(224.5mg，1.2mmol)和DMF(5mL)到反应瓶中，冰水冷却下加入钠氢(48mg，60wt％，1.6mmol)，加完室温搅拌反应30分钟；冰水冷却，滴入6-溴-8-氟咪唑并[1,5-a]吡啶(13E)(215mg，1mmol)的DMF溶液(5mL)，加完室温搅拌反应3小时。TLC监控反应完全，加入乙酸乙酯(100mL)和水(100mL)，分层，水层用乙酸乙酯(100mL×1)提取一次，有机层合并，饱和氯化钠溶液(100mL×2)洗涤，无水硫酸钠干燥，过滤，40℃减压浓缩干，残余物硅胶柱层析纯化(洗脱剂PE/EA＝5/1)得32A，白色固体(340mg，产率89％)。Under nitrogen protection, tert-butyl cis-(3-hydroxycyclobutyl)carbamate (224.5 mg, 1.2 mmol) and DMF (5 mL) were added to the reaction flask, and 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, 6-bromo-8-fluoroimidazo[1,5-a]pyridine (13E) (215 mg, 1 mmol) in DMF solution (5 mL) was added dropwise, After the addition, 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 aqueous layer was extracted once with ethyl acetate (100 mL×1), the organic layers were combined, and washed with saturated sodium chloride solution (100 mL×2). , dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure at 40°C, and the residue was purified by silica gel column chromatography (eluent PE/EA=5/1) to obtain 32A as a white solid (340 mg, yield 89%).
第二步：顺式-叔丁基(3-((6-(4-(苄氧基)-2-乙基-5-氟苯基)咪唑并[1,5-a]吡啶-8-基)氧基)环丁基)氨基甲酸酯(32B)The second step: cis-tert-butyl(3-((6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)imidazo[1,5-a]pyridine-8- yl)oxy)cyclobutyl)carbamate (32B)
cis-tert-butyl(3-((6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)carbamatecis-tert-butyl(3-((6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)carbamate
氮气保护，将2-(4-(苄氧基)-2-乙基-5-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(480.9mg，1.35mmol)，七水磷酸钾(913mg，2.7mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(73.5mg，0.09mmol)，分别加入至32A(340mg，0.89mmol)的1,4-二氧六环(20mL)和水(5mL)的溶液中，110℃搅拌1h，饱和碳酸氢钠溶液(20mL)淬 灭，乙酸乙酯(20mL*3)萃取，合并有机层用无水硫酸钠干燥，抽滤，滤液减压浓缩，残余物硅胶柱层析纯化(石油醚/乙酸乙酯(v/v)＝2:1)，得到32B，灰色固体(413mg，产率87.3％)。Under nitrogen protection, 2-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (480.9 mg, 1.35 mmol), potassium phosphate heptahydrate (913 mg, 2.7 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (73.5 mg, 0.09 mmol), respectively, were added to a solution of 32A (340 mg, 0.89 mmol) in 1,4-dioxane (20 mL) and water (5 mL), stirred at 110 °C for 1 h, and quenched with saturated sodium bicarbonate solution (20 mL) , extracted with ethyl acetate (20 mL*3), the combined organic layers were dried over anhydrous sodium sulfate, filtered with suction, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2 : 1) to give 32B as a grey solid (413 mg, 87.3% yield).
第三步：顺式-叔丁基(3-((6-(2-乙基-5-氟-4-羟基苯基)咪唑并[1,5-a]吡啶-8-基)氧基)环丁基)氨基甲酸酯(32C)The third step: cis-tert-butyl(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy ) cyclobutyl) carbamate (32C)
cis-tert-butyl(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)carbamatecis-tert-butyl(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)carbamate
将32B(413mg，0.78mmol)加入反应瓶中，加入钯碳(41mg)和甲醇溶液(30mL)，氢气换气三次，室温搅拌反应6h。反应液通过硅藻土过滤，乙酸乙酯洗脱。减压浓缩干，得32C(343mg)，直接用于下一步反应。32B (413 mg, 0.78 mmol) was added to the reaction flask, palladium carbon (41 mg) and methanol solution (30 mL) were added, the hydrogen was purged three times, and the reaction was stirred at room temperature for 6 h. The reaction solution was filtered through celite and eluted with ethyl acetate. Concentrated to dryness under reduced pressure to obtain 32C (343 mg), which was directly used in the next reaction.
第八步:顺式-4-(8-((3-氨基环丁氧基)咪唑并[1,5-a]吡啶-6-基)-5-乙基-2-氟苯酚(32D)的三氟乙酸盐Step 8: cis-4-(8-((3-aminocyclobutoxy)imidazo[1,5-a]pyridin-6-yl)-5-ethyl-2-fluorophenol (32D) Trifluoroacetate
cis-4-(8-(3-aminocyclobutoxy)imidazo[1,5-a]pyridin-6-yl)-5-ethyl-2-fluorophenol；trifluoroacetic acidcis-4-(8-(3-aminocyclobutoxy)imidazo[1,5-a]pyridin-6-yl)-5-ethyl-2-fluorophenol; trifluoroacetic acid
将32C粗品(343mg)溶于二氯甲烷(10mL)溶液中并加入三氟乙酸(3mL)，室温反应1小时。将反应液直接浓缩，得到32D的三氟乙酸盐，白色固体(355mg)，直接用于下一步反应。The crude 32C (343 mg) was dissolved in dichloromethane (10 mL) solution and trifluoroacetic acid (3 mL) was added, and the reaction was carried out at room temperature for 1 hour. The reaction solution was directly concentrated to obtain the trifluoroacetate salt of 32D as a white solid (355 mg), which was directly used in the next reaction.
第九步:顺式-N-(3-((6-(2-乙基-5-氟-4-羟基苯基)咪唑并[1,5-a]吡啶-8-基)氧基)环丁基)丙烯酰胺(化合物32)Step 9: cis-N-(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy) Cyclobutyl)acrylamide (Compound 32)
cis-N-(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)acrylamidecis-N-(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)acrylamide
氮气保护，50mL三口瓶中，将6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯(62mg,0.15mmol)加入到丙烯酸(11mg,0.15mmol)的N,N-二甲基甲酰胺(2mL)溶液中，室温反应10min，0℃下，再将32D的三氟乙酸盐粗品(59mg)溶于1mL N,N-二甲基甲酰胺中滴加到上述反应液中，0℃搅拌1min后，再将N,N-二异丙基乙胺(101mg,0.78mmol)溶于1mL N,N-二甲基甲酰胺中滴加到上述反应液中，0℃搅拌3h，饱和碳酸氢钠溶液(5mL)淬灭，乙酸乙酯(20*3mL)萃取，减压浓缩，残留物通过制备液相(仪器：waters 2767制备液相；色谱柱:SunFire@Prep C18(19mm×150mm)；.流动相组成：流动相A：乙腈流动相B：水(含5mM乙酸铵))分离纯化得到化合物32(6.8mg，产率13.3％)。Under nitrogen protection, in a 50mL three-necked flask, add 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate (62mg, 0.15mmol) to acrylic acid (11mg, 0.15mmol). In N,N-dimethylformamide (2 mL) solution, react at room temperature for 10 min, and at 0°C, the crude trifluoroacetate (59 mg) of 32D was dissolved in 1 mL of N,N-dimethylformamide dropwise Added to the above reaction solution, after stirring for 1min at 0°C, N,N-diisopropylethylamine (101mg, 0.78mmol) was dissolved in 1mL of N,N-dimethylformamide and added dropwise to the above reaction solution , 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)) was isolated and purified to obtain compound 32 (6.8 mg, yield 13.3%).
LCMS m/z＝396.2[M+1] + LCMS m/z=396.2[M+1] +
实施例33：顺式-N-(3-(((6-(2-乙基-5-氟-4-羟基苯基)咪唑并[1,5-a]吡啶-8-基)氧基)环丁基)-2-氟丙烯酰胺(化合物33)Example 33: cis-N-(3-(((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy ) cyclobutyl)-2-fluoroacrylamide (compound 33)
cis-N-(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)-2-fluoroacrylamidecis-N-(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)-2-fluoroacrylamide
Figure PCTCN2021117545-appb-000260
Figure PCTCN2021117545-appb-000260
氮气保护，50mL三口瓶中，将6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯(62mg,0.15mmol)加入到2-氟丙烯酸(14mg,0.15mmol)的N,N-二甲基甲酰胺(2mL)溶液中，室温反应10min，0℃下，再将32D的三氟乙酸盐粗品(68.3mg)溶于1mL N,N-二甲基甲酰胺中滴加到上述反应液中，0℃搅拌1min后，再将N,N-二异丙基乙胺(101mg,0.78mmol)溶于1mL N,N-二甲基甲酰胺中滴加到上述反应液中，0℃搅拌3h，饱和碳酸氢钠溶液(5mL)淬灭，乙酸乙酯(20*3mL)萃取，减压浓缩，残留物通过制备液相(仪器：waters 2767制备液相；色谱柱:SunFire@Prep C18(19mm×150mm)；.流动相组成：流动相A：乙腈流动相B：水(含5mM乙酸铵))分离纯化得到化合物33(14mg，产率17.6％)。Under nitrogen protection, in a 50mL three-necked flask, add 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate (62mg, 0.15mmol) to 2-fluoroacrylic acid (14mg, 0.15mg) mmol) in N,N-dimethylformamide (2mL) solution, react at room temperature for 10min, at 0°C, then dissolve the crude trifluoroacetate (68.3mg) of 32D in 1mL N,N-dimethylformamide Formamide was added dropwise to the above reaction solution, and after stirring at 0°C for 1 min, N,N-diisopropylethylamine (101mg, 0.78mmol) was dissolved in 1mL N,N-dimethylformamide and added dropwise In the above reaction solution, 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 preparing the liquid phase (apparatus: waters 2767). ; Chromatographic column: SunFire@Prep C18 (19mm×150mm);. Mobile phase composition: Mobile phase A: acetonitrile Mobile phase B: water (containing 5mM ammonium acetate)) separation and purification to obtain compound 33 (14 mg, yield 17.6%).
LCMS m/z＝414.2[M+1] + LCMS m/z=414.2[M+1] +
实施例34：反式-(2E)-4-(二甲基氨基)-N-(2-甲氧基乙基)-N-[3-[(6-(4-羟苯基)-1H-吲唑-4-基)氧基]环丁基]丁-2-烯酰胺(化合物34)Example 34: trans-(2E)-4-(dimethylamino)-N-(2-methoxyethyl)-N-[3-[(6-(4-hydroxyphenyl)-1H -Indazol-4-yl)oxy]cyclobutyl]but-2-enamide (compound 34)
trans-(2E)-4-(dimethylamino)-N-(2-methoxyethyl)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamidetrans-(2E)-4-(dimethylamino)-N-(2-methoxyethyl)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2 -enamide
Figure PCTCN2021117545-appb-000261
Figure PCTCN2021117545-appb-000261
第一步：反式-叔丁基N-(2-甲氧基乙基)-N-[3-[(6-溴-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基]环丁基]氨基甲酸酯(34A)The first step: trans-tert-butyl N-(2-methoxyethyl)-N-[3-[(6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H -Indazol-4-yl)oxy]cyclobutyl]carbamate (34A)
trans-tert-butyl N-(2-methoxyethyl)-N-[3-[(6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy]cyclobutyl]carbamatetrans-tert-butyl N-(2-methoxyethyl)-N-[3-[(6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy]cyclobutyl] carbamate
在50mL反应瓶中，依次加入反式-N-[3-(6-溴-1-四氢吡喃-2-基-吲唑-4-基)氧基环丁基]氨基甲酸叔丁酯(1C)(0.5g，1.07mmol)、N,N-二甲基甲酰胺(15mL)，碘化钠(0.08g,0.54mmol)和氢化钠(0.85g，21.4mmol，60wt％)，加完后在25℃下搅拌10分钟，加入2-溴乙基甲醚(0.59g，4.28mmol)，升温至50℃搅拌反应5h。冷却至室温，用1mL水淬灭反应，反应液中加入乙酸乙酯(50mL)，然后依次用水(30mL×1)、饱和食盐水(30mL×1)洗涤，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(乙酸乙酯/石油醚(V/V)＝1/20-1/5)得到34A，白色固体(0.4g，收率：71％)。In a 50mL reaction flask, add trans-N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]carbamic acid tert-butyl ester in turn (1C) (0.5 g, 1.07 mmol), N,N-dimethylformamide (15 mL), sodium iodide (0.08 g, 0.54 mmol) and sodium hydride (0.85 g, 21.4 mmol, 60 wt %), complete addition After stirring at 25° C. for 10 minutes, 2-bromoethyl methyl ether (0.59 g, 4.28 mmol) was added, and the temperature was raised to 50° C. and stirred for 5 h. Cool to room temperature, quench the reaction with 1 mL of water, add ethyl acetate (50 mL) to the reaction solution, then wash with water (30 mL×1) and saturated brine (30 mL×1) successively, and dry the organic layer with anhydrous sodium sulfate, Filtration, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (ethyl acetate/petroleum ether (V/V)=1/20-1/5) to obtain 34A as a white solid (0.4 g, yield: 71%) ).
LCMS m/z＝524.2/526.2[M+H] + LCMS m/z=524.2/526.2[M+H] +
第二步：反式-叔丁基N-(2-甲氧基乙基)-N-[3-[[6-(4-羟苯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧]环丁基]氨基甲酸酯(34B)The second step: trans-tert-butyl N-(2-methoxyethyl)-N-[3-[[6-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyran- 2-yl)-1H-indazol-4-yl)oxy]cyclobutyl]carbamate (34B)
trans-tert-butyl N-(2-methoxyethyl)-N-[3-[(6-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy]cyclobutyl]carbamatetrans-tert-butyl N-(2-methoxyethyl)-N-[3-[(6-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl) oxy]cyclobutyl]carbamate
在50mL反应瓶中，依次加入上一步的34A(0.40g，0.76mmol)、4-羟基苯硼酸(0.16g，1.14mmol)、七水合磷酸钾(0.77g，2.28mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(73mg，0.089mmol)和二氧六环/水(v/v＝4/1，10mL)，氮气置换三次后，在 90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(乙酸乙酯/石油醚(V/V)＝1/10-1/1)得到34B，白色固体(0.4g，产率98％)。In a 50mL reaction flask, sequentially added 34A (0.40g, 0.76mmol), 4-hydroxyphenylboronic acid (0.16g, 1.14mmol), potassium phosphate heptahydrate (0.77g, 2.28mmol), [1,1' - Bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (73 mg, 0.089 mmol) and dioxane/water (v/v=4/1, 10 mL), nitrogen replaced three times After that, the reaction was stirred at 90°C for 2 hours. 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 (ethyl acetate). /petroleum ether (V/V)=1/10-1/1) to give 34B as a white solid (0.4 g, 98% yield).
LCMS m/z＝538.3[M+H] + LCMS m/z=538.3[M+H] +
第三步：反式-(2E)-4-(二甲基氨基)-N-(2-甲氧基乙基)-N-[3-[(6-(4-羟苯基)-1H-吲唑-4-基)氧基]环丁基]丁-2-烯酰胺(化合物34)The third step: trans-(2E)-4-(dimethylamino)-N-(2-methoxyethyl)-N-[3-[(6-(4-hydroxyphenyl)-1H -Indazol-4-yl)oxy]cyclobutyl]but-2-enamide (compound 34)
trans-(2E)-4-(dimethylamino)-N-(2-methoxyethyl)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamidetrans-(2E)-4-(dimethylamino)-N-(2-methoxyethyl)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2 -enamide
在50mL反应瓶中，加入化合物34B(0.12g，0.21mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用甲基叔丁基醚(10mL×3)洗，然后减压浓缩干，加入5mL乙腈溶解，加入二异丙基乙胺(0.35g，2.7mmol)搅拌10min，待用。In a 50 mL reaction flask, compound 34B (0.12 g, 0.21 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with methyl tert-butyl ether (10 mL×3), then concentrated to dryness under reduced pressure, dissolved in 5 mL of acetonitrile, added with diisopropylethylamine (0.35 g, 2.7 mmol) and stirred for 10 min ,stand-by.
将反式-4-二甲基胺基巴豆酸盐酸盐(0.041g，0.25mmol)和二异丙基乙胺(83mg，0.64mmol)溶于二氯甲烷(5mL)和乙腈(5mL)的混合溶液中，加入三吡咯烷基溴化鏻六氟磷酸盐(0.12g，0.25mmol)，室温搅拌20分钟。将此反应液缓慢滴加到上述待用的乙腈溶液中，继续搅拌1h。加入10mL饱和碳酸氢钠水溶液碱化，分液后，有机层用无水硫酸钠干燥后，减压浓缩，残留物柱层析纯化(DCM/MeOH/NH 3H 2O(V/V/V)＝50/1/0.5-25/1/0.25)，得到化合物34，淡黄色固体(70mg,收率：71％)。 Trans-4-dimethylaminocrotonate hydrochloride (0.041 g, 0.25 mmol) and diisopropylethylamine (83 mg, 0.64 mmol) were dissolved in dichloromethane (5 mL) and acetonitrile (5 mL) To the mixed solution, tripyrrolidinophosphonium bromide hexafluorophosphate (0.12 g, 0.25 mmol) was added, and the mixture was 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. Add 10 mL of saturated aqueous sodium bicarbonate solution to basify, after separation, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM/MeOH/NH 3 H 2 O (V/V/V )=50/1/0.5-25/1/0.25) to obtain compound 34 as a pale yellow solid (70 mg, yield: 71%).
LCMS m/z＝465.2[M+H] + LCMS m/z=465.2[M+H] +
实施例35:反式-N-甲基-N-[3-[[6-(2-乙基-5-氟-4-羟基苯基)咪唑并[1,5-a]吡啶-8-基)氧基]环丁基]丙-2-酰胺(化合物35)的三氟乙酸盐Example 35: trans-N-methyl-N-[3-[[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridine-8- yl)oxy]cyclobutyl]propan-2-amide (compound 35) trifluoroacetate salt
trans-N-methyl-N-[3-[(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy]cyclobutyl]prop-2-enamide；trifluoroacetic acidtrans-N-methyl-N-[3-[(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy]cyclobutyl]prop-2- enamide; trifluoroacetic acid
Figure PCTCN2021117545-appb-000262
Figure PCTCN2021117545-appb-000262
Figure PCTCN2021117545-appb-000263
Figure PCTCN2021117545-appb-000263
第一步：反式-N-甲基-N-[3-[[6-溴咪唑并[1,5-a]吡啶-8-基)氧基]环丁基]氨基甲酸叔丁酯(35A)The first step: tert-butyl trans-N-methyl-N-[3-[[6-bromoimidazo[1,5-a]pyridin-8-yl)oxy]cyclobutyl]carbamate ( 35A)
trans-tert-butyl N-methyl-N-[3-[(6-bromoimidazo[1,5-a]pyridin-8-yl)oxy]cyclobutyl]carbamatetrans-tert-butyl N-methyl-N-[3-[(6-bromoimidazo[1,5-a]pyridin-8-yl)oxy]cyclobutyl]carbamate
在50mL反应瓶中，依次加入反式-叔丁基(3-((6-溴咪唑并[1,5-a]吡啶-8-基)氧基)环丁基)氨基甲酸酯(13F)(0.83g，2.17mmol)、N,N-二甲基甲酰胺(30mL)和氢化钠(1.6g，40mmol，60wt％)，加完后在25℃下搅拌30分钟，缓慢滴加碘甲烷(4.26g，30mmol)并在45℃搅拌反应2h。反应液中加入乙酸乙酯(50mL)，然后依次用水(30mL×3)、饱和食盐水(30mL×1)洗涤，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过硅胶柱层析分离纯化(PE/EA＝9/1)得到35A，淡黄色油状物(0.4g，收率：46％)。In a 50 mL reaction flask, add trans-tert-butyl (3-((6-bromoimidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)carbamate (13F ) (0.83 g, 2.17 mmol), N,N-dimethylformamide (30 mL) and sodium hydride (1.6 g, 40 mmol, 60 wt%), and after the addition, the mixture was stirred at 25° C. for 30 minutes, and methyl iodide was slowly added dropwise. (4.26 g, 30 mmol) and the reaction was stirred at 45 °C for 2 h. Ethyl acetate (50 mL) was added to the reaction solution, then washed with water (30 mL×3) and saturated brine (30 mL×1) successively, the organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was passed through silica gel Separation and purification by column chromatography (PE/EA=9/1) gave 35A as a pale yellow oil (0.4 g, yield: 46%).
LCMS m/z＝396.1/398.0[M+H] + LCMS m/z=396.1/398.0[M+H] +
第二步：反式-N-甲基-N-[3-[(6-(4-(苄氧基)-2-乙基-5-氟苯基)咪唑[1,5-a]吡啶-8-基]氧基]环丁基]氨基甲酸叔丁酯(35B)Step 2: trans-N-methyl-N-[3-[(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)imidazo[1,5-a]pyridine -8-yl]oxy]cyclobutyl]carbamate tert-butyl ester (35B)
trans-tert-butyl N-methyl-N-[3-[(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)imidazo[1,5-a]pyridin-8-yl)oxy]cyclobutyl]carbamatetrans-tert-butyl N-methyl-N-[3-[(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)imidazo[1,5-a]pyridin-8-yl)oxy]cyclobutyl ]carbamate
在50mL反应瓶中，依次加入35A(0.378g，0.95mmol)、2-(4-(苄氧基)-2-乙基-5-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(0.41g，1.14mmol)、七水合磷酸钾(0.97g，2.87mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(78mg，0.096mmol)和二氧六环/水(v/v＝4/1，10mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(PE/EA＝3/1)得到35B粗品，淡黄色固体(0.32g)，直接用于下一步反应。In a 50 mL reaction flask, 35A (0.378 g, 0.95 mmol), 2-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-4,4,5,5-tetramethyl were sequentially added yl-1,3,2-dioxaborane (0.41 g, 1.14 mmol), potassium phosphate heptahydrate (0.97 g, 2.87 mmol), [1,1'-bis(diphenylphosphino)ferrocene] Palladium dichloride dichloromethane complex (78 mg, 0.096 mmol) and dioxane/water (v/v=4/1, 10 mL) were replaced with nitrogen three times, and the reaction was stirred at 90° C. for 2 hours. 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 obtain crude 35B as a pale yellow solid (0.32 g), which was directly used in the next reaction.
第三步：反式-N-甲基-N-[3-[(6-(2-乙基-5-氟-4-羟基苯基)咪唑并[1,5-a]吡啶-8-基)氧基]环丁基]氨基甲酸叔丁酯(35C)The third step: trans-N-methyl-N-[3-[(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridine-8- tert-butyl)oxy]cyclobutyl]carbamate (35C)
trans-tert-butyl N-methyl-N-[3-[(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy]cyclobutyl]carbamatetrans-tert-butyl N-methyl-N-[3-[(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy]cyclobutyl]carbamate
将35B粗品(320mg)加入反应瓶中，加入钯碳(41mg)和甲醇溶液(30mL)，氢气换气三次，室温搅拌反应6h。反应液通过硅藻土过滤，乙酸乙酯洗脱。减压浓缩干，得35C粗品(260mg)，直接用于下一步反应。The crude 35B (320 mg) was added to the reaction flask, palladium carbon (41 mg) and methanol solution (30 mL) were added, the hydrogen was purged three times, and the reaction was stirred at room temperature for 6 h. The reaction solution was filtered through celite and eluted with ethyl acetate. Concentrated to dryness under reduced pressure to obtain 35C crude product (260 mg), which was directly used in the next reaction.
LCMS m/z＝456.2[M+H] + LCMS m/z=456.2[M+H] +
第四步：反式-N-甲基-N-[3-[[6-(2-乙基-5-氟-4-羟基苯基)咪唑并[1,5-a]吡啶-8-基)氧基]环丁基]丙-2-酰胺(化合物35)的三氟乙酸盐Step 4: Trans-N-methyl-N-[3-[[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridine-8- yl)oxy]cyclobutyl]propan-2-amide (compound 35) trifluoroacetate salt
trans-N-methyl-N-[3-[(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy]cyclobutyl]prop-2-enamide；trifluoroacetic acidtrans-N-methyl-N-[3-[(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy]cyclobutyl]prop-2- enamide; trifluoroacetic acid
在50mL反应瓶中，加入35C粗品(260mg)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用MTBE(10mL×3)洗，然后减压浓缩干得到黑色泡沫状固体残留物(400mg)。In a 50 mL reaction flask, crude 35C (260 mg) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with MTBE (10 mL×3), and then concentrated to dryness under reduced pressure to obtain a black foamy solid residue (400 mg).
在50mL反应瓶中，加入上述黑色泡沫状固体残留物(0.22g)、N,N-二异丙基乙胺(0.29g，2.26mmol)和二氯甲烷(10mL)，加完后在室温下搅拌5分钟，然后滴加丙烯酰氯(0.034g，0.38mmol)，加完后在室温下搅拌10分钟。反应液中加入饱和碳酸氢钠(50mL)，然后用二氯甲烷/甲醇(v/v＝10/1)(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物制备HPLC(仪器：waters 2767制备液相；色谱柱:SunFire@Prep C18(19mm×150mm)；流动相组成：流动相A：乙腈，流动相B：水(含0.1％三氟乙酸))纯化得到化合物35的三氟乙酸盐(44mg，产率18％)。In a 50 mL reaction flask, add the above black foamy solid residue (0.22 g), N,N-diisopropylethylamine (0.29 g, 2.26 mmol) and dichloromethane (10 mL). After stirring for 5 minutes, acryloyl chloride (0.034 g, 0.38 mmol) was added dropwise, followed by stirring at room temperature for 10 minutes. Saturated sodium bicarbonate (50 mL) was added to the reaction solution, then extracted with dichloromethane/methanol (v/v=10/1) (50 mL×2), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced in pressure Concentrated, the residue was preparative HPLC (instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm×150mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid) )) was purified to give compound 35 as trifluoroacetate salt (44 mg, 18% yield).
LCMS m/z＝410.2[M+H] + LCMS m/z=410.2[M+H] +
1H NMR(400MHz,CD 3OD)δ9.39(d,1H),8.12(s,1H),8.04(s,1H),7.01(d,1H),6.92(d,1H),6.71(dd,1H),6.30(s,1H),6.25-6.06(m,1H),5.82-5.65(m,1H),5.30-4.90(m,2H),3.17-2.97(m,3H),2.95–2.72(m,2H),2.69-2.51(m,4H),1.13(t,3H). 1 H NMR (400MHz, CD 3 OD) δ9.39(d,1H), 8.12(s,1H), 8.04(s,1H), 7.01(d,1H), 6.92(d,1H), 6.71(dd ,1H),6.30(s,1H),6.25-6.06(m,1H),5.82-5.65(m,1H),5.30-4.90(m,2H),3.17-2.97(m,3H),2.95-2.72 (m, 2H), 2.69-2.51(m, 4H), 1.13(t, 3H).
实施例36：反式-(2E)-4-(二甲基氨基)-N-[(3-[[6-(4-羟基苯基)-1H-吲唑-4-基)氧基]-2,2,4,4-四甲基环丁基]丁-2-烯酰胺(化合物36)Example 36: trans-(2E)-4-(dimethylamino)-N-[(3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy] -2,2,4,4-Tetramethylcyclobutyl]but-2-enamide (Compound 36)
trans-(2E)-4-(dimethylamino)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]-2,2,4,4-tetramethylcyclobutyl]but-2-enamidetrans-(2E)-4-(dimethylamino)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]-2,2,4,4-tetramethylcyclobutyl]but- 2-enamide
Figure PCTCN2021117545-appb-000264
Figure PCTCN2021117545-appb-000264
Figure PCTCN2021117545-appb-000265
Figure PCTCN2021117545-appb-000265
第一步：反式-3-[(6-溴-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基]-2,2,4,4-四甲基环丁-1-胺(36A)The first step: trans-3-[(6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy]-2,2,4, 4-Tetramethylcyclobutan-1-amine (36A)
trans-3-[(6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy]-2,2,4,4-tetramethylcyclobutan-1-aminetrans-3-[(6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy]-2,2,4,4-tetramethylcyclobutan-1-amine
将化合物6-溴-4-氟-1-四氢吡喃-2-基-吲唑(1c)(0.3g,1.00mmol)，反式-N-[3-羟基-2,2,4,4-四甲基环丁基]氨基甲酸叔丁酯(0.29g,1.2mmol)，四丁基溴化铵(0.97g,3mmol)和氢氧化钾(0.56g,10mmol)混合于甲苯(10ml)和水(3ml)的混合溶剂中，升温至80℃，搅拌反应48h。冷却至室温，加入10mL水和10mL乙酸乙酯萃取，有机层分液后减压浓缩，柱层析纯化(DCM/MeOH(V/V)＝100/1-20/1)得到36A，白色固体(180mg,收率：43％)。The compound 6-bromo-4-fluoro-1-tetrahydropyran-2-yl-indazole (1c) (0.3 g, 1.00 mmol), trans-N-[3-hydroxy-2,2,4, 4-Tetramethylcyclobutyl]carbamate (0.29g, 1.2mmol), tetrabutylammonium bromide (0.97g, 3mmol) and potassium hydroxide (0.56g, 10mmol) were mixed in toluene (10ml) In a mixed solvent of water (3 ml), the temperature was raised to 80 °C, and the reaction was stirred for 48 h. Cooled to room temperature, added 10 mL of water and 10 mL of ethyl acetate for extraction, the organic layer was separated, concentrated under reduced pressure, and purified by column chromatography (DCM/MeOH (V/V)=100/1-20/1) to obtain 36A as a white solid (180 mg, yield: 43%).
1H NMR(400MHz,DMSO-d 6)δ8.09(s,1H),7.58(s,1H),6.51(s,1H),5.81(dd,1H),4.33(s,1H),3.91-3.83(m,1H),3.80–3.71(m,1H),3.01(s,1H),2.41-2.27(m,1H),2.08–1.88(m,2H),1.79-1.65(m,1H),1.63-1.51(m,2H),1.27(s,6H),1.16-1.09(m,6H). 1 H NMR (400MHz, DMSO-d 6 )δ8.09(s,1H), 7.58(s,1H), 6.51(s,1H), 5.81(dd,1H), 4.33(s,1H), 3.91- 3.83(m,1H), 3.80–3.71(m,1H), 3.01(s,1H), 2.41-2.27(m,1H), 2.08–1.88(m,2H), 1.79-1.65(m,1H), 1.63-1.51(m, 2H), 1.27(s, 6H), 1.16-1.09(m, 6H).
第二步：反式-4-(1-(四氢-2H-吡喃-2-基)-4-[(3-氨基-2,2,4,4-四甲基环丁氧基]-1H-吲唑-6-基)苯酚(36B)The second step: trans-4-(1-(tetrahydro-2H-pyran-2-yl)-4-[(3-amino-2,2,4,4-tetramethylcyclobutoxy] -1H-Indazol-6-yl)phenol (36B)
trans-4-(1-(tetrahydro-2H-pyran-2-yl)-4-[(1s,3s)-3-amino-2,2,4,4-tetramethylcyclobutoxy]-1H-indazol-6-yl)phenoltrans-4-(1-(tetrahydro-2H-pyran-2-yl)-4-[(1s,3s)-3-amino-2,2,4,4-tetramethylcyclobutoxy]-1H-indazol-6-yl )phenol
在50mL反应瓶中，依次加入上一步的36A(0.18g，0.43mmol)、4-羟基苯硼酸(0.071g，0.52mmol)、七水合磷酸钾(0.44g，1.29mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(35mg，0.043mmol)和二氧六环/水(v/v＝4/1，10mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(乙酸乙酯/石油醚(V/V)＝1/10-1/1)得到36B，白色固体(0.1g，产率53％)。In a 50mL reaction flask, successively added 36A (0.18g, 0.43mmol), 4-hydroxyphenylboronic acid (0.071g, 0.52mmol), potassium phosphate heptahydrate (0.44g, 1.29mmol), [1,1' - Bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (35 mg, 0.043 mmol) and dioxane/water (v/v=4/1, 10 mL), nitrogen replaced three times After that, the reaction was stirred at 90°C for 2 hours. 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 (ethyl acetate). /petroleum ether (V/V)=1/10-1/1) to give 36B as a white solid (0.1 g, 53% yield).
LCMS m/z＝436.2[M+H] + LCMS m/z=436.2[M+H] +
第三步：反式-(2E)-4-(二甲基氨基)-N-[(3-[[6-(4-羟基苯基)-1H-吲唑-4-基)氧基]-2,2,4,4-四甲基环丁基]丁-2-烯酰胺(化合物36)The third step: trans-(2E)-4-(dimethylamino)-N-[(3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy] -2,2,4,4-Tetramethylcyclobutyl]but-2-enamide (Compound 36)
trans-(2E)-4-(dimethylamino)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]-2,2,4,4-tetramethylcyclobutyl]but-2-enamidetrans-(2E)-4-(dimethylamino)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]-2,2,4,4-tetramethylcyclobutyl]but- 2-enamide
在50mL反应瓶中，加入化合物36B(0.1g，0.23mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用甲基叔丁基醚(10mL×3)洗，然后减压浓缩干，加入5mL乙腈溶解，加入二异丙基乙胺(0.35g，2.7mmol)搅拌10min，待用。In a 50 mL reaction flask, compound 36B (0.1 g, 0.23 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with methyl tert-butyl ether (10 mL×3), then concentrated to dryness under reduced pressure, dissolved in 5 mL of acetonitrile, added with diisopropylethylamine (0.35 g, 2.7 mmol) and stirred for 10 min ,stand-by.
将反式-4-二甲基胺基巴豆酸盐酸盐(0.041g，0.25mmol)和二异丙基乙胺(83mg，0.64mmol)溶于二氯甲烷(5mL)和乙腈(5mL)的混合溶液中，加入三吡咯烷基溴化鏻六氟磷酸盐(0.12g，0.25mmol)，室温搅拌20分钟。将此反应液缓慢滴加到上述待用的乙腈溶液中，继续搅拌1h。加入10mL饱和碳酸氢钠水溶液碱化，分液后，有机层用无水硫酸钠干燥后，减压浓缩，残留物柱层析纯化(DCM/MeOH/NH 3H 2O(V/V/V)＝50/1/0.5-25/1/0.25)，得到化合物36(40mg,收率：38％)。 Trans-4-dimethylaminocrotonate hydrochloride (0.041 g, 0.25 mmol) and diisopropylethylamine (83 mg, 0.64 mmol) were dissolved in dichloromethane (5 mL) and acetonitrile (5 mL) To the mixed solution, tripyrrolidinophosphonium bromide hexafluorophosphate (0.12 g, 0.25 mmol) was added, and the mixture was 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. Add 10 mL of saturated aqueous sodium bicarbonate solution to basify, after separation, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM/MeOH/NH 3 H 2 O (V/V/V )=50/1/0.5-25/1/0.25) to obtain compound 36 (40 mg, yield: 38%).
LCMS m/z＝463.2[M+H] + LCMS m/z=463.2[M+H] +
1H NMR(400MHz,DMSO-d 6)δ13.01(s,1H),9.55(s,1H),8.03(s,1H),7.70(d,1H),7.54-7.43(m,2H),7.16(s,1H),6.93-6.83(m,2H),6.65-6.54(m,1H),6.49(s,1H),6.38-6.28(m,1H),4.31(s,1H),4.03-3.97(m,1H),3.04-2.98(m,2H),2.17(s,6H),1.19(s,6H),1.17(s,6H). 1 H NMR (400MHz, DMSO-d 6 )δ13.01(s,1H), 9.55(s,1H), 8.03(s,1H), 7.70(d,1H), 7.54-7.43(m,2H), 7.16(s,1H),6.93-6.83(m,2H),6.65-6.54(m,1H),6.49(s,1H),6.38-6.28(m,1H),4.31(s,1H),4.03- 3.97(m,1H),3.04-2.98(m,2H),2.17(s,6H),1.19(s,6H),1.17(s,6H).
实施例37：反式-(E)-4-(二甲基氨基)-N-(3-((6-(2-氟-4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)-N-甲基丁-2-烯酰胺(化合物37)的乙酸盐Example 37: trans-(E)-4-(dimethylamino)-N-(3-((6-(2-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl) Acetate salt of oxy)cyclobutyl)-N-methylbut-2-enamide (compound 37)
trans-(E)-4-(dimethylamino)-N-(3-((6-(2-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-methylbut-2-enamide；acetic acidtrans-(E)-4-(dimethylamino)-N-(3-((6-(2-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-methylbut-2- enamide; acetic acid
Figure PCTCN2021117545-appb-000266
Figure PCTCN2021117545-appb-000266
第一步：反式-(3-((6-(2-氟-4-羟基苯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基)环丁基)(甲基)氨基甲酸叔丁酯(37A)The first step: trans-(3-((6-(2-fluoro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl )oxy)cyclobutyl)(methyl)carbamate (37A)
trans-tert-butyl(3-((6-(2-fluoro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)(methyl)carbamatetrans-tert-butyl(3-((6-(2-fluoro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)(methyl )carbamate
在50mL反应瓶中，依次加入化合物7A(0.48g，1.00mmol)、2-氟-4-羟基苯硼酸(0.19g，1.20mmol)、七水合磷酸钾(1.02g，3.00mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(120mg，0.15mmol)和二氧六环/水(v/v＝4/1，20mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(乙酸乙酯/石油醚(V/V)＝1/10-1/1)得到37A(0.51g，产率99％)。In a 50mL reaction flask, compound 7A (0.48g, 1.00mmol), 2-fluoro-4-hydroxyphenylboronic acid (0.19g, 1.20mmol), potassium phosphate heptahydrate (1.02g, 3.00mmol), [1, 1'-Bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (120 mg, 0.15 mmol) and dioxane/water (v/v=4/1, 20 mL), nitrogen After three replacements, the reaction was stirred at 90°C for 2 hours. 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 (ethyl acetate). /petroleum ether (V/V)=1/10-1/1) to give 37A (0.51 g, 99% yield).
LCMS m/z＝512.2[M+H] + LCMS m/z=512.2[M+H] +
第二步：反式-(E)-4-(二甲基氨基)-N-(3-((6-(2-氟-4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)-N-甲基丁-2-烯酰胺(化合物37)的乙酸盐The second step: trans-(E)-4-(dimethylamino)-N-(3-((6-(2-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl) Acetate salt of oxy)cyclobutyl)-N-methylbut-2-enamide (compound 37)
trans-(E)-4-(dimethylamino)-N-(3-((6-(2-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-methylbut-2-enamide；acetic acidtrans-(E)-4-(dimethylamino)-N-(3-((6-(2-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-methylbut-2- enamide; acetic acid
在50mL反应瓶中，加入化合物37A(0.51g，1.00mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用甲基叔丁基醚(10mL×3)洗，然后减压浓缩干，加入10mL乙腈溶解，加入二异丙基乙胺(0.37g，2.84mmol)搅拌10min，待用。In a 50 mL reaction flask, compound 37A (0.51 g, 1.00 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with methyl tert-butyl ether (10 mL×3), then concentrated to dryness under reduced pressure, dissolved in 10 mL of acetonitrile, added with diisopropylethylamine (0.37 g, 2.84 mmol) and stirred for 10 min ,stand-by.
将反式-4-二甲基胺基巴豆酸盐酸盐(0.165g，1.00mmol)和二异丙基乙胺(0.367mg，2.84mmol)溶于二氯甲烷(10mL)和乙腈(10mL)的混合溶液中，加入三吡咯烷基溴化鏻六氟磷酸盐(0.466g，1.00mmol)，室温搅拌20分钟。将此反应液缓慢滴加到上一操作待用的乙腈溶液中，继续搅拌1h。加入20mL饱和碳酸氢钠水溶液，分液后，有机层用无水硫酸钠干燥后，减压浓缩，残留物通过制备液相(仪器：waters 2767制备液相；色谱柱:SunFire@Prep C18(19mm×150mm)；流动相组成：流动相A：乙腈流动相B：水(含5mM乙酸铵))分离纯化，冻干后得到化合物37的乙酸盐(56mg,收率：11.82％)。Trans-4-dimethylaminocrotonate hydrochloride (0.165 g, 1.00 mmol) and diisopropylethylamine (0.367 mg, 2.84 mmol) were dissolved in dichloromethane (10 mL) and acetonitrile (10 mL) To the mixed solution, tripyrrolidinophosphonium bromide hexafluorophosphate (0.466 g, 1.00 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was slowly added dropwise to the acetonitrile solution to be used in the previous operation, and stirring was continued for 1 h. 20 mL of saturated aqueous sodium bicarbonate was added, and after separation, the organic layer was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was prepared by preparative liquid phase (apparatus: 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, lyophilized to obtain the acetate salt of compound 37 (56 mg, yield: 11.82%).
LCMS m/z＝439.3[M+H] + LCMS m/z=439.3[M+H] +
1H NMR(400MHz,CD 3OD)δ8.07(s,1H),7.33(t,1H),7.18(s,1H),6.74–6.56(m,4H),6.43(s,1H),5.33–4.95(m,2H),3.48–3.37(m,2H),3.17–3.00(m,3H),2.95–2.70(m,2H),2.70–2.53(m,2H),2.46(s,6H),1.95(s,3H). 1 H NMR (400MHz, CD 3 OD) δ 8.07(s, 1H), 7.33(t, 1H), 7.18(s, 1H), 6.74–6.56(m, 4H), 6.43(s, 1H), 5.33 –4.95(m, 2H), 3.48 – 3.37(m, 2H), 3.17 – 3.00(m, 3H), 2.95 – 2.70(m, 2H), 2.70 – 2.53(m, 2H), 2.46(s, 6H) ,1.95(s,3H).
实施例37-1：反式-(E)-4-(二甲基氨基)-N-(3-((6-(2-氟-4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)-N-甲基丁-2-烯酰胺(化合物37)Example 37-1: trans-(E)-4-(dimethylamino)-N-(3-((6-(2-fluoro-4-hydroxyphenyl)-1H-indazole-4- yl)oxy)cyclobutyl)-N-methylbut-2-enamide (compound 37)
trans-(E)-4-(dimethylamino)-N-(3-((6-(2-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-methylbut-2-enamidetrans-(E)-4-(dimethylamino)-N-(3-((6-(2-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-methylbut-2- enamide
100mL单口圆底烧瓶中，加入化合物37的乙酸盐(47mg)，然后加入二氯甲烷(20mL)与饱和碳酸氢钠溶液(15mL)，搅拌半小时。静置分层，水相用二氯甲烷/甲醇(v/v＝4/1；20mL x 3)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩化合物37(20mg).In a 100 mL single-necked round-bottom flask, the acetate salt of compound 37 (47 mg) was added, then dichloromethane (20 mL) and saturated sodium bicarbonate solution (15 mL) were added, and the mixture was stirred for half an hour. The layers were left to stand, the aqueous phase was extracted with dichloromethane/methanol (v/v=4/1; 20 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and compound 37 (20 mg) was concentrated under reduced pressure.
LCMS m/z＝439.2[M+H] + LCMS m/z=439.2[M+H] +
1H NMR(400MHz,CD 3OD)δ8.07(s,1H),7.33(t,1H),7.18(s,1H),6.80–6.50(m,4H),6.43(s,1H),5.31–4.92(m,2H),3.22–2.98(m,5H),2.96–2.70(m,2H),2.70–2.50(m,2H),2.27(s,6H). 1 H NMR (400MHz, CD 3 OD) δ 8.07(s, 1H), 7.33(t, 1H), 7.18(s, 1H), 6.80–6.50(m, 4H), 6.43(s, 1H), 5.31 –4.92(m,2H),3.22–2.98(m,5H),2.96–2.70(m,2H),2.70–2.50(m,2H),2.27(s,6H).
实施例38：反式-(E)-4-(二甲基氨基)-N-(3-((6-(4-羟基-2-甲基苯基)-1H-吲唑-4-基)氧基)环丁基)-N-甲基丁-2-烯酰胺(化合物38)Example 38: trans-(E)-4-(dimethylamino)-N-(3-((6-(4-hydroxy-2-methylphenyl)-1H-indazol-4-yl )oxy)cyclobutyl)-N-methylbut-2-enamide (compound 38)
trans-(E)-4-(dimethylamino)-N-(3-((6-(4-hydroxy-2-methylphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-methylbut-2-enamidetrans-(E)-4-(dimethylamino)-N-(3-((6-(4-hydroxy-2-methylphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-methylbut-2- enamide
Figure PCTCN2021117545-appb-000267
Figure PCTCN2021117545-appb-000267
第一步：反式-(3-((6-(4-羟基-2-甲基苯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基)环丁基)(甲基)氨基甲酸叔丁酯(38A)The first step: trans-(3-((6-(4-hydroxy-2-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4- tert-Butyl)oxy)cyclobutyl)(methyl)carbamate (38A)
trans-tert-butyl(3-((6-(4-hydroxy-2-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)(methyl)carbamatetrans-tert-butyl(3-((6-(4-hydroxy-2-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)(methyl )carbamate
在50mL反应瓶中，依次加入化合物7A(0.48g，1.00mmol)、4-羟基-2-甲基苯硼酸(0.17g，1.10mmol)、七水合磷酸钾(1.02g，3.00mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(120mg，0.15mmol)和二氧六环/水(v/v＝4/1，20mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(乙酸乙酯/石油醚(V/V)＝1/10-1/1)得到38A(0.507g，产率99％)。In a 50 mL reaction flask, compound 7A (0.48 g, 1.00 mmol), 4-hydroxy-2-methylphenylboronic acid (0.17 g, 1.10 mmol), potassium phosphate heptahydrate (1.02 g, 3.00 mmol), [1 ,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (120mg, 0.15mmol) and dioxane/water (v/v=4/1, 20mL), After three nitrogen replacements, the reaction was stirred at 90°C for 2 hours. 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 (ethyl acetate). /petroleum ether (V/V)=1/10-1/1) to give 38A (0.507 g, 99% yield).
LCMS m/z＝508.2[M+H] + LCMS m/z=508.2[M+H] +
第二步：反式-(E)-4-(二甲基氨基)-N-(3-((6-(4-羟基-2-甲基苯基)-1H-吲唑-4-基)氧基)环丁基)-N-甲基丁-2-烯酰胺(化合物38)The second step: trans-(E)-4-(dimethylamino)-N-(3-((6-(4-hydroxy-2-methylphenyl)-1H-indazol-4-yl )oxy)cyclobutyl)-N-methylbut-2-enamide (compound 38)
trans-(E)-4-(dimethylamino)-N-(3-((6-(4-hydroxy-2-methylphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-methylbut-2-enamidetrans-(E)-4-(dimethylamino)-N-(3-((6-(4-hydroxy-2-methylphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-methylbut-2- enamide
在50mL反应瓶中，加入化合物38A(0.507g，1.00mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用甲基叔丁基醚(10mL×3)洗，然后减压浓缩干，加入10mL乙腈溶解，加入二异丙基乙胺(0.367g，2.84mmol)搅拌10min，待用。In a 50 mL reaction flask, compound 38A (0.507 g, 1.00 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with methyl tert-butyl ether (10 mL×3), then concentrated to dryness under reduced pressure, dissolved in 10 mL of acetonitrile, added with diisopropylethylamine (0.367 g, 2.84 mmol) and stirred for 10 min ,stand-by.
将反式-4-二甲基胺基巴豆酸盐酸盐(0.165g，1.00mmol)和二异丙基乙胺(0.367mg，2.84mmol)溶于二氯甲烷(10mL)和乙腈(10mL)的混合溶液中，加入三吡咯烷基溴化鏻六氟磷酸盐(0.466g，1.00mmol)，室温搅拌20分钟。将此反应液缓慢滴加到上一步操作待用的乙腈溶液中，继续搅拌1h。加入20mL饱和碳酸氢钠水溶液，分液后，有机层用无水硫酸钠干燥后，减压浓缩，残留物柱层析纯化(DCM/MeOH/NH 3H 2O(V/V/V)＝50/1/0.5-25/1/0.25)得到化合物38(62mg,收率：25.24％)。 Trans-4-dimethylaminocrotonate hydrochloride (0.165 g, 1.00 mmol) and diisopropylethylamine (0.367 mg, 2.84 mmol) were dissolved in dichloromethane (10 mL) and acetonitrile (10 mL) To the mixed solution, tripyrrolidinophosphonium bromide hexafluorophosphate (0.466 g, 1.00 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was slowly added dropwise to the acetonitrile solution to be used in the previous operation, and stirring was continued for 1 h. 20 mL of saturated aqueous sodium bicarbonate solution was added, and after separation, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM/MeOH/NH 3 H 2 O (V/V/V)= 50/1/0.5-25/1/0.25) to obtain compound 38 (62 mg, yield: 25.24%).
LCMS m/z＝435.3[M+H] + LCMS m/z=435.3[M+H] +
1H NMR(400MHz,CD 3OD)δ8.07(d,1H),7.05(d,1H),6.95(s,1H),6.78–6.49(m,4H),6.21(s,1H),5.32–4.90(m,2H),3.15(d,2H),3.12–2.95(m,3H),2.89–2.69(m,2H),2.65–2.48(m,2H),2.26(s,6H),2.19(s,3H). 1 H NMR (400MHz, CD 3 OD) δ 8.07(d,1H), 7.05(d,1H), 6.95(s,1H), 6.78–6.49(m,4H), 6.21(s,1H), 5.32 –4.90(m, 2H), 3.15(d, 2H), 3.12 – 2.95(m, 3H), 2.89 – 2.69(m, 2H), 2.65 – 2.48(m, 2H), 2.26(s, 6H), 2.19 (s,3H).
实施例39：顺式-(E)-4-(二甲氨基)-N-((3-((6-(4-羟基-2-甲基苯基)-1H-吲唑-4-基)氧基)环丁基)-N-甲基丁-2-烯酰胺(化合物39)Example 39: cis-(E)-4-(dimethylamino)-N-((3-((6-(4-hydroxy-2-methylphenyl)-1H-indazol-4-yl )oxy)cyclobutyl)-N-methylbut-2-enamide (compound 39)
cis-(E)-4-(dimethylamino)-N-(3-((6-(4-hydroxy-2-methylphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-methylbut-2-enamidecis-(E)-4-(dimethylamino)-N-(3-((6-(4-hydroxy-2-methylphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-methylbut-2- enamide
Figure PCTCN2021117545-appb-000268
Figure PCTCN2021117545-appb-000268
Figure PCTCN2021117545-appb-000269
Figure PCTCN2021117545-appb-000269
第一步：顺式-(3-((6-(4-羟基-2-甲基苯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基)环丁基)(甲基)氨基甲酸叔丁酯(39A)The first step: cis-(3-((6-(4-hydroxy-2-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4- tert-butyl)oxy)cyclobutyl)(methyl)carbamate (39A)
cis-tert-butyl(3-((6-(4-hydroxy-2-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)(methyl)carbamatecis-tert-butyl(3-((6-(4-hydroxy-2-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)(methyl )carbamate
在100mL反应瓶中，依次加入顺式-N-[3-(6-溴-1-四氢吡喃-2-基-吲唑-4-基)氧基环丁基]-N-甲基-氨基甲酸叔丁酯(16A)(0.48g，1.0mmol)、4-羟基-2-甲基苯硼酸(0.18g，1.2mmol)、七水合磷酸钾(1.01g，3.0mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(82mg，0.1mmol)和二氧六环/水(v/v＝4/1，10mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(PE/EA＝3/1)得到39A(0.47g，产率92％)。In a 100mL reaction flask, add cis-N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]-N-methyl - tert-butyl carbamate (16A) (0.48 g, 1.0 mmol), 4-hydroxy-2-methylphenylboronic acid (0.18 g, 1.2 mmol), potassium phosphate heptahydrate (1.01 g, 3.0 mmol), [1, 1'-Bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (82 mg, 0.1 mmol) and dioxane/water (v/v=4/1, 10 mL), nitrogen After three replacements, the reaction was stirred at 90°C for 2 hours. 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 39A (0.47 g, 92% yield).
LCMS m/z＝508.3[M+H] + LCMS m/z=508.3[M+H] +
第二步：顺式-(E)-4-(二甲氨基)-N-((3-((6-(4-羟基-2-甲基苯基)-1H-吲唑-4-基)氧基)环丁基)-N-甲基丁-2-烯酰胺(化合物39)The second step: cis-(E)-4-(dimethylamino)-N-((3-((6-(4-hydroxy-2-methylphenyl)-1H-indazol-4-yl )oxy)cyclobutyl)-N-methylbut-2-enamide (compound 39)
cis-(E)-4-(dimethylamino)-N-(3-((6-(4-hydroxy-2-methylphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-methylbut-2-enamidecis-(E)-4-(dimethylamino)-N-(3-((6-(4-hydroxy-2-methylphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-methylbut-2- enamide
在50mL反应瓶中，加入化合物39A(0.3g，0.59mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用甲基叔丁基醚(10mL×3)洗，然后减压浓缩干，加入5mL乙腈溶解，加入二异丙基乙胺(0.46g，3.54mmol)搅拌10min，待用。In a 50 mL reaction flask, compound 39A (0.3 g, 0.59 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with methyl tert-butyl ether (10 mL×3), then concentrated to dryness under reduced pressure, dissolved in 5 mL of acetonitrile, added with diisopropylethylamine (0.46 g, 3.54 mmol) and stirred for 10 min ,stand-by.
将反式-4-二甲基胺基巴豆酸盐酸盐(0.098g，0.59mmol)和二异丙基乙胺(229mg，1.77mmol)溶于二氯甲烷(15mL)和乙腈(5mL)的混合溶液中，加入三吡咯烷基溴化鏻六氟磷酸盐(0.275g，0.59mmol)，室温搅拌20分钟。将此反应液缓慢滴加到上述待用的乙腈溶液中，继续搅拌1h。加入30mL饱和碳酸氢钠水溶液碱化，分液后，有机层用无水硫酸钠干燥后，减压浓缩，残留物柱层析纯化(DCM/MeOH/NH 3H 2O(V/V/V)＝50/1/0.5-25/1/0.25)，得到化合物39(148mg,收率：57.6％)。 Trans-4-dimethylaminocrotonate hydrochloride (0.098 g, 0.59 mmol) and diisopropylethylamine (229 mg, 1.77 mmol) were dissolved in dichloromethane (15 mL) and acetonitrile (5 mL) To the mixed solution, tripyrrolidinophosphonium bromide hexafluorophosphate (0.275 g, 0.59 mmol) was added, and the mixture was 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. Add 30 mL of saturated aqueous sodium bicarbonate solution to basify, after separation, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM/MeOH/NH 3 H 2 O (V/V/V )=50/1/0.5-25/1/0.25) to obtain compound 39 (148 mg, yield: 57.6%).
LCMS m/z＝435.2[M+H] + LCMS m/z=435.2[M+H] +
1H NMR(400MHz,CD 3OD)δ8.05(s,1H),7.06(d,1H),6.94(s,1H),6.81-6.69(m,2H),6.66(dd,1H),6.57(d,1H),6.33(s,1H),4.73–4.28(m,2H),3.15(dd,2H),3.06(d,3H),2.96-2.82(m,2H),2.60–2.33(m,2H),2.27(s,6H),2.21(s,3H). 1 H NMR (400MHz, CD 3 OD) δ 8.05(s, 1H), 7.06(d, 1H), 6.94(s, 1H), 6.81-6.69(m, 2H), 6.66(dd, 1H), 6.57 (d, 1H), 6.33 (s, 1H), 4.73–4.28 (m, 2H), 3.15 (dd, 2H), 3.06 (d, 3H), 2.96–2.82 (m, 2H), 2.60–2.33 (m ,2H),2.27(s,6H),2.21(s,3H).
实施例40：反式-(E)-4-(二甲氨基)-N-乙基-N-(3-((6-(4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)丁-2-烯酰胺(化合物40)Example 40: trans-(E)-4-(dimethylamino)-N-ethyl-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl) Oxy)cyclobutyl)but-2-enamide (Compound 40)
trans-(E)-4-(dimethylamino)-N-ethyl-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)but-2-enamidetrans-(E)-4-(dimethylamino)-N-ethyl-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)but-2-enamide
Figure PCTCN2021117545-appb-000270
Figure PCTCN2021117545-appb-000270
第一步：反式-叔丁基(3-((6-溴-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基)环丁基)(乙基)氨基甲酸酯(40B)The first step: trans-tert-butyl(3-((6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl ) (ethyl) carbamate (40B)
trans-tert-butyl(3-((6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)(ethyl)carbamatetrans-tert-butyl(3-((6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)(ethyl)carbamate
在50mL反应瓶中，依次加入反式-N-[3-(6-溴-1-四氢吡喃-2-基-吲唑-4-基)氧基环丁基]氨基甲酸叔丁酯(1C)(0.70g，1.50mmol)，碘乙烷(4.68g，30mmol)和DMF(20mL)，室温搅拌下加入氢化钠(1.2g，30mmol)，加完油浴50℃搅拌反应3小时，TLC监控反应完全。冰水冷却下加入乙酸乙酯(100mL)，加入饱和氯化铵水溶液(50mL)和水(50mL)，有机层饱和氯化钠溶液(50mL×2)洗涤，无水硫酸钠干燥，过滤，减压浓缩干。残余物柱层析分离纯化(石油醚/乙酸乙酯(V/V)＝5/1)，得到40B(0.65g，产率：87.6％)。In a 50mL reaction flask, add trans-N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]carbamic acid tert-butyl ester in turn (1C) (0.70 g, 1.50 mmol), iodoethane (4.68 g, 30 mmol) and DMF (20 mL), sodium hydride (1.2 g, 30 mmol) was added under stirring at room temperature, and the reaction was stirred at 50° C. for 3 hours after adding an oil bath, The reaction was complete as monitored by TLC. Under ice-water cooling, ethyl acetate (100 mL) was added, saturated aqueous ammonium chloride solution (50 mL) and water (50 mL) were added, the organic layer was washed with saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, reduced Pressed and concentrated to dryness. The residue was separated and purified by column chromatography (petroleum ether/ethyl acetate (V/V)=5/1) to obtain 40B (0.65 g, yield: 87.6%).
第二步：反式-叔丁基乙基(3-((6-(4-羟基苯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基)环丁基)氨基甲酸酯(40C)The second step: trans-tert-butylethyl (3-((6-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4- yl)oxy)cyclobutyl)carbamate (40C)
trans-tert-butyl ethyl(3-((6-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)carbamatetrans-tert-butyl ethyl(3-((6-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)carbamate
在50mL反应瓶中，依次加入上一步的化合物40B(0.65g，1.31mmol)、4-羟基苯硼酸(0.27g，1.97mmol)、七水合磷酸钾(1.33g，3.93mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(160mg，0.19mmol)和二氧六环/水(v/v＝4/1，15mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过柱层析分离纯化(石油醚/乙酸乙酯(V/V)＝5/1-1/1)得到40C(0.33g，产率49.4％)。In a 50 mL reaction flask, compound 40B (0.65 g, 1.31 mmol), 4-hydroxyphenylboronic acid (0.27 g, 1.97 mmol), potassium phosphate heptahydrate (1.33 g, 3.93 mmol), [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (160 mg, 0.19 mmol) and dioxane/water (v/v=4/1, 15 mL), nitrogen replacement After three times, the reaction was stirred at 90°C for 2 hours. Water (50 mL) was added to the reaction solution, followed by extraction 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 (petroleum ether/ Ethyl acetate (V/V)=5/1-1/1) gave 40C (0.33 g, 49.4% yield).
第三步：反式-(E)-4-(二甲氨基)-N-乙基-N-(3-((6-(4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)丁-2-烯酰胺(化合物40)The third step: trans-(E)-4-(dimethylamino)-N-ethyl-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl) Oxy)cyclobutyl)but-2-enamide (Compound 40)
trans-(E)-4-(dimethylamino)-N-ethyl-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)but-2-enamidetrans-(E)-4-(dimethylamino)-N-ethyl-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)but-2-enamide
在50mL反应瓶中，加入上一步的化合物40C(0.30g，0.59mmol)，二氯甲烷(3mL)，三氟乙酸(3mL)，室温搅拌反应5小时，TLC监控反应完全，减压浓缩干，加入二氯甲烷(3mL)，N,N-二异丙基乙胺(0.22g，1.77mmol)，搅拌溶解待用。In a 50 mL reaction flask, add compound 40C (0.30 g, 0.59 mmol) of the previous step, dichloromethane (3 mL), and trifluoroacetic acid (3 mL), and the reaction was stirred at room temperature for 5 hours. TLC monitored the completion of the reaction and concentrated to dryness under reduced pressure. Dichloromethane (3 mL), N,N-diisopropylethylamine (0.22 g, 1.77 mmol) were added, and the mixture was stirred and dissolved for later use.
在50mL反应瓶中，加入4-N,N-二甲氨基巴豆酸盐酸盐(0.13g，0.82mmol)，二氯甲烷(4mL)和三吡咯烷基溴化鏻六氟磷酸盐(0.35g，0.76mmol)，滴入N,N-二异丙基乙胺(0.22g，1.77mmol)，室温搅拌反应30分钟；冰水冷却下将该溶液加入到上一操作的反应液中，室温搅拌反应4小时；TLC监控反应完全，加入二氯甲烷10mL，反应液饱和碳酸氢钠(20mL×3)洗涤，有机层无水硫酸钠干燥，过滤，减压浓缩干，残余物通过硅胶柱层析分离纯化(二氯甲烷/甲醇(V/V)＝20/1)得到化合物40(0.13g，产率：50.2％)。In a 50 mL reaction flask, add 4-N,N-dimethylaminocrotonate hydrochloride (0.13 g, 0.82 mmol), dichloromethane (4 mL) and tripyrrolidinophosphonium bromide hexafluorophosphate (0.35 g , 0.76mmol), N,N-diisopropylethylamine (0.22g, 1.77mmol) was added dropwise, and the reaction was stirred at room temperature for 30 minutes; the solution was added to the reaction solution of the previous operation under ice-water cooling, and stirred at room temperature The reaction was completed for 4 hours; TLC monitored the completion of the reaction, 10 mL of dichloromethane was added, the reaction solution was washed with saturated sodium bicarbonate (20 mL×3), the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the residue was subjected to silica gel column chromatography Separation and purification (dichloromethane/methanol (V/V)=20/1) gave compound 40 (0.13 g, yield: 50.2%).
LCMS m/z＝435.2[M+H] + LCMS m/z=435.2[M+H] +
1H NMR(400MHz,DMSO-d 6)δ13.03(s,1H),9.55(s,1H),8.02(s,1H),7.56–7.44(m,2H),7.19(d,1H),6.93–6.81(m,2H),6.71–6.39(m,3H),5.14–5.03(m,1H),5.01–4.79(m,1H),3.48(q,2H),3.13(d,2H),2.80–2.67(m,2H),2.61–2.51(m,2H),2.21(s,6H),1.11(t,3H). 1 H NMR (400MHz, DMSO-d 6 )δ13.03(s,1H), 9.55(s,1H), 8.02(s,1H), 7.56–7.44(m,2H), 7.19(d,1H), 6.93–6.81 (m, 2H), 6.71–6.39 (m, 3H), 5.14–5.03 (m, 1H), 5.01–4.79 (m, 1H), 3.48 (q, 2H), 3.13 (d, 2H), 2.80–2.67(m, 2H), 2.61–2.51(m, 2H), 2.21(s, 6H), 1.11(t, 3H).
实施例41：反式-(E)-N-(环丙基甲基)-4-(二甲氨基)-N-(3-((6-(4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)丁-2-烯酰胺(化合物41)的三氟乙酸盐Example 41: trans-(E)-N-(cyclopropylmethyl)-4-(dimethylamino)-N-(3-((6-(4-hydroxyphenyl)-1H-indazole Trifluoroacetate salt of -4-yl)oxy)cyclobutyl)but-2-enamide (compound 41)
trans-(E)-N-(cyclopropylmethyl)-4-(dimethylamino)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)but-2-enamide；trifluoroacetic acidtrans-(E)-N-(cyclopropylmethyl)-4-(dimethylamino)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)but-2-enamide ;trifluoroacetic acid
Figure PCTCN2021117545-appb-000271
Figure PCTCN2021117545-appb-000271
第一步：反式-叔丁基(3-((6-溴-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基)环丁基)(环丙基甲基)氨基甲酸酯(41B)The first step: trans-tert-butyl(3-((6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl )(cyclopropylmethyl)carbamate (41B)
trans-tert-butyl(3-((6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)(cyclopropylmethyl)carbamatetrans-tert-butyl(3-((6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)(cyclopropylmethyl)carbamate
在50mL反应瓶中，依次加入反式-N-[3-(6-溴-1-四氢吡喃-2-基-吲唑-4-基)氧基环丁基]氨基甲酸叔丁酯(1C)(0.70g，1.50mmol)，溴甲基环丙烷(4.05g，30mmol)，碘化钠(0.22g，1.5mmol)和DMF(20mL)，室温搅拌下加入氢化钠(1.2g，30mmol)，加完油浴50℃搅拌反应3小时，TLC监控反应完全。冰水冷却下加入乙酸乙酯(100mL)，加入饱和氯化铵水溶液(50mL)和水(50mL)，有机层饱和氯化钠溶液(50mL×2)洗涤，无水硫酸钠干燥，过滤，减压浓缩干。残余物柱层析分离纯化(石油醚/乙酸乙酯(V/V)＝5/1)，得到41B(0.75g，产率：96.1％)。In a 50mL reaction flask, add trans-N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]carbamic acid tert-butyl ester in turn (1C) (0.70 g, 1.50 mmol), bromomethylcyclopropane (4.05 g, 30 mmol), sodium iodide (0.22 g, 1.5 mmol) and DMF (20 mL), sodium hydride (1.2 g, 30 mmol) was added with stirring at room temperature ), after adding the oil bath, the reaction was stirred at 50°C for 3 hours, and the reaction was completed by TLC monitoring. Under ice-water cooling, ethyl acetate (100 mL) was added, saturated aqueous ammonium chloride solution (50 mL) and water (50 mL) were added, the organic layer was washed with saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, reduced Pressed and concentrated to dryness. The residue was separated and purified by column chromatography (petroleum ether/ethyl acetate (V/V)=5/1) to obtain 41B (0.75 g, yield: 96.1%).
第二步：反式-叔丁基(环丙基甲基)(3-((6-(4-羟基苯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基)环丁基)氨基甲酸酯(41C)The second step: trans-tert-butyl(cyclopropylmethyl)(3-((6-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H- Indazol-4-yl)oxy)cyclobutyl)carbamate (41C)
trans-tert-butyl(cyclopropylmethyl)(3-((6-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)carbamatetrans-tert-butyl(cyclopropylmethyl)(3-((6-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)carbamate
在50mL反应瓶中，依次加入上一步的化合物41B(0.75g，1.44mmol)、4-羟基苯硼酸(0.30g，2.16mmol)、七水合磷酸钾(1.46g，4.32mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(171mg，0.21mmol)和二氧六环/水(v/v＝4/1，15mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过柱层析分离纯化(石油醚/乙酸乙酯(V/V)＝5/1-1/1)得到41C(0.65g，产率84.5％)。In a 50 mL reaction flask, compound 41B (0.75 g, 1.44 mmol), 4-hydroxyphenylboronic acid (0.30 g, 2.16 mmol), potassium phosphate heptahydrate (1.46 g, 4.32 mmol), [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (171 mg, 0.21 mmol) and dioxane/water (v/v=4/1, 15 mL), nitrogen replacement After three times, the reaction was stirred at 90°C for 2 hours. Water (50 mL) was added to the reaction solution, followed by extraction 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 (petroleum ether/ Ethyl acetate (V/V)=5/1-1/1) gave 41C (0.65 g, 84.5% yield).
第三步：反式-(E)-N-(环丙基甲基)-4-(二甲氨基)-N-(3-((6-(4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)丁-2-烯酰胺(化合物41)的三氟乙酸盐The third step: trans-(E)-N-(cyclopropylmethyl)-4-(dimethylamino)-N-(3-((6-(4-hydroxyphenyl)-1H-indazole Trifluoroacetate salt of -4-yl)oxy)cyclobutyl)but-2-enamide (compound 41)
trans-(E)-N-(cyclopropylmethyl)-4-(dimethylamino)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)but-2-enamide；trifluoroacetic acidtrans-(E)-N-(cyclopropylmethyl)-4-(dimethylamino)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)but-2-enamide ;trifluoroacetic acid
在50mL反应瓶中，加入上一步的化合物41C(0.30g，0.56mmol)，二氯甲烷(3mL)，三氟乙酸(3mL)，室温搅拌反应5小时，TLC监控反应完全，减压浓缩干，加入二氯甲烷(3mL)，N,N-二异丙基乙胺(0.22g，1.68mmol)，搅拌溶解，待用。In a 50 mL reaction flask, add compound 41C (0.30 g, 0.56 mmol) of the previous step, dichloromethane (3 mL), and trifluoroacetic acid (3 mL), and the reaction was stirred at room temperature for 5 hours. TLC monitored the completion of the reaction and concentrated to dryness under reduced pressure. Dichloromethane (3 mL), N,N-diisopropylethylamine (0.22 g, 1.68 mmol) were added, and the mixture was stirred to dissolve and set aside.
在50mL反应瓶中，加入4-N,N-二甲氨基巴豆酸盐酸盐(0.13g，0.78mmol)，二氯甲烷(4mL)，和三吡咯烷基溴化鏻六氟磷酸盐(0.34g，0.73mmol)，滴入N,N-二异丙基乙胺(0.22g，1.68mmol)，室温搅拌反应30分钟；冰水冷却下将该反应液加入上一操作的反应液中，室温搅拌反应4小时；TLC监控反应完全，加入二氯甲烷10ml，反应液饱和碳酸氢钠(20mL×3)洗涤，有机层无水硫酸钠干燥，过滤，减压浓缩干，残余物通过柱层析分离纯化(二氯甲烷/甲醇(V/V)＝20/1)，所得化合物制备HPLC(仪器：waters 2767制备液相；色谱柱:SunFire@Prep C18(19mm×150mm)；流动相组成：流动相A：乙腈，流动相B：水(含0.1％三氟乙酸))纯化后冻干得到化合物41的三氟乙酸盐(51mg，产率：13.1％)。In a 50 mL reaction flask, add 4-N,N-dimethylaminocrotonate hydrochloride (0.13 g, 0.78 mmol), dichloromethane (4 mL), and tripyrrolidinophosphonium bromide hexafluorophosphate (0.34 g, 0.73 mmol), N,N-diisopropylethylamine (0.22 g, 1.68 mmol) was added dropwise, and the reaction was stirred at room temperature for 30 minutes; the reaction solution was added to the reaction solution of the previous operation under ice-water cooling, and the room temperature The reaction was stirred for 4 hours; TLC monitored the completion of the reaction, 10 ml of dichloromethane was added, the reaction solution was washed with saturated sodium bicarbonate (20 mL×3), the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the residue was subjected to column chromatography Separation and purification (dichloromethane/methanol (V/V)=20/1), the obtained compound was prepared by HPLC (apparatus: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm×150mm); mobile phase composition: mobile phase Phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid)) after purification and lyophilization gave compound 41 as trifluoroacetic acid salt (51 mg, yield: 13.1%).
LCMS m/z＝461.3[M+H] + LCMS m/z=461.3[M+H] +
1H NMR(400MHz,DMSO-d 6)δ13.01(s,1H),9.54(s,1H),8.02(s,1H),7.55–7.45(m,2H),7.18(s,1H),6.90–6.81(m,2H),6.70–6.38(m,3H),5.16–5.02(m,1H),4.86–4.67(m,1H),3.36(d,2H),3.08(d,2H),2.85–2.73(m,2H),2.60–2.51(m,2H),2.18(s,6H),1.01–0.88(m,1H),0.52–0.39(m,2H),0.34–0.15(m,2H). 1 H NMR (400MHz, DMSO-d 6 )δ13.01(s,1H), 9.54(s,1H), 8.02(s,1H), 7.55–7.45(m,2H), 7.18(s,1H), 6.90–6.81 (m, 2H), 6.70–6.38 (m, 3H), 5.16–5.02 (m, 1H), 4.86–4.67 (m, 1H), 3.36 (d, 2H), 3.08 (d, 2H), 2.85–2.73 (m, 2H), 2.60–2.51 (m, 2H), 2.18 (s, 6H), 1.01–0.88 (m, 1H), 0.52–0.39 (m, 2H), 0.34–0.15 (m, 2H) ).
实施例42：反式-(2E)-4-(二甲基氨基)-N-(2-羟乙基)-N-[-3-[(6-(4-羟苯基)-1H-吲唑-4-基)氧基]环丁基]丁-2-烯酰胺(化合物42)Example 42: trans-(2E)-4-(dimethylamino)-N-(2-hydroxyethyl)-N-[-3-[(6-(4-hydroxyphenyl)-1H- Indazol-4-yl)oxy]cyclobutyl]but-2-enamide (Compound 42)
trans-(2E)-4-(dimethylamino)-N-(2-hydroxyethyl)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamidetrans-(2E)-4-(dimethylamino)-N-(2-hydroxyethyl)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2 -enamide
Figure PCTCN2021117545-appb-000272
Figure PCTCN2021117545-appb-000272
Figure PCTCN2021117545-appb-000273
Figure PCTCN2021117545-appb-000273
第一步：反式-叔丁基N-(2-(苄氧基)乙基)-N-[-3-[(6-溴-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基]氧基]环丁基]氨基甲酸酯(42A)The first step: trans-tert-butyl N-(2-(benzyloxy)ethyl)-N-[-3-[(6-bromo-1-(tetrahydro-2H-pyran-2-yl) )-1H-Indazol-4-yl]oxy]cyclobutyl]carbamate (42A)
trans-tert-butyl N-(2-(benzyloxy)ethyl)-N-[3-[(6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy]cyclobutyl]carbamatetrans-tert-butyl N-(2-(benzyloxy)ethyl)-N-[3-[(6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy ]cyclobutyl]carbamate
在50mL反应瓶中，依次加入反式-N-[3-(6-溴-1-四氢吡喃-2-基-吲唑-4-基)氧基环丁基]氨基甲酸叔丁酯(1C)(0.4g，0.86mmol)、二甲基亚砜(10mL)和氢化钠(0.17g，4.3mmol，60wt％)，加完后在25℃下搅拌10分钟，加入2-溴乙基苄醚(0.55g，2.58mmol)，升温至50℃搅拌反应2h。冷却至室温，用1mL水淬灭反应，反应液中加入乙酸乙酯(50mL)，然后依次用水(30mL×1)、饱和食盐水(30mL×1)洗涤，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过快速硅胶柱层析分离纯化(乙酸乙酯/石油醚(V/V)＝1/20-1/5)得到42A粗品(0.53g)。In a 50mL reaction flask, add trans-N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]carbamic acid tert-butyl ester in turn (1C) (0.4 g, 0.86 mmol), dimethyl sulfoxide (10 mL) and sodium hydride (0.17 g, 4.3 mmol, 60 wt%), stir at 25°C for 10 minutes after the addition, and add 2-bromoethyl Benzyl ether (0.55g, 2.58mmol) was heated to 50°C and stirred for 2h. Cool to room temperature, quench the reaction with 1 mL of water, add ethyl acetate (50 mL) to the reaction solution, then wash with water (30 mL×1) and saturated brine (30 mL×1) successively, and dry the organic layer with anhydrous sodium sulfate, Filtration, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by flash silica gel column chromatography (ethyl acetate/petroleum ether (V/V)=1/20-1/5) to obtain crude 42A (0.53 g).
第二步：反式-叔丁基N-(2-(苄氧基)乙基)-N-[3-[(6-(4-羟基苯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基]氧基]环丁基]氨基甲酸酯(42B)The second step: trans-tert-butyl N-(2-(benzyloxy)ethyl)-N-[3-[(6-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyridine) Furan-2-yl)-1H-indazol-4-yl]oxy]cyclobutyl]carbamate (42B)
trans-tert-butyl N-(2-(benzyloxy)ethyl)-N-[3-[(6-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy]cyclobutyl]carbamatetrans-tert-butyl N-(2-(benzyloxy)ethyl)-N-[3-[(6-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4 -yl)oxy]cyclobutyl]carbamate
在50mL反应瓶中，依次加入上一步的42A(0.53g)、4-羟基苯硼酸(0.16g，1.14mmol)、七水合磷酸钾(0.77g，2.28mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(73mg，0.089mmol)和二氧六环/水(v/v＝4/1，10mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(乙酸乙酯/石油醚(V/V)＝1/10-1/1)得到42B(0.4g，两步产率74％)。In a 50mL reaction flask, sequentially added 42A (0.53g), 4-hydroxyphenylboronic acid (0.16g, 1.14mmol), potassium phosphate heptahydrate (0.77g, 2.28mmol), [1,1'-bis( Diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (73mg, 0.089mmol) and dioxane/water (v/v=4/1, 10mL), after nitrogen replacement three times, in The reaction was stirred at 90°C for 2 hours. 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 (ethyl acetate). /petroleum ether (V/V)=1/10-1/1) to give 42B (0.4 g, 74% yield in two steps).
LCMS m/z＝614.4[M+H] + LCMS m/z=614.4[M+H] +
第三步：反式-叔丁基N-(2-羟乙基)-N-[-3-[[6-(4-羟苯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧]环丁基]氨基甲酸酯(42C)The third step: trans-tert-butyl N-(2-hydroxyethyl)-N-[-3-[[6-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2 -yl)-1H-indazol-4-yl)oxy]cyclobutyl]carbamate (42C)
trans-tert-butyl N-(2-hydroxyethyl)-N-[3-[(6-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy]cyclobutyl]carbamatetrans-tert-butyl N-(2-hydroxyethyl)-N-[3-[(6-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl) oxy]cyclobutyl]carbamate
将化合物42B(0.4g,0.65mmol)溶于甲醇(10ml)中，加入钯碳(10％wt,0.35g)，氢气置换三次，室温搅拌过夜。过滤，滤液减压浓缩，得到42C(0.3g，产率88％)。Compound 42B (0.4 g, 0.65 mmol) was dissolved in methanol (10 ml), palladium on carbon (10% wt, 0.35 g) was added, hydrogen was replaced three times, and the mixture was stirred at room temperature overnight. Filtration and concentration of the filtrate under reduced pressure gave 42C (0.3 g, 88% yield).
LCMS m/z＝524.3[M+H] + LCMS m/z=524.3[M+H] +
第四步：反式(2E)-4-(二甲基氨基)-N-(2-羟乙基)-N-[-3-[(6-(4-羟苯基)-1H-吲唑-4-基)氧基]环丁基]丁-2-烯酰胺(化合物42)The fourth step: trans (2E)-4-(dimethylamino)-N-(2-hydroxyethyl)-N-[-3-[(6-(4-hydroxyphenyl)-1H-indium Azol-4-yl)oxy]cyclobutyl]but-2-enamide (Compound 42)
trans-(2E)-4-(dimethylamino)-N-(2-hydroxyethyl)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamidetrans-(2E)-4-(dimethylamino)-N-(2-hydroxyethyl)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2 -enamide
在50mL反应瓶中，加入化合物42C(0.14g，0.27mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，4mL)，然后在35℃下搅拌反应3小时。反应液减压浓缩干，残留物用甲基叔丁基醚(10mL×3)洗，然后减压浓缩干，加入5mL乙腈溶解，加入二异丙基乙胺(0.35g，2.7mmol)搅拌10min，待用。In a 50 mL reaction flask, compound 42C (0.14 g, 0.27 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 4 mL) were added, and the reaction was stirred at 35°C for 3 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with methyl tert-butyl ether (10 mL×3), then concentrated to dryness under reduced pressure, dissolved in 5 mL of acetonitrile, added with diisopropylethylamine (0.35 g, 2.7 mmol) and stirred for 10 min ,stand-by.
将反式-4-二甲基胺基巴豆酸盐酸盐(0.044g，0.27mmol)和二异丙基乙胺(83mg，0.64mmol)溶于二氯甲烷(5mL)和乙腈(5mL)的混合溶液中，加入三吡咯烷基溴化鏻六氟磷酸盐(0.126g，0.27mmol)，室温搅拌20分钟。将此反应液缓慢滴加到上一步操作待用的乙腈溶液中，继续搅拌1h。加入10mL饱和碳酸氢钠水溶液，分液后，有机层用无水硫酸钠干燥后，减压浓缩，残留物柱层析纯化(DCM/MeOH/NH 3H 2O(V/V/V)＝50/1/0.5-25/1/0.25)，得到化合物42(15mg,收率：13％)。 Trans-4-dimethylaminocrotonate hydrochloride (0.044 g, 0.27 mmol) and diisopropylethylamine (83 mg, 0.64 mmol) were dissolved in dichloromethane (5 mL) and acetonitrile (5 mL) To the mixed solution, tripyrrolidinophosphonium bromide hexafluorophosphate (0.126 g, 0.27 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was slowly added dropwise to the acetonitrile solution to be used in the previous operation, and stirring was continued for 1 h. 10 mL of saturated aqueous sodium bicarbonate solution was added, and after separation, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM/MeOH/NH 3 H 2 O (V/V/V)= 50/1/0.5-25/1/0.25) to obtain compound 42 (15 mg, yield: 13%).
LCMS m/z＝451.3[M+H] + LCMS m/z=451.3[M+H] +
1H NMR(400MHz,CD 3OD)δ8.05(s,1H),7.48(d,2H),7.21(s,1H),6.87(d,2H),6.82–6.51(m,2H),6.50(s,1H),5.17-5.01(m,1H),5.00-4.85(m,1H),3.75-3.55(m,4H),3.15(d,2H),2.92–2.77(m,2H),2.72-2.60(m,2H),2.27(s,6H). 1 H NMR (400MHz, CD 3 OD) δ 8.05(s, 1H), 7.48(d, 2H), 7.21(s, 1H), 6.87(d, 2H), 6.82–6.51(m, 2H), 6.50 (s, 1H), 5.17-5.01(m, 1H), 5.00-4.85(m, 1H), 3.75-3.55(m, 4H), 3.15(d, 2H), 2.92-2.77(m, 2H), 2.72 -2.60(m, 2H), 2.27(s, 6H).
实施例43：反式-(E)-4-(二甲基氨基)-N-(3-((6-(4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)-N-(3-甲氧基丙基)-2-烯酰胺(化合物43)Example 43: trans-(E)-4-(dimethylamino)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cycle Butyl)-N-(3-methoxypropyl)-2-enamide (compound 43)
trans-(E)-4-(dimethylamino)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-(3-methoxypropyl)but-2-enamidetrans-(E)-4-(dimethylamino)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-(3-methoxypropyl)but-2 -enamide
Figure PCTCN2021117545-appb-000274
Figure PCTCN2021117545-appb-000274
Figure PCTCN2021117545-appb-000275
Figure PCTCN2021117545-appb-000275
第一步：反式-(3-((6-溴-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基)环丁基)(3-甲氧基丙基)氨基甲酸叔丁酯(43A)The first step: trans-(3-((6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)(3 -Methoxypropyl) tert-butyl carbamate (43A)
trans-tert-butyl(3-((6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)(3-methoxypropyl)carbamatetrans-tert-butyl(3-((6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)(3-methoxypropyl)carbamate
称取化合物1C(0.600g,1.29mmol)，用二甲亚砜(25mL)溶解于100mL单口圆底烧瓶中，称取氢化钠(155mg,3.87mmol)加入反应瓶中，加入3-溴丙基甲基醚(0.328g,2.14mmol)和无水碘化钠(16mg,0.11mmol)，加热至50℃搅拌反应1小时。将反应液向盛有饱和氯化铵水溶液(60mL)的250mL单口圆底烧瓶中滴加，滴加完毕加入水(30mL)，用乙酸乙酯(50mL x3)萃取，合并有机相，依次用水(50mL)、饱和食盐水(50mL)洗涤一次，无水硫酸钠干燥。过滤，减压浓缩，残留物柱层析纯化得43A(0.675g,收率：97.2％)。Weigh compound 1C (0.600g, 1.29mmol), dissolve it in a 100mL single-neck round bottom flask with dimethyl sulfoxide (25mL), weigh sodium hydride (155mg, 3.87mmol) into the reaction flask, add 3-bromopropyl Methyl ether (0.328 g, 2.14 mmol) and anhydrous sodium iodide (16 mg, 0.11 mmol) were heated to 50°C and stirred for 1 hour. The reaction solution was added dropwise to a 250mL single-necked round-bottomed flask filled with saturated aqueous ammonium chloride solution (60mL), water (30mL) was added after the dropwise addition, extracted with ethyl acetate (50mL×3), the organic phases were combined, followed by water ( 50 mL), saturated brine (50 mL), washed once, and dried over anhydrous sodium sulfate. Filtration, concentration under reduced pressure, and purification of the residue by column chromatography gave 43A (0.675 g, yield: 97.2%).
LCMS m/z＝538.2[M+H] + LCMS m/z=538.2[M+H] +
第二步：反式-(3-((6-溴-(4-羟基苯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基)环丁基)(3-甲氧基丙基)氨基甲酸叔丁酯(43B)The second step: trans-(3-((6-bromo-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxygen yl)cyclobutyl)(3-methoxypropyl)carbamate (43B)
trans-tert-butyl(3-((6-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)(3-methoxypropyl)carbamatetrans-tert-butyl(3-((6-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)(3-methoxypropyl)carbamate
在50mL反应瓶中，依次加入43A(0.675g，1.25mmol)、4-羟基-2-甲基苯硼酸(0.26g，1.88mmol)、七水合磷酸钾(2.451g，6.25mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(152mg，0.188mmol)和二氧六环/水(v/v＝4/1，25mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化得到43B(0.64g，产率92.81％)。In a 50mL reaction flask, 43A (0.675g, 1.25mmol), 4-hydroxy-2-methylphenylboronic acid (0.26g, 1.88mmol), potassium phosphate heptahydrate (2.451g, 6.25mmol), [1, 1'-Bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (152 mg, 0.188 mmol) and dioxane/water (v/v=4/1, 25 mL), nitrogen After three replacements, the reaction was stirred at 90°C for 2 hours. 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 to obtain 43B (0.64 g, yield 92.81%).
LCMS m/z＝552.3[M+H] + LCMS m/z=552.3[M+H] +
第三步：反式-(E)-4-(二甲基氨基)-N-(3-((6-(4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)-N-(3-甲氧基丙基)-2-烯酰胺(化合物43)The third step: trans-(E)-4-(dimethylamino)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy) ring Butyl)-N-(3-methoxypropyl)-2-enamide (compound 43)
trans-(E)-4-(dimethylamino)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-(3-methoxypropyl)but-2-enamidetrans-(E)-4-(dimethylamino)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-(3-methoxypropyl)but-2 -enamide
在50mL反应瓶中，加入化合物43B(0.64g，1.16mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，14mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用甲基叔丁基醚(10mL×3)洗，然后减压浓缩干，加入10mL乙腈溶解，加入二异丙基乙胺(0.367g，2.84mmol)搅拌10min，待用。In a 50 mL reaction flask, compound 43B (0.64 g, 1.16 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 14 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with methyl tert-butyl ether (10 mL×3), then concentrated to dryness under reduced pressure, dissolved in 10 mL of acetonitrile, added with diisopropylethylamine (0.367 g, 2.84 mmol) and stirred for 10 min ,stand-by.
将反式-4-二甲基胺基巴豆酸盐酸盐(0.193g，1.16mmol)和二异丙基乙胺(0.367mg，2.84mmol)溶于二氯甲烷(10mL)和乙腈(10mL)的混合溶液中，加入三吡咯烷基溴化鏻六氟磷酸盐(0.541g，1.16mmol)，室温搅拌20分钟。将此反应液缓慢滴加到上一步操作待用的乙腈溶液中，继续搅拌1h。加入20mL饱和碳酸氢钠水溶液，分液后，有机层用无水硫酸钠干燥后，减压浓缩，残留物柱层析纯化(DCM/MeOH/NH 3H 2O(V/V/V)＝50/1/0.5-25/1/0.25)得到化合物43(284mg,收率：51.16％)。 Trans-4-dimethylaminocrotonate hydrochloride (0.193 g, 1.16 mmol) and diisopropylethylamine (0.367 mg, 2.84 mmol) were dissolved in dichloromethane (10 mL) and acetonitrile (10 mL) To the mixed solution, tripyrrolidinophosphonium bromide hexafluorophosphate (0.541 g, 1.16 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was slowly added dropwise to the acetonitrile solution to be used in the previous operation, and stirring was continued for 1 h. 20 mL of saturated aqueous sodium bicarbonate solution was added, and after separation, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM/MeOH/NH 3 H 2 O (V/V/V)= 50/1/0.5-25/1/0.25) to obtain compound 43 (284 mg, yield: 51.16%).
LCMS m/z＝479.3[M+H] + LCMS m/z=479.3[M+H] +
1H NMR(400MHz,CD 3OD)δ8.05(s,1H),7.59–7.40(m,2H),7.21(s,1H),6.91–6.84(m,2H),6.83–6.41(m,3H),5.15–4.84(m,2H),3.66–3.50(m,2H),3.49–3.38(m,2H),3.33(s,3H),3.23–3.03(m,2H),2.90–2.76(m,2H),2.74–2.56(m,2H),2.26(s,6H),1.89–1.72(m,2H). 1 H NMR (400MHz, CD 3 OD) δ8.05(s, 1H), 7.59-7.40(m, 2H), 7.21(s, 1H), 6.91-6.84(m, 2H), 6.83-6.41(m, 3H), 5.15–4.84 (m, 2H), 3.66–3.50 (m, 2H), 3.49–3.38 (m, 2H), 3.33 (s, 3H), 3.23–3.03 (m, 2H), 2.90–2.76 ( m, 2H), 2.74–2.56 (m, 2H), 2.26 (s, 6H), 1.89–1.72 (m, 2H).
实施例44：反式-(E)-4-(二甲基氨基)-N-((3-((6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-4-基)氧基]环丁基)-N-(2-甲氧基乙基)丁-2-烯酰胺(化合物44)Example 44: trans-(E)-4-(dimethylamino)-N-((3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indium Azol-4-yl)oxy]cyclobutyl)-N-(2-methoxyethyl)but-2-enamide (Compound 44)
trans-(E)-4-(dimethylamino)-N-(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-(2-methoxyethyl)but-2-enamidetrans-(E)-4-(dimethylamino)-N-(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N- (2-methoxyethyl)but-2-enamide
Figure PCTCN2021117545-appb-000276
Figure PCTCN2021117545-appb-000276
第一步：反式-(3-((6-(2-乙基-5-氟-4-羟基苯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-yl)氧基)环丁基)(2-甲氧基乙基)氨基甲酸叔丁酯(44A)The first step: trans-(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indium oxazol-4-yl)oxy)cyclobutyl)(2-methoxyethyl)carbamate (44A)
trans-tert-butyl(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)(2-methoxyethyl)carbamatetrans-tert-butyl(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy) cyclobutyl)(2-methoxyethyl)carbamate
在100mL反应瓶中，依次加入化合物34A(0.52g，1.0mmol)、5-乙基-2-氟-4-(4,4,5,5-四甲基-1,3-二氧戊环-2-基)苯酚(0.32g，1.2mmol)、七水合磷酸钾(1.01g，3.0mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(82mg，0.1mmol)和二氧 六环/水(v/v＝4/1，10mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(PE/EA＝3/1)得到44A(0.45g，产率77％)。In a 100 mL reaction flask, compound 34A (0.52 g, 1.0 mmol), 5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3-dioxolane) were sequentially added -2-yl)phenol (0.32 g, 1.2 mmol), potassium phosphate heptahydrate (1.01 g, 3.0 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane The complex (82 mg, 0.1 mmol) and dioxane/water (v/v=4/1, 10 mL) were replaced with nitrogen three times, and the reaction was stirred at 90° C. for 2 hours. 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 44A (0.45 g, 77% yield).
LCMS m/z＝584.3[M+H] + LCMS m/z=584.3[M+H] +
第二步：反式-(E)-4-(二甲基氨基)-N-((3-((6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-4-基)氧基]环丁基)-N-(2-甲氧基乙基)丁-2-烯酰胺(化合物44)The second step: trans-(E)-4-(dimethylamino)-N-(((3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indium Azol-4-yl)oxy]cyclobutyl)-N-(2-methoxyethyl)but-2-enamide (Compound 44)
trans-(E)-4-(dimethylamino)-N-(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-(2-methoxyethyl)but-2-enamidetrans-(E)-4-(dimethylamino)-N-(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N- (2-methoxyethyl)but-2-enamide
在50mL反应瓶中，加入化合物44A(0.2g，0.34mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用甲基叔丁基醚(10mL×3)洗，然后减压浓缩干，加入5mL乙腈溶解，加入二异丙基乙胺(0.266g，2.06mmol)搅拌10min，待用。In a 50 mL reaction flask, compound 44A (0.2 g, 0.34 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with methyl tert-butyl ether (10 mL×3), then concentrated to dryness under reduced pressure, dissolved in 5 mL of acetonitrile, added with diisopropylethylamine (0.266 g, 2.06 mmol) and stirred for 10 min ,stand-by.
将反式-4-二甲基胺基巴豆酸盐酸盐(0.057g，0.34mmol)和二异丙基乙胺(132mg，1.02mmol)溶于二氯甲烷(15mL)和乙腈(5mL)的混合溶液中，加入三吡咯烷基溴化鏻六氟磷酸盐(0.159g，0.34mmol)，室温搅拌20分钟。将此反应液缓慢滴加到上述待用的乙腈溶液中，继续搅拌1h。加入30mL饱和碳酸氢钠水溶液碱化，分液后，有机层用无水硫酸钠干燥后，减压浓缩，残留物柱层析纯化(DCM/MeOH/NH 3H 2O(V/V/V)＝50/1/0.5-25/1/0.25)，得到化合物44(60mg,收率：35％)。 Trans-4-dimethylaminocrotonate hydrochloride (0.057 g, 0.34 mmol) and diisopropylethylamine (132 mg, 1.02 mmol) were dissolved in dichloromethane (15 mL) and acetonitrile (5 mL) To the mixed solution, tripyrrolidinophosphonium bromide hexafluorophosphate (0.159 g, 0.34 mmol) was added, and the mixture was 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. Add 30 mL of saturated aqueous sodium bicarbonate solution to basify, after separation, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM/MeOH/NH 3 H 2 O (V/V/V )=50/1/0.5-25/1/0.25) to obtain compound 44 (60 mg, yield: 35%).
LCMS m/z＝511.3[M+H] + LCMS m/z=511.3[M+H] +
1H NMR(400MHz,CD 3OD)δ8.09(s,1H),7.00–6.80(m,3H),6.80-6.47(m,2H),6.21(s,1H),5.10-4.81(m,2H),3.67(t,2H),3.57-3.44(m,2H),3.33(s,3H),3.16(d,2H),2.90-2.75(m,2H),2.68–2.56(m,2H),2.52(q,2H),2.28(s,6H),1.06(t,3H). 1 H NMR (400MHz, CD 3 OD) δ8.09(s, 1H), 7.00-6.80(m, 3H), 6.80-6.47(m, 2H), 6.21(s, 1H), 5.10-4.81(m, 2H), 3.67(t, 2H), 3.57-3.44(m, 2H), 3.33(s, 3H), 3.16(d, 2H), 2.90-2.75(m, 2H), 2.68–2.56(m, 2H) ,2.52(q,2H),2.28(s,6H),1.06(t,3H).
实施例45：反式-(E)-4-(二甲基氨基)-N-((3-((6-(4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)-N-((1-甲基-1H-咪唑-5-基)甲基)丁-2-烯酰胺(化合物45)的乙酸盐Example 45: trans-(E)-4-(dimethylamino)-N-((3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy) Cyclobutyl)-N-((1-methyl-1H-imidazol-5-yl)methyl)but-2-enamide (compound 45) acetate salt
trans-(E)-4-(dimethylamino)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-((1-methyl-1H-imidazol-5-yl)methyl)but-2-enamide；acetic acidtrans-(E)-4-(dimethylamino)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-((1-methyl-1H- imidazol-5-yl)methyl)but-2-enamide;acetic acid
Figure PCTCN2021117545-appb-000277
Figure PCTCN2021117545-appb-000277
Figure PCTCN2021117545-appb-000278
Figure PCTCN2021117545-appb-000278
第一步：5-(氯甲基)-1-甲基-1H-咪唑(45B)The first step: 5-(chloromethyl)-1-methyl-1H-imidazole (45B)
5-(chloromethyl)-1-methyl-1H-imidazole5-(chloromethyl)-1-methyl-1H-imidazole
在50mL反应瓶中，依次加入(1-甲基-1H-咪唑-5-基)甲醇(45A)(112mg，1mmol)，二氯亚砜(10mL),在60℃下搅拌反应2小时,减压浓缩，得到45B粗品(130mg)，直接用于下一步反应。In a 50 mL reaction flask, (1-methyl-1H-imidazol-5-yl) methanol (45A) (112 mg, 1 mmol) and thionyl chloride (10 mL) were added in sequence, and the reaction was stirred at 60 ° C for 2 hours, and then reduced Concentrated under pressure to obtain crude 45B (130 mg), which was directly used in the next reaction.
1H NMR(400MHz,DMSO-d6)δ9.26(s,1H),7.84(s,1H),5.04(s,2H),3.89(s,3H). 1 H NMR (400MHz, DMSO-d6) δ9.26(s,1H), 7.84(s,1H), 5.04(s,2H), 3.89(s,3H).
第二步：反式-叔丁基(-3-((6-溴-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基)环丁基)((1-甲基1H-咪唑-5-基)甲基氨基甲酸酯(45C)The second step: trans-tert-butyl(-3-((6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutane base)((1-methyl 1H-imidazol-5-yl)methylcarbamate (45C)
trans-tert-butyl(3-((6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)((1-methyl-1H-imidazol-5-yl)methyl)carbamatetrans-tert-butyl(3-((6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)((1-methyl-1H-imidazol- 5-yl)methyl)carbamate
在50mL反应瓶中，依次加入反式-N-[3-(6-溴-1-四氢吡喃-2-基-吲唑-4-基)氧基环丁基]氨基甲酸叔丁酯(1C)(0.3g，0.65mmol)、四氢呋喃(50mL)和氢化钠(0.28g，7.05mmol，60wt％)，加完后在25℃下搅拌30分钟，缓慢滴加5-(氯甲基)-1-甲基-1H-咪唑(45B)(130mg)并在室温下搅拌反应1.2h。反应液中加入乙酸乙酯(50mL)，然后依次用水(30mL×1)、饱和食盐水(30mL×1)洗涤，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(PE/EA＝1/1)得到45C(0.26g，产率72％)。In a 50mL reaction flask, add trans-N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]carbamic acid tert-butyl ester in turn (1C) (0.3 g, 0.65 mmol), tetrahydrofuran (50 mL) and sodium hydride (0.28 g, 7.05 mmol, 60 wt %), after the addition, the mixture was stirred at 25 °C for 30 minutes, and 5-(chloromethyl) was slowly added dropwise. -1-Methyl-1H-imidazole (45B) (130 mg) and the reaction was stirred at room temperature for 1.2 h. Ethyl acetate (50 mL) was added to the reaction solution, then washed with water (30 mL×1) and saturated brine (30 mL×1) successively, the organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was passed through a column Purification by chromatography (PE/EA=1/1) gave 45C (0.26 g, 72% yield).
第三步：反式-叔丁基(3-((6-(4-羟基苯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基)环丁基)((1-甲基-1H-咪唑-5-基)甲基氨基甲酸酯(45D)The third step: trans-tert-butyl (3-((6-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl) Oxy)cyclobutyl)((1-methyl-1H-imidazol-5-yl)methylcarbamate (45D)
trans-tert-butyl(3-((6-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)((1-methyl-1H-imidazol-5-yl)methyl)carbamatetrans-tert-butyl(3-((6-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)((1-methyl- 1H-imidazol-5-yl)methyl)carbamate
在50mL反应瓶中，依次加入45C(224mg，0.4mmol)、4-羟基苯硼酸(0.08g，0.58mmol)、七水合磷酸钾(0.243g，0.720mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(20mg，0.024mmol)和二氧六环/水(v/v＝4/1，10mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(PE/EA＝3/1)得到45D，淡黄色固体(130mg，产率56.7％)。In a 50 mL reaction flask, 45C (224 mg, 0.4 mmol), 4-hydroxyphenylboronic acid (0.08 g, 0.58 mmol), potassium phosphate heptahydrate (0.243 g, 0.720 mmol), [1,1'-bis(di(bis(bis(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di(di)))”) however were added to a 50 mL reaction flask. Phenylphosphine)ferrocene]dichloropalladium dichloromethane complex (20mg, 0.024mmol) and dioxane/water (v/v=4/1, 10mL), after nitrogen replacement three times, at 90 The reaction was stirred at °C for 2 hours. 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 45D as a pale yellow solid (130 mg, 56.7% yield).
LCMS m/z＝574.3[M+H] + LCMS m/z=574.3[M+H] +
第四步：反式-(E)-4-(二甲基氨基)-N-((3-((6-(4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)-N-((1-甲基-1H-咪唑-5-基)甲基)丁-2-烯酰胺(化合物45)的乙酸盐The fourth step: trans-(E)-4-(dimethylamino)-N-((3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy) Cyclobutyl)-N-((1-methyl-1H-imidazol-5-yl)methyl)but-2-enamide (compound 45) acetate salt
trans-(E)-4-(dimethylamino)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-((1-methyl-1H-imidazol-5-yl)methyl)but-2-enamide；acetic acidtrans-(E)-4-(dimethylamino)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-((1-methyl-1H- imidazol-5-yl)methyl)but-2-enamide;acetic acid
在50mL反应瓶中，加入45D(0.12g，0.21mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用甲基叔丁基醚(10mL×3)洗，然后减压浓缩干，加入5mL乙腈溶解，加入二异丙基乙胺(0.35g，2.7mmol)搅拌10min，待用。In a 50 mL reaction flask, 45D (0.12 g, 0.21 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with methyl tert-butyl ether (10 mL×3), then concentrated to dryness under reduced pressure, dissolved in 5 mL of acetonitrile, added with diisopropylethylamine (0.35 g, 2.7 mmol) and stirred for 10 min ,stand-by.
将反式-4-二甲基胺基巴豆酸盐酸盐(0.041g，0.25mmol)和二异丙基乙胺(83mg，0.64mmol)溶于二氯甲烷(5mL)和乙腈(5mL)的混合溶液中，加入三吡咯烷基溴化鏻六氟磷酸盐(0.12g，0.25mmol)，室温搅拌20分钟。将此反应液缓慢滴加到上述待用的乙腈溶液中，继续搅拌1h。加入10mL饱和碳酸氢钠水溶液碱化，分液后，有机层用无水硫酸钠干燥后，减压浓缩，残留物通过制备液相(仪器：waters 2767制备液相；色谱柱:SunFire@Prep C18(19mm×150mm)；流动相组成：流动相A：乙腈流动相B：水(含5mM乙酸铵))分离纯化后冻干得到化合物45的乙酸盐(23mg，产率19.6％)。Trans-4-dimethylaminocrotonate hydrochloride (0.041 g, 0.25 mmol) and diisopropylethylamine (83 mg, 0.64 mmol) were dissolved in dichloromethane (5 mL) and acetonitrile (5 mL) To the mixed solution, tripyrrolidinophosphonium bromide hexafluorophosphate (0.12 g, 0.25 mmol) was added, and the mixture was 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. Add 10mL saturated aqueous sodium bicarbonate solution to alkalize, after liquid separation, the organic layer is dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the residue is prepared by preparative liquid phase (apparatus: 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)) after separation and purification, lyophilized to obtain the acetate salt of compound 45 (23 mg, yield 19.6%).
LCMS m/z＝501.2[M+H] + LCMS m/z=501.2[M+H] +
实施例46：顺式-N-(2-(二甲基氨基)乙基)-2-氟-N-(3-((6-(4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)丙烯酰胺(化合物46)Example 46: cis-N-(2-(dimethylamino)ethyl)-2-fluoro-N-(3-((6-(4-hydroxyphenyl)-1H-indazole-4- yl)oxy)cyclobutyl)acrylamide (Compound 46)
cis-N-(2-(dimethylamino)ethyl)-2-fluoro-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)acrylamidecis-N-(2-(dimethylamino)ethyl)-2-fluoro-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)acrylamide
Figure PCTCN2021117545-appb-000279
Figure PCTCN2021117545-appb-000279
第一步：顺式-叔丁基(3-((6-溴-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基)环丁基)(2-(二甲基氨基)乙基)氨基甲酸酯(46A)The first step: cis-tert-butyl (3-((6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl )(2-(dimethylamino)ethyl)carbamate (46A)
cis-tert-butyl(3-((6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)(2-(dimethylamino)ethyl)carbamatecis-tert-butyl(3-((6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)(2-(dimethylamino)ethyl)carbamate
在50mL反应瓶中，依次加入顺式-N-[3-(6-溴-1-四氢吡喃-2-基-吲唑-4-基)氧基环丁基]氨基甲酸叔丁酯(2C)(0.72g，1.54mmol)、二甲基亚砜(15mL)，碘化钠(0.12g,0.77mmol)和氢化钠(1.23g，30.8mmol，60wt％)，加完后在25℃下搅拌10分钟，加入2-氯乙基二甲胺(0.66g，6.16mmol)，升温至50℃搅拌反应3h。冷却至室温，用1mL水淬灭反应，反应液中加入乙酸乙酯(50mL)，然后依次用水(30mL×1)、饱和食盐水(30mL×1)洗涤，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(DCM/MeOH(V/V)＝100/0-100/5)得到46A(0.48g，收率：58％)。In a 50mL reaction flask, add cis-N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]carbamic acid tert-butyl ester in turn (2C) (0.72 g, 1.54 mmol), dimethyl sulfoxide (15 mL), sodium iodide (0.12 g, 0.77 mmol) and sodium hydride (1.23 g, 30.8 mmol, 60 wt%) at 25°C after addition Under stirring for 10 minutes, 2-chloroethyldimethylamine (0.66 g, 6.16 mmol) was added, the temperature was raised to 50° C. and the reaction was stirred for 3 h. Cool to room temperature, quench the reaction with 1 mL of water, add ethyl acetate (50 mL) to the reaction solution, then wash with water (30 mL×1) and saturated brine (30 mL×1) successively, and dry the organic layer with anhydrous sodium sulfate, Filtration, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (DCM/MeOH (V/V)=100/0-100/5) to obtain 46A (0.48 g, yield: 58%).
LCMS m/z＝537.1/539.1[M+H] + LCMS m/z=537.1/539.1[M+H] +
第二步：顺式-叔丁基N-(2-(二甲基氨基)乙基)-N-[3-[[6-(4-羟基苯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基]环丁基]氨基甲酸酯(46B)The second step: cis-tert-butyl N-(2-(dimethylamino)ethyl)-N-[3-[[6-(4-hydroxyphenyl)-1-(tetrahydro-2H- Pyran-2-yl)-1H-indazol-4-yl)oxy]cyclobutyl]carbamate (46B)
cis-tert-butyl N-(2-(dimethylamino)ethyl)-N-[3-[(6-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy]cyclobutyl]carbamatecis-tert-butyl N-(2-(dimethylamino)ethyl)-N-[3-[(6-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4 -yl)oxy]cyclobutyl]carbamate
在50mL反应瓶中，依次加入46A(0.48g,0.89mmol)、4-羟基苯硼酸(0.18g，1.33mmol)、七水合磷酸钾(0.9g，2.67mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(73mg，0.089mmol)和二氧六环/水(v/v＝4/1，10mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(DCM/MeOH(V/V)＝100/0-100/5)得到46B(0.49g，产率98％)。In a 50mL reaction flask, 46A (0.48g, 0.89mmol), 4-hydroxyphenylboronic acid (0.18g, 1.33mmol), potassium phosphate heptahydrate (0.9g, 2.67mmol), [1,1'-bis( Diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (73mg, 0.089mmol) and dioxane/water (v/v=4/1, 10mL), after nitrogen replacement three times, in The reaction was stirred at 90°C for 2 hours. Water (50 mL) was added to the reaction solution, followed by extraction 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 (DCM/MeOH). (V/V)=100/0-100/5) to give 46B (0.49 g, 98% yield).
LCMS m/z＝551.4[M+H] + LCMS m/z=551.4[M+H] +
第三步：顺式-N-(2-(二甲基氨基)乙基)-2-氟-N-(3-((6-(4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)丙烯酰胺(化合物46)The third step: cis-N-(2-(dimethylamino)ethyl)-2-fluoro-N-(3-((6-(4-hydroxyphenyl)-1H-indazole-4- yl)oxy)cyclobutyl)acrylamide (Compound 46)
cis-N-(2-(dimethylamino)ethyl)-2-fluoro-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)acrylamidecis-N-(2-(dimethylamino)ethyl)-2-fluoro-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)acrylamide
在50mL反应瓶中，加入化合物46B(0.14g，0.25mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用甲基叔丁基醚(10mL×3)洗，然后减压浓缩干，加入5mL乙腈溶解，加入二异丙基乙胺(0.35g，2.7mmol)搅拌10min，待用。In a 50 mL reaction flask, compound 46B (0.14 g, 0.25 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with methyl tert-butyl ether (10 mL×3), then concentrated to dryness under reduced pressure, dissolved in 5 mL of acetonitrile, added with diisopropylethylamine (0.35 g, 2.7 mmol) and stirred for 10 min ,stand-by.
将2-氟丙烯酸(0.029g，0.32mmol)和二异丙基乙胺(83mg，0.64mmol)溶于二氯甲烷(5mL)和乙腈(5mL)的混合溶液中，加入三吡咯烷基溴化鏻六氟磷酸盐(0.15g，0.32mmol)，室温搅拌20min。将此反应液缓慢滴加到上述待用的乙腈溶液中，继续搅拌1h。加入10mL饱和碳酸氢钠水溶液，分液后，有机层用无水硫酸钠干燥后，减压浓缩， 残留物柱层析纯化(DCM/MeOH/NH 3H 2O(V/V/V)＝50/1/0.5-25/1/0.25)，得到化合物46(58mg,收率：57％)。 2-Fluoroacrylic acid (0.029 g, 0.32 mmol) and diisopropylethylamine (83 mg, 0.64 mmol) were dissolved in a mixed solution of dichloromethane (5 mL) and acetonitrile (5 mL), and tripyrrolidinyl bromide was added. Phosphonium hexafluorophosphate (0.15 g, 0.32 mmol), stirred at room temperature for 20 min. The reaction solution was slowly added dropwise to the above-mentioned acetonitrile solution to be used, and stirring was continued for 1 h. 10 mL of saturated aqueous sodium bicarbonate solution was added, and after separation, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM/MeOH/NH 3 H 2 O (V/V/V)= 50/1/0.5-25/1/0.25) to obtain compound 46 (58 mg, yield: 57%).
LCMS m/z＝439.1[M+H] + LCMS m/z=439.1[M+H] +
1H NMR(400MHz,DMSO-d 6)δ13.01(s,1H),9.54(s,1H),7.98(s,1H),7.53(d,2H),7.19(s,1H),6.87(d,2H),6.61(s,1H),5.31-5.07(m,2H),4.84-4.74(m,1H),4.18-4.02(m,1H),3.51(t,2H),3.03-2.88(m,2H),2.42-2.25(m,4H),2.19(s,6H). 1 H NMR (400MHz, DMSO-d 6 )δ13.01(s,1H), 9.54(s,1H), 7.98(s,1H), 7.53(d,2H), 7.19(s,1H), 6.87( d, 2H), 6.61(s, 1H), 5.31-5.07(m, 2H), 4.84-4.74(m, 1H), 4.18-4.02(m, 1H), 3.51(t, 2H), 3.03-2.88( m,2H),2.42-2.25(m,4H),2.19(s,6H).
实施例47：反式-N-(2-(二甲基氨基)乙基)-2-氟-N-[3-[[6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-4-酰基)氧基]环丁基]丙-2-烯酰胺(化合物47)的三氟乙酸盐Example 47: trans-N-(2-(dimethylamino)ethyl)-2-fluoro-N-[3-[[6-(2-ethyl-5-fluoro-4-hydroxyphenyl )-1H-indazol-4-acyl)oxy]cyclobutyl]prop-2-enamide (compound 47) trifluoroacetate salt
trans-N-(2-(dimethylamino)ethyl)-2-fluoro-N-[-3-[(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]prop-2-enamide；trifluoroacetic acidtrans-N-(2-(dimethylamino)ethyl)-2-fluoro-N-[-3-[(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy ]cyclobutyl]prop-2-enamide; trifluoroacetic acid
Figure PCTCN2021117545-appb-000280
Figure PCTCN2021117545-appb-000280
第一步：反式-叔丁基N-(2-(二甲基氨基)乙基)-N-[3-[(6-(2-乙基-5-氟-4-羟基苯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基]环丁基]氨基甲酸酯(47A)The first step: trans-tert-butyl N-(2-(dimethylamino)ethyl)-N-[3-[(6-(2-ethyl-5-fluoro-4-hydroxyphenyl) -1-(Tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy]cyclobutyl]carbamate (47A)
trans-tert-butyl N-(2-(dimethylamino)ethyl)-N-[3-[(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy]cyclobutyl]carbamatetrans-tert-butyl N-(2-(dimethylamino)ethyl)-N-[3-[(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-4-yl)oxy]cyclobutyl]carbamate
在50mL反应瓶中，依次加入反式-叔丁基(3-((6-溴-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基)环丁基)(2-(二甲基氨基)乙基)氨基甲酸酯(23A)(0.29g,0.54mmol)、5-乙基-2-氟-4-(四甲基-1,3,2-二氧杂硼硼烷-2-基)苯酚(0.17g，0.65mmol)、七水合磷酸钾(0.55g，1.62mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(44mg，0.054mmol)和二氧六环/水(v/v＝4/1，10mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(DCM/MeOH(V/V)＝100/0-100/5)得到47A(0.3g，产率98％)。In a 50 mL reaction flask, add trans-tert-butyl(3-((6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy ) cyclobutyl) (2-(dimethylamino)ethyl)carbamate (23A) (0.29 g, 0.54 mmol), 5-ethyl-2-fluoro-4-(tetramethyl-1, 3,2-Dioxaborolane-2-yl)phenol (0.17g, 0.65mmol), potassium phosphate heptahydrate (0.55g, 1.62mmol), [1,1'-bis(diphenylphosphine)di Ferrocene] palladium dichloride dichloromethane complex (44 mg, 0.054 mmol) and dioxane/water (v/v=4/1, 10 mL), after nitrogen replacement three times, the reaction was stirred at 90 °C for 2 Hour. Water (50 mL) was added to the reaction solution, followed by extraction 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 (DCM/MeOH). (V/V)=100/0-100/5) to give 47A (0.3 g, 98% yield).
LCMS m/z＝597.3[M+H] + LCMS m/z=597.3[M+H] +
第二步：反式-N-(2-(二甲基氨基)乙基)-2-氟-N-[3-[[6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-4-酰基)氧基]环丁基]丙-2-烯酰胺(化合物47)的三氟乙酸盐The second step: trans-N-(2-(dimethylamino)ethyl)-2-fluoro-N-[3-[[6-(2-ethyl-5-fluoro-4-hydroxyphenyl )-1H-indazol-4-acyl)oxy]cyclobutyl]prop-2-enamide (compound 47) trifluoroacetate salt
trans-N-(2-(dimethylamino)ethyl)-2-fluoro-N-[-3-[(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]prop-2-enamide；trifluoroacetic acidtrans-N-(2-(dimethylamino)ethyl)-2-fluoro-N-[-3-[(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy ]cyclobutyl]prop-2-enamide; trifluoroacetic acid
在50mL反应瓶中，加入化合物47A(0.14g，0.23mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用甲基叔丁基醚(10mL×3)洗，然后减压浓缩干，加入5mL乙腈溶解，加入二异丙基乙胺(0.35g，2.7mmol)搅拌10min，待用。In a 50 mL reaction flask, compound 47A (0.14 g, 0.23 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with methyl tert-butyl ether (10 mL×3), then concentrated to dryness under reduced pressure, dissolved in 5 mL of acetonitrile, added with diisopropylethylamine (0.35 g, 2.7 mmol) and stirred for 10 min ,stand-by.
将2-氟丙烯酸(0.021g，0.23mmol)和二异丙基乙胺(60mg，0.46mmol)溶于二氯甲烷(5mL)和乙腈(5mL)的混合溶液中，加入三吡咯烷基溴化鏻六氟磷酸盐(0.11g，0.24mmol)，室温搅拌20min。将此反应液缓慢滴加到上述待用的乙腈溶液中，继续搅拌1h。加入10mL饱和碳酸氢钠水溶液，分液后，有机层用无水硫酸钠干燥后，减压浓缩，残留物用制备HPLC(仪器：waters 2767制备液相；色谱柱:SunFire@Prep C18(19mm×150mm)；流动相组成：流动相A：乙腈，流动相B：水(含0.1％三氟乙酸))分离纯化后冻干得到化合物47的三氟乙酸盐(20mg,收率：12％)。2-Fluoroacrylic acid (0.021 g, 0.23 mmol) and diisopropylethylamine (60 mg, 0.46 mmol) were dissolved in a mixed solution of dichloromethane (5 mL) and acetonitrile (5 mL), and tripyrrolidinyl bromide was added. Phosphonium hexafluorophosphate (0.11 g, 0.24 mmol), stirred at room temperature for 20 min. The reaction solution was slowly added dropwise to the above-mentioned acetonitrile solution to be used, and stirring was continued for 1 h. 10 mL of saturated aqueous sodium bicarbonate was added, and after separation, the organic layer was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was prepared by preparative HPLC (apparatus: waters 2767; chromatographic column: SunFire@Prep C18 (19mm× 150mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid)) after separation and purification, lyophilized to obtain the trifluoroacetic acid salt of compound 47 (20 mg, yield: 12%) .
LCMS m/z＝485.2[M+H] + LCMS m/z=485.2[M+H] +
1H NMR(400MHz,CD 3OD)δ8.09(s,1H),6.98(s,1H),6.93-6.84(m,2H),6.21(s,1H),5.37-5.21(m,2H),5.01–4.90(m,2H),3.86(t,2H),3.34(t,2H),2.99(s,6H),2.86–2.73(m,2H),2.70-2.60(m,2H),2.51(q,2H),1.06(t,3H). 1 H NMR (400MHz, CD 3 OD) δ8.09(s, 1H), 6.98(s, 1H), 6.93-6.84(m, 2H), 6.21(s, 1H), 5.37-5.21(m, 2H) ,5.01–4.90(m,2H),3.86(t,2H),3.34(t,2H),2.99(s,6H),2.86–2.73(m,2H),2.70-2.60(m,2H),2.51 (q,2H),1.06(t,3H).
实施例47-1：反式-N-(2-(二甲基氨基)乙基)-2-氟-N-[3-[[6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-4-酰基)氧基]环丁基]丙-2-烯酰胺(化合物47)Example 47-1: trans-N-(2-(dimethylamino)ethyl)-2-fluoro-N-[3-[[6-(2-ethyl-5-fluoro-4-hydroxyl Phenyl)-1H-indazol-4-acyl)oxy]cyclobutyl]prop-2-enamide (Compound 47)
trans-N-(2-(dimethylamino)ethyl)-2-fluoro-N-[-3-[(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]prop-2-enamidetrans-N-(2-(dimethylamino)ethyl)-2-fluoro-N-[-3-[(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy ]cyclobutyl]prop-2-enamide
在50mL反应瓶中，加入47A(0.18g，0.30mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用甲基叔丁基醚(10mL×3)洗，然后减压浓缩干，加入5mL乙腈溶解，加入二异丙基乙胺(0.35g，2.7mmol)搅拌10min，待用。In a 50 mL reaction flask, 47A (0.18 g, 0.30 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with methyl tert-butyl ether (10 mL×3), then concentrated to dryness under reduced pressure, dissolved in 5 mL of acetonitrile, added with diisopropylethylamine (0.35 g, 2.7 mmol) and stirred for 10 min ,stand-by.
将2-氟丙烯酸(0.027g，0.30mmol)和二异丙基乙胺(77mg，0.60mmol)溶于二氯甲烷(5mL)和乙腈(5mL)的混合溶液中，加入三吡咯烷基溴化鏻六氟磷酸盐(0.14g，0.30mmol)，室温搅拌20min。将此反应液缓慢滴加到上述待用的乙腈溶液中，继续搅拌1h。加入10mL饱和碳酸氢钠水溶液，分液后，有机层用无水硫酸钠干燥后，减压浓缩，残留物柱层析纯化(DCM/MeOH/NH 3H 2O(V/V/V)＝50/1/0.5-20/1/0.20)，得到化合物47(35mg,收率：24％)。 2-Fluoroacrylic acid (0.027 g, 0.30 mmol) and diisopropylethylamine (77 mg, 0.60 mmol) were dissolved in a mixed solution of dichloromethane (5 mL) and acetonitrile (5 mL), and tripyrrolidinyl bromide was added. Phosphonium hexafluorophosphate (0.14 g, 0.30 mmol), stirred at room temperature for 20 min. The reaction solution was slowly added dropwise to the above-mentioned acetonitrile solution to be used, and stirring was continued for 1 h. 10 mL of saturated aqueous sodium bicarbonate solution was added, and after separation, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM/MeOH/NH 3 H 2 O (V/V/V)= 50/1/0.5-20/1/0.20) to obtain compound 47 (35 mg, yield: 24%).
LCMS m/z＝485.2[M+H] + LCMS m/z=485.2[M+H] +
1H NMR(400MHz,CDCl 3)δ8.16(s,1H),6.94-6.82(m,3H),6.10(s,1H),5.33-5.06(m,2H),4.90-4.66(m,2H),3.68-3.54(m,2H),2.82-2.69(m,2H),2.69-2.52(m,4H),2.45(q,2H),2.39(s,6H),1.02(t,3H). 1 H NMR (400MHz, CDCl 3 ) δ 8.16(s, 1H), 6.94-6.82(m, 3H), 6.10(s, 1H), 5.33-5.06(m, 2H), 4.90-4.66(m, 2H) ),3.68-3.54(m,2H),2.82-2.69(m,2H),2.69-2.52(m,4H),2.45(q,2H),2.39(s,6H),1.02(t,3H).
实施例48：反式-2-氟-N-((3-((6-(4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)丙烯酰胺(化合物48)Example 48: trans-2-fluoro-N-((3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)acrylamide (Compound 48 )
trans-2-fluoro-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)acrylamidetrans-2-fluoro-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)acrylamide
Figure PCTCN2021117545-appb-000281
Figure PCTCN2021117545-appb-000281
第一步：4-硝基苯基-2-氟丙烯酸酯(48A)The first step: 4-nitrophenyl-2-fluoroacrylate (48A)
4-nitrophenyl 2-fluoroacrylate4-nitrophenyl 2-fluoroacrylate
在100mL反应瓶中，将2-氟丙烯酸(1.00g，11.10mmol)溶解到N,N-二甲基甲酰胺(15mL)中，加入4-硝基苯酚(1.85g,13.33mmol)和1-羟基苯并三唑(1.50g,11.10mmol),室温下加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(3.20g,16.64mmol),搅拌4小时。加入水(30mL)和二氯甲烷(40mL x 2)萃取，合并有机层，无水硫酸钠干燥，过滤，减压浓缩后，残留物硅胶柱层析分离纯化得48A(1.5g,收率：64.10％)。In a 100 mL reaction flask, dissolve 2-fluoroacrylic acid (1.00 g, 11.10 mmol) into N,N-dimethylformamide (15 mL), add 4-nitrophenol (1.85 g, 13.33 mmol) and 1- Hydroxybenzotriazole (1.50g, 11.10mmol) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.20g, 16.64mmol) at room temperature, stirred for 4 hours . Water (30 mL) and dichloromethane (40 mL x 2) were added for extraction, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain 48A (1.5 g, yield: 64.10%).
LCMS m/z＝212.1[M+H] + LCMS m/z=212.1[M+H] +
第二步：反式-2-氟-N-((3-((6-(4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)丙烯酰胺(化合物48)The second step: trans-2-fluoro-N-((3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)acrylamide (compound 48 )
trans-2-fluoro-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)acrylamidetrans-2-fluoro-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)acrylamide
在50mL反应瓶中，加入1D(0.401g，0.84mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，20mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用甲基叔丁基醚(10mL×3)洗，然后减压浓缩干，加入20mL乙腈溶解，加入48A(0.282g，1.34mmol)和三乙胺(0.582g,5.76mmol)，室温搅拌反应1小时。加入饱和碳酸氢钠水溶液(20mL)淬灭，加入乙酸乙酯(20mL)萃取，水相用二氯甲烷(40x 2mL)萃取，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩，残留物硅胶柱层析分离纯化得化合物48(130mg，收率：39.76％)。In a 50 mL reaction flask, 1D (0.401 g, 0.84 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 20 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with methyl tert-butyl ether (10 mL×3), then concentrated to dryness under reduced pressure, added 20 mL of acetonitrile to dissolve, added 48A (0.282 g, 1.34 mmol) and triethylamine (0.582 g) , 5.76 mmol), and the reaction was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution (20 mL) was added to quench, ethyl acetate (20 mL) was added for extraction, the aqueous phase was extracted with dichloromethane (40×2 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain compound 48 (130 mg, yield: 39.76%).
LCMS m/z＝368.1[M+H] + LCMS m/z=368.1[M+H] +
1H NMR(400MHz,CD 3OD)δ8.04(s,1H),7.48(d,2H),7.20(s,1H),6.87(d,2H),6.51(s,1H),5.58(dd,1H),5.19(dd,1H),5.16–5.09(m,1H),4.67–4.54(m,1H),2.76–2.57(m,4H). 1 H NMR (400MHz, CD 3 OD) δ 8.04(s, 1H), 7.48(d, 2H), 7.20(s, 1H), 6.87(d, 2H), 6.51(s, 1H), 5.58(dd , 1H), 5.19 (dd, 1H), 5.16–5.09 (m, 1H), 4.67–4.54 (m, 1H), 2.76–2.57 (m, 4H).
实施例49：反式-2-氟-N-(2-羟乙基)-N-[3-[(6-(4-羟苯基)-1H-吲唑-4-基)氧基]环丁基]丙-2-烯酰胺(化合物49)的三氟乙酸盐Example 49: trans-2-Fluoro-N-(2-hydroxyethyl)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy] Trifluoroacetate salt of cyclobutyl]prop-2-enamide (compound 49)
trans-2-fluoro-N-(2-hydroxyethyl)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]prop-2-enamide；trifluoroacetic acidtrans-2-fluoro-N-(2-hydroxyethyl)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]prop-2-enamide; trifluoroacetic acid
Figure PCTCN2021117545-appb-000282
Figure PCTCN2021117545-appb-000282
在50mL反应瓶中，加入化合物42C(0.18g，0.34mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用甲基叔丁基醚(10mL×3)洗，然后减压浓缩干，加入5mL乙腈溶解，加入二异丙基乙胺(0.35g，2.7mmol)搅拌10min，待用。In a 50 mL reaction flask, compound 42C (0.18 g, 0.34 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with methyl tert-butyl ether (10 mL×3), then concentrated to dryness under reduced pressure, dissolved in 5 mL of acetonitrile, added with diisopropylethylamine (0.35 g, 2.7 mmol) and stirred for 10 min ,stand-by.
将2-氟丙烯酸(0.030g，0.34mmol)和二异丙基乙胺(83mg，0.68mmol)溶于二氯甲烷(5mL)和乙腈(5mL)的混合溶液中，加入三吡咯烷基溴化鏻六氟磷酸盐(0.16g，0.34mmol)，室温搅拌20min。将此反应液缓慢滴加到上述待用的乙腈溶液中，继续搅拌1h。加入10mL饱和碳酸氢钠水溶液，分液后，有机层用无水硫酸钠干燥后，减压浓缩，残留物用制备HPLC(仪器：waters 2767制备液相；色谱柱:SunFire@Prep C18(19mm×150mm)；流动相组成：流动相A：乙腈，流动相B：水(含0.1％三氟乙酸))分离纯化，冻干后得到化合物49的三氟乙酸盐(9mg,收率：5％)。2-Fluoroacrylic acid (0.030 g, 0.34 mmol) and diisopropylethylamine (83 mg, 0.68 mmol) were dissolved in a mixed solution of dichloromethane (5 mL) and acetonitrile (5 mL), and tripyrrolidinyl bromide was added. Phosphonium hexafluorophosphate (0.16 g, 0.34 mmol), stirred at room temperature for 20 min. The reaction solution was slowly added dropwise to the above-mentioned acetonitrile solution to be used, and stirring was continued for 1 h. 10 mL of saturated aqueous sodium bicarbonate was added, and after separation, the organic layer was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was prepared by preparative HPLC (apparatus: waters 2767; chromatographic column: SunFire@Prep C18 (19mm× 150mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid)) separation and purification, after lyophilization, the trifluoroacetic acid salt of compound 49 (9 mg, yield: 5%) was obtained ).
LCMS m/z＝412.2[M+H] + LCMS m/z=412.2[M+H] +
1H NMR(400MHz,DMSO-d 6)δ13.03(br.s,1H),9.54(br.s,1H),8.01(s,1H),7.51(d,2H),7.18(s,1H),6.86(d,2H),6.47(s,1H),5.28–5.04(m,3H),4.79–4.59(m,1H),3.54-3.48(m,4H),2.88–2.74(m,2H),2.58–2.51(m,2H). 1 H NMR (400MHz, DMSO-d 6 )δ13.03(br.s,1H), 9.54(br.s,1H), 8.01(s,1H), 7.51(d,2H), 7.18(s,1H) ),6.86(d,2H),6.47(s,1H),5.28–5.04(m,3H),4.79–4.59(m,1H),3.54-3.48(m,4H),2.88–2.74(m,2H) ),2.58–2.51(m,2H).
实施例50：反式-(E)-N-((3-((6-(4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)-4-((2-甲氧基乙基)(甲基)氨基)-2-烯酰胺(化合物50)的乙酸盐Example 50: trans-(E)-N-((3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-4-(( 2-Methoxyethyl)(methyl)amino)-2-enamide (compound 50) acetate salt
trans-(E)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-4-((2-methoxyethyl)(methyl)amino)but-2-enamide；acetic acidtrans-(E)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-4-((2-methoxyethyl)(methyl)amino)but-2 -enamide; acetic acid
Figure PCTCN2021117545-appb-000283
Figure PCTCN2021117545-appb-000283
第一步：(E)-4-(((2-甲氧基乙基)(甲基)氨基)丁-2-烯酸酯(50B)The first step: (E)-4-(((2-methoxyethyl)(methyl)amino)but-2-enoate (50B)
methyl(E)-4-((2-methoxyethyl)(methyl)amino)but-2-enoatemethyl(E)-4-((2-methoxyethyl)(methyl)amino)but-2-enoate
将E-4-溴-2-丁烯酸甲酯(1.8g，10mmol)，三乙胺(1.01g，10mmol)溶于四氢呋喃(50ml)中，室温下缓慢滴加2-甲氧基-N-甲基乙-1-胺(890mg，10mmol)，加毕，室温搅拌2h。加入20mL水和20mL乙酸乙酯萃取，有机层用饱和食盐水20mL洗涤一次，无水硫酸钠干燥，减压浓缩得到50B粗品(1.87g)，直接用于下一步。Methyl E-4-bromo-2-butenoate (1.8g, 10mmol), triethylamine (1.01g, 10mmol) were dissolved in tetrahydrofuran (50ml), and 2-methoxy-N was slowly added dropwise at room temperature -Methylethan-1-amine (890 mg, 10 mmol) was added and stirred at room temperature for 2 h. 20 mL of water and 20 mL of ethyl acetate were added for extraction, the organic layer was washed once with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 50B (1.87 g), which was directly used in the next step.
第二步：(E)-4-(((2-甲氧基乙基)(甲基)氨基)丁-2-烯酸(50C)的盐酸盐The second step: hydrochloride of (E)-4-(((2-methoxyethyl)(methyl)amino)but-2-enoic acid (50C)
(E)-4-((2-methoxyethyl)(methyl)amino)but-2-enoic acid；hydrochloric acid(E)-4-((2-methoxyethyl)(methyl)amino)but-2-enoic acid; hydrochloric acid
将化合物50B(1.8g)溶于甲醇(9mL)和水(3mL)的混合溶剂中，加入固体氢氧化钾(1.31g，23.36mmol)，室温搅拌2h。用浓盐酸调节pH＝5-6，减压浓缩，加入二氯甲烷/甲醇(V/V＝10/1，20mL)溶解残留物，过滤，向滤液中加入3N的氯化氢/乙酸乙酯溶液5mL，减压浓缩滤液，残留物加入乙酸乙酯/乙腈(20mL，V/V＝1/1)打浆，过滤，滤饼减压干燥得50C的盐酸盐(1.05g，产率：50％)。Compound 50B (1.8 g) was dissolved in a mixed solvent of methanol (9 mL) and water (3 mL), solid potassium hydroxide (1.31 g, 23.36 mmol) was added, and the mixture was stirred at room temperature for 2 h. Adjust pH=5-6 with concentrated hydrochloric acid, concentrate under reduced pressure, add dichloromethane/methanol (V/V=10/1, 20 mL) to dissolve the residue, filter, add 5 mL of 3N hydrogen chloride/ethyl acetate solution to the filtrate , the filtrate was concentrated under reduced pressure, ethyl acetate/acetonitrile (20 mL, V/V=1/1) was added to the residue to make a slurry, filtered, and the filter cake was dried under reduced pressure to obtain 50°C hydrochloride (1.05 g, yield: 50%) .
第三步：反式-(E)-N-((3-((6-(4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)-4-((2-甲氧基乙基)(甲基)氨基)-2-烯酰胺(化合物50)的乙酸盐The third step: trans-(E)-N-((3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-4-(( 2-Methoxyethyl)(methyl)amino)-2-enamide (compound 50) acetate salt
trans-(E)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-4-((2-methoxyethyl)(methyl)amino)but-2-enamide；acetic acidtrans-(E)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-4-((2-methoxyethyl)(methyl)amino)but-2 -enamide; acetic acid
在50mL反应瓶中，加入反式-N-[3-[6-(4-羟基苯基)-1-四氢吡喃-2-基-吲唑-4-基]氧环丁基]氨基甲酸叔丁酯(1D)(0.27g，0.56mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用MTBE(10mL×3)洗，然后减压浓缩干。所得残留物中依次加入50C的盐酸盐(117mg，0.56mmol)、1-(3- 二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.216g，1.13mmol)、1-羟基苯并三唑(0.098g，0.73mmol)和N,N-二甲基甲酰胺(40mL)，加完后在室温下搅拌10分钟，加入N,N-二异丙基乙胺(0.45g，3.48mmol)，加完后在室温下搅拌50分钟。反应液中加入饱和碳酸氢钠(50mL)，然后用二氯甲烷/甲醇(v/v＝10/1)(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过制备液相(仪器：waters 2767制备液相；色谱柱:SunFire@Prep C18(19mm×150mm)；流动相组成：流动相A：乙腈流动相B：水(含5mM乙酸铵))分离纯化得到化合物50的乙酸盐(53mg，产率18.5％)。In a 50 mL reaction flask, add trans-N-[3-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclobutyl]amino tert-Butyl formate (1D) (0.27 g, 0.56 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL), then the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with MTBE (10 mL×3), and then concentrated to dryness under reduced pressure. To the obtained residue, 50C hydrochloride (117mg, 0.56mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.216g, 1.13mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.216g, 1.13mmol), 1 -Hydroxybenzotriazole (0.098g, 0.73mmol) and N,N-dimethylformamide (40mL), stir at room temperature for 10 minutes after addition, add N,N-diisopropylethylamine (0.45 g, 3.48 mmol) and stirred at room temperature for 50 minutes after the addition was complete. Saturated sodium bicarbonate (50 mL) was added to the reaction solution, then extracted with dichloromethane/methanol (v/v=10/1) (50 mL×2), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced in pressure Concentrated, the residue was passed through preparative liquid phase (instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm×150mm); mobile phase composition: mobile phase A: acetonitrile Mobile phase B: water (containing 5mM ammonium acetate) ) was isolated and purified to obtain the acetate salt of compound 50 (53 mg, yield 18.5%).
LCMS m/z＝451.3[M+H] +； LCMS m/z=451.3[M+H] + ;
1H NMR(400MHz,CD 3OD)δ8.03(d,1H),7.51–7.43(m,2H),7.20(s,1H),6.95–6.68(m,3H),6.50(s,1H),6.20-6.12(m,1H),5.24–5.01(m,1H),4.65–4.50(m,1H),3.56(t,2H),3.42–3.33(m,5H),2.76(t,2H),2.74-2.65(m,2H),2.64-2.53(m,2H),2.41(s,3H),1.96(s,3H). 1 H NMR (400MHz, CD 3 OD) δ 8.03(d, 1H), 7.51–7.43 (m, 2H), 7.20 (s, 1H), 6.95–6.68 (m, 3H), 6.50 (s, 1H) ,6.20-6.12(m,1H),5.24-5.01(m,1H),4.65-4.50(m,1H),3.56(t,2H),3.42-3.33(m,5H),2.76(t,2H) ,2.74-2.65(m,2H),2.64-2.53(m,2H),2.41(s,3H),1.96(s,3H).
实施例51：反式-(E)-N-((3-((6-(4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)-N-甲基-3-((S)-1-甲基吡咯烷基-2-基)丙烯酰胺(化合物51)的乙酸盐Example 51: trans-(E)-N-((3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-methyl -Acetate salt of 3-((S)-1-methylpyrrolidin-2-yl)acrylamide (compound 51)
trans-(E)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-methyl-3-((S)-1-methylpyrrolidin-2-yl)acrylamide；acetic acidtrans-(E)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-methyl-3-((S)-1-methylpyrrolidin-2 -yl)acrylamide;acetic acid
Figure PCTCN2021117545-appb-000284
Figure PCTCN2021117545-appb-000284
在50mL反应瓶中，加入反式-N-[3-[6-(4-羟基苯基)-1-四氢吡喃-2-基-吲唑-4-基]氧环丁基]-N-甲基-氨基甲酸叔丁酯(7B)(0.071g，0.132mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用MTBE(10mL×3)洗，然后减压浓缩干。In a 50 mL reaction flask, add trans-N-[3-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclobutyl]- N-methyl-carbamic acid tert-butyl ester (7B) (0.071 g, 0.132 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL), then the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with MTBE (10 mL×3), and then concentrated to dryness under reduced pressure.
在50mL反应瓶中，加入(2E)-3-[((2S)-1-甲基吡咯烷-2-基]丙-2-烯酸(26C)的盐酸盐(22.5mg，0.145mmol)、6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯(0.071g，0.172mmol)和DMF(10mL)，加完后在室温下搅拌30分钟，然后加入上一操作所得残留物的DMF(5mL)溶液，加完后在室温下搅拌10分钟，加入N,N-二异丙基乙胺(0.102g，0.79mmol)，加完后在室温下搅拌50分钟。反应液中加入饱和碳酸氢钠(50 mL)，然后用二氯甲烷/甲醇(v/v＝10/1)(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通，残留物通过制备液相(仪器：waters 2767制备液相；色谱柱:SunFire@Prep C18(19mm×150mm)；流动相组成：流动相A：乙腈流动相B：水(含5mM乙酸铵))分离纯化后冻干得到化合物51的乙酸盐(15.3mg，产率21％)。In a 50 mL reaction flask, add (2E)-3-[((2S)-1-methylpyrrolidin-2-yl]prop-2-enoic acid (26C) hydrochloride (22.5 mg, 0.145 mmol) , 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate (0.071 g, 0.172 mmol) and DMF (10 mL) were added and stirred at room temperature for 30 minutes, then Add the DMF (5 mL) solution of the residue obtained in the previous operation, stir at room temperature for 10 minutes after the addition, add N,N-diisopropylethylamine (0.102 g, 0.79 mmol), and stir at room temperature after the addition 50 minutes. Add saturated sodium bicarbonate (50 mL) to the reaction solution, then extract with dichloromethane/methanol (v/v=10/1) (50 mL×2), combine the organic layers and dry with anhydrous sodium sulfate, filter , the filtrate was concentrated under reduced pressure, the residue was passed through, and the residue was passed through preparative liquid phase (instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm×150mm); mobile phase composition: mobile phase A: acetonitrile mobile phase B : water (containing 5 mM ammonium acetate)) was isolated and purified, and lyophilized to obtain the acetate salt of compound 51 (15.3 mg, yield 21%).
LCMS m/z＝447.1[M+H] +； LCMS m/z=447.1[M+H] + ;
1H NMR(400MHz,CD 3OD)δ8.04(s,1H),7.56–7.43(m,2H),7.21(s,1H),6.94–6.83(m,2H),6.68–6.43(m,3H),5.31-4.95(m,2H),3.30–2.99(m,5H),2.95-2.73(m,2H),2.70-2.51(m,3H),2.44(s,3H),2.20-2.09(m,1H),2.01-1.86(m,5H),1.83-1.69(m,1H). 1 H NMR (400MHz, CD 3 OD) δ 8.04(s, 1H), 7.56–7.43 (m, 2H), 7.21 (s, 1H), 6.94–6.83 (m, 2H), 6.68–6.43 (m, 3H), 5.31-4.95(m, 2H), 3.30-2.99(m, 5H), 2.95-2.73(m, 2H), 2.70-2.51(m, 3H), 2.44(s, 3H), 2.20-2.09( m,1H),2.01-1.86(m,5H),1.83-1.69(m,1H).
实施例52：反式-(E)-N-(3-((6-(4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)-N-甲基-4-(吡咯烷-1-基)丁-2-烯酰胺(化合物52)Example 52: trans-(E)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-methyl- 4-(Pyrrolidin-1-yl)but-2-enamide (Compound 52)
trans-(E)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-methyl-4-(pyrrolidin-1-yl)but-2-enamidetrans-(E)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-methyl-4-(pyrrolidin-1-yl)but-2 -enamide
Figure PCTCN2021117545-appb-000285
Figure PCTCN2021117545-appb-000285
第一步：(E)-4-(吡咯烷-1-基)丁-2-烯酸甲酯(52A)The first step: (E)-4-(pyrrolidin-1-yl)but-2-enoic acid methyl ester (52A)
methyl(E)-4-(pyrrolidin-1-yl)but-2-enoatemethyl(E)-4-(pyrrolidin-1-yl)but-2-enoate
在50mL反应瓶中，依次加入四氢吡咯(1.4g，20mmol)和二氯甲烷(20mL)，冰水冷却下加入反式-4-溴-2-丁烯酸甲酯(1.79g，10mmol)，加完室温搅拌反应2小时。反应液中加入水(20mL×2)洗，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过柱层析分离纯化(二氯甲烷/甲醇(V/V)＝20/1)得到52A(1.1g，产率65.0％)。In a 50 mL reaction flask, tetrahydropyrrole (1.4 g, 20 mmol) and dichloromethane (20 mL) were sequentially added, and methyl trans-4-bromo-2-butenoate (1.79 g, 10 mmol) was added under ice-water cooling. , and the reaction was stirred at room temperature for 2 hours. The reaction solution was washed with water (20 mL×2), the organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (dichloromethane/methanol (V/V)=20/ 1) 52A was obtained (1.1 g, 65.0% yield).
第二步：(E)-4-(吡咯烷-1-基)丁-2-烯酸(52B)的盐酸盐The second step: hydrochloride of (E)-4-(pyrrolidin-1-yl)but-2-enoic acid (52B)
(E)-4-(pyrrolidin-1-yl)but-2-enoic acid；HCl(E)-4-(pyrrolidin-1-yl)but-2-enoic acid; HCl
在50mL反应瓶中，依次加入(E)-4-(吡咯烷-1-基)丁-2-烯酸甲酯(52A)(1.1g，6.50mmol)和四氢呋喃(10mL)，搅拌下加入一水合氢氧化锂(0.55g，13mmol)和水(2mL)，加完室温搅拌反应2小时。反应液滴入1N盐酸调pH2-3，减压浓缩干，直接用于下一步。In a 50 mL reaction flask, add (E)-4-(pyrrolidin-1-yl)but-2-enoic acid methyl ester (52A) (1.1 g, 6.50 mmol) and tetrahydrofuran (10 mL) in turn, add a Lithium hydroxide hydrate (0.55 g, 13 mmol) and water (2 mL) were added, and the reaction was stirred at room temperature for 2 hours. The reaction was dropped into 1N hydrochloric acid to adjust the pH to 2-3, concentrated under reduced pressure to dryness, and used directly in the next step.
第三步：反式-(E)-N-(3-((6-(4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)-N-甲基-4-(吡咯烷-1-基)丁-2-烯酰胺(化合物52)The third step: trans-(E)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-methyl- 4-(Pyrrolidin-1-yl)but-2-enamide (Compound 52)
trans-(E)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-methyl-4-(pyrrolidin-1-yl)but-2-enamidetrans-(E)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-N-methyl-4-(pyrrolidin-1-yl)but-2 -enamide
在50mL反应瓶中，加入反式-N-[3-[6-(4-羟基苯基)-1-四氢吡喃-2-基-吲唑-4-基]氧环丁基]-N-甲基-氨基甲酸叔丁酯(7B)(0.30g，0.61mmol)，二氯甲烷(3mL)，三氟乙酸(3mL)，室温搅拌反应5小时，TLC监控反应完全，减压浓缩干，加入二氯甲烷(3mL)，N,N-二异丙基乙胺(0.23g，1.83mmol)，搅拌溶解待用。In a 50 mL reaction flask, add trans-N-[3-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclobutyl]- N-methyl-carbamic acid tert-butyl ester (7B) (0.30 g, 0.61 mmol), dichloromethane (3 mL), trifluoroacetic acid (3 mL), the reaction was stirred at room temperature for 5 hours, TLC monitored the completion of the reaction, and concentrated to dryness under reduced pressure , was added with dichloromethane (3 mL), N,N-diisopropylethylamine (0.23 g, 1.83 mmol), stirred and dissolved for use.
在50mL反应瓶中，加入(E)-4-(吡咯烷-1-基)丁-2-烯酸(52B)的盐酸盐(0.13g)，二氯甲烷(4mL)，和三吡咯烷基溴化鏻六氟磷酸盐(0.37g，0.79mmol)，滴入N,N-二异丙基乙胺(0.23g，1.83mmol)，室温搅拌反应30分钟；冰水冷却下将该反应液加入上一操作的反应液中，室温搅拌反应4小时；TLC监控反应完全，加入二氯甲烷10mL，反应液饱和碳酸氢钠(20mL×3)洗涤，有机层无水硫酸钠干燥，过滤，减压浓缩干，残余物通过柱层析分离纯化(二氯甲烷/甲醇(V/V)＝20/1)，所得化合物制备HPLC(仪器：waters 2767制备液相；色谱柱:SunFire@Prep C18(19mm×150mm)；流动相组成：流动相A：乙腈，流动相B：水(含0.1％三氟乙酸))纯化，用饱和碳酸氢钠水溶液处理制备液，二氯甲烷萃取，有机相浓缩后加入少量水和甲醇冻干，得到化合物52(40mg，产率：14.7％)。In a 50 mL reaction flask, add (E)-4-(pyrrolidin-1-yl)but-2-enoic acid (52B) hydrochloride (0.13 g), dichloromethane (4 mL), and tripyrrolidine phosphonium bromide hexafluorophosphate (0.37g, 0.79mmol), N,N-diisopropylethylamine (0.23g, 1.83mmol) was added dropwise, and the reaction was stirred at room temperature for 30 minutes; the reaction solution was cooled with ice water It was added to the reaction solution of the previous operation, and the reaction was stirred at room temperature for 4 hours; TLC monitored the completion of the reaction, 10 mL of dichloromethane was added, the reaction solution was washed with saturated sodium bicarbonate (20 mL×3), and the organic layer was dried over anhydrous sodium sulfate, filtered, and reduced in size. It was concentrated to dryness under pressure, the residue was separated and purified by column chromatography (dichloromethane/methanol (V/V)=20/1), and the obtained compound was prepared by HPLC (apparatus: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 ( 19mm×150mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid)), purified, treated with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was concentrated. A small amount of water and methanol were added for lyophilization to obtain compound 52 (40 mg, yield: 14.7%).
LCMS m/z＝447.1[M+H] + LCMS m/z=447.1[M+H] +
1H NMR(400MHz,DMSO-d 6)δ13.01(s,1H),9.53(s,1H),8.02(s,1H),7.58–7.45(m,2H),7.18(s,1H),6.95–6.79(m,2H),6.72–6.40(m,3H),5.36–4.75(m,2H),3.18(d,2H),3.14–2.89(m,3H),2.86–2.70(m,2H),2.50–2.30(m,6H),1.81–1.51(m,4H). 1 H NMR (400MHz, DMSO-d 6 )δ13.01(s,1H), 9.53(s,1H), 8.02(s,1H), 7.58–7.45(m,2H), 7.18(s,1H), 6.95–6.79 (m, 2H), 6.72–6.40 (m, 3H), 5.36–4.75 (m, 2H), 3.18 (d, 2H), 3.14–2.89 (m, 3H), 2.86–2.70 (m, 2H) ), 2.50–2.30 (m, 6H), 1.81–1.51 (m, 4H).
实施例53：反式-N-甲基-N-[3-[(6-(4-羟基苯基)咪唑并[1,5-a]吡啶-8-基)氧基]环丁基]丙-2-烯酰胺(化合物53)Example 53: trans-N-methyl-N-[3-[(6-(4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy]cyclobutyl] Prop-2-enamide (Compound 53)
trans-N-methyl-N-[3-[(6-(4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy]cyclobutyl]prop-2-enamidetrans-N-methyl-N-[3-[(6-(4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy]cyclobutyl]prop-2-enamide
Figure PCTCN2021117545-appb-000286
Figure PCTCN2021117545-appb-000286
第一步：反式-N-甲基-N-[3-[(6-(4-羟基苯基)咪唑并[1,5-a]吡啶-8-基)氧基]环丁基]氨基甲酸叔丁酯(53A)The first step: trans-N-methyl-N-[3-[(6-(4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy]cyclobutyl] tert-Butyl carbamate (53A)
trans-tert-butyl N-methyl-N-[-3-[(6-(4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy]cyclobutyl]carbamatetrans-tert-butyl N-methyl-N-[-3-[(6-(4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy]cyclobutyl]carbamate
在50mL反应瓶中，依次加入35A(0.40g，1.0mmol)、4-羟基苯硼酸(0.17g，1.2mmol)、七水合磷酸钾(1.02g，3mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(82mg，0.1mmol)和二氧六环/水(v/v＝4/1，10mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(乙酸乙酯/石油醚(V/V)＝1/10-1/1)得到53A(0.4g，产率98％)。In a 50 mL reaction flask, 35A (0.40 g, 1.0 mmol), 4-hydroxyphenylboronic acid (0.17 g, 1.2 mmol), potassium phosphate heptahydrate (1.02 g, 3 mmol), [1,1'-bis(di) Phenylphosphine)ferrocene]dichloropalladium dichloromethane complex (82mg, 0.1mmol) and dioxane/water (v/v=4/1, 10mL), after nitrogen replacement three times, at 90 The reaction was stirred at °C for 2 hours. 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 (ethyl acetate). /Petroleum ether (V/V)=1/10-1/1) to give 53A (0.4 g, 98% yield).
第二步：反式-N-甲基-N-[3-[(6-(4-羟基苯基)咪唑并[1,5-a]吡啶-8-基)氧基]环丁基]丙-2-烯酰胺(化合物53)Step 2: trans-N-methyl-N-[3-[(6-(4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy]cyclobutyl] Prop-2-enamide (Compound 53)
trans-N-methyl-N-[3-[(6-(4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy]cyclobutyl]prop-2-enamidetrans-N-methyl-N-[3-[(6-(4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy]cyclobutyl]prop-2-enamide
在50mL反应瓶中，加入化合物53A(0.15g，0.37mmol)和二氯甲烷/三氟乙酸(v/v＝2/1，10mL)，然后在室温下搅拌反应2小时。反应液减压浓缩干，加入5mL二氯甲烷溶解，依次在冰浴下加入二异丙基乙胺(0.35g，2.7mmol)和丙烯酰氯(33mg,0.37mmol)，此温度下搅拌30min后加入10mL饱和碳酸氢钠水溶液和10mL二氯甲烷萃取，有机层减压浓缩，残留物通过柱层析分离纯化(DCM/MeOH(V/V)＝100/0-100/5)得到化合物53(0.3g，产率23％)。In a 50 mL reaction flask, compound 53A (0.15 g, 0.37 mmol) and dichloromethane/trifluoroacetic acid (v/v=2/1, 10 mL) were added, and the reaction was stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, 5 mL of dichloromethane was added to dissolve, and diisopropylethylamine (0.35 g, 2.7 mmol) and acryloyl chloride (33 mg, 0.37 mmol) were successively added in an ice bath. 10 mL of saturated aqueous sodium bicarbonate solution and 10 mL of dichloromethane were extracted, the organic layer was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (DCM/MeOH (V/V)=100/0-100/5) to obtain compound 53 (0.3 g, 23% yield).
LCMS m/z＝364.2[M+H]+LCMS m/z=364.2[M+H]+
1H NMR(400MHz,CDCl 3)δ8.15(s,1H),7.69(s,1H),7.56(s,1H),7.34(d,2H),6.96(d,2H),6.61-6.50(m,1H),6.38-6.22(m,1H),5.95(s,1H),5.71(d,1H),5.20-4.84(m,2H),3.07(s,3H),2.82-2.62(m,4H). 1 H NMR (400MHz, CDCl 3 )δ8.15(s,1H), 7.69(s,1H), 7.56(s,1H), 7.34(d,2H), 6.96(d,2H), 6.61-6.50( m,1H),6.38-6.22(m,1H),5.95(s,1H),5.71(d,1H),5.20-4.84(m,2H),3.07(s,3H),2.82-2.62(m, 4H).
实施例54：反式-(E)-4-(二甲基氨基)-N-(3-((6-(2-氯-4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)-N-甲基丁-2-烯酰胺(化合物54)的三氟乙酸盐Example 54: trans-(E)-4-(dimethylamino)-N-(3-((6-(2-chloro-4-hydroxyphenyl)-1H-indazol-4-yl) Trifluoroacetate salt of oxy)cyclobutyl)-N-methylbut-2-enamide (compound 54)
trans-(E)-N-(3-((6-(2-chloro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-4-(dimethylamino)-N-methylbut-2-enamide；trifluoroacetic acidtrans-(E)-N-(3-((6-(2-chloro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-4-(dimethylamino)-N-methylbut-2- enamide; trifluoroacetic acid
Figure PCTCN2021117545-appb-000287
Figure PCTCN2021117545-appb-000287
第一步：反式-(3-((6-(2-氯-4-羟基苯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基)环丁基)(甲基)氨基甲酸叔丁酯(54A)The first step: trans-(3-((6-(2-chloro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl )oxy)cyclobutyl)(methyl)carbamate (54A)
trans-tert-butyl(3-((6-(2-chloro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)(methyl)carbamatetrans-tert-butyl(3-((6-(2-chloro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)(methyl )carbamate
在50mL反应瓶中，依次加入7A(0.48g，1.00mmol)、2-氯-4-羟基苯硼酸(0.19g，1.10mmol)、七水合磷酸钾(1.02g，3.00mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(120mg，0.15mmol)和二氧六环/水(v/v＝4/1，20mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(乙酸乙酯/石油醚(V/V)＝1/10-1/1)得到54A(0.51g，产率96.58％)。In a 50mL reaction flask, 7A (0.48g, 1.00mmol), 2-chloro-4-hydroxyphenylboronic acid (0.19g, 1.10mmol), potassium phosphate heptahydrate (1.02g, 3.00mmol), [1,1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (120 mg, 0.15 mmol) and dioxane/water (v/v=4/1, 20 mL), nitrogen replacement After three times, the reaction was stirred at 90°C for 2 hours. 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 (ethyl acetate). /Petroleum ether (V/V)=1/10-1/1) to give 54A (0.51 g, 96.58% yield).
LCMS m/z＝528.2[M+H] + LCMS m/z=528.2[M+H] +
第二步：反式-(E)-4-(二甲基氨基)-N-(3-((6-(2-氯-4-羟基苯基)-1H-吲唑-4-基)氧基)环丁基)-N-甲基丁-2-烯酰胺(化合物54)的三氟乙酸盐The second step: trans-(E)-4-(dimethylamino)-N-(3-((6-(2-chloro-4-hydroxyphenyl)-1H-indazol-4-yl) Trifluoroacetate salt of oxy)cyclobutyl)-N-methylbut-2-enamide (compound 54)
trans-(E)-N-(3-((6-(2-chloro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-4-(dimethylamino)-N-methylbut-2-enamide；trifluoroacetic acidtrans-(E)-N-(3-((6-(2-chloro-4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-4-(dimethylamino)-N-methylbut-2- enamide; trifluoroacetic acid
在50mL反应瓶中，加入化合物54A(0.51g，0.97mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用甲基叔丁基醚(10mL×3)洗，然后减压浓缩干，加入10mL乙腈溶解，加入二异丙基乙胺(0.367g，2.84mmol)搅拌10min，待用。In a 50 mL reaction flask, compound 54A (0.51 g, 0.97 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with methyl tert-butyl ether (10 mL×3), then concentrated to dryness under reduced pressure, dissolved in 10 mL of acetonitrile, added with diisopropylethylamine (0.367 g, 2.84 mmol) and stirred for 10 min ,stand-by.
将反式-4-二甲基胺基巴豆酸盐酸盐(0.165g，1.00mmol)和二异丙基乙胺(0.367mg，2.84mmol)溶于二氯甲烷(10mL)和乙腈(10mL)的混合溶液中，加入三吡咯烷基溴化鏻六氟磷酸盐(0.466g，1.00mmol)，室温搅拌20分钟。将此反应液缓慢滴加到上一步操作待用的乙腈溶液中，继续搅拌1h。加入20mL饱和碳酸氢钠水溶液碱化，分液后，有机层用无水硫酸钠干燥后，减压浓缩，残留物制备HPLC(仪器：waters 2767制备液相；色谱柱:SunFire@Prep C18(19mm×150mm)；流动相组成：流动相A：乙腈，流动相B：水(含0.1％三氟乙酸))纯化后冻干得到化合物54的三氟乙酸盐(81mg,收率：14.99％)。Trans-4-dimethylaminocrotonate hydrochloride (0.165 g, 1.00 mmol) and diisopropylethylamine (0.367 mg, 2.84 mmol) were dissolved in dichloromethane (10 mL) and acetonitrile (10 mL) To the mixed solution, tripyrrolidinophosphonium bromide hexafluorophosphate (0.466 g, 1.00 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was slowly added dropwise to the acetonitrile solution to be used in the previous operation, and stirring was continued for 1 h. Add 20mL saturated aqueous sodium bicarbonate solution for alkalization, after separation, the organic layer was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was prepared by HPLC (apparatus: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm ×150mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid)) and lyophilized after purification to obtain the trifluoroacetic acid salt of compound 54 (81 mg, yield: 14.99%) .
LCMS m/z＝455.2[M+H] + LCMS m/z=455.2[M+H] +
1H NMR(400MHz,CD 3OD)δ8.15–8.02(m,1H),7.23(d,1H),7.06(s,1H),6.96–6.77(m,3H),6.73–6.54(m,1H),6.33(s,1H),5.29–4.94(m,2H),4.04–3.82(m,2H),3.21–3.02(m,3H),2.97–2.51(m,10H). 1 H NMR (400MHz, CD 3 OD) δ8.15–8.02 (m, 1H), 7.23 (d, 1H), 7.06 (s, 1H), 6.96–6.77 (m, 3H), 6.73–6.54 (m, 1H), 6.33 (s, 1H), 5.29–4.94 (m, 2H), 4.04–3.82 (m, 2H), 3.21–3.02 (m, 3H), 2.97–2.51 (m, 10H).
实施例55：反式-N-(2-(二甲基氨基)乙基)-2-氟-N-[3-[(6-(4-羟基-2-甲基苯基)-1H-吲唑-4-基)氧基]环丁基]丙-2-烯酰胺(化合物55)的三氟乙酸盐Example 55: trans-N-(2-(dimethylamino)ethyl)-2-fluoro-N-[3-[(6-(4-hydroxy-2-methylphenyl)-1H- Indazol-4-yl)oxy]cyclobutyl]prop-2-enamide (compound 55) trifluoroacetate salt
trans-N-(2-(dimethylamino)ethyl)-2-fluoro-N-[3-[(6-(4-hydroxy-2-methylphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]prop-2-enamide；trifluoroacetic acidtrans-N-(2-(dimethylamino)ethyl)-2-fluoro-N-[3-[(6-(4-hydroxy-2-methylphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]prop- 2-enamide; trifluoroacetic acid
Figure PCTCN2021117545-appb-000288
Figure PCTCN2021117545-appb-000288
第一步：反式-叔丁基N-(2-(二甲基氨基)乙基)-N-[3-[(6-(4-羟基-2-甲基苯基)-1-(四氢-2H-吡喃-2-基)-1H]-吲唑-4-基)氧基]环丁基]氨基甲酸酯(55A)The first step: trans-tert-butyl N-(2-(dimethylamino)ethyl)-N-[3-[(6-(4-hydroxy-2-methylphenyl)-1-( Tetrahydro-2H-pyran-2-yl)-1H]-indazol-4-yl)oxy]cyclobutyl]carbamate (55A)
trans-tert-butyl N-(2-(dimethylamino)ethyl)-N-[3-[(6-(4-hydroxy-2-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy]cyclobutyl]carbamatetrans-tert-butyl N-(2-(dimethylamino)ethyl)-N-[3-[(6-(4-hydroxy-2-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H -indazol-4-yl)oxy]cyclobutyl]carbamate
在50mL反应瓶中，依次加入23A(0.29g,0.54mmol)、3-甲基-4-(四甲基-1,3,2-二氧杂硼烷-2-基)苯酚(0.15g，0.65mmol)、七水合磷酸钾(0.55g，1.62mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(44mg，0.054mmol)和二氧六环/水(v/v＝4/1，10mL)，氮气置换三次后，在90℃下搅拌反应2小时。反应液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(DCM/MeOH(V/V)＝100/0-100/5)得到55A(0.29g，产率98％)。In a 50 mL reaction flask, were sequentially added 23A (0.29 g, 0.54 mmol), 3-methyl-4-(tetramethyl-1,3,2-dioxaboran-2-yl)phenol (0.15 g, 0.65 mmol), potassium phosphate heptahydrate (0.55 g, 1.62 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (44 mg, 0.054 mmol) and Dioxane/water (v/v=4/1, 10 mL), after nitrogen replacement three times, the reaction was stirred at 90° C. for 2 hours. 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 (DCM/MeOH (V/V)=100/0-100/5) to give 55A (0.29 g, 98% yield).
LCMS m/z＝565.3[M+H] + LCMS m/z=565.3[M+H] +
第二步：反式-N-(2-(二甲基氨基)乙基)-2-氟-N-[3-[(6-(4-羟基-2-甲基苯基)-1H-吲唑-4-基)氧基]环丁基]丙-2-烯酰胺(化合物55)的三氟乙酸盐The second step: trans-N-(2-(dimethylamino)ethyl)-2-fluoro-N-[3-[(6-(4-hydroxy-2-methylphenyl)-1H- Indazol-4-yl)oxy]cyclobutyl]prop-2-enamide (compound 55) trifluoroacetate salt
trans-N-(2-(dimethylamino)ethyl)-2-fluoro-N-[3-[(6-(4-hydroxy-2-methylphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]prop-2-enamide；trifluoroacetic acidtrans-N-(2-(dimethylamino)ethyl)-2-fluoro-N-[3-[(6-(4-hydroxy-2-methylphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]prop- 2-enamide; trifluoroacetic acid
在50mL反应瓶中，加入55A(0.14g，0.25mmol)和二氯甲烷/三氟乙酸(v/v＝1/1，10mL)，然后在室温下搅拌反应5小时。反应液减压浓缩干，残留物用甲基叔丁基醚(10mL×3)洗，然后减压浓缩干，加入5mL乙腈溶解，加入二异丙基乙胺(0.35g，2.7mmol)搅拌10min，待用。In a 50 mL reaction flask, 55A (0.14 g, 0.25 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with methyl tert-butyl ether (10 mL×3), then concentrated to dryness under reduced pressure, dissolved in 5 mL of acetonitrile, added with diisopropylethylamine (0.35 g, 2.7 mmol) and stirred for 10 min ,stand-by.
将2-氟丙烯酸(0.023g，0.25mmol)和二异丙基乙胺(60mg，0.46mmol)溶于二氯甲烷(5mL)和乙腈(5mL)的混合溶液中，加入三吡咯烷基溴化鏻六氟磷酸盐(0.12g，0.25mmol)，室温搅拌20min。将此反应液缓慢滴加到上述待用的乙腈溶液中，继续搅拌1h。加入10mL饱和碳酸氢钠水溶液，分液后，有机层用无水硫酸钠干燥后，减压浓缩，残留物用制备HPLC(仪器：waters 2767制备液相；色谱柱:SunFire@Prep C18(19mm×150mm)；流动相组成：流动相A：乙腈，流动相B：水(含0.1％三氟乙酸))分离纯化，得到化合物55的三氟乙酸盐(30mg,收率：27％)。2-Fluoroacrylic acid (0.023 g, 0.25 mmol) and diisopropylethylamine (60 mg, 0.46 mmol) were dissolved in a mixed solution of dichloromethane (5 mL) and acetonitrile (5 mL), and tripyrrolidinyl bromide was added. Phosphonium hexafluorophosphate (0.12 g, 0.25 mmol), stirred at room temperature for 20 min. The reaction solution was slowly added dropwise to the above-mentioned acetonitrile solution to be used, and stirring was continued for 1 h. 10 mL of saturated aqueous sodium bicarbonate was added, and after separation, the organic layer was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was prepared by preparative HPLC (apparatus: waters 2767; chromatographic column: SunFire@Prep C18 (19mm× 150mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid)) separation and purification to obtain compound 55 trifluoroacetic acid salt (30 mg, yield: 27%).
LCMS m/z＝453.3[M+H] + LCMS m/z=453.3[M+H] +
1H NMR(400MHz,CD 3OD)δ8.07(s,1H),7.06(d,1H),6.97(s,1H),6.72(d,1H),6.68-6.63(m,1H),6.22(s,1H),5.38-5.20(m,2H),5.01-4.92(m,2H),3.86(t,2H),3.34(t,2H),2.99(s,6H),2.85–2.73(m,2H),2.71-2.61(m,2H),2.20(s,3H). 1 H NMR (400MHz, CD 3 OD) δ 8.07(s, 1H), 7.06(d, 1H), 6.97(s, 1H), 6.72(d, 1H), 6.68-6.63(m, 1H), 6.22 (s,1H),5.38-5.20(m,2H),5.01-4.92(m,2H),3.86(t,2H),3.34(t,2H),2.99(s,6H),2.85–2.73(m ,2H),2.71-2.61(m,2H),2.20(s,3H).
生物测试例Biological test case
测试例1：对JAK1、JAK2、JAK3、TYK2激酶的抑制活性Test Example 1: Inhibitory activity against JAK1, JAK2, JAK3, TYK2 kinases
采用Cisbio公司的HTRF KinEASE-TK kit(货号：62TK0PEC)进行检测，具体方法如下：The HTRF KinEASE-TK kit (Item No.: 62TK0PEC) from Cisbio was used for detection. The specific method is as follows:
用1×kinase buffer稀释化合物，使其为终浓度的2.5倍；分别将酶JAK1、JAK2、JAK3与Tyk2(Carna；08-144、08-045、08-046与08-147)稀释成15μg/mL、0.185μg/mL、1.665μg/mL与5μg/mL；将ATP分别稀释成19.6μM(JAK1)、19.8μM(JAK2)、7.15μM(JAK3)与25.3μM(Tyk2)；将TK Substrate-biotin储存液稀释成10μM。Compounds were diluted with 1× kinase buffer to 2.5 times the final concentration; enzymes JAK1, JAK2, JAK3 and Tyk2 (Carna; 08-144, 08-045, 08-046 and 08-147) were diluted to 15 μg/ mL, 0.185 μg/mL, 1.665 μg/mL and 5 μg/mL; ATP was diluted to 19.6 μM (JAK1), 19.8 μM (JAK2), 7.15 μM (JAK3) and 25.3 μM (Tyk2), respectively; TK Substrate-biotin Stock solutions were diluted to 10 μM.
用1×kinase buffer进行10μL激酶反应：测试化合物或阳性4μL+TK Substrate-biotin 2μL+酶2μL+ATP 2μL，混匀并室温孵育2小时(JAK1)、30分钟(JAK2与JAK3)或50分钟(Tyk2)后，加入5μL Streptavidin-XL665(500nM)和5μL TK Antibody-cryptate(1×)，继续室温孵育1小时。酶标仪(PHERAstar FSX)测定665nm与620nm荧光值。根据式(1)计算信号比值Ratio，使用origin 9.2计算和分析IC 50。 10 μL kinase reaction with 1× kinase buffer: test compound or positive 4 μL + TK Substrate-biotin 2 μL + enzyme 2 μL + ATP 2 μL, mix well and incubate at room temperature for 2 hours (JAK1), 30 minutes (JAK2 and JAK3) or 50 minutes (Tyk2) ), 5 μL Streptavidin-XL665 (500 nM) and 5 μL TK Antibody-cryptate (1×) were added, and the incubation was continued for 1 hour at room temperature. Fluorescence values at 665 nm and 620 nm were measured by a microplate reader (PHERAstar FSX). Calculate the signal ratio Ratio according to formula (1), and use origin 9.2 to calculate and analyze IC 50 .
Ratio＝[Signal 665]/[Signal 620]×10 4    (式1) Ratio=[Signal 665]/[Signal 620]×10 4 (Formula 1)
本发明化合物JAK1、JAK2、JAK3与Tyk2激酶的抑制活性通过以上的实验进行测定，测得的IC 50值见下表1。 The inhibitory activities of the compounds of the present invention JAK1, JAK2, JAK3 and Tyk2 kinases were determined by the above experiments, and the measured IC50 values are shown in Table 1 below.
表1测试化合物JAK1、JAK2、JAK3与Tyk2激酶的抑制活性结果Table 1 Results of inhibitory activity of test compounds JAK1, JAK2, JAK3 and Tyk2 kinases
Figure PCTCN2021117545-appb-000289
Figure PCTCN2021117545-appb-000289
Figure PCTCN2021117545-appb-000290
Figure PCTCN2021117545-appb-000290
Figure PCTCN2021117545-appb-000291
Figure PCTCN2021117545-appb-000291
结论：本发明的化合物对JAK激酶家族有选择性抑制作用，对JAK3激酶有很好的抑制作用，对JAK3激酶具有高选择性。化合物1、6、7、9、10、11、12、13、15、16、17、18、19、20、24、28、29、31、32、34、35、36、37、38、39、40、41、42、44、45、46、47、48、49、50、51、52、53、55对JAK3的活性IC 50为0.1～5nM，化合物2、3、5、14、22、23、25、26、27、30、43、54对JAK3的活性IC 50为5～10nM。 Conclusion: The compounds of the present invention have selective inhibitory effect on JAK kinase family, have good inhibitory effect on JAK3 kinase, and have high selectivity to JAK3 kinase. Compounds 1, 6, 7, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19, 20, 24, 28, 29, 31, 32, 34, 35, 36, 37, 38, 39 , 40, 41, 42, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 55 had an activity IC 50 of 0.1 to 5 nM for JAK3, compounds 2, 3, 5, 14, 22, The IC50 of 23, 25, 26, 27, 30, 43, 54 against JAK3 was 5-10 nM.
测试例2：IL-2与anti-CD3刺激hPBMC分泌IFNγ实验Test Example 2: IL-2 and anti-CD3 stimulate hPBMC to secrete IFNγ
取健康志愿者外周血至含肝素钠的抗凝管中，加入等体积无菌PBS充分混匀，以降低血液粘稠度并减少红细胞聚集。向50mL离心管加入密度为1.077的Ficoll(GE Healthcare；17-1440-02)，然后用移液枪吸取稀释后的血液，在离分层液面上1厘米处，沿管壁缓慢加入分层液面上(外周血、PBS与Ficoll最终体积比为1:1:1)。400g、室温下离心30min，离心时升降速率均调整为1。用移液枪沿管壁周缘插入到单个核细胞层，吸取单个核细胞于另一离心管中，加入5倍以上体积的PBS，300g、室温下离心10min(升降速率均调整为9)，洗涤细胞两次。弃上清，加入1mL完全培养基(RPMI 1640+10％胎牛血清+1×青霉素-链霉素溶液)重悬细胞并计数，调整细胞密度至细胞密度至4×10 6/mL。 The peripheral blood of healthy volunteers was taken into an anticoagulant tube containing heparin sodium, and an equal volume of sterile PBS was added to mix thoroughly to reduce blood viscosity and red blood cell aggregation. Ficoll (GE Healthcare; 17-1440-02) with a density of 1.077 was added to a 50 mL centrifuge tube, and then the diluted blood was drawn with a pipette, and the layer was slowly added along the tube wall at 1 cm from the surface of the separation layer. Liquid surface (final volume ratio of peripheral blood, PBS and Ficoll is 1:1:1). Centrifuge at 400 g for 30 min at room temperature, and adjust the lift rate to 1 during centrifugation. Use a pipette to insert into the mononuclear cell layer along the periphery of the tube wall, suck the mononuclear cells into another centrifuge tube, add more than 5 times the volume of PBS, centrifuge at 300 g for 10 min at room temperature (the lift rate is adjusted to 9), wash cells twice. The supernatant was discarded, and 1 mL of complete medium (RPMI 1640+10% fetal bovine serum+1×penicillin-streptomycin solution) was added to resuspend the cells and counted, and the cell density was adjusted to 4×10 6 /mL.
以每孔2×10 5个细胞(50μL)铺板于96孔板中，在37℃、5％CO 2条件下孵育1h，然后加入化合物100μL/孔，继续在37℃、5％CO 2条件下孵育1h。每孔加入50μL终浓度为100ng/mL的IL-2(R&D Systems；202-IL-050)与终浓度为1μg/mL的anti-CD3(BD Pharmingen；555329)，在37℃、5％CO 2条件下孵育24h。在4℃、500g条件下离心5min，取上清150μL。使用人IFNγQuantikine ELISA试剂盒(R&D Systems；SIF50C)检测上清中IFNγ浓度，并使用Origin 2019b拟合并计算化合物的IC 50值。 Plate 2×10 5 cells (50 μL) per well in a 96-well plate, incubate at 37°C, 5% CO 2 for 1 h, then add compound 100 μL/well, continue at 37° C, 5% CO 2 condition Incubate for 1h. 50 μL of IL-2 (R&D Systems; 202-IL-050) at a final concentration of 100 ng/mL and anti-CD3 (BD Pharmingen; 555329) at a final concentration of 1 μg/mL were added to each well at 37°C, 5% CO 2 . Incubate for 24h under conditions. Centrifuge at 4 °C and 500 g for 5 min, and take 150 μL of the supernatant. The IFNγ concentration in the supernatant was detected using a human IFNγ Quantikine ELISA kit (R&D Systems; SIF50C), and the IC50 values of the compounds were fitted and calculated using Origin 2019b.
表2测试化合物对IL-2与anti-CD3刺激hPBMC分泌IFNγ的抑制活性结果Table 2 Inhibitory activity results of test compounds on IL-2 and anti-CD3 stimulated hPBMC to secrete IFNγ
化合物编号Compound number IC 50(nM) IC50 (nM)
化合物6Compound 6 <100<100
化合物13Compound 13 11.711.7
化合物24Compound 24 <100<100
化合物31Compound 31 3.093.09
化合物37的乙酸盐Acetate salt of compound 37 10.810.8
化合物38Compound 38 <100<100
化合物47的三氟乙酸盐Trifluoroacetate salt of compound 47 <100<100
化合物50的乙酸盐Acetate salt of compound 50 <100<100
化合物52Compound 52 <100<100
化合物53Compound 53 19.719.7
结论：本发明的化合物对IL-2与anti-CD3刺激hPBMC分泌IFNγ具有很好的抑制作用，实施例化合物对IL-2与anti-CD3刺激hPBMC分泌IFNγ的抑制作用IC 50<1μM，例如化合物13、31、37和53的IC 50见表2。 Conclusion: The compounds of the present invention have a good inhibitory effect on the secretion of IFNγ from hPBMC stimulated by IL-2 and anti-CD3. The inhibitory effect of the compounds in the examples on the secretion of IFNγ from hPBMC stimulated by IL-2 and anti-CD3 IC 50 <1μM, such as the compound The IC50s of 13, 31 , 37 and 53 are shown in Table 2.
测试例3：大鼠肠血比实验Test Example 3: Rat Intestinal Blood Ratio Experiment
3.1.试验动物：SD大鼠，200-250g，雄性，6～8周龄，42只，购于成都达硕实验动物有限公司，生产许可证号：SCXK(川)2020-030。3.1. Experimental animals: SD rats, 200-250 g, male, 6-8 weeks old, 42, purchased from Chengdu Dashuo Laboratory Animal Co., Ltd., production license number: SCXK (Chuan) 2020-030.
3.2.实验设计：3.2. Experimental design:
Figure PCTCN2021117545-appb-000292
Figure PCTCN2021117545-appb-000292
静脉给药溶媒：5％DMA(N,N-二甲基乙酰胺)+5％Solutol(聚乙二醇-15-羟基硬脂酸酯)+90％Saline(生理盐水)；灌胃给药溶媒：0.5％MC(甲基纤维素)Vehicle for intravenous administration: 5% DMA (N,N-dimethylacetamide) + 5% Solutol (polyethylene glycol-15-hydroxystearate) + 90% Saline (physiological saline); intragastric administration Solvent: 0.5% MC (methyl cellulose)
于给药前及给药后异氟烷麻醉经眼眶取血0.1mL，置于EDTAK2离心管中，5000rpm，4℃离心10min，收集血浆。静脉组采血时间点：0min,5min,0.25h,0.5h,1h,2h,4h,6h,8h和24h；灌胃组采血时间点：1h,2h,4h,6h,8h和24h；分析检测前，所有血浆样品存于-80℃。Before and after administration of isoflurane anesthesia, 0.1 mL of blood was collected from the orbit, placed in an EDTAK2 centrifuge tube, centrifuged at 5000 rpm for 10 min at 4°C, and plasma was collected. Blood collection time points of venous group: 0min, 5min, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h and 24h; blood collection time points of gavage group: 1h, 2h, 4h, 6h, 8h and 24h; before analysis and detection , all plasma samples were stored at -80°C.
灌胃组结肠组织样本采集时间点：1h,2h,4h,6h,8h以及24h。动物放血干净安乐死后取结肠组织，生理盐水清洗干净后用50％冰甲醇按m/v＝1:10比例匀浆后-80°冰箱保存待分析。The collection time points of colon tissue samples in the gavage group: 1h, 2h, 4h, 6h, 8h and 24h. After the animals were bled and euthanized, colon tissue was collected, washed with normal saline, homogenized with 50% ice methanol at a ratio of m/v=1:10, and stored in a -80° refrigerator for analysis.
表3.测试化合物大鼠肠血比的结果Table 3. Results of test compound rat intestinal blood ratio
Figure PCTCN2021117545-appb-000293
Figure PCTCN2021117545-appb-000293
Figure PCTCN2021117545-appb-000294
Figure PCTCN2021117545-appb-000294
结论：发明的实施例化合物在大鼠结肠中表现出良好的暴露量，结肠/血浆药物浓度(暴露)比值高，且暴露量和结肠/血浆药物浓度(暴露)比值明显优于WO2019027960-化合物1。Conclusion: The example compounds of the invention show good exposure in rat colon, the colon/plasma drug concentration (exposure) ratio is high, and the exposure and colon/plasma drug concentration (exposure) ratio are significantly better than WO2019027960-Compound 1 .
测试例4：小鼠肠血比实验Test Example 4: Mouse Intestinal Blood Ratio Experiment
4.1.试验动物：BALB/c小鼠，～25g，雄性，6～8周龄，90只，购于成都达硕实验动物有限公司，生产许可证号：SCXK(川)2020-030。4.1. Experimental animals: BALB/c mice, ~25 g, male, 6-8 weeks old, 90 mice, purchased from Chengdu Dashuo Laboratory Animal Co., Ltd., production license number: SCXK (Chuan) 2020-030.
4.2.实验设计：4.2. Experimental design:
Figure PCTCN2021117545-appb-000295
Figure PCTCN2021117545-appb-000295
灌胃给药溶媒：0.5％MC(甲基纤维素)Oral administration vehicle: 0.5% MC (methyl cellulose)
于给药前及给药后异氟烷麻醉经眼眶取血0.06mL，置于EDTAK2离心管中，5000rpm，4℃离心10min，收集血浆。采血时间点：2h,6h,8h,10h以及16h。分析检测前，所有血浆样品存于-80℃。Before and after administration of isoflurane anesthesia, 0.06 mL of blood was collected from the orbit, placed in an EDTAK2 centrifuge tube, centrifuged at 5000 rpm for 10 min at 4°C, and plasma was collected. Blood collection time points: 2h, 6h, 8h, 10h and 16h. All plasma samples were stored at -80°C prior to analytical testing.
给药组结肠组织样本采集时间点：2h,6h,8h,10h以及16h。动物放血干净安乐死后取结肠组织，生理盐水清洗干净后用50％甲醇按m/v＝1:9比例匀浆后-80°冰箱保存待分析。Time points of colon tissue sample collection in the administration group: 2h, 6h, 8h, 10h and 16h. After the animals were bled and euthanized, colon tissue was collected, washed with normal saline, homogenized with 50% methanol at a ratio of m/v=1:9, and stored in a -80° refrigerator for analysis.
表4.测试化合物小鼠肠血比的结果Table 4. Results of test compound mouse intestinal blood ratio
Figure PCTCN2021117545-appb-000296
Figure PCTCN2021117545-appb-000296
结论：发明的实施例化合物在小鼠结肠中表现出良好的暴露量，结肠/血浆药物浓度(暴露)比值高。Conclusion: The inventive example compounds showed good exposure in mouse colon with a high colon/plasma drug concentration (exposure) ratio.
测试例5：IL-2/anti-CD3诱导人PBMC细胞中STAT5磷酸化实验Test Example 5: IL-2/anti-CD3-induced STAT5 phosphorylation experiment in human PBMC cells
取健康志愿者外周血至抗凝管中，将其与PBS按照1:1充分混匀稀释。在10mL离心分离管(Greiner bioone，Cat#163290)底部加入适量Ficoll，将稀释后的血液沿管壁缓慢加入，在室温、400×g条件下离心30分钟，离心后吸取单个核细胞置入另一离心管中，加入5倍体积PBS。在室温、300×g条件下离心10分钟后，洗涤细胞两次。末次离心后，弃上清，加入1mL HBSS重悬细胞并计数。化合物用DMSO溶解配成10mM母液，用HBSS稀释至3倍终浓度备用；384孔板每孔加入4μL细胞液与2μL化合物在37℃、5％CO 2条件下培养1小时(空白孔和阴性对照孔加2μL含3‰DMSO的HBSS)。加入2 μL含400ng/mL IL-2(R&D，Cat#202-IL-050)与4μg/mL anti-CD3(BD，Cat#555329)的混合液后，在37℃、5％CO 2条件下孵育0.5小时。后续使用p-STAT5 AlphaLisa试剂盒(PE，Cat#ALSU-PST5-B500)按如下步骤检测：每孔加入2μL的5×裂解液，封板，低速震荡10分钟；配制受体混合液(包含反应缓冲液1、反应缓冲液2、激活缓冲液与受体微珠)，每孔加入2.5μL受体混合液，封板，避光低速震荡2分钟后室温孵育1.5小时；配制供体混合液(包含稀释缓冲液与受体微珠)，并每孔加入2.5μL供体混合液，封板，避光低速震荡2分钟后室温孵育1.5小时。用BMG酶标仪(PHERAstar FSX)读板检测后，使用Origin 9.2软件中DoseResp函数拟合得出IC 50值。 The peripheral blood of healthy volunteers was taken into anticoagulation tubes, and it was thoroughly diluted with PBS at 1:1. Add an appropriate amount of Ficoll to the bottom of a 10 mL centrifuge tube (Greiner bioone, Cat#163290), slowly add the diluted blood along the tube wall, and centrifuge at room temperature and 400 × g for 30 minutes. In a centrifuge tube, add 5 volumes of PBS. After centrifugation at 300 x g for 10 min at room temperature, cells were washed twice. After the final centrifugation, the supernatant was discarded, and 1 mL of HBSS was added to resuspend the cells and counted. Compounds were dissolved in DMSO to prepare a 10 mM stock solution, diluted with HBSS to 3 times the final concentration for use; 4 μL of cell fluid and 2 μL of compound were added to each well of a 384-well plate and incubated for 1 hour at 37°C under 5% CO 2 (blank wells and negative controls). Add 2 μL of HBSS containing 3‰ DMSO to the wells). After adding 2 μL of a mixture containing 400 ng/mL IL-2 (R&D, Cat#202-IL-050) and 4 μg/mL anti-CD3 (BD, Cat#555329), at 37°C, 5% CO 2 Incubate for 0.5 hours. Subsequently, the p-STAT5 AlphaLisa kit (PE, Cat#ALSU-PST5-B500) was used for detection as follows: add 2 μL of 5× lysis buffer to each well, seal the plate, and shake at low speed for 10 minutes; Buffer 1, Reaction Buffer 2, Activation Buffer and Acceptor Beads), add 2.5 μL of the acceptor mixture to each well, seal the plate, shake at low speed in the dark for 2 minutes, and then incubate at room temperature for 1.5 hours; prepare the donor mixture ( Including dilution buffer and acceptor beads), add 2.5 μL of donor mixture to each well, seal the plate, shake at low speed in the dark for 2 minutes, and then incubate at room temperature for 1.5 hours. After plate reading and detection with BMG microplate reader (PHERAstar FSX), the IC 50 value was obtained by fitting the DoseResp function in Origin 9.2 software.
表5.化合物对IL-2/anti-CD3诱导人PBMC细胞中STAT5磷酸化的抑制活性IC 50值 Table 5. IC50 values of compound inhibitory activity on IL-2/anti-CD3-induced STAT5 phosphorylation in human PBMC cells
化合物compound IC 50(nM) IC50 (nM)
化合物37Compound 37 <500<500
结论：本发明的实施例化合物对IL-2/anti-CD3诱导人PBMC细胞中STAT5磷酸化具有抑制活性。Conclusion: The example compounds of the present invention have inhibitory activity on IL-2/anti-CD3-induced STAT5 phosphorylation in human PBMC cells.

Claims (12)

  1. 一种化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，化合物选自通式(I)所示的化合物，其中A compound or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, the compound is selected from the compound represented by the general formula (I), wherein
    Figure PCTCN2021117545-appb-100001
    Figure PCTCN2021117545-appb-100001
    Y 1、Y 2、Y 3各自独立的选自CH或N； Y 1 , Y 2 , and Y 3 are each independently selected from CH or N;
    环A选自5至6元杂环或杂芳环，所述的杂环或杂芳环任选进一步被0至3个R a取代基所取代，所述的杂环或杂芳环含有1至4个选自O、S、N的杂原子； Ring A is selected from a 5- to 6-membered heterocyclic or heteroaromatic ring optionally further substituted by 0 to 3 R a substituents, and the heterocyclic or heteroaromatic ring contains 1 to 4 heteroatoms selected from O, S, N;
    R a各自独立的选自H、＝O、卤素、氰基、C 1-6烷基、C 1-6烷氧基、-(CH 2) q-C(＝O)-NR a1R a2、-(CH 2) q-NR a1R a2、-(CH 2) qNR a1C(＝O)-R a2、-(CH 2) q-C 3-10碳环或-(CH 2) q-3至12元杂环，所述的CH 2、烷基、烷氧基、碳环或杂环任选进一步被0至4个选自H、卤素、CF 3、OH、氰基、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子； R a is each independently selected from H, =O, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, -(CH 2 ) q -C(=O)-NR a1 R a2 , -(CH 2 ) q -NR a1 R a2 , -(CH 2 ) q NR a1 C(=O)-R a2 , -(CH 2 ) q -C 3-10 carbocyclic or -(CH 2 ) q - 3- to 12-membered heterocycle, said CH 2 , alkyl, alkoxy, carbocycle or heterocycle is optionally further 0 to 4 selected from H, halogen, CF 3 , OH, cyano, COOH, NH 2. Substituted by C 1-4 alkyl or C 1-4 alkoxy substituent, the heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
    环B选自C 3-10碳环，所述的碳环任选进一步被0至4个R b取代； Ring B is selected from C 3-10 carbocyclic rings optionally further substituted by 0 to 4 R b ;
    R b各自独立的选自H、卤素、氰基、C 1-6烷基或C 1-6烷氧基，所述的烷基或烷氧基任选进一步被0至4个选自H、卤素、CF 3、OH、氰基、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基或C 3-8环烷基的取代基所取代； Each R b is independently selected from H, halogen, cyano, C 1-6 alkyl or C 1-6 alkoxy, and said alkyl or alkoxy is optionally further 0 to 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 substituents;
    L 1选自键、-S(O) n-、-NR 1a-、-CR 1bR 1c-、-O(CR 1bR 1c) s-、-(CR 1bR 1c) sO-、-NR 1aCR 1bR 1c-、-NR 1aS(O) n-、-S(O) nNR 1a-、-NR 1aC(O)-、-C(O)NR 1a-、-SCR 1bR 1c-或-CR 1bR 1cS-； 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或R 1c各自独立的选自H、C 1-4烷基或-(CH 2) p-C 3-6碳环，所述的烷基或碳环任选进一步被0至4个选自H、卤素、OH、CF 3、氰基、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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 optionally further substituted by 0 to substituted with 4 substituents selected from H, halogen, OH, CF 3 , cyano, C 1-4 alkyl or C 1-4 alkoxy;
    作为选择，R 1b、R 1c与其直接相连的碳原子一起形成3元碳环； Alternatively, R 1b and R 1c together with the carbon atoms to which they are directly connected form a 3-membered carbocyclic ring;
    环C选自5-6元杂芳基或苯基，所述的杂芳基或苯基任选进一步被0至4个R c取代； Ring C is selected from 5-6 membered heteroaryl or phenyl, and said heteroaryl or phenyl is optionally further substituted by 0 to 4 R c ;
    R c各自独立的选自H、卤素、OH、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、-(CH 2) m-C(＝O)-NR 3aR 3b、-(CH 2) m-NR 3aR 3b、-(CH 2) mNR 3aC(＝O)-R 3b、-(CH 2) m-C(＝O)R 3a、-(CH 2) m-C(＝O)OR 3a、-(CH 2) m-OC(＝O)R 3a、-(CH 2) m-3至12元杂环基或-(CH 2) m-C 3-10碳环基，所述的CH 2、烷基、烯基、炔基、烷氧基、碳环或杂环任选进一步被0至4个选自H、卤素、 CF 3、＝O、OH、氰基、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、-C 1-4亚烷基-羟基、C 3-6碳环基或3至8元杂环基的取代基所取代，所述的杂环基含有1至3个选自O、S、N的杂原子； R c is each independently selected from H, halogen, OH, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -(CH 2 ) m -C(=O)-NR 3a R 3b , -(CH 2 ) m -NR 3a R 3b , -(CH 2 ) m NR 3a C(=O)-R 3b , -(CH 2 ) m -C (=O)R 3a , -(CH 2 ) m -C(=O)OR 3a , -(CH 2 ) m -OC(=O)R 3a , -(CH 2 ) m -3- to 12-membered heterocycle or -(CH 2 ) m -C 3-10 carbocyclyl, said CH 2 , alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle are optionally further selected from 0 to 4 From H, halogen, CF 3 , =O, OH, cyano, COOH, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , C 1-4 alkyl , C 1-4 alkoxy, -C 1-4 alkylene-hydroxyl, C 3-6 carbocyclyl or 3- to 8-membered heterocyclyl substituents, the heterocyclyl containing 1 to 8 3 heteroatoms selected from O, S, N;
    R a1、R a2、R 3a、R 3b各自独立的选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-12碳环基或3至12元杂环基，所述的烷基、烯基、炔基、烷氧基、碳环基或杂环基任选进一步被0至4个选自H、卤素、CF 3、OH、氰基、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环基含有1至3个选自O、S、N的杂原子； 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 is optionally further 0 to 4 selected from H, halogen, Substituents of CF 3 , OH, cyano, COOH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy, the heterocyclic group contains 1 to 3 selected from O, S, heteroatom of N;
    R 5选自
    Figure PCTCN2021117545-appb-100002
    R 5 is selected from
    Figure PCTCN2021117545-appb-100002
    R 5a、R 5b、R 5c各自独立的选自H、卤素、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8碳环基或3至10元杂环基，所述的烷基、烷氧基、碳环基或杂环基任选进一步被0至4个选自H、卤素、CF 3、＝O、OH、氰基、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3-6环烷基)、C 1-4烷基、C 1-4烷氧基或-SC 1-4烷基的取代基所取代，所述的杂环基含有1至3个选自O、S、N的杂原子； R 5a , R 5b , R 5c are each independently selected from H, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 carbocyclyl or 3- to 10-membered heterocyclyl , the alkyl group, alkoxy group, carbocyclic group or heterocyclic group is optionally further selected from 0 to 4 groups selected from H, halogen, CF 3 , =O, OH, cyano group, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -NH(C 3-6 cycloalkyl), C 1-4 alkyl, C 1-4 alkoxy or -SC 1- 4 is substituted by a substituent of an alkyl group, and the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;
    作为选择，R 5b与R 5c可形成化学键； Alternatively, R 5b and R 5c may form a chemical bond;
    R 5d、R 5e各自独立的选自H、C 1-6烷基、C 3-8碳环基或3至10元杂环基，所述的烷基、碳环基或杂环基任选进一步被0至4个选自H、卤素、CF 3、＝O、OH、氰基、NH 2、-NH(C 1- 4烷基)、-N(C 1-4烷基) 2、-NH(C 3-6环烷基)、C 1-4烷基、C 1-4烷氧基或-SC 1-4烷基的取代基所取代，所述的杂环基含有1至3个选自O、S、N的杂原子； 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, and said alkyl, carbocyclyl or heterocyclyl are optional is further selected from H, halogen, CF 3 , =O, OH, cyano, NH 2 , -NH(C 1-4 alkyl ) , -N(C 1-4 alkyl) 2 , - NH (C 3-6 cycloalkyl), C 1-4 alkyl, C 1-4 alkoxy or -SC 1-4 alkyl substituent, the heterocyclic group contains 1 to 3 Heteroatoms selected from O, S, N;
    作为选择，R 5d、R 5e与其直接相连的氮原子一起形成4至8元杂环基，所述杂环基任选进一步被0至4个选自H、卤素、CF 3、＝O、OH、氰基、C 1-4烷基、C 1-4烷氧基或-C 1-4亚烷基-C 1-4烷氧基的取代基取代，所述杂环基含有1至3个选自O、S、N的杂原子； Alternatively, R 5d , R 5e together with the nitrogen atom to which they are directly attached form a 4- to 8-membered heterocyclyl group optionally further substituted by 0 to 4 members selected from H, halogen, CF 3 , =O, OH , cyano, C 1-4 alkyl, C 1-4 alkoxy or -C 1-4 alkylene-C 1-4 alkoxy substituent, the heterocyclic group contains 1 to 3 Heteroatoms selected from O, S, N;
    R 5f选自H、C 1-6烷基、-C 0-4烷基-3至8元杂环基、-C 1-4烷基-C 3-6环烷基、C 3-6环烷基，所述的烷基、环烷基或杂环基任选进一步被0至4个选自H、卤素、CF 3、＝O、OH、氰基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、NH 2、-C(＝O)NH(C 1-4烷基)、-C(＝O)N(C 1-4烷基) 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3-6环烷基)、3至8元杂环基的取代基取代，所述杂环基含有1至3个选自O、S、N的杂原子； R 5f is selected from H, C 1-6 alkyl, -C 0-4 alkyl-3- to 8-membered heterocyclyl, -C 1-4 alkyl-C 3-6 cycloalkyl, C 3-6 ring Alkyl, said alkyl, cycloalkyl or heterocyclyl optionally further selected from 0 to 4 groups selected from H, halogen, CF 3 , =O, OH, cyano, C 1-4 alkyl, C 1 -4 alkoxy, C 3-6 cycloalkyl, NH 2 , -C(=O)NH(C 1-4 alkyl), -C(=O)N(C 1-4 alkyl) 2 , Substituents of -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -NH(C 3-6 cycloalkyl), 3- to 8-membered heterocyclic groups, the heterocyclic group The cyclic group contains 1 to 3 heteroatoms selected from O, S, N;
    n、s选自0、1或2；n and s are selected from 0, 1 or 2;
    m、p、q各自独立的选自0、1、2、3或4。m, p, q are each independently selected from 0, 1, 2, 3 or 4.
  2. 根据权利要求1所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，The compound of claim 1, or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
    Figure PCTCN2021117545-appb-100003
    选自
    Figure PCTCN2021117545-appb-100004
    右侧与L 1直接连接；
    Figure PCTCN2021117545-appb-100003
    selected from
    Figure PCTCN2021117545-appb-100004
    The right side is directly connected to L 1 ;
    Figure PCTCN2021117545-appb-100005
    选自
    Figure PCTCN2021117545-appb-100006
    Figure PCTCN2021117545-appb-100005
    selected from
    Figure PCTCN2021117545-appb-100006
    X 1选自N或CR a； X 1 is selected from N or CR a ;
    R a选自H、卤素、氰基、C 1-4烷基、C 1-4烷氧基、-(CH 2) q-C(＝O)-NR a1R a2、-(CH 2) q-NR a1R a2、-(CH 2) qNR a1C(＝O)-R a2、-(CH 2) q-C 3-6碳环或-(CH 2) q-3至6元杂环，所述的CH 2、烷基、烷氧基、碳环或杂环任选进一步被0至4个选自H、卤素、CF 3、OH、氰基、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子； R a is selected from H, halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, -(CH 2 ) q -C(=O)-NR a1 R a2 , -(CH 2 ) q -NR a1 R a2 , -(CH 2 ) q NR a1 C(=O)-R a2 , -(CH 2 ) q -C 3-6 carbocycle or -(CH 2 ) q -3- to 6-membered heterocycle , the CH 2 , alkyl, alkoxy, carbocycle or heterocycle is optionally further selected from 0 to 4 groups selected from H, halogen, CF 3 , OH, cyano, COOH, NH 2 , C 1-4 Alkyl or C 1-4 alkoxy substituents, the heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
    环B选自C 3-6饱和或不饱和单环碳环、C 5-10饱和或不饱和螺环碳环、C 5-10饱和或不饱和并环碳环、C 5-10饱和或不饱和桥环碳环，所述碳环任选进一步被0至4个R b取代； 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 carbocycle optionally further substituted with 0 to 4 R;
    R b各自独立的选自H、卤素、氰基、C 1-4烷基或C 1-4烷氧基，所述的烷基或烷氧基任选进一步被0至4个选自H、卤素、CF 3、OH、氰基、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基或C 3-8环烷基的取代基所取代； R b is each independently selected from H, halogen, cyano, C 1-4 alkyl or C 1-4 alkoxy, and said alkyl or alkoxy is optionally further 0 to 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 substituents;
    L 1选自键、-O-、-S(O) n-、-NR 1a-、-CR 1bR 1c-、-OCR 1bR 1c-、-O(CR 1bR 1c) 2-、-CR 1bR 1cO-、-NR 1aCR 1bR 1c-、-SCR 1bR 1c-或-CR 1bR 1cS-； 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 1、R 2、R 3、R 4各自独立的选自H、卤素、OH、氰基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、-(CH 2) m-C(＝O)-NR 3aR 3b、-(CH 2) m-NR 3aR 3b、-(CH 2) mNR 3aC(＝O)-R 3b、-(CH 2) m-C(＝O)R 3a、-(CH 2) m-C(＝O)OR 3a、-(CH 2) m-OC(＝O)R 3a、-(CH 2) m-3至10元杂环或-(CH 2) m-C 3-8碳环，所述的CH 2、烷基、烯基、炔基、烷氧基、碳环或杂环任选进一步被0至4个选自H、卤素、CF 3、＝O、OH、氰基、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、-C 1-4亚烷基-羟基、C 3-6环烷基或3至8元杂环基的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子； R 1 , R 2 , R 3 , R 4 are each independently selected from H, halogen, OH, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 Alkoxy, -(CH 2 ) m -C(=O)-NR 3a R 3b , -(CH 2 ) m -NR 3a R 3b , -(CH 2 ) m NR 3a C(=O)-R 3b , -(CH 2 ) m -C(=O)R 3a , -(CH 2 ) m -C(=O)OR 3a , -(CH 2 ) m -OC(=O)R 3a , -(CH 2 ) m -3 to 10-membered heterocycle or -(CH 2 ) m -C 3-8 carbocycle, said CH 2 , alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle are optional is further selected from 0 to 4 by H, halogen, CF 3 , =O, OH, cyano, COOH, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, -C 1-4 alkylene-hydroxy, C 3-6 cycloalkyl or 3- to 8-membered heterocyclic substituents, the said The heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, N;
    R a1、R a2、R 3a、R 3b各自独立的选自H、C 1-4烷基、C 3-6碳环基或3至6元杂环基，所述的烷基、碳环基或杂环基任选进一步被0至4个选自H、卤素、CF 3、OH、氰基、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环基含有1至3个选自O、S、N的杂原子； 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 optionally further substituted with 0 to 4 substituents selected from H, halogen, CF3 , OH, cyano, COOH, NH2 , C1-4alkyl or C1-4alkoxy , the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, N;
    R 5a、R 5b、R 5c各自独立的选自H、卤素、氰基、C 1-4烷基、C 1-4烷氧基、3至6元碳环基或3至8元杂环基，所述的烷基、烷氧基、碳环基或杂环基任选进一步被0至4个选自H、卤素、＝O、OH、氰基、CF 3、C 1-4烷基、C 1-4烷氧基或-SC 1-4烷基的取代基所取代，所述的杂环基含有1至3个选自O、S、N的杂原子； R 5a , R 5b , R 5c are each independently selected from H, halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, 3- to 6-membered carbocyclyl or 3- to 8-membered heterocyclyl , the alkyl group, alkoxy group, carbocyclic group or heterocyclic group is optionally further selected from 0 to 4 groups selected from H, halogen, =O, OH, cyano, CF 3 , C 1-4 alkyl, C 1-4 alkoxy or -SC 1-4 alkyl substituent, the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, N;
    作为选择，R 5b与R 5c可形成化学键； Alternatively, R 5b and R 5c may form a chemical bond;
    R 5d、R 5e各自独立的选自H、C 1-4烷基、3至6元碳环或3至8元杂环，所述的烷基、碳环或杂环任选进一步被0至4个选自H、卤素、CF 3、＝O、OH、氰基、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3-6环烷基)、C 1-4烷基、C 1-4烷氧基或-SC 1-4烷基的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子； 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, and the alkyl, carbocycle or heterocycle is optionally further substituted by 0 to 8 4 selected from H, halogen, CF 3 , =O, OH, cyano, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -NH(C 3 -6 cycloalkyl), C 1-4 alkyl, C 1-4 alkoxy or -SC 1-4 alkyl substituent, the heterocycle contains 1 to 3 selected from O, S , N heteroatoms;
    作为选择，R 5d、R 5e与其直接相连的氮原子一起形成4至6元杂环，所述杂环任选进一步被0至4个选自H、卤素、CF 3、＝O、OH、氰基、C 1-4烷基、C 1-4烷氧基或-C 1-4亚烷基-C 1- 4烷氧基的取代基取代，所述杂环含有1至3个选自O、S、N的杂原子； Alternatively, R 5d , R 5e together with the nitrogen atom to which they are directly attached form a 4- to 6-membered heterocycle optionally further substituted by 0 to 4 selected from H, halogen, CF 3 , =O, OH, cyano substituted by substituents of radical, C 1-4 alkyl, C 1-4 alkoxy or -C 1-4 alkylene-C 1-4 alkoxy, the heterocycle contains 1 to 3 selected from O , S, N heteroatoms;
    R 5f选自H、C 1-4烷基、3至8元杂环基、-C 1-4烷基-3至8元杂环基、-C 1-4烷基-C 3-6环烷基或C 3-6环烷基，所述的烷基、环烷基或杂环基任选进一步被0至4个选自H、卤素、CF 3、＝O、OH、氰基、C 1-4烷基、C 1-4烷氧基、NH 2、-C(＝O)NH(C 1-4烷基)、-C(＝O)N(C 1-4烷基) 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3-6环烷基)、3至8元杂环基、C 3-6环烷基的取代基取代，所述杂环基含有1至3个选自O、S、N的杂原子。 R 5f is selected from H, C 1-4 alkyl, 3- to 8-membered heterocyclyl, -C 1-4 alkyl-3 to 8-membered heterocyclyl, -C 1-4 alkyl-C 3-6 ring Alkyl or C 3-6 cycloalkyl, said alkyl, cycloalkyl or heterocyclyl optionally further selected from 0 to 4 groups selected from H, halogen, CF 3 , =O, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy, NH 2 , -C(=O)NH(C 1-4 alkyl), -C(=O)N(C 1-4 alkyl) 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -NH(C 3-6 cycloalkyl), 3- to 8-membered heterocyclyl, C 3-6 cycloalkyl The heterocyclic group contains 1 to 3 heteroatoms selected from O, S, N.
  3. 根据权利要求2所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中The compound of claim 2, or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
    L 1选自键、-O-、-S-、-NH-、-CH 2-、-S(O) 2-、-OCH 2-、-OCH(CH 3)-、-OC(CH 3) 2-、-OCH 2CH 2-、-CH 2O-、-NHCH 2-或-N(CH 3)-； 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 ) - ;
    环B选自取代或者未取代的如下基团之一：环丙基、环丁基、环戊基、环己基、金刚烷基、双环[1.1.1]戊烷基、双环[2.2.1]庚烷基、立方烷基、双环[3.1.0]己烷基、双环[3.2.0]庚烷基、环戊基并环戊基、双环[4.2.0]辛烷基、双环[2.2.2]辛烷基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环己基，当被取代时，任选进一步被0至4个R b取代； 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. 2] Octyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclohexyl, when substituted, optionally further by 0 to 4 Rs b replace;
    R b各自独立的选自H、F、Cl、Br、I、氰基、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基或丙氧基，所述的甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基或丙氧基任选进一步被0至4个选自H、卤素、CF 3、OH、氰基、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基所取代； 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 from 0 to 4 groups selected from H, halogen, CF 3 , OH, cyano, Substitution of 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 base substituted;
    R a选自H、F、Cl、Br、I、氰基、甲基、乙基、异丙基、丙基、甲氧基、乙氧基、丙氧基、-(CH 2) q-C(＝O)-NR a1R a2、-(CH 2) q-NR a1R a2、-(CH 2) qNR a1C(＝O)-R a2、环丙基、环丁基、环戊基、环己基、-CH 2-环丙基、-CH 2-环丁基、-CH 2-环戊基或-CH 2-环己基，所述的CH 2、甲基、乙基、异丙基、丙基、甲氧基、乙氧基、丙氧基、环丙基、环丁基或环戊基任选进一步被0至4个选自H、卤素、CF 3、OH、氰基、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； Ra is selected from H, F, Cl, Br, I, cyano, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, -( CH2 ) q -C (=O)-NR a1 R a2 , -(CH 2 ) q -NR a1 R a2 , -(CH 2 ) q NR a1 C(=O)-R a2 , cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl or -CH 2 -cyclohexyl, said CH 2 , methyl, ethyl, isopropyl , propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl or cyclopentyl optionally further selected from 0 to 4 groups selected from H, halogen, CF3 , OH, cyano, COOH , NH 2 , C 1-4 alkyl or C 1-4 alkoxy substituent;
    R 1、R 2、R 3、R 4各自独立的选自H、F、Cl、Br、I、OH、氰基、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基、丙氧基、乙烯基、丙烯基、乙炔基、丙炔基、-(CH 2) m-C(＝O)-NR 3aR 3b、-(CH 2) m-NR 3aR 3b、-(CH 2) mNR 3aC(＝O)-R 3b、-(CH 2) m-环丙基、-(CH 2) m-环丁基、-(CH 2) m-环戊基、-(CH 2) m-环己基、-(CH 2) m-氮杂环丁基、-(CH 2) m-氧杂环丁基、-(CH 2) m-吡咯烷基、-(CH 2) m-四氢呋喃基、-(CH 2) m-哌啶基、-(CH 2) m-四氢吡喃基、-(CH 2) m-吗啉基、-(CH 2) m-哌嗪基或-(CH 2) m-氮杂环庚基，所述的CH 2、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基、丙氧基、环丙基、乙烯基、丙烯基、乙炔基、丙炔基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、四氢吡喃基、吗啉基、哌嗪基或氮杂环庚基任选进一步被0至4个选自H、卤素、CF 3、＝O、OH、氰基、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、-C 1-4亚烷基-羟基、C 3-6环烷基或3至8元杂环基的取代基所取代，所述的杂环基含有1至3个选自O、S、N的杂原子； R 1 , R 2 , R 3 , R 4 are each independently selected from H, F, Cl, Br, I, OH, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy , ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, -(CH 2 ) m -C(=O)-NR 3a R 3b , -(CH 2 ) m -NR 3a R 3b , -(CH 2 ) m NR 3a C(=O)-R 3b , -(CH 2 ) m -cyclopropyl, -(CH 2 ) m -cyclobutyl, -(CH 2 ) m -cyclopentane radical, -(CH 2 ) m -cyclohexyl, -(CH 2 ) m -azetidinyl, -(CH 2 ) m -oxetanyl, -(CH 2 ) m -pyrrolidinyl, - (CH 2 ) m -tetrahydrofuranyl, -(CH 2 ) m -piperidinyl, -(CH 2 ) m -tetrahydropyranyl, -(CH 2 ) m -morpholinyl, -(CH 2 ) m -piperazinyl or -( CH2 ) m -azepanyl, said CH2 , methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy radical, cyclopropyl, vinyl, propenyl, ethynyl, propynyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, pipette pyridinyl, tetrahydropyranyl, morpholinyl, piperazinyl or azepanyl optionally further selected from 0 to 4 groups selected from H, halogen, CF3 , =O, OH, cyano, COOH, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, -C 1-4 alkylene-hydroxy , C 3-6 cycloalkyl or substituents of 3- to 8-membered heterocyclic groups containing 1 to 3 heteroatoms selected from O, S, N;
    R a1、R a2、R 3a、R 3b各自独立的选自H、甲基、乙基、丙基、异丙基、丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基或哌啶基，所述的甲基、乙基、丙基、异丙基、丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基或哌啶基任选进一步被0至4个选自H、卤素、CF 3、OH、氰基、COOH、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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 0 to 4 selected from H, halogen, CF3 , OH, cyano, COOH, C1-4 Substituted by alkyl or C 1-4 alkoxy substituent;
    R 5选自
    Figure PCTCN2021117545-appb-100007
    R 5 is selected from
    Figure PCTCN2021117545-appb-100007
    R 5a、R 5b、R 5c各自独立的选自H、F、Cl、Br、I、氰基、甲基、乙基、丙基、异丙基、丁基、甲氧基、乙氧基、丙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基或哌啶基，所述的甲基、乙基、丙基、异丙基、丁基、甲氧基、乙氧基、丙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基或哌啶基任选进一步被0至4个选自H、卤素、＝O、OH、氰基、CF 3、C 1-4烷基、C 1-4烷氧基或-SC 1-4烷基的取代基所取代； R 5a , R 5b , 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, the methyl, ethyl, propyl , isopropyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl is optionally further 0 to 4 selected from H, halogen, =O, OH, cyano, CF 3 , C 1-4 alkyl, C 1-4 alkoxy or -SC 1-4 alkane substituted by the substituent of the base;
    作为选择，R 5b与R 5c可形成化学键； Alternatively, R 5b and R 5c may form a chemical bond;
    R 5d、R 5e各自独立的选自H、甲基、乙基、丙基、异丙基、丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基或吗啉基，所述的甲基、乙基、丙基、异丙基、丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基或吗啉基任选进一步被0至4个选自H、卤素、CF 3、＝O、OH、氰基、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3-6环烷基)、C 1-4烷基、C 1-4烷氧基或-SC 1-4烷基的取代基所取代； R 5d and R 5e are each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, oxygen Heterocyclobutyl, pyrrolidinyl, piperidinyl or morpholinyl, said methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , azetidine, oxetanyl, pyrrolidinyl, piperidinyl or morpholinyl optionally further selected from 0 to 4 groups selected from H, halogen, CF3 , =O, OH, cyano, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -NH(C 3-6 cycloalkyl), C 1-4 alkyl, C 1-4 alkoxy substituted by substituents of -SC 1-4 alkyl groups;
    作为选择，R 5d、R 5e与其直接相连的氮原子一起形成氮杂环丁基、吡咯基、吡咯烷基、哌嗪基、哌啶基、吗啉基或硫代吗啉基，所述氮杂环丁基、吡咯基、吡咯烷基、哌嗪基、哌啶基、吗啉基或硫代吗啉基任选进一步被0至4个选自H、卤素、CF 3、＝O、OH、氰基、C 1- 4烷基、C 1-4烷氧基或-C 1-4亚烷基-C 1-4烷氧基的取代基取代； Alternatively, 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 from 0 to 4 groups selected from H, halogen, CF3 , =O, OH , cyano, C 1-4 alkyl, C 1-4 alkoxy or -C 1-4 alkylene-C 1-4 alkoxy substituent;
    R 5f选自H或者取代的或者未取代的如下基团之一：甲基、乙基、丙基、丁基、异丙基、异丁基、氮杂环丁基、氮杂环戊基、氮杂环已基、哌嗪基、氧杂环丁基、氧杂环戊基、氧杂环已基、吗啉基、-CH 2-氮杂环丁基、-CH 2-氮杂环戊基、-CH 2-氮杂环已基、-CH 2-哌嗪、-CH 2-氧杂环丁基、-CH 2-氧杂环戊基、-CH 2-氧杂环已基、-CH 2-吗啉、-CH 2CH 2-氮杂环丁基、-CH 2CH 2-氮杂环戊基、-CH 2CH 2-氮杂环已基、-CH 2CH 2-哌嗪、-CH 2CH 2-氧杂环丁基、-CH 2CH 2-氧杂环戊基、-CH 2CH 2-氧杂环已基、-CH 2CH 2-吗啉、-CH 2-噻唑、-CH 2-噻吩、-CH 2-吡咯、-CH 2-吡唑、-CH 2-咪唑、-CH 2-呋喃、-CH 2-噁唑、-CH 2-吡咯、-CH 2-吡啶、
    Figure PCTCN2021117545-appb-100008
    Figure PCTCN2021117545-appb-100009
    当被取代时，任选进一步被0至4个选自H、卤素、CF 3、＝O、OH、氰基、C 1-4烷基、C 1-4烷氧基、NH 2、-C(＝O)NH(C 1-4烷基)、-C(＝O)N(C 1-4烷基) 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3-6环烷基)、3至8元杂环基、C 3-6环烷基的取代基取代，所述杂环基含有1至3个选自O、S、N的杂原子。     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, -CH2CH2 - piperazine , -CH 2 CH 2 -oxetanyl, -CH 2 CH 2 -oxolane, -CH 2 CH 2 -oxane, -CH 2 CH 2 -morpholine, -CH 2 - Thiazole, -CH2 -thiophene, -CH2 -pyrrole, -CH2 -pyrazole, -CH2 -imidazole, -CH2 -furan, -CH2 -oxazole, -CH2 -pyrrole, -CH2- pyridine,
    Figure PCTCN2021117545-appb-100008
    Figure PCTCN2021117545-appb-100009
    When substituted, optionally further 0 to 4 selected from H, halogen, CF 3 , =O, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy, NH 2 , -C (=O)NH(C 1-4 alkyl), -C(=O)N(C 1-4 alkyl) 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkane base) 2 , -NH(C 3-6 cycloalkyl), 3- to 8-membered heterocyclic group, C 3-6 cycloalkyl substituent, the heterocyclic group contains 1 to 3 selected from O, S and N heteroatoms.
  4. 根据权利要求3所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中The compound of claim 3, or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
    环B选自取代的或者未取代的如下基团之一：
    Figure PCTCN2021117545-appb-100010
    Figure PCTCN2021117545-appb-100011
    Figure PCTCN2021117545-appb-100012
    当被取代时，任选进一步被0至4个R b取代，其左侧与L 1相连；     Ring B is selected from one of the following groups, substituted or unsubstituted:
    Figure PCTCN2021117545-appb-100010
    Figure PCTCN2021117545-appb-100011
    Figure PCTCN2021117545-appb-100012
    When substituted, optionally further substituted by 0 to 4 R b , the left side of which is connected to L 1 ;
    R b各自独立的选自H、F、Cl、Br、I、氰基、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基或丙氧基，所述的甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基或丙氧基任选进一步被0至4个选自H、F、CF 3、OH、氰基、NH 2、-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 2CH 3) 2、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基、丙氧基、环丙基、环丁基或环戊基的取代基所取代； 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 from 0 to 4 groups 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, butyl, methoxy , ethoxy, propoxy, cyclopropyl, cyclobutyl or cyclopentyl substituents;
    R a选自H、F、Cl、氰基、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 2CH 3、-C(O)N(CH 2CH 3) 2、-C(O)NHCH 2CH 2OCH 3、-C(O)NH-环丙基、-C(O)NH-环丁基、-C(O)NH-环戊基、-C(O)NH-环已基、-NHC(O)CH 3、-NHC(O)CH 2CH 3、-NHC(O)-环丙基、-NHC(O)-环丁基、-NHC(O)-环戊基、-NHC(O)-环已基、环丙基、环丁基、环戊基、环己基、-CH 2-环丙基、-CH 2-环丁基、-CH 2-环戊基或-CH 2-环己基； 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)-cyclohexyl, cyclopropyl, cyclobutyl cyclopentyl, cyclopentyl, cyclohexyl, -CH2 -cyclopropyl, -CH2 -cyclobutyl, -CH2 -cyclopentyl or -CH2 -cyclohexyl;
    R 1、R 2、R 3各自独立的选自H、F、Cl、Br、I、OH、氰基、-(CH 2) m-C(＝O)-NR 3aR 3b、-(CH 2) m-NR 3aR 3b、-(CH 2) mNR 3aC(＝O)-R 3b、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基或丙氧基，所述的CH 2、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基或丙氧基任选进一步被0至4个选自H、F、CF 3、OH、氰基、COOH、NH 2、-NHCH 3、-N(CH 3) 2、甲基、乙基、异丙基、丙基、甲氧基、乙氧基、丙氧基、-CH 2OH或-CH 2CH 2OH的取代基所取代； R 1 , R 2 , R 3 are each independently selected from H, F, Cl, Br, I, OH, cyano, -(CH 2 ) m -C(=O)-NR 3a R 3b , -(CH 2 ) m -NR 3a R 3b , -(CH 2 ) m NR 3a C(=O)-R 3b , methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propyl Oxy group, the CH 2 , methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy are optionally further selected from 0 to 4 groups selected from H, F, CF 3 , OH, cyano, COOH, NH 2 , -NHCH 3 , -N(CH 3 ) 2 , methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, -CH 2 OH or -CH 2 CH 2 OH substituent;
    R 3a、R 3b各自独立的选自H、甲基、乙基、丙基、异丙基、丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基或哌啶基，所述的甲基、乙基、丙基、异丙基、丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基或 哌啶基任选进一步被0至4个选自H、F、CF 3、OH、氰基、COOH、甲基、乙基、异丙基、丙基、甲氧基、乙氧基或丙氧基的取代基所取代； 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 selected from 0 to 4 groups selected from H, F, CF3 , OH, cyano, COOH, methyl, ethyl, isopropyl, substituted with propyl, methoxy, ethoxy or propoxy substituents;
    R 4选自H、F、Cl、Br、I、OH、氰基、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基、丙氧基、乙烯基、丙烯基、乙炔基、丙炔基、-(CH 2) m-C(＝O)-NR 3aR 3b、-(CH 2) m-NR 3aR 3b、-(CH 2) mNR 3aC(＝O)-R 3b、-(CH 2) m-环丙基、-(CH 2) m-环丁基、-(CH 2) m-环戊基、-(CH 2) m-环己基、-(CH 2) m-氮杂环丁基、-(CH 2) m-氧杂环丁基、-(CH 2) m-吡咯烷基、-(CH 2) m-四氢呋喃基、-(CH 2) m-哌啶基、-(CH 2) m-四氢吡喃基、-(CH 2) m-吗啉基、-(CH 2) m-哌嗪基或-(CH 2) m-氮杂环庚基，所述的CH 2、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基、丙氧基、环丙基、乙烯基、丙烯基、乙炔基、丙炔基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、四氢吡喃基、吗啉基、哌嗪基或氮杂环庚基任选进一步被0至4个选自H、F、＝O、OH、氰基、CF 3、COOH、NH 2、-NHCH 3、-N(CH 3) 2、甲基、乙基、异丙基、丙基、甲氧基、乙氧基、丙氧基、-CH 2OH、-CH 2CH 2OH、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、四氢吡喃基、吗啉基、哌嗪基或氮杂环庚基所取代； R 4 is selected from H, F, Cl, Br, I, OH, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, -(CH 2 ) m -C(=O)-NR 3a R 3b , -(CH 2 ) m -NR 3a R 3b , -(CH 2 ) m NR 3a C( =O)-R 3b , -(CH 2 ) m -cyclopropyl, -(CH 2 ) m -cyclobutyl, -(CH 2 ) m -cyclopentyl, -(CH 2 ) m -cyclohexyl, -(CH 2 ) m -azetidine, -(CH 2 ) m -oxetanyl, -(CH 2 ) m -pyrrolidinyl, -(CH 2 ) m -tetrahydrofuranyl, -(CH 2 ) m -piperidinyl, -( CH2 ) m -tetrahydropyranyl, -( CH2 ) m -morpholinyl, -( CH2 ) m -piperazinyl or -( CH2 ) m- Azacycloheptyl, said CH 2 , methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, vinyl, propenyl, Ethynyl, propynyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl , piperazinyl or azepanyl optionally further selected from 0 to 4 groups selected from H, F, =O, OH, cyano, CF 3 , COOH, NH 2 , -NHCH 3 , -N(CH 3 ) 2 , methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, -CH 2 OH, -CH 2 CH 2 OH, cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, azetidine, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl or azepanyl;
    R 5选自
    Figure PCTCN2021117545-appb-100013
    Figure PCTCN2021117545-appb-100014
    Figure PCTCN2021117545-appb-100015
    R 5 is selected from
    Figure PCTCN2021117545-appb-100013
    Figure PCTCN2021117545-appb-100014
    Figure PCTCN2021117545-appb-100015
    或者R 5选自
    Figure PCTCN2021117545-appb-100016
    Figure PCTCN2021117545-appb-100017
    or R 5 is selected from
    Figure PCTCN2021117545-appb-100016
    Figure PCTCN2021117545-appb-100017
    或者R 5选自
    Figure PCTCN2021117545-appb-100018
    Figure PCTCN2021117545-appb-100019
    Figure PCTCN2021117545-appb-100020
    or R 5 is selected from
    Figure PCTCN2021117545-appb-100018
    Figure PCTCN2021117545-appb-100019
    Figure PCTCN2021117545-appb-100020
    或者R 5选自
    Figure PCTCN2021117545-appb-100021
    Figure PCTCN2021117545-appb-100022
    or R 5 is selected from
    Figure PCTCN2021117545-appb-100021
    Figure PCTCN2021117545-appb-100022
    Figure PCTCN2021117545-appb-100023
    Figure PCTCN2021117545-appb-100023
  5. 根据权利要求4所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中The compound of claim 4, or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
    L 1选自-O-、-NH-、-OCH 2-、-OC(CH 3) 2-、-CH 2O-或-NHCH 2-； L 1 is selected from -O-, -NH-, -OCH 2 -, -OC(CH 3 ) 2 -, -CH 2 O- or -NHCH 2 -;
    R b各自独立的选自H、F、Cl、氰基、甲基、乙基、异丙基、丙基、甲氧基或乙氧基，所述的甲基、乙基、异丙基、丙基、甲氧基或乙氧基任选进一步被0至4个选自H、F、CF 3、OH、氰基、NH 2、-N(CH 3) 2、-N(CH 2CH 3) 2、甲基、乙基、异丙基、丙基、环丙基或环丁基的取代基所取代； 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 from 0 to 4 groups selected from H, F, CF3 , OH, cyano, NH2 , -N( CH3 ) 2 , -N( CH2CH3 ) 2 , substituted by the substituents of methyl, ethyl, isopropyl, propyl, cyclopropyl or cyclobutyl;
    X 1选自N或CH； X 1 is selected from N or CH;
    R 1、R 2各自独立的选自H、F、Cl、OH、CF 3、氰基、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基或丙氧基； 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;
    R 3选自H、F、Cl、OH、CF 3、-CN、-CH 2CN、-CH 2CH 2CN、NH 2、-N(CH 3) 2、-N(CH 2CH 3) 2、-C(O)NH 2、-CH 2C(O)NH 2、-C(O)NHCH 3、-NHC(O)CH 3、甲基、乙基、异丙基、丙基、丁基、甲氧基、乙氧基或丙氧基； 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;
    R 4选自H、F、OH、CF 3、NH 2、-CN、-CH 2CN、-CH 2CH 2CN、-NHCH 3、-N(CH 3) 2、-C(O)-NH 2、-CH 2C(O)-NH 2、-CH 2CH 2C(O)-NH 2、-C(O)NHCH 3、-C(O)N(CH 3) 2、-NHC(O)CH 3、甲基、乙基、异丙基、丙基、甲氧基、乙氧基、丙氧基、环丙基、-CH 2-环丙基、环丁基、-CH 2-环丁基、环戊基、-CH 2-环戊基、环己基、-CH 2-环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、四氢吡喃基、吗啉基或哌嗪基； 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, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydro pyranyl, morpholinyl or piperazinyl;
    R 5选自
    Figure PCTCN2021117545-appb-100024
    Figure PCTCN2021117545-appb-100025
    R 5 is selected from
    Figure PCTCN2021117545-appb-100024
    Figure PCTCN2021117545-appb-100025
    或者R 5选自
    Figure PCTCN2021117545-appb-100026
    Figure PCTCN2021117545-appb-100027
    or R 5 is selected from
    Figure PCTCN2021117545-appb-100026
    Figure PCTCN2021117545-appb-100027
    或者R 5选自
    Figure PCTCN2021117545-appb-100028
    Figure PCTCN2021117545-appb-100029
    Figure PCTCN2021117545-appb-100030
    or R 5 is selected from
    Figure PCTCN2021117545-appb-100028
    Figure PCTCN2021117545-appb-100029
    Figure PCTCN2021117545-appb-100030
    或者R 5选自
    Figure PCTCN2021117545-appb-100031
    Figure PCTCN2021117545-appb-100032
    or R 5 is selected from
    Figure PCTCN2021117545-appb-100031
    Figure PCTCN2021117545-appb-100032
    Figure PCTCN2021117545-appb-100033
    Figure PCTCN2021117545-appb-100033
  6. 根据权利要求5所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中The compound of claim 5, or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
    L 1选自-O-、-OCH 2-、-OC(CH 3) 2-或-CH 2O-； L 1 is selected from -O-, -OCH 2 -, -OC(CH 3 ) 2 - or -CH 2 O-;
    环B选自
    Figure PCTCN2021117545-appb-100034
    Figure PCTCN2021117545-appb-100035
    其左侧与L 1相连；     Ring B is selected from
    Figure PCTCN2021117545-appb-100034
    Figure PCTCN2021117545-appb-100035
    Its left side is connected to L1 ;
    Figure PCTCN2021117545-appb-100036
    选自
    Figure PCTCN2021117545-appb-100037
    右侧与L 1直接连接；
    Figure PCTCN2021117545-appb-100036
    selected from
    Figure PCTCN2021117545-appb-100037
    The right side is directly connected to L 1 ;
    R 5选自
    Figure PCTCN2021117545-appb-100038
    Figure PCTCN2021117545-appb-100039
    R 5 is selected from
    Figure PCTCN2021117545-appb-100038
    Figure PCTCN2021117545-appb-100039
    或者R 5选自
    Figure PCTCN2021117545-appb-100040
    Figure PCTCN2021117545-appb-100041
    or R 5 is selected from
    Figure PCTCN2021117545-appb-100040
    Figure PCTCN2021117545-appb-100041
    或者R 5选自
    Figure PCTCN2021117545-appb-100042
    Figure PCTCN2021117545-appb-100043
    or R 5 is selected from
    Figure PCTCN2021117545-appb-100042
    Figure PCTCN2021117545-appb-100043
    Figure PCTCN2021117545-appb-100044
    Figure PCTCN2021117545-appb-100044
    或者R 5选自
    Figure PCTCN2021117545-appb-100045
    Figure PCTCN2021117545-appb-100046
    or R 5 is selected from
    Figure PCTCN2021117545-appb-100045
    Figure PCTCN2021117545-appb-100046
    Figure PCTCN2021117545-appb-100047
    Figure PCTCN2021117545-appb-100047
    R 1选自H、F、Cl、氰基、CF 3、甲基、乙基或甲氧基； R 1 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy;
    R 2选自H、F、Cl、氰基、CF 3、甲基、乙基或甲氧基； R 2 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy;
    R 3选自H、F、Cl、氰基、CF 3、甲基、乙基或甲氧基； R3 is selected from H, F, Cl, cyano, CF3 , methyl, ethyl or methoxy;
    R 4选自H、F、Cl、氰基、CF 3、甲基、乙基或甲氧基。 R4 is selected from H, F, Cl, cyano, CF3 , methyl, ethyl or methoxy.
  7. 根据权利要求3所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中The compound of claim 3, or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
    R 5选自
    Figure PCTCN2021117545-appb-100048
    Figure PCTCN2021117545-appb-100049
    R 5 is selected from
    Figure PCTCN2021117545-appb-100048
    Figure PCTCN2021117545-appb-100049
    R 5f选自H或者取代的或者未取代的如下基团之一：甲基、乙基、丙基、丁基、异丙基、异丁基、氮杂环丁基、氮杂环戊基、氮杂环已基、哌嗪基、氧杂环丁基、氧杂环戊基、氧杂环已基、吗啉基、-CH 2-氮杂环丁基、-CH 2-氮杂环戊基、-CH 2-氮杂环已基、-CH 2-哌嗪、-CH 2-氧杂环丁基、-CH 2-氧杂环戊基、-CH 2-氧杂环已基、-CH 2-吗啉、-CH 2CH 2-氮杂环丁基、-CH 2CH 2-氮杂环戊基、-CH 2CH 2-氮杂环已基、-CH 2CH 2-哌嗪、-CH 2CH 2-氧杂环丁基、-CH 2CH 2-氧杂环戊基、-CH 2CH 2-氧杂环已基、-CH 2CH 2-吗啉、-CH 2-噻唑、-CH 2-噻吩、-CH 2-吡咯、-CH 2-吡唑、-CH 2-咪唑、-CH 2-呋喃、-CH 2-噁唑、-CH 2-吡咯、-CH 2-吡啶、
    Figure PCTCN2021117545-appb-100050
    Figure PCTCN2021117545-appb-100051
    当被取代时，任选进一步被0、1、2、3或4个选自H、F、CF 3、＝O、OH、氰基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、NH 2、-C(＝O)NH(CH 3)、C(＝O)N(CH 3) 2、-C(＝O)NH(CH 2CH 3)、-C(＝O)N(CH 2CH 3) 2、-NH(CH 3)、-NH(CH 2CH 3)、-N(CH 2CH 3) 2、-N(CH 3)(CH 2CH 3)、-NH(C 3-6环烷基)、氮杂环丁基、氮杂环戊基、氮杂环已基、哌嗪基、氧杂环丁基、氧杂环戊基、氧杂环已基、吗啉基、环丙基、环丁基、环戊基、环己基、噻唑基、噻吩基、吡咯基、吡唑基、咪唑基、呋喃基、噁唑基、吡咯基、吡啶基的取代基取代。     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, -CH2CH2 - piperazine , -CH 2 CH 2 -oxetanyl, -CH 2 CH 2 -oxolane, -CH 2 CH 2 -oxane, -CH 2 CH 2 -morpholine, -CH 2 - Thiazole, -CH2 -thiophene, -CH2 -pyrrole, -CH2 -pyrazole, -CH2 -imidazole, -CH2 -furan, -CH2 -oxazole, -CH2 -pyrrole, -CH2- pyridine,
    Figure PCTCN2021117545-appb-100050
    Figure PCTCN2021117545-appb-100051
    When substituted, optionally further by 0, 1, 2, 3 or 4 selected from H, F, CF3 , =O, OH, cyano, methyl, ethyl, propyl, isopropyl, methyl Oxy, ethoxy, propoxy, NH 2 , -C(=O)NH(CH 3 ), C(=O)N(CH 3 ) 2 , -C(=O)NH(CH 2 CH 3 ), -C(=O)N(CH 2 CH 3 ) 2 , -NH(CH 3 ), -NH(CH 2 CH 3 ), -N(CH 2 CH 3 ) 2 , -N(CH 3 )( CH 2 CH 3 ), -NH(C 3-6 cycloalkyl), azetidine, azacyclopentyl, azacyclohexyl, piperazinyl, oxetanyl, oxolane base, oxetyl, morpholinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, Substituents of pyrrolyl and pyridyl are substituted.
  8. 根据权利要求7所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中The compound of claim 7, or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
    L 1选自-O-、-OCH 2-、-OC(CH 3) 2-或-CH 2O-； L 1 is selected from -O-, -OCH 2 -, -OC(CH 3 ) 2 - or -CH 2 O-;
    环B选自
    Figure PCTCN2021117545-appb-100052
    Figure PCTCN2021117545-appb-100053
    其左侧与L 1相连；     Ring B is selected from
    Figure PCTCN2021117545-appb-100052
    Figure PCTCN2021117545-appb-100053
    Its left side is connected to L1 ;
    Figure PCTCN2021117545-appb-100054
    选自
    Figure PCTCN2021117545-appb-100055
    右侧与L 1直接连接；
    Figure PCTCN2021117545-appb-100054
    selected from
    Figure PCTCN2021117545-appb-100055
    The right side is directly connected to L 1 ;
    R 1选自H、F、Cl、氰基、CF 3、甲基、乙基或甲氧基； R 1 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy;
    R 2选自H、F、Cl、氰基、CF 3、甲基、乙基或甲氧基； R 2 is selected from H, F, Cl, cyano, CF 3 , methyl, ethyl or methoxy;
    R 3选自H、F、Cl、氰基、CF 3、甲基、乙基或甲氧基； R3 is selected from H, F, Cl, cyano, CF3 , methyl, ethyl or methoxy;
    R 4选自H、F、Cl、氰基、CF 3、甲基、乙基或甲氧基。 R4 is selected from H, F, Cl, cyano, CF3 , methyl, ethyl or methoxy.
  9. 根据权利要求1所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中该化合物选自如下结构之一：The compound of claim 1 or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from one of the following structures:
    Figure PCTCN2021117545-appb-100056
    Figure PCTCN2021117545-appb-100056
    Figure PCTCN2021117545-appb-100057
    Figure PCTCN2021117545-appb-100057
    Figure PCTCN2021117545-appb-100058
    Figure PCTCN2021117545-appb-100058
    Figure PCTCN2021117545-appb-100059
    Figure PCTCN2021117545-appb-100059
    Figure PCTCN2021117545-appb-100060
    Figure PCTCN2021117545-appb-100060
    Figure PCTCN2021117545-appb-100061
    Figure PCTCN2021117545-appb-100061
    Figure PCTCN2021117545-appb-100062
    Figure PCTCN2021117545-appb-100062
    Figure PCTCN2021117545-appb-100063
    Figure PCTCN2021117545-appb-100063
    Figure PCTCN2021117545-appb-100064
    Figure PCTCN2021117545-appb-100064
    Figure PCTCN2021117545-appb-100065
    Figure PCTCN2021117545-appb-100065
    Figure PCTCN2021117545-appb-100066
    Figure PCTCN2021117545-appb-100066
    Figure PCTCN2021117545-appb-100067
    Figure PCTCN2021117545-appb-100067
    Figure PCTCN2021117545-appb-100068
    Figure PCTCN2021117545-appb-100068
    Figure PCTCN2021117545-appb-100069
    Figure PCTCN2021117545-appb-100069
    Figure PCTCN2021117545-appb-100070
    Figure PCTCN2021117545-appb-100070
    Figure PCTCN2021117545-appb-100071
    Figure PCTCN2021117545-appb-100071
    Figure PCTCN2021117545-appb-100072
    Figure PCTCN2021117545-appb-100072
    Figure PCTCN2021117545-appb-100073
    Figure PCTCN2021117545-appb-100073
  10. 一种药物组合物，包括权利要求1-9任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，以及药学上可接受的载体。A pharmaceutical composition comprising the compound of any one of claims 1-9 or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmacy an acceptable carrier.
  11. 根据权利要求1-9任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶在用于制备预防或治疗与JAK3激酶活性或表达量相关疾病的药物中的用途。The compound according to any one of claims 1-9, or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, for use in the preparation of prophylaxis or treatment with JAK3 Use in medicines for diseases related to kinase activity or expression level.
  12. 根据权利要求11所述的用途，其特征在于，所述的疾病选自免疫系统相关疾病。The use according to claim 11, wherein the disease is selected from immune system related diseases.
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