CN116157388A - Carbocyclic amide derivative and application thereof in medicine - Google Patents

Carbocyclic amide derivative and application thereof in medicine Download PDF

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CN116157388A
CN116157388A CN202180058261.7A CN202180058261A CN116157388A CN 116157388 A CN116157388 A CN 116157388A CN 202180058261 A CN202180058261 A CN 202180058261A CN 116157388 A CN116157388 A CN 116157388A
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alkyl
cyano
group
ethyl
alkoxy
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张晨
王健民
黄安邦
叶飞
黄正刚
唐平明
李瑶
倪佳
严庞科
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Sichuan Haisco Pharmaceutical Co Ltd
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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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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

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Abstract

Provides a compound shown in a general formula (I) or a stereoisomer, a deuterated compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, an intermediate and a preparation method thereof, and application in preparing medicaments for treating diseases related to JAK3 kinase activity or expression level.

Description

Carbocyclic amide derivative and application thereof in medicine Technical Field
The invention relates to a compound shown in a general formula (I) or a stereoisomer, a deuterated compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, an intermediate and a preparation method thereof, and application in preparing a medicament for treating diseases related to JAK3 kinase activity or expression level.
Background
Protein kinases are a class of enzymes that are dependent on intracellular messengers, catalyze the phosphorylation of specific proteins and complete signaling processes, and mainly include tyrosine protein kinases such as JAKs, src, abl, EGFR, FGFR, TOGFR, etc.; serine/threonine protein kinases such as PKC, MAPK, rho kinase and the like; bispecific protein kinases such as MPKK and the like and phosphatidylinositol kinases such as PI3K. The protein kinase phosphorylation/dephosphorylation process is capable of modulating a variety of biological processes of different cells, such as metabolism, cell differentiation, cell survival, apoptosis, organogenesis, angiogenesis, immune responses, etc. (Folia biol.2006,52,81-100.).
The Janus family (JAKs) consists of four members, including JAK1, JAK2, JAK3 and TYK2. Cytokines trigger dimerization of receptors by binding to receptors in JAKs, causing phosphorylation of JAK kinase tyrosine residues, thereby activating JAKs. Phosphorylated JAKs kinase further binds to and phosphorylates various STAT (Signal Transducers and Activators of Transcription) proteins, induces them to dimerize, and intranucleally solubilize, directly regulates gene transcription and activates downstream disease signaling factors. JAKs form a vital signaling pathway in innate immunity, inflammation and hematopoiesis; this dysregulation of pathways is associated with immune diseases and cancers, so JAKs are targets for the treatment of many disease indications (immunol. Rev.2008,223, 132-142.).
The pan-JAKs inhibitor Tofacitinib of Pfizer company, month 11 2012, has been FDA approved for the treatment of RA. However, tofacitinib has side effects including causing decreased numbers of erythrocytes and leukocytes, increased cholesterol levels, etc., which may be associated with its high JAK2 inhibitory activity (j.med. Chem.2012,55, 6176-6193). Therefore, scientists in organizations such as large pharmaceutical companies have focused their attention on the research and discovery of selective JAK inhibitors.
Unlike JAK1, JAK2 and TYK2, which are widely distributed in various tissue cells of the human body, JAK3 is mainly distributed in the bone marrow and lymphatic system, and JAK3 regulates cell signaling by binding to the gamma co-chain (yc) in cytokine receptor complexes such as IL-2, IL-4, IL-7, IL-9, IL-15, IL-21, etc. Based on their functional characteristics and special tissue distribution, JAK3 is an attractive drug target for immune system related diseases, and inhibitors thereof have important clinical application value in the treatment/prevention of Rheumatoid Arthritis (RA), inflammatory bowel disease, crohn's disease, systemic lupus erythematosus, 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).
Disclosure of Invention
One of the purposes of the present invention is to provide a compound capable of inhibiting JAK3 kinase or stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, as well as intermediates and preparation methods thereof, and application thereof in preparing medicaments for treating diseases related to JAK3 activity or expression level.
The present invention provides a compound of formula (I) or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
Figure PCTCN2021117545-APPB-000001
In certain embodiments, Y 1 、Y 2 、Y 3 Each independently selected from CH or N;
in certain embodiments, Y 1 、Y 2 Selected from CH, Y 3 Selected from N;
in certain embodiments, Y 1 、Y 2 、Y 3 Selected from CH;
in certain embodiments, Y 1 、Y 2 Selected from N, Y 3 Selected from N;
in certain embodiments, Y 1 Selected from N, Y 2 Selected from CH, Y 3 Selected from CH;
in certain embodiments, Y 1 Selected from CH, Y 2 Selected from N, Y 3 Selected from CH;
in certain embodiments, Y 1 Selected from CH, Y 2 Selected from N, Y 3 Selected from N;
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 3R a Substituted by a substituent, said heterocyclic or heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from O, S, N;
in some embodiments of the present invention, in some embodiments,
Figure PCTCN2021117545-APPB-000002
selected from the group consisting of
Figure PCTCN2021117545-APPB-000003
In some embodiments of the present invention, in some embodiments,
Figure PCTCN2021117545-APPB-000004
selected from the group consisting of
Figure PCTCN2021117545-APPB-000005
X 1 Selected from N or CR a ；
In some embodiments of the present invention, in some embodiments,
Figure PCTCN2021117545-APPB-000006
selected from the group consisting of
Figure PCTCN2021117545-APPB-000007
In some embodiments of the present invention, in some embodiments,
Figure PCTCN2021117545-APPB-000008
selected from the group consisting of
Figure PCTCN2021117545-APPB-000009
In certain embodiments, R a 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 Carbocycle or- (CH) 2 ) q -3 to 12 membered heterocycle, said CH 2 Optionally further substituted with 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 Substituted with an alkoxy substituent, said heterocycle containing 1, 2 or 3 heteroatoms selected from O, S, N;
in certain embodiments, R a 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, said CH 2 Optionally further substituted with 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 Substituted with an alkoxy substituent, said heterocycle containing 1, 2 or 3 heteroatoms selected from O, S, N;
in certain embodiments, R a 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 Optionally further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl or cyclopentyl 3 OH, cyano, COOH, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
in certain embodiments, R a 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) CH 3 、-NHC(O)CH 2 CH 3 -NHC (O) -cyclopropyl, -NHC (O) -cyclobutyl, -NHC (O) -cyclopentyl, -NHC (O) -cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 Cyclopentyl or CH 2 -a cyclohexyl group;
in certain embodiments, R a Selected from H;
in certain embodiments, ring B is selected from C 3-10 A carbocycle, optionally furtherStep quilt 0, 1, 2, 3 or 4R b Substitution;
in certain embodiments, ring B is selected from C 3-6 Carbocycles, C, of saturated or unsaturated monocyclic rings 5-10 Saturated or unsaturated spiro carbocyclic ring, C 5-10 Saturated or unsaturated carbocyclic ring, C 5-10 A saturated or unsaturated bridged carbocyclic ring, said carbocyclic ring optionally being further substituted with 0, 1, 2, 3 or 4R b Substitution;
in certain embodiments, ring B is selected from one of the following substituted or unsubstituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, bicyclo [1.1.1]Pentanyl and bicyclo [2.2.1]Heptyl, cubanyl, bicyclo [3.1.0 ]Hexalkyl and bicyclo [3.2.0]Heptyl, cyclopentyl, and bicyclo [4.2.0]Octyl and bicyclo [2.2.2]Octane, cyclobutylspirobutyl, cyclobutylspiropentyl, cyclobutylspirohexyl, cyclopentylpspirohexyl, optionally further substituted with 0, 1, 2, 3 or 4R b Substitution;
in certain embodiments, ring B is selected from one of the following substituted or unsubstituted groups:
Figure PCTCN2021117545-APPB-000010
Figure PCTCN2021117545-APPB-000011
Figure PCTCN2021117545-APPB-000012
when substituted, optionally further substituted with 0, 1, 2, 3 or 4R b Substituted, left side and L 1 Are connected;
in certain embodiments, ring B is selected from
Figure PCTCN2021117545-APPB-000013
Figure PCTCN2021117545-APPB-000014
Left side and L 1 Are connected;
in certain embodiments, R b Each independently selected from H, halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy or C 3-8 Substituted cycloalkyl;
in certain embodiments, R b Each independently selected from H, halogen, cyano, C 1-4 Alkyl or C 1-4 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy or C 3-8 Substituted cycloalkyl;
in certain embodiments, R b Each independently selected from H, F, cl, br, I, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy, said methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted cycloalkyl;
in certain embodiments, R b Are each independently selected from H, F, cl, br, I, cyano, methylA methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy group, said methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy group optionally being further substituted with 0, 1, 2, 3 or 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 A methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, or cyclopentyl substituent;
in certain embodiments, R b Each independently selected from H, F, cl, cyano, methyl, ethyl, isopropyl, propyl, methoxy or ethoxy, said methyl, ethyl, isopropyl, propyl, methoxy or ethoxy optionally being further selected from H, F, CF by 0, 1, 2, 3 or 4 3 OH, cyano, NH 2 、-N(CH 3 ) 2 、-N(CH 2 CH 3 ) 2 A methyl, ethyl, isopropyl, propyl, cyclopropyl or cyclobutyl substituent;
in certain embodiments, L 1 Selected from the group consisting of 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-；
In certain embodiments, L 1 Selected from the group consisting of 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-；
In certain embodiments, L 1 Selected from bonds, -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 )-；
In certain embodiments, L 1 Selected from-O-, -NH-, -OCH 2 -、-OC(CH 3 ) 2 -、-CH 2 O-or-NHCH 2 -；
In certain embodiments, L 1 Selected from-O-, -OCH 2 -、-OC(CH 3 ) 2 -or-CH 2 O-；
In certain embodiments, R 1a 、R 1b Or R is 1c Each independently selected from H, C 1-4 Alkyl or- (CH) 2 ) p -C 3-6 Carbocycles, said alkyl or carbocycle optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, OH, CF 3 Cyano, C 1- 4 Alkyl or C 1-4 Substituted with alkoxy;
in certain embodiments, R 1b 、R 1c Together with the carbon atom to which it is directly attached, form a 3-membered carbocyclic ring;
in some embodiments of the present invention, in some embodiments,
Figure PCTCN2021117545-APPB-000015
selected from the group consisting of
Figure PCTCN2021117545-APPB-000016
Figure PCTCN2021117545-APPB-000017
X 1 Selected from N or CR a The method comprises the steps of carrying out a first treatment on the surface of the Right side and L 1 Directly connecting;
in some embodiments of the present invention, in some embodiments,
Figure PCTCN2021117545-APPB-000018
selected from the group consisting of
Figure PCTCN2021117545-APPB-000019
Figure PCTCN2021117545-APPB-000020
X 1 Selected from N or CH; right side and L 1 Directly connecting;
in some embodiments of the present invention, in some embodiments,
Figure PCTCN2021117545-APPB-000021
selected from the group consisting of
Figure PCTCN2021117545-APPB-000022
Figure PCTCN2021117545-APPB-000023
Right side and L 1 Directly connecting;
in certain embodiments, ring C is selected from 5-6 membered heteroaryl or phenyl, optionally further substituted with 0, 1, 2, 3 or 4R c Substitution;
in certain embodiments, ring C is selected from the group consisting of pyriPyridine optionally further substituted with 0, 1, 2 or 3R c Substitution;
in some embodiments of the present invention, in some embodiments,
Figure PCTCN2021117545-APPB-000024
selected from the group consisting of
Figure PCTCN2021117545-APPB-000025
In certain embodiments, R c 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 Optionally further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (n), = O, OH, cyano, COOH, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy, -C 1-4 Alkylene-hydroxy, C 3-6 A carbocyclyl or a 3 to 8 membered heterocyclyl substituted with 1, 2 or 3 heteroatoms selected from O, S, N;
in certain embodiments, R c Each independently of the otherIs selected from R 1 、R 2 、R 3 Or R is 4 ；
In certain embodiments, R 1 、R 2 、R 3 、R 4 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 Optionally further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (n), = O, OH, cyano, COOH, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy, -C 1-4 Alkylene-hydroxy, C 3-6 A carbocyclyl or a 3 to 8 membered heterocyclyl substituted with 1, 2 or 3 heteroatoms selected from O, S, N;
in certain embodiments, R 1 、R 2 、R 3 、R 4 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 Carbocycles, said CH 2 Optionally further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (n), = O, OH, cyano, COOH, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy, -C 1-4 Alkylene-hydroxy, C 3-6 Cycloalkyl or a substituent of a 3 to 8 membered heterocyclic group, said heterocyclic ring containing 1, 2 or 3 heteroatoms selected from O, S, N;
in certain embodiments, R 1 、R 2 、R 3 、R 4 Each independently selected from H, F, cl, br, I, OH, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, ethenyl, 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 Azacyclobutyl, - (CH) 2 ) m -oxetanyl, - (CH) 2 ) m Pyrrolidinyl radical、-(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 Optionally further 0, 1, 2, 3 or 4 are selected from H, halogen, CF, optionally further 0, 1, 2, 3 or 4 are selected from methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, ethenyl, propenyl, ethynyl, propynyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl or azepanyl 3 (n), = O, OH, cyano, COOH, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy, -C 1-4 Alkylene-hydroxy, C 3-6 Cycloalkyl or a substituent of a 3 to 8 membered heterocyclic group, said heterocyclic ring containing 1, 2 or 3 heteroatoms selected from O, S, N;
in certain embodiments, R 1 、R 2 、R 3 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 Optionally further substituted with 0, 1, 2, 3 or 4 groups selected from H, F, CF 3 OH, cyano, COOH, NH 2 、-NHCH 3 、-N(CH 3 ) 2 Methyl, ethyl, isopropyl, propyl, acetyleneRadical, methoxy, ethoxy, propoxy, -CH 2 OH or-CH 2 CH 2 A substituent of OH;
in certain embodiments, R 4 Selected from H, F, cl, br, I, OH, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, ethenyl, 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 Azacyclobutyl, - (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 Optionally further 0, 1, 2, 3 or 4 are 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, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl or azepanyl;
in certain embodiments, R 1 、R 2 Each independently selected from H, F, cl, OH, CF 3 Cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy;
in certain embodiments, R 3 Selected from H, F, cl, OH, CF 3 、-CN、-CH 2 CN、-CH 2 CH 2 CN、NH 2 、-N(CH 3 ) 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, propyl, butyl, methoxy, ethoxy or propoxy;
in certain embodiments, R 4 Selected from H, F, OH, CF 3 、NH 2 、-CN、-CH 2 CN、-CH 2 CH 2 CN、-NHCH 3 、-N(CH 3 ) 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)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, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl or piperazinyl;
in certain embodiments, R 1 Selected from H, F, cl, cyano, CF 3 Methyl, ethyl or methoxy;
in certain embodiments, R 2 Selected from H, F, cl, cyano, CF 3 Methyl, ethyl or methoxy;
in certain embodiments, R 3 Selected from H, F, cl, cyano, CF 3 Methyl, ethyl or methoxy;
in certain embodiments, R 4 Selected from H, F, cl, cyano, CF 3 Methyl, ethyl or methoxy;
in certain embodiments, R a1 、R a2 、R 3a 、R 3b 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 being further substituted with 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 Substituted with an alkoxy substituent, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N;
in certain embodiments, R a1 、R a2 、R 3a 、R 3b 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 being further substituted with 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 Substituted with an alkoxy substituent, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N;
In certain embodiments, R a1 、R a2 、R 3a 、R 3b Each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl, said methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl optionally being further substituted with 0, 1, 2, 3 or 4 moieties selected from H, halogen, CF 3 OH, cyano, COOH, C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
in certain embodiments, R 3a 、R 3b Each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl, said methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, F, CF 3 Substituted with OH, cyano, COOH, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, or propoxy substituents;
In certain embodiments, R 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000026
In certain embodiments, R 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000027
In certain embodiments, R 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000028
Figure PCTCN2021117545-APPB-000029
Figure PCTCN2021117545-APPB-000030
Figure PCTCN2021117545-APPB-000031
Figure PCTCN2021117545-APPB-000032
Figure PCTCN2021117545-APPB-000033
In certain embodiments, R 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000034
Figure PCTCN2021117545-APPB-000035
Figure PCTCN2021117545-APPB-000036
In certain embodiments, R 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000037
Figure PCTCN2021117545-APPB-000038
In certain embodiments, R 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000039
In certain embodiments, R 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000040
Figure PCTCN2021117545-APPB-000041
In certain embodiments, R 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000042
Figure PCTCN2021117545-APPB-000043
In certain embodiments, R 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000044
Figure PCTCN2021117545-APPB-000045
In certain embodiments, R 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000046
Figure PCTCN2021117545-APPB-000047
In certain embodiments, R 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000048
Figure PCTCN2021117545-APPB-000049
Figure PCTCN2021117545-APPB-000050
In certain embodiments, R 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000051
Figure PCTCN2021117545-APPB-000052
Figure PCTCN2021117545-APPB-000053
In certain embodiments, R 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000054
Figure PCTCN2021117545-APPB-000055
In certain embodiments, R 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000056
Figure PCTCN2021117545-APPB-000057
Figure PCTCN2021117545-APPB-000058
Figure PCTCN2021117545-APPB-000059
In certain embodiments, R 5a 、R 5b 、R 5c 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, said alkyl, alkoxy, carbocyclyl or heterocyclyl optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (n), = O, OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-4 Alkyl, C 1-4 Alkoxy or-SC 1-4 Alkyl, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N;
in certain embodiments, R 5b And R is R 5c Chemical bonds may be formed;
in certain embodiments, R 5d 、R 5e Each independently selected from H, C 1-6 Alkyl, C 3-8 Carbocyclyl or 3-to 10-membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (n), = O, OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-4 Alkyl, C 1-4 Alkoxy or-SC 1-4 Alkyl, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N;
in certain embodiments, R 5d 、R 5e Together with the nitrogen atom to which it is directly attached, form a 4 to 8 membered heterocyclic group, said heterocyclic group optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (v), = O, OH, cyano, C 1-4 Alkyl, C 1-4 Alkoxy or-C 1-4 alkylene-C 1-4 A substituent of an alkoxy group, said heterocyclic group containing 1, 2 or 3 heteroatoms selected from O, S, N;
in certain embodiments, R 5a 、R 5b 、R 5c 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, said alkyl, alkoxy, carbocyclyl or heterocyclyl optionally being further substituted with 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, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N;
In certain embodiments, R 5d 、R 5e Each independently selected from H, C 1-4 An alkyl group, a 3 to 6 membered carbocyclic ring or a 3 to 8 membered heterocyclic ring, said alkyl, carbocyclic or heterocyclic ring optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (n), = O, OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-4 Alkyl, C 1-4 Alkoxy or-SC 1-4 Substitution of alkyl groupsSubstituted by a group, said heterocycle containing 1, 2 or 3 heteroatoms selected from O, S, N;
in certain embodiments, R 5d 、R 5e Together with the nitrogen atom to which it is directly attached, form a 4 to 6 membered heterocyclic ring, said heterocyclic ring optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (v), = O, OH, cyano, C 1-4 Alkyl, C 1- 4 Alkoxy or-C 1-4 alkylene-C 1-4 A substituent of an alkoxy group, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R 5a 、R 5b 、R 5c Each independently selected from H, F, cl, br, I, cyano, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl, said methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halo, = O, OH, cyano, CF 3 、C 1-4 Alkyl, C 1-4 Alkoxy or-SC 1-4 Substituted by alkyl;
in certain embodiments, R 5d 、R 5e Each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl or morpholinyl, said methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl or morpholinyl optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (n), = O, OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-4 Alkyl, C 1-4 Alkoxy or-SC 1-4 Alkyl, said heterocycle containing 1, 2 or 3 heteroatoms selected from O, S, N;
in certain embodiments, R 5d 、R 5e Together with the nitrogen atom to which it is directly attached, forms an azetidinyl, pyrrolyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl or thiomorpholinyl group, which is optionally further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (v), = O, OH, cyano, C 1-4 Alkyl, C 1-4 Alkoxy or-C 1-4 alkylene-C 1-4 Substitution of the substituent of the alkoxy group;
in certain embodiments, R 5f 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 Cycloalkyl, said alkyl, cycloalkyl or heterocyclyl optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (v), = 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 group 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl), a 3 to 8 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N;
in certain embodiments, R 5f 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 Cycloalkyl or C 3-6 Cycloalkyl, said alkyl, cycloalkyl or heterocyclyl being optionally further substituted0. 1, 2, 3 or 4 are selected from H, halogen, CF 3 (v), = 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 group 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl), 3-to 8-membered heterocyclyl, C 3-6 A substituent of cycloalkyl substituted, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N;
in certain embodiments, R 5f Selected from H, C 1-4 Alkyl, 3-to 8-membered heterocyclyl, -C 1-2 Alkyl-3 to 8 membered heterocyclyl, -C 1-2 alkyl-C 3-6 Cycloalkyl or C 3-6 Cycloalkyl, said alkyl, cycloalkyl or heterocyclyl optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (v), = 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 group 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl), 3-to 8-membered heterocyclyl, C 3-6 A substituent of cycloalkyl substituted, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N;
in certain embodiments, R 5f Selected from H or one of the following substituted or unsubstituted groups: methyl, ethyl, propyl, butyl, isopropyl, isobutyl, azetidinyl, piperazinyl, oxetanyl, oxolanyl, morpholinyl, -CH 2 -azetidinyl, -CH 2 Azacyclopentyl, -CH 2 -azacyclyl, -CH 2 Piperazine, -CH 2 -oxetanyl, -CH 2 -oxacyclopentyl, -CH 2 -oxacyclohexanyl, -CH 2 Morpholine (III),-CH 2 CH 2 -azetidinyl, -CH 2 CH 2 Azacyclopentyl, -CH 2 CH 2 -azacyclyl, -CH 2 CH 2 Piperazine, -CH 2 CH 2 -oxetanyl, -CH 2 CH 2 -oxacyclopentyl, -CH 2 CH 2 -oxacyclohexanyl, -CH 2 CH 2 -morpholine, -CH 2 -thiazole, -CH 2 Thiophene, -CH 2 -pyrrole, -CH 2 -pyrazole, -CH 2 -imidazole, -CH 2 -furan, -CH 2 -oxazole, -CH 2 -pyrrole, -CH 2 -pyridine,
Figure PCTCN2021117545-APPB-000060
When substituted, optionally further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (v), = 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 group 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl), 3-to 8-membered heterocyclyl, C 3-6 A substituent of cycloalkyl substituted, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N;
in certain embodiments, R 5f Selected from H or one of the following substituted or unsubstituted groups: methyl, ethyl, propyl, butyl, isopropyl, isobutyl, azetidinyl, piperazinyl, oxetanyl, oxolanyl, morpholinyl, -CH 2 -azetidinyl, -CH 2 Azacyclopentyl, -CH 2 -azacyclyl, -CH 2 Piperazine, -CH 2 -oxetanyl, -CH 2 -oxygen heterocycleAmyl, -CH 2 -oxacyclohexanyl, -CH 2 -morpholine, -CH 2 CH 2 -azetidinyl, -CH 2 CH 2 Azacyclopentyl, -CH 2 CH 2 -azacyclyl, -CH 2 CH 2 Piperazine, -CH 2 CH 2 -oxetanyl, -CH 2 CH 2 -oxacyclopentyl, -CH 2 CH 2 -oxacyclohexanyl, -CH 2 CH 2 -morpholine, -CH 2 -thiazole, -CH 2 Thiophene, -CH 2 -pyrrole, -CH 2 -pyrazole, -CH 2 -imidazole, -CH 2 -furan, -CH 2 -oxazole, -CH 2 -pyrrole, -CH 2 -pyridine,
Figure PCTCN2021117545-APPB-000061
When substituted, optionally further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen (e.g. F, cl, br), CF 3 (n) = 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(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), azetidinyl, piperazine, oxetanyl, oxolanyl, oxetanyl, morpholinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, pyrrolyl, pyridyl;
at a certain positionIn some embodiments, R 5f Selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (v), = O, OH, cyano, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituents of cycloalkyl groups;
in certain embodiments, R 5f Selected from H, C 1-4 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (v), = O, OH, cyano, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituents of cycloalkyl groups;
in certain embodiments, R 5f Selected from H, methyl, ethyl,
Figure PCTCN2021117545-APPB-000062
n, s are selected from 0, 1 or 2;
m, p, q are each independently selected from 0, 1, 2, 3 or 4.
As a first embodiment of the present invention, the compound represented by the above general formula (I) or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
Y 1 、Y 2 、Y 3 each independently selected from CH or N;
ring A is selected from 5 to 6 membered heterocyclic or heteroaromatic rings optionally further substituted with 0, 1, 2 or 3R a Substituted by a substituent, said heterocyclic or heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from O, S, N;
R a 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 Carbocycle or- (CH) 2 ) q -3 to 12 membered heterocycle, said CH 2 Optionally further substituted with 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 Substituted with an alkoxy substituent, said heterocycle containing 1, 2 or 3 heteroatoms selected from O, S, N;
ring B is selected from C 3-10 Carbocycles, said carbocycles optionally being further substituted with 0, 1, 2, 3 or 4R b Substitution;
R b each independently selected from H, halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy or C 3-8 Substituted cycloalkyl;
L 1 selected from the group consisting of 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 is 1c Each independently selected from H, C 1-4 Alkyl or- (CH) 2 ) p -C 3-6 Carbocycles, said alkyl or carbocycle optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, OH, CF 3 Cyano, C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
alternatively, R 1b 、R 1c Together with the carbon atom to which it is directly attached, form a 3-membered carbocyclic ring;
ring C is selected from 5-6 membered heteroaryl or phenyl, said heteroaryl or phenyl optionally being further substituted with 0, 1, 2, 3 or 4R c Substitution;
R c 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 Optionally further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (n), = O, OH, cyano, COOH, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy, -C 1-4 Alkylene-hydroxy, C 3-6 Substituted by carbocyclic groups or substituents of 3-to 8-membered heterocyclic groups containing1, 2 or 3 heteroatoms selected from O, S, N;
R a1 、R a2 、R 3a 、R 3b 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 being further substituted with 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 Substituted with an alkoxy substituent, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N;
R 5 selected from the group consisting of
Figure PCTCN2021117545-APPB-000063
R 5a 、R 5b 、R 5c 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, said alkyl, alkoxy, carbocyclyl or heterocyclyl optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (n), = O, OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-4 Alkyl, C 1-4 Alkoxy or-SC 1-4 Alkyl, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N;
alternatively, R 5b And R is R 5c Chemical bonds may be formed;
R 5d 、R 5e each independently selected from H, C 1-6 Alkyl, C 3-8 Carbocyclyl or 3-to 10-membered heterocyclyl, said alkyl, carbocyclyl Or heterocyclyl optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, halogen, CF 3 (n), = O, OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-4 Alkyl, C 1-4 Alkoxy or-SC 1-4 Alkyl, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N;
alternatively, R 5d 、R 5e Together with the nitrogen atom to which it is directly attached, form a 4 to 8 membered heterocyclic group, said heterocyclic group optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (v), = O, OH, cyano, C 1-4 Alkyl, C 1-4 Alkoxy or-C 1-4 alkylene-C 1-4 A substituent of an alkoxy group, said heterocyclic group containing 1, 2 or 3 heteroatoms selected from O, S, N;
R 5f 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 Cycloalkyl, said alkyl, cycloalkyl or heterocyclyl optionally being further substituted with 0 to 4 substituents selected from H, halogen, CF 3 (v), = 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 group 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl), a 3 to 8 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N;
n, s are selected from 0, 1 or 2;
m, p, q are each independently selected from 0, 1, 2, 3 or 4.
As a second embodiment of the present invention, the compound represented by the above general formula (I) or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
Figure PCTCN2021117545-APPB-000064
selected from the group consisting of
Figure PCTCN2021117545-APPB-000065
Right side and L 1 Directly connecting;
Figure PCTCN2021117545-APPB-000066
selected from the group consisting of
Figure PCTCN2021117545-APPB-000067
X 1 Selected from N or CR a ；
R a 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, said CH 2 Optionally further substituted with 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 Substituted with an alkoxy substituent, said heterocycle containing 1, 2 or 3 heteroatoms selected from O, S, N;
ring B is selected from C 3-6 Saturated or unsaturated monocyclic carbonRing, C 5-10 Saturated or unsaturated spiro carbocyclic ring, C 5-10 Saturated or unsaturated carbocyclic ring, C 5-10 A saturated or unsaturated bridged carbocyclic ring, said carbocyclic ring optionally being further substituted with 0, 1, 2, 3 or 4R b Substitution;
R b each independently selected from H, halogen, cyano, C 1-4 Alkyl or C 1-4 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy or C 3-8 Substituted cycloalkyl;
L 1 Selected from the group consisting of 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 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 Carbocycles, said CH 2 Optionally further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (n), = O, OH, cyano, COOH, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy, -C 1-4 Alkylene-hydroxy, C 3-6 Cycloalkyl or a substituent of a 3 to 8 membered heterocyclic group, said heterocyclic ring containing 1, 2 or 3 heteroatoms selected from O, S, N;
R a1 、R a2 、R 3a 、R 3b 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 being further substituted with 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 Substituted with an alkoxy substituent, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N;
R 5a 、R 5b 、R 5c 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, said alkyl, alkoxy, carbocyclyl or heterocyclyl optionally being further substituted with 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, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N;
alternatively, R 5b And R is R 5c Chemical bonds may be formed;
R 5d 、R 5e each independently selected from H, C 1-4 An alkyl group, a 3 to 6 membered carbocyclic ring or a 3 to 8 membered heterocyclic ring, said alkyl, carbocyclic or heterocyclic ring optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (n), = O, OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-4 Alkyl, C 1-4 Alkoxy or-SC 1-4 Alkyl, said heterocycle containing 1, 2 or 3 heteroatoms selected from O, S, N;
alternatively, R 5d 、R 5e Together with the nitrogen atom to which it is directly attached, form a 4 to 6 membered heterocyclic ring, said heterocyclic ring optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (v), = O, OH, cyano, C 1-4 Alkyl, C 1-4 Alkoxy or-C 1-4 alkylene-C 1-4 A substituent of an alkoxy group, said heterocycle containing 1, 2 or 3 heteroatoms selected from O, S, N;
R 5f 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 Cycloalkyl or C 3-6 Cycloalkyl, said alkyl, cycloalkyl or heterocyclyl optionally being further substituted with 0 to 4 substituents selected from H, halogen, CF 3 (v), = 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 group 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl), 3-to 8-membered heterocyclyl, C 3-6 A substituent of cycloalkyl substituted, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N;
the remaining groups are as defined in the first embodiment.
As a third embodiment of the present invention, the compound represented by the aforementioned general formula (I) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof,
L 1 selected from bonds, -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 )-；
Ring B is selected from one of the following substituted or unsubstituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, bicyclo [1.1.1]Pentanyl and bicyclo [2.2.1]Heptyl, cubanyl, bicyclo [3.1.0]Hexalkyl and bicyclo [3.2.0]Heptyl, cyclopentyl, and bicyclo [4.2.0]Octyl and bicyclo [2.2.2]Octyl, cyclobutylspirobutyl, cyclobutylspiropentyl, cyclobutylspirohexyl, cyclopentylpspirohexyl, optionally further substituted with 0, 1, 2, 3 or 4R when substituted b Substitution;
R b each independently selected from H, F, cl, br, I, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy, said methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted cycloalkyl;
R a 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 groupCyclobutyl, cyclopentyl, cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 Cyclopentyl or CH 2 -cyclohexyl, said CH 2 Optionally further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl or cyclopentyl 3 OH, cyano, COOH, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R 1 、R 2 、R 3 、R 4 each independently selected from H, F, cl, br, I, OH, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, ethenyl, 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 Azacyclobutyl, - (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, ethenyl, propenyl, ethynyl, propynyl, cyclobutyl, cyclopentyl, cycloHexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl or azepanyl optionally further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (n), = O, OH, cyano, COOH, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy, -C 1-4 Alkylene-hydroxy, C 3-6 Cycloalkyl or a substituent of a 3 to 8 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N;
R a1 、R a2 、R 3a 、R 3b each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl, said methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl optionally being further substituted with 0, 1, 2, 3 or 4 moieties selected from H, halogen, CF 3 OH, cyano, COOH, C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R 5 selected from the group consisting of
Figure PCTCN2021117545-APPB-000068
R 5a 、R 5b 、R 5c Each independently selected from H, F, cl, br, I, cyano, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, or piperidinyl, said methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, picolineThe pyrrolidinyl or piperidinyl group is optionally further substituted with 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 Substituted by alkyl;
alternatively, R 5b And R is R 5c Chemical bonds may be formed;
R 5d 、R 5e each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl or morpholinyl, said methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl or morpholinyl optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (n), = O, OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-4 Alkyl, C 1-4 Alkoxy or-SC 1-4 Substituted by alkyl;
alternatively, R 5d 、R 5e Together with the nitrogen atom to which it is directly attached, forms an azetidinyl, pyrrolyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl or thiomorpholinyl group, which is optionally further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (v), = O, OH, cyano, C 1-4 Alkyl, C 1-4 Alkoxy or-C 1-4 alkylene-C 1-4 Substitution of the substituent of the alkoxy group;
R 5f selected from H or one of the following substituted or unsubstituted groups: methyl, ethyl, propyl, butyl, isopropyl, isobutyl, azetidinyl, piperazinyl, oxetanyl, and oxolanylOxacyclohexyl, morpholinyl, -CH 2 -azetidinyl, -CH 2 Azacyclopentyl, -CH 2 -azacyclyl, -CH 2 Piperazine, -CH 2 -oxetanyl, -CH 2 -oxacyclopentyl, -CH 2 -oxacyclohexanyl, -CH 2 -morpholine, -CH 2 CH 2 -azetidinyl, -CH 2 CH 2 Azacyclopentyl, -CH 2 CH 2 -azacyclyl, -CH 2 CH 2 Piperazine, -CH 2 CH 2 -oxetanyl, -CH 2 CH 2 -oxacyclopentyl, -CH 2 CH 2 -oxacyclohexanyl, -CH 2 CH 2 -morpholine, -CH 2 -thiazole, -CH 2 Thiophene, -CH 2 -pyrrole, -CH 2 -pyrazole, -CH 2 -imidazole, -CH 2 -furan, -CH 2 -oxazole, -CH 2 -pyrrole, -CH 2 -pyridine,
Figure PCTCN2021117545-APPB-000069
When substituted, optionally further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (v), = 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 group 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl), 3-to 8-membered heterocyclyl, C 3-6 A substituent of cycloalkyl substituted, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N;
the remaining groups are defined in accordance with either the first or second embodiments of the invention.
As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof,
ring B is selected from one of the following substituted or unsubstituted groups:
Figure PCTCN2021117545-APPB-000070
Figure PCTCN2021117545-APPB-000071
Figure PCTCN2021117545-APPB-000072
when substituted, optionally further substituted with 0, 1, 2, 3 or 4R b Substituted, left side and L 1 Are connected;
R b each independently selected from H, F, cl, br, I, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy, said methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy optionally being further substituted with 0, 1, 2, 3 or 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 A methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, or cyclopentyl substituent;
R a 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) CH 3 、-NHC(O)CH 2 CH 3 -NHC (O) -cyclopropyl, -NHC (O) -cyclobutyl, -NHC (O) -cyclopentyl, -NHC (O) -cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 Cyclopentyl or CH 2 -a cyclohexyl group;
R 1 、R 2 、R 3 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 Optionally further substituted with 0, 1, 2, 3 or 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 A substituent of OH;
R 3a 、R 3b each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl, said methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, F, CF 3 Substituents for OH, cyano, COOH, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy or propoxySubstituted;
R 4 selected from H, F, cl, br, I, OH, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, ethenyl, 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 Azacyclobutyl, - (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 Optionally further 0, 1, 2, 3 or 4 are 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, azetidinyl, oxetanyl, pyrrolidinyl, tetrakisA hydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, or azepanyl group;
R 5 selected from the group consisting of
Figure PCTCN2021117545-APPB-000073
Figure PCTCN2021117545-APPB-000074
Or R is 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000075
Figure PCTCN2021117545-APPB-000076
Or R is 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000077
Figure PCTCN2021117545-APPB-000078
Or R is 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000079
Figure PCTCN2021117545-APPB-000080
Figure PCTCN2021117545-APPB-000081
The remaining groups are defined in accordance with any of the second or third embodiments of the present invention.
As a fifth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof,
L 1 selected from-O-, -NH-, -OCH 2 -、-OC(CH 3 ) 2 -、-CH 2 O-or-NHCH 2 -；
R b Each independently selected from H, F, cl, cyano, methyl, ethyl, isopropyl, propyl, methoxy or ethoxy, said methyl, ethyl, isopropyl, propyl, methoxy or ethoxy optionally being further selected from H, F, CF by 0, 1, 2, 3 or 4 3 OH, cyano, NH 2 、-N(CH 3 ) 2 、-N(CH 2 CH 3 ) 2 A methyl, ethyl, isopropyl, propyl, cyclopropyl or cyclobutyl substituent;
X 1 selected from N or CH;
R 1 、R 2 each independently selected from H, F, cl, OH, CF 3 Cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy;
R 3 Selected from H, F, cl, OH, CF 3 、-CN、-CH 2 CN、-CH 2 CH 2 CN、NH 2 、-N(CH 3 ) 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, propyl, butyl, methoxy, ethoxy or propoxy;
R 4 selected from H, F, OH, CF 3 、NH 2 、-CN、-CH 2 CN、-CH 2 CH 2 CN、-NHCH 3 、-N(CH 3 ) 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)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, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl or piperazinyl;
R 5 selected from the group consisting of
Figure PCTCN2021117545-APPB-000082
Figure PCTCN2021117545-APPB-000083
Or R is 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000084
Figure PCTCN2021117545-APPB-000085
Or R is 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000086
Figure PCTCN2021117545-APPB-000087
Figure PCTCN2021117545-APPB-000088
Or R is 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000089
Figure PCTCN2021117545-APPB-000090
Figure PCTCN2021117545-APPB-000091
The remaining groups are defined in accordance with any of the second, third or fourth embodiments of the present invention.
As a sixth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof,
L 1 selected from-O-, -OCH 2 -、-OC(CH 3 ) 2 -or-CH 2 O-；
Ring B is selected from
Figure PCTCN2021117545-APPB-000092
Figure PCTCN2021117545-APPB-000093
Left side and L 1 Are connected;
Figure PCTCN2021117545-APPB-000094
selected from the group consisting of
Figure PCTCN2021117545-APPB-000095
Right side and L 1 Directly connecting;
R 5 selected from the group consisting of
Figure PCTCN2021117545-APPB-000096
Figure PCTCN2021117545-APPB-000097
Or R is 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000098
Figure PCTCN2021117545-APPB-000099
Or R is 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000100
Figure PCTCN2021117545-APPB-000101
Or R is 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000102
Figure PCTCN2021117545-APPB-000103
Figure PCTCN2021117545-APPB-000104
Figure PCTCN2021117545-APPB-000105
R 1 Selected from H, F, cl, cyano, CF 3 Methyl, ethyl or methoxy;
R 2 selected from H, F, cl, cyano, CF 3 Methyl, ethyl or methoxy;
R 3 Selected from H, F, cl, cyano, CF 3 Methyl, ethyl or methoxy;
R 4 selected from H, F, cl, cyano, CF 3 Methyl, ethyl or methoxy;
the remaining groups are defined in accordance with any of the second, third, fourth or fifth embodiments of the present invention.
As a seventh embodiment of the present invention, the compound represented by the aforementioned general formula (I) or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
R 5 selected from the group consisting of
Figure PCTCN2021117545-APPB-000106
Figure PCTCN2021117545-APPB-000107
R 5f Selected from H or one of the following substituted or unsubstituted groups: methyl, ethyl, propyl, butyl, isopropyl, isobutyl, azetidinyl, piperazinyl, oxetanyl, oxolanyl, morpholinyl, -CH 2 -azetidinyl, -CH 2 Azacyclopentyl, -CH 2 -azacyclyl, -CH 2 Piperazine, -CH 2 -oxetanyl, -CH 2 -oxacyclopentyl, -CH 2 -oxacyclohexanyl, -CH 2 -morpholine, -CH 2 CH 2 -azetidinyl, -CH 2 CH 2 Azacyclopentyl, -CH 2 CH 2 -azacyclyl, -CH 2 CH 2 Piperazine, -CH 2 CH 2 -oxetanyl, -CH 2 CH 2 -oxacyclopentyl, -CH 2 CH 2 -oxacyclohexanyl, -CH 2 CH 2 -morpholine, -CH 2 -thiazole, -CH 2 Thiophene, -CH 2 -pyrrole, -CH 2 -pyrazole, -CH 2 -imidazole, -CH 2 -furan, -CH 2 -oxazole, -CH 2 -pyrrole, -CH 2 -pyridine,
Figure PCTCN2021117545-APPB-000108
When substituted, optionally further substituted with 0, 1, 2, 3 or 4 members selected from H, F, CF 3 (n) = 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(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), azetidinyl, piperazinyl, oxetanyl, oxolanyl, morpholinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, thiazolyl,Thienyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, pyrrolyl, pyridyl;
the definition of the remaining groups is consistent with any of the first, second and third embodiments of the present invention.
As an eighth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
L 1 selected from-O-, -OCH 2 -、-OC(CH 3 ) 2 -or-CH 2 O-；
Ring B is selected from
Figure PCTCN2021117545-APPB-000109
Figure PCTCN2021117545-APPB-000110
Left side and L 1 Are connected;
Figure PCTCN2021117545-APPB-000111
selected from the group consisting of
Figure PCTCN2021117545-APPB-000112
Right side and L 1 Directly connecting;
R 1 selected from H, F, cl, cyano, CF 3 Methyl, ethyl or methoxy;
R 2 Selected from H, F, cl, cyano, CF 3 Methyl, ethyl or methoxy;
R 3 selected from H, F, cl, cyano, CF 3 Methyl, ethyl or methoxy;
R 4 selected from H, F, cl, cyano, CF 3 Methyl, ethyl or methoxy;
the definition of the remaining groups is consistent with the seventh embodiment of the present invention.
As a ninth embodiment of the present invention, a compound represented by the following general formula (Ia) or (Ib) or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,
Figure PCTCN2021117545-APPB-000113
the definition of each group is consistent with any one of the second, third, fourth, fifth, sixth, seventh or eight embodiments of the present invention.
As an eleventh embodiment of the present invention, a compound represented by the following general formula (Ia) or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
L 1 selected from-O-, -OCH 2 -、-OC(CH 3 ) 2 -or-CH 2 O-；
Ring B is selected from
Figure PCTCN2021117545-APPB-000114
Figure PCTCN2021117545-APPB-000115
Left side and L 1 Are connected;
Figure PCTCN2021117545-APPB-000116
selected from the group consisting of
Figure PCTCN2021117545-APPB-000117
Right side and L 1 Directly connecting;
R 1 selected from H, F, cl, cyano, CF 3 Methyl, ethyl or methoxy;
R 2 selected from H, F, cl, cyano, CF 3 Methyl, ethyl or methoxy;
R 3 selected from H, F, cl, cyano, CF 3 Methyl, ethyl or methoxy;
R 4 Selected from H, F, cl, cyano, CF 3 Methyl, ethyl or methoxy;
R 5 selected from the group consisting of
Figure PCTCN2021117545-APPB-000118
Figure PCTCN2021117545-APPB-000119
Figure PCTCN2021117545-APPB-000120
As a twelfth embodiment of the present invention, a compound represented by the following general formula (Ia) or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,
Y 1 、Y 2 selected from CH, Y 3 Selected from N or C;
Figure PCTCN2021117545-APPB-000121
selected from the group consisting of
Figure PCTCN2021117545-APPB-000122
Right side and L 1 Directly connecting;
L 1 selected from-O-, -OCH 2 -；
Ring B is selected from
Figure PCTCN2021117545-APPB-000123
Left side and L 1 Are connected;
R 1 selected from H, F, cl, cyano, CF 3 Methyl, ethyl or methoxy;
R 2 selected from H, F, cl, cyano, CF 3 Methyl, ethyl or methoxy;
R 3 selected from H, F, cl, cyano, CF 3 Methyl, ethyl or methoxy;
R 4 selected from H, F, cl, cyano, CF 3 Methyl, ethyl or methoxy;
R 5 the same as in the eleventh embodiment.
The present invention provides a compound as shown below or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
Figure PCTCN2021117545-APPB-000124
Figure PCTCN2021117545-APPB-000125
Figure PCTCN2021117545-APPB-000126
Figure PCTCN2021117545-APPB-000127
Figure PCTCN2021117545-APPB-000128
Figure PCTCN2021117545-APPB-000129
Figure PCTCN2021117545-APPB-000130
Figure PCTCN2021117545-APPB-000131
Figure PCTCN2021117545-APPB-000132
Figure PCTCN2021117545-APPB-000133
Figure PCTCN2021117545-APPB-000134
Figure PCTCN2021117545-APPB-000135
Figure PCTCN2021117545-APPB-000136
Figure PCTCN2021117545-APPB-000137
Figure PCTCN2021117545-APPB-000138
Figure PCTCN2021117545-APPB-000139
Figure PCTCN2021117545-APPB-000140
Figure PCTCN2021117545-APPB-000141
the present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), Y 1 、Y 2 、Y 3 Each independently selected from C, CH or N.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), Y 1 、Y 2 Selected from CH, Y 3 Selected from N.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), Y 1 、Y 2 、Y 3 Selected from CH.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), Y 1 、Y 2 Selected from CH, Y 3 Selected from C.
The invention relates toAnd certain embodiments of the compounds of formula (I), (Ia), (Ib), Y 1 、Y 2 Selected from N, Y 3 Selected from N.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), Y 1 Selected from N, Y 2 Selected from CH, Y 3 Selected from C.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), Y 1 Selected from CH, Y 2 Selected from N, Y 3 Selected from C.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), Y 1 Selected from CH, Y 2 Selected from N, Y 3 Selected from N.
The present invention relates to certain embodiments of compounds of formula (I), (Ia), (Ib) wherein ring A is selected from 5-to 6-membered heterocyclic or heteroaromatic rings optionally further substituted with 0, 1, 2 or 3R a Substituted by a substituent, said heterocyclic or heteroaromatic ring containing from 1 to 4 heteroatoms selected from O, S, N.
The invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib),
Figure PCTCN2021117545-APPB-000142
Selected from the group consisting of
Figure PCTCN2021117545-APPB-000143
Figure PCTCN2021117545-APPB-000144
The invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib),
Figure PCTCN2021117545-APPB-000145
selected from the group consisting of
Figure PCTCN2021117545-APPB-000146
Figure PCTCN2021117545-APPB-000147
X 1 Selected from N or CR a 。
The invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib),
Figure PCTCN2021117545-APPB-000148
selected from the group consisting of
Figure PCTCN2021117545-APPB-000149
Figure PCTCN2021117545-APPB-000150
The invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib),
Figure PCTCN2021117545-APPB-000151
selected from the group consisting of
Figure PCTCN2021117545-APPB-000152
Figure PCTCN2021117545-APPB-000153
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R a 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 Carbocycle or- (CH) 2 ) q -3 to 12 membered heterocycle, said CH 2 Optionally further substituted with 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 The heterocyclic ring contains 1, 2 or 3 hetero atoms selected from O, S, N.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R a 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, said CH 2 Optionally further substituted with 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 The heterocyclic ring contains 1, 2 or 3 hetero atoms selected from O, S, N.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R a 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 Optionally further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl or cyclopentyl 3 OH, cyano, COOH, NH 2 、C 1-4 Alkyl or C 1-4 The substituent of the alkoxy group is substituted.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R a 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) CH 3 、-NHC(O)CH 2 CH 3 -NHC (O) -cyclopropyl, -NHC (O) -cyclobutyl, -NHC (O) -cyclopentyl, -NHC (O) -cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 Cyclopentyl or CH 2 -a cyclohexyl group.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R a Selected from H.
In some embodiments of the invention, which relate to compounds of the general formula (I), (Ia), (Ib), ring B is selected from C 3-10 Carbocycles, said carbocycles optionally being further substituted with 0, 1, 2, 3 or 4R b And (3) substitution.
In some embodiments of the invention, which relate to compounds of the general formula (I), (Ia), (Ib), ring B is selected from C 3-6 Carbocycles, C, of saturated or unsaturated monocyclic rings 5-10 Saturated or unsaturated spiro carbocyclic ring, C 5-10 Saturated or unsaturated carbocyclic ring, C 5-10 A saturated or unsaturated bridged carbocyclic ring, said carbocyclic ring optionally being further substituted with 0, 1, 2, 3 or 4R b And (3) substitution.
In some embodiments of the present invention, ring B is selected from one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, bicyclo [1.1.1]Pentanyl and bicyclo [2.2.1]Heptyl, cubanyl, bicyclo [3.1.0]Hexalkyl and bicyclo [3.2.0]Heptyl, cyclopentyl, and bicyclo [4.2.0]Octyl and bicyclo [2.2.2]Octyl, cyclobutylspirobutyl, cyclobutylspiropentyl, cyclobutylspirohexyl, cyclopentylpspirohexyl, optionally further substituted with 0, 1, 2, 3 or 4R when substituted b And (3) substitution.
In some embodiments of the compounds of 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, optionally further substituted with 0, 1, 2, 3 or 4R b Substituted, left side and L 1 Are connected.
In some embodiments of the invention, which relate to compounds of the general formula (I), (Ia), (Ib), ring B is selected from
Figure PCTCN2021117545-APPB-000157
Figure PCTCN2021117545-APPB-000158
Left side and L 1 Are connected.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R b Each independently selected from H, halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy or C 3-8 The substituents of cycloalkyl groups are substituted.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R b Each independently selected from H, halogen, cyano, C 1-4 Alkyl or C 1-4 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy or C 3-8 The substituents of cycloalkyl groups are substituted.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R b Each independently selected from H, F, cl, br, I, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy, said methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 The substituents of cycloalkyl groups are substituted.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R b Each independently selected from H, F, cl, br, I, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy, said methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy optionally being further substituted with 0, 1, 2, 3 or 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 A methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, or cyclopentyl substituent.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R b Each independently selected from H, F, cl, cyano, methyl, ethyl, isopropyl, propyl, methoxy or ethoxy, said methyl, ethyl, isopropyl, propyl, methoxy or ethoxy optionally being further selected from H, F, CF by 0, 1, 2, 3 or 4 3 OH, cyano, NH 2 、-N(CH 3 ) 2 、-N(CH 2 CH 3 ) 2 A methyl, ethyl, isopropyl, propyl, cyclopropyl or cyclobutyl substituent.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), L 1 Selected from the group consisting of 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-。
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), L 1 Selected from the group consisting of 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-。
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), L 1 Selected from bonds, -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 certain embodiments of compounds of the general formula (I), (Ia), (Ib), L 1 Selected from-O-, -NH-, -OCH 2 -、-OC(CH 3 ) 2 -、-CH 2 O-or-NHCH 2 -。
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), L 1 Selected from-O-, -OCH 2 -、-OC(CH 3 ) 2 -or-CH 2 O-。
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 1a 、R 1b Or R is 1c Each independently selected from H, C 1-4 Alkyl or- (CH) 2 ) p -C 3-6 Carbocycles, said alkyl or carbocycle optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, OH, CF 3 Cyano, C 1-4 Alkyl or C 1-4 The substituent of the alkoxy group is substituted.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 1b 、R 1c Together with the carbon atom to which it is directly attached, form a 3-membered carbocyclic ring.
The invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib),
Figure PCTCN2021117545-APPB-000159
selected from the group consisting of
Figure PCTCN2021117545-APPB-000160
X 1 Selected from N or CR a Right side and L 1 And directly connected.
The invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib),
Figure PCTCN2021117545-APPB-000161
selected from the group consisting of
Figure PCTCN2021117545-APPB-000162
X 1 Selected from N or CH, right side and L 1 And directly connected.
The invention relates to some embodiments of compounds represented by general formula (I), (Ia), (Ib),
Figure PCTCN2021117545-APPB-000163
selected from the group consisting of
Figure PCTCN2021117545-APPB-000164
Right side and L 1 Direct connection
The present invention relates to certain embodiments of compounds of formula (I), (Ia), (Ib) wherein ring C is selected from 5-6 membered heteroaryl or phenyl optionally further substituted with 0, 1, 2, 3 or 4R c And (3) substitution.
In some embodiments of the invention, which relate to compounds of the general formula (I), (Ia), (Ib), ring C is selected from pyridine optionally further substituted with 0, 1, 2 or 3R c And (3) substitution.
The invention relates to some embodiments of the compounds of formula (I),
Figure PCTCN2021117545-APPB-000165
selected from the group consisting of
Figure PCTCN2021117545-APPB-000166
Figure PCTCN2021117545-APPB-000167
The present invention relates to certain embodiments of compounds of formula (I), R c 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 Optionally further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (n), = O, OH, cyano, COOH, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy, -C 1-4 Alkylene-hydroxy, C 3-6 Carbocyclyl or a 3 to 8 membered heterocyclyl, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N.
The present invention relates to certain embodiments of compounds of formula (I), R c Each independently is selected from R 1 、R 2 、R 3 Or R is 4 。
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 1 、R 2 、R 3 、R 4 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 Optionally further substituted with 0, 1, 2, alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle 3 or 4 are selected from H, halogen, CF 3 (n), = O, OH, cyano, COOH, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy, -C 1-4 Alkylene-hydroxy, C 3-6 Carbocyclyl or a 3 to 8 membered heterocyclyl, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 1 、R 2 、R 3 、R 4 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 Carbocycles, said CH 2 Optionally further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (n), = O, OH, cyano, COOH, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy, -C 1-4 Alkylene-hydroxy, C 3-6 Cycloalkyl or a substituent of a 3 to 8 membered heterocyclic group, said heterocyclic ring containing 1, 2 or 3 heteroatoms selected from O, S, N.
The invention relates to a compound of the general formula (I),In some embodiments of the compounds of formula (Ia), (Ib), R 1 、R 2 、R 3 、R 4 Each independently selected from H, F, cl, br, I, OH, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, ethenyl, 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 Azacyclobutyl, - (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 Optionally further 0, 1, 2, 3 or 4 are selected from H, halogen, CF, optionally further 0, 1, 2, 3 or 4 are selected from methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, ethenyl, propenyl, ethynyl, propynyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl or azepanyl 3 (n), = O, OH, cyano, COOH, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy, -C 1-4 Alkylene-hydroxy, C 3-6 Cycloalkyl or 3-to 8-memberedA heterocyclic group substituted with a substituent, said heterocyclic ring containing 1, 2 or 3 heteroatoms selected from O, S, N.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 1 、R 2 、R 3 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 Optionally further substituted with 0, 1, 2, 3 or 4 groups selected from H, F, CF 3 OH, cyano, COOH, NH 2 、-NHCH 3 、-N(CH 3 ) 2 Methyl, ethyl, isopropyl, propyl, ethynyl, methoxy, ethoxy, propoxy, -CH 2 OH or-CH 2 CH 2 The substituent of OH is substituted.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 4 Selected from H, F, cl, br, I, OH, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, ethenyl, 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 Azacyclobutyl, - (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 Optionally further 0, 1, 2, 3 or 4 are 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, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl or azepanyl.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 1 、R 2 Each independently selected from H, F, cl, OH, CF 3 Cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 3 Selected from H, F, cl, OH, CF 3 、-CN、-CH 2 CN、-CH 2 CH 2 CN、NH 2 、-N(CH 3 ) 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, propyl, butyl, methoxy, ethoxy or propoxy.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 4 Selected from H, F, OH, CF 3 、NH 2 、-CN、-CH 2 CN、-CH 2 CH 2 CN、-NHCH 3 、-N(CH 3 ) 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)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, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl or piperazinyl.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 1 Selected from H, F, cl, cyano, CF 3 Methyl, ethyl or methoxy.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 2 Selected from H, F, cl, cyano, CF 3 Methyl, ethyl or methoxy.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 3 Selected from H, F, cl, cyano, CF 3 Methyl, ethyl or methoxy.
The present invention relates to certain embodiments of compounds of formula (I), (Ia), R 4 Selected from H, F, cl, cyano, CF 3 Methyl, ethyl or methoxy.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R a1 、R a2 、R 3a 、R 3b 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 being further substituted with 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 The heterocyclic group contains 1 to 3 hetero atoms selected from O, S, N.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R a1 、R a2 、R 3a 、R 3b 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 being further substituted with 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 The heterocyclic group contains 1 to 3 hetero atoms selected from O, S, N.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R a1 、R a2 、R 3a 、R 3b Each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl, said methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl optionally being further substituted with 0, 1, 2, 3 or 4 moieties selected from H, halogen, CF 3 OH, cyano, COOH, C 1-4 Alkyl or C 1-4 The substituent of the alkoxy group is substituted.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 3a 、R 3b Each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl, said methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, F, CF 3 Substituted with OH, cyano, COOH, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, or propoxy substituents.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000168
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000169
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000170
Figure PCTCN2021117545-APPB-000171
Figure PCTCN2021117545-APPB-000172
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000173
Figure PCTCN2021117545-APPB-000174
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000175
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000176
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000177
Figure PCTCN2021117545-APPB-000178
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000179
Figure PCTCN2021117545-APPB-000180
Figure PCTCN2021117545-APPB-000181
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000182
Figure PCTCN2021117545-APPB-000183
Figure PCTCN2021117545-APPB-000184
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000185
Figure PCTCN2021117545-APPB-000186
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000187
Figure PCTCN2021117545-APPB-000188
Figure PCTCN2021117545-APPB-000189
Figure PCTCN2021117545-APPB-000190
Figure PCTCN2021117545-APPB-000191
Figure PCTCN2021117545-APPB-000192
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000193
Figure PCTCN2021117545-APPB-000194
Figure PCTCN2021117545-APPB-000195
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000196
Figure PCTCN2021117545-APPB-000197
Figure PCTCN2021117545-APPB-000198
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 5 Selected from the group consisting of
Figure PCTCN2021117545-APPB-000199
Figure PCTCN2021117545-APPB-000200
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 5a 、R 5b 、R 5c 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, said alkyl, alkoxy, carbocyclyl or heterocyclyl optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (n), = O, OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-4 Alkyl, C 1-4 Alkoxy or-SC 1-4 The heterocyclic group is substituted by substituent of alkyl, and contains 1, 2 or 3 hetero atoms selected from O, S, N.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 5b And R is R 5c Chemical bonds may be formed.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 5d 、R 5e Each independently selected from H, C 1-6 Alkyl, C 3-8 Carbocyclyl or 3-to 10-membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (n), = O, OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-4 Alkyl, C 1-4 Alkoxy or-SC 1-4 The heterocyclic group is substituted by substituent of alkyl, and contains 1, 2 or 3 hetero atoms selected from O, S, N.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 5d 、R 5e Together with the nitrogen atom to which it is directly attached, form a 4 to 8 membered heterocyclic group, said heterocyclic group optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (v), = O, OH, cyano, C 1-4 Alkyl, C 1-4 Alkoxy or-C 1-4 alkylene-C 1-4 The substituent of the alkoxy is substituted, and the heterocyclic group contains 1, 2 or 3 hetero atoms selected from O, S, N.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 5a 、R 5b 、R 5c 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, said alkyl, alkoxy, carbocyclyl or heterocyclyl optionally being further substituted with 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 The heterocyclic group is substituted by substituent of alkyl, and contains 1, 2 or 3 hetero atoms selected from O, S, N.
The invention relates toAnd compounds of the general formula (I), (Ia), (Ib), R 5d 、R 5e Each independently selected from H, C 1-4 An alkyl group, a 3 to 6 membered carbocyclic ring or a 3 to 8 membered heterocyclic ring, said alkyl, carbocyclic or heterocyclic ring optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (n), = O, OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-4 Alkyl, C 1-4 Alkoxy or-SC 1-4 The heterocyclic ring contains 1, 2 or 3 hetero atoms selected from O, S, N.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 5d 、R 5e Together with the nitrogen atom to which it is directly attached, form a 4 to 6 membered heterocyclic ring, said heterocyclic ring optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (v), = O, OH, cyano, C 1-4 Alkyl, C 1-4 Alkoxy or-C 1-4 alkylene-C 1-4 A substituent of an alkoxy group, said heterocycle containing 1, 2 or 3 heteroatoms selected from O, S, N;
the present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 5a 、R 5b 、R 5c Each independently selected from H, F, cl, br, I, cyano, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl, said methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halo, = O, OH, cyano, CF 3 、C 1-4 Alkyl, C 1-4 Alkoxy or-SC 1-4 Substituted by substituents of alkyl radicals。
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 5d 、R 5e Each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl or morpholinyl, said methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl or morpholinyl optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (n), = O, OH, cyano, NH 2 、- NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-4 Alkyl, C 1-4 Alkoxy or-SC 1-4 The heterocyclic ring contains 1, 2 or 3 hetero atoms selected from O, S, N.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 5d 、R 5e Together with the nitrogen atom to which it is directly attached, forms an azetidinyl, pyrrolyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl or thiomorpholinyl group, which is optionally further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (v), = O, OH, cyano, C 1-4 Alkyl, C 1-4 Alkoxy or-C 1-4 alkylene-C 1-4 The substituent of the alkoxy group is substituted.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 5f Selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (v), = O, OH, cyano, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 The substituents of cycloalkyl groups are substituted.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 5f 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 Cycloalkyl, said alkyl, cycloalkyl or heterocyclyl optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (v), = 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 group 2 、NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl), a 3 to 8 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 5f 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 Cycloalkyl or C 3-6 Cycloalkyl, said alkyl, cycloalkyl or heterocyclyl optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (v), = 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 group 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl), 3-to 8-membered heterocyclyl, C 3-6 A substituent of cycloalkyl, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 5f Selected from H, C 1-4 Alkyl group,3-to 8-membered heterocyclyl, -C 1-2 Alkyl-3 to 8 membered heterocyclyl, -C 1-2 alkyl-C 3-6 Cycloalkyl or C 3-6 Cycloalkyl, said alkyl, cycloalkyl or heterocyclyl optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (v), = 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 group 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl), 3-to 8-membered heterocyclyl, C 3-6 A substituent of cycloalkyl, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 5f Selected from H or one of the following substituted or unsubstituted groups: methyl, ethyl, propyl, butyl, isopropyl, isobutyl, azetidinyl, piperazinyl, oxetanyl, oxolanyl, morpholinyl, -CH 2 -azetidinyl, -CH 2 Azacyclopentyl, -CH 2 -azacyclyl, -CH 2 Piperazine, -CH 2 -oxetanyl, -CH 2 -oxacyclopentyl, -CH 2 -oxacyclohexanyl, -CH 2 -morpholine, -CH 2 CH 2 -azetidinyl, -CH 2 CH 2 Azacyclopentyl, -CH 2 CH 2 -azacyclyl, -CH 2 CH 2 Piperazine, -CH 2 CH 2 -oxetanyl, -CH 2 CH 2 -oxacyclopentyl, -CH 2 CH 2 -oxacyclohexanyl, -CH 2 CH 2 -morpholine, -CH 2 -thiazole, -CH 2 Thiophene, -CH 2 -pyrrole, -CH 2 -pyrazole, -CH 2 -imidazole, -CH 2 -furan, -CH 2 -oxazole, -CH 2 -pyrrole, -CH 2 -pyridine,
Figure PCTCN2021117545-APPB-000201
Figure PCTCN2021117545-APPB-000202
When substituted, optionally further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (v), = 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 group 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl), 3-to 8-membered heterocyclyl, C 3-6 A substituent of cycloalkyl, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 5f Selected from H, C 1-4 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from H, halogen, CF 3 (v), = O, OH, cyano, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 The substituents of cycloalkyl groups are substituted.
The present invention relates to certain embodiments of compounds of the general formula (I), (Ia), (Ib), R 5f Selected from H, methyl, ethyl,
Figure PCTCN2021117545-APPB-000203
The invention relates to some embodiments of compounds of general formula (I), (Ia), (Ib), n, s are selected from 0, 1 or 2.
In some embodiments, m, p, q are each independently selected from 0, 1, 2, 3, or 4.
The present invention relates to a pharmaceutical composition comprising any of the above compounds or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, and a pharmaceutically acceptable carrier.
The present invention relates to the use of any of the above compounds, or stereoisomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or co-crystals thereof, for the manufacture of a medicament for the prevention or treatment of a disease associated with JAK3 kinase activity or expression level. In certain embodiments, the disease is selected from immune system related diseases.
In certain embodiments, the disease is selected from Rheumatoid Arthritis (RA), inflammatory bowel disease, crohn's disease.
In another aspect, the present invention provides a method for preventing or treating a disease associated with JAK kinase activity or expression level (e.g., a disease as described above), comprising the steps of: a prophylactically or therapeutically effective amount of a compound of the invention, or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, or a pharmaceutical composition as described above, is administered to a subject in need thereof.
The term "individual" (or subject) refers to a human or non-human animal.
The art references and monographs describe in detail the synthesis of reactants useful in the preparation of the compounds described herein or articles describing the preparation process are provided for reference. These references and monographs include: "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; gilchrist, "Heterocyclic Chemistry",2nd Ed., john Wiley & Sons, new York,1992; march, "Advanced Organic Chemistry: reactions, mechanisms and Structure",4th Ed., wiley-Interscience, new York,1992; fuhrhop, J.and Penzlin G. "Organic Synthesis: peptides, 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.
Specific and similar reactants can be selectively identified by indexes of known chemicals prepared by american chemical abstracts, which are available in most public and university libraries and online. Chemicals known but not commercially available in catalogs are optionally prepared by custom chemical synthesis plants, many of which provide custom synthesis services (e.g., those listed above). References to the preparation and selection of pharmaceutically acceptable salts of the compounds described herein are p.h.stahl & c.g.weruth "Handbook of Pharmaceutical Salts", verlag Helvetica Chimica Acta, zurich,2002.
The synthesis method comprises the following steps:
Figure PCTCN2021117545-APPB-000204
R 10 selected from halogen or OH;
R 11 selected from halogen, preferably from Br, cl;
R 12 selected from amino protecting groups or H;
PG 1 selected from amino protecting groups;
the definition of the rest groups is consistent with the specification;
the compound of the general formula (Ia-1) is subjected to nucleophilic substitution reaction or coupling reaction to obtain a compound of the general formula (Ia-2);
the compound of the general formula (Ia-2) is subjected to a coupling reaction to obtain a compound of the general formula (Ia-3); or the compound of the general formula (Ia-2) is subjected to a coupling reaction and then subjected to hydroxy protecting group removal to obtain the compound of the general formula (Ia-3);
removing amino protecting groups from the compound of the general formula (Ia-3) to obtain a compound of the general formula (Ia-4);
The compound of the general formula (Ia-4) is subjected to condensation reaction or nucleophilic substitution reaction to obtain the compound of the general formula (I).
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The carbon, hydrogen, oxygen, sulfur, nitrogen or F, cl, br, I referred to in the groups and compounds of the invention each include their isotopic condition, and the carbon, hydrogen, oxygen, sulfur or nitrogen referred to in the groups and compounds of the invention are optionally further replaced by one or more of their corresponding isotopes, where the isotopes of carbon include 12 C、 13 C and C 14 Isotopes of C, hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super heavy hydrogen), isotopes of oxygen include 16 O、 17 O and 18 isotopes of O, sulfur include 32 S、 33 S、 34 S and 36 isotopes of S, nitrogen include 14 N and 15 isotopes of N, fluorine include 17 F and F 19 Isotopes of F, chlorine include 35 Cl and Cl 37 Isotopes of Cl, bromine include 79 Br and 81 Br。
"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, and even more preferably 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 various branched isomers thereof; the alkyl group may optionally be further substituted with 0 to 6 groups selected from F, cl, br, I, hydroxy, 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 8 membered carbocyclyloxy, 3 to 8 membered heterocyclyloxy, carboxyl or carboxylate groups, where alkyl groups appear are defined in accordance with the present definition.
"alkylene" means a straight and branched chain divalent saturated hydrocarbon radical, including- (CH) 2 ) v - (v is an integer of 1 to 10), alkylene examples include, but are not limited to, methylene, ethylene, propylene, butylene and the like; the alkylene group may be optionally further substituted with 0 to 5 substituents selected from F, cl, br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxy or carboxylate. Alkylene groups appear herein, the definition of which is consistent with the definition.
"cycloalkyl" refers to a monovalent saturated carbocyclic hydrocarbon group, typically having 3 to 10 carbon atoms, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. The cycloalkyl group may be optionally further substituted with 0 to 5 substituents selected from F, cl, br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxy or carboxylate. Cycloalkyl groups as herein presented are defined as described above.
"alkenyl" refers to straight and branched monovalent unsaturated hydrocarbon radicals having at least 1, typically 1, 2 or 3 carbon-carbon double bonds, a backbone comprising 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms in the backbone, alkenyl examples including, but 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-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-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 1, 4-decenyl, 1, 3-pentadienyl, 1, 4-pentadienyl and the like; the alkenyl group may be optionally further substituted with 0 to 5 substituents selected from F, cl, br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxy or carboxylate. Alkenyl groups appear herein, the definition of which is consistent with the definition.
"alkynyl" refers to straight and branched monovalent unsaturated hydrocarbon radicals having at least 1, typically 1, 2 or 3 carbon-carbon triple bonds, and the backbone comprises 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms in the backbone, and examples of alkynyl radicals include, but are not limited to, ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl and the like; the alkynyl group may be optionally further substituted with 0 to 5 substituents selected from F, cl, br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxy or carboxylate. Alkynyl groups as herein appear, the definition of which is consistent with the definition.
"alkoxy" refers to an-O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy and cyclobutoxy. The alkoxy group may be optionally further substituted with 0 to 5 substituents selected from F, cl, br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxy or carboxylate. Alkoxy groups appear herein, the definition of which is consistent with the 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 ring, a 4 to 12 membered bicyclic ring, or a 10 to 15 membered tricyclic ring system, to which carbocyclyl may be attached, optionally in the form of a monocyclic, bridged, or spiro ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring,
Figure PCTCN2021117545-APPB-000205
The carbocycle may optionally be furtherSteps are substituted with 0 to 5 substituents selected from F, cl, br, I, =o, hydroxy, mercapto, nitro, cyano, amino, alkylamino, amido, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxy or carboxylate. Carbocycles or carbocyclyl groups appear herein, the definition of which is consistent with the definition.
"heterocyclyl" or "heterocycle" 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 bicyclic or 10 to 15 membered tricyclic ring system and contains 1 to 3 heteroatoms selected from N, O or S, preferably 3 to 8 membered heterocyclyl, wherein N, S which is optionally substituted in the ring of the heterocyclyl may be oxidized to various oxidation states. The heterocyclic group may be attached to a heteroatom or a carbon atom, the heterocyclic group may be attached to an aromatic ring or a non-aromatic ring, the heterocyclic group may be attached to a bridged ring or a spiro ring, non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxanyl, azepanyl, pyridinyl, furanyl, thiophenyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1, 3-dithianyl, dihydrofuranyl, dihydropyranyl, dithianyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo [ 3.1.1 ] ]Octyl and azabicyclo [5.2.0]Nonylalkyl oxatricyclo [5.3.1.1 ]]Dodecyl, azaadamantyl, oxaspiro [3.3 ]]Heptyl radical,
Figure PCTCN2021117545-APPB-000206
Figure PCTCN2021117545-APPB-000207
Figure PCTCN2021117545-APPB-000208
The heterocyclic group may be optionally further substituted with 0 to 5 substituents selected from F, cl, br, I, =o, hydroxy, mercapto, nitro, cyano, amino, alkylamino, amido, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxy or carboxylate. Heterocyclyl groups as present herein are defined in accordance with the present definition.
"spiro" means a 5 to 20 membered polycyclic group sharing one atom (referred to as spiro atom) between substituted or unsubstituted monocyclic rings, which may contain 0 to 5 double bonds and may contain 0 to 5 groups selected from N, O or S (=o) n Wherein n is 0, 1, 2). Preferably 6 to 14 membered, more preferably 6 to 12 membered, more preferably 6 to 10 membered, non-limiting examples of which include:
Figure PCTCN2021117545-APPB-000209
Figure PCTCN2021117545-APPB-000210
when substituted, the substituents may be 1 to 5 groups selected from F, cl, br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spirocyclic, and cyclic, 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 is 0, 1 or 2), arylthio, thiocarbonyl, silane or-NR b R c Etc., wherein R is b And R is R c Independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally R b And R is R c Five-or six-membered cycloalkyl or heterocyclyl groups may be formed. R is R a And R is R d Each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spirocyclic, or fused ring. Spiro rings appear herein, the definition of which is consistent with the definition.
"parallel ring" means that each ring in the system shares an adjacent pair of atoms of a polycyclic group with the other rings in the system, wherein one or more of the rings may contain 0 or more double bonds and may be substituted or unsubstituted, and each ring in the ring system may contain 0 to 5 atoms selected from N, S (=o) n Or a heteroatom of O (wherein n is 0, 1, 2). Preferably 5 to 20 membered, more preferably 5 to 14 membered, still more preferably 5 to 12 membered, still more preferably 5 to 10 membered. Non-limiting examples include:
Figure PCTCN2021117545-APPB-000211
Figure PCTCN2021117545-APPB-000212
when substituted, the substituents may be 1 to 5 groups selected from F, cl, br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring Group, spirocyclic group, parallel ring group, hydroxyalkyl group, =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 is 0, 1 or 2), arylthio, thiocarbonyl, silane or-NR b R c Etc., wherein R is b And R is R c Independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally R b And R is R c Five-or six-membered cycloalkyl or heterocyclyl groups may be formed. R is R a And R is R d Each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spirocyclic, or fused ring. The merging rings appearing herein are defined in accordance with the present definition.
"bridged ring" means any two polycyclic groups of atoms not directly attached, which may contain 0 or more double bonds, and which may be substituted or unsubstituted, and any ring in the ring system may contain 0 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, further preferably 5 to 12, and further preferably 5 to 10. Non-limiting examples include
Figure PCTCN2021117545-APPB-000213
Figure PCTCN2021117545-APPB-000214
And adamantane. When taken outAt the time of substitution, the substituent may be 1 to 5 substituents selected from F, cl, br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spirocyclic, and cyclic, 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 is 0, 1 or 2), arylthio, thiocarbonyl, silane or-NR b R c Etc., wherein R is b And R is R c Independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally R b And R is R c Five-or six-membered cycloalkyl or heterocyclyl groups may be formed. R is R a And R is R d Each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spirocyclic, or fused ring. The bridged rings appearing herein are defined in accordance with this definition.
"carbospiro", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spiro" ring system consisting of only carbon atoms. "carbospiro", "spirocarbocyclyl" or "carbospirocyclyl" as appearing herein are defined in accordance with the present definition. "carbon-fused", "fused carbocyclyl" or "carbon-fused cyclic" refers to a "fused ring" in which the ring system has only carbon atoms. "carbo-cyclic", "carbocyclyl" or "carbo-cyclic" as used herein is defined in accordance with the present definition.
"carbon bridged ring", "bridged carbocyclyl" or "carbon bridged cyclyl" refers to a "bridged ring" in which the ring system has only carbon atoms. "carbobridged ring", "bridged ring carbocyclyl", "bridged carbocyclyl" or "carbobridged ring radical" as used herein is defined in accordance with the present definition.
"heteromonocyclic", "monocyclic heterocyclyl" or "heteromonocyclic" refers to a "heterocyclyl" or "heterocycle" of a monocyclic system, and the "monocyclic heterocyclyl" or "heteromonocyclic" radicals appearing herein are defined in accordance with the present definition.
"heterobicyclic", "heterobicyclic radical", "fused-to-heterocyclic radical" or "heterobicyclic radical" refers to a "fused ring" containing a heteroatom. The term "fused ring", "fused ring heterocyclyl" or "fused ring" as used herein is defined in accordance with the present definition.
"Heterospiro", "spirocyclic heterocyclyl" or "Heterospiro" refers to a "spiro" containing heteroatoms. As used herein, a heterospiro, "heterospirocyclic", "spirocyclic heterocyclyl" or "heterospirocyclic" is defined in accordance with the present definition.
"heterobridged", "bridged heterocyclyl" or "heterobridged heterocyclyl" refers to a "bridged ring" that contains a heteroatom. The term "heterobridged ring," as used herein, refers to a bridged ring, or "heterobridged ring.
"aryl" or "aromatic ring" refers to a monovalent aromatic hydrocarbon radical having a single or fused ring, typically 6 to 12 carbon atoms, and may be substituted or unsubstituted. When substituted, the substituents may be 1 to 5 groups selected from F, cl, br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spirocyclic, and cyclic, 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 is 0, 1 or 2), arylthio, thiocarbonyl, silane or-NR b R c Etc., wherein R is b And R is R c Independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally R b And R is R c Five-or six-membered cycloalkyl or heterocyclyl groups may be formed. R is R a And R is R d Each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spirocyclic, or fused ring. Aryl or aromatic ring as herein defined is consistent with the present definition.
"heteroaryl" means a substituted or unsubstituted 5 to 15 membered aromatic ring and contains 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, further preferably 5 to 6 membered. 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, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include
Figure PCTCN2021117545-APPB-000215
When substituted, the substituents may be 1 to 5 groups selected from F, cl, br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spirocyclicA fused ring group, a hydroxyalkyl group, =o, a carbonyl group, an aldehyde, a carboxylic acid, a formate, a- (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 is 0, 1 or 2), arylthio, thiocarbonyl, silane or-NR b R c Etc., wherein R is b And R is R c Independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally R b And R is R c Five-or six-membered cycloalkyl or heterocyclyl groups may be formed. R is R a And R is R d Each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spirocyclic, or fused ring. Heteroaryl groups as herein appear, the definition of which is consistent with the definition.
"containing 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, X being selected from any integer between 1 and 10. By "substituted with 0 to 4 substituents" is meant substituted with 0, 1, 2, 3 or 4 substituents. By "substituted with 0 to 5 substituents" is meant substituted with 0, 1, 2, 3, 4 or 5 substituents. By "the hetero-bridge ring is optionally further substituted with 0 to 4 substituents selected from H or F" is meant that the hetero-bridge ring is optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H or F.
The X-Y membered ring (X is selected from an integer of 3 or less and Y is selected from any integer of 4 to 12) includes X+1, X+2, X+3, X+4 …. The ring includes heterocyclic, carbocyclic, aromatic, aryl, heteroaryl, cycloalkyl, heteromonocyclic, heterobicyclic, heterospiro, or heterobridged rings. For example, "4-7 membered heteromonocyclic ring" means 4-, 5-, 6-or 7-membered heteromonocyclic ring, and "5-10 membered heteromonocyclic ring" means 5-, 6-, 7-, 8-, 9-or 10-membered heteromonocyclic ring.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. Such as: "alkyl optionally substituted with F" means that the alkyl may be, but is not necessarily, substituted with F, and is intended to include both cases where the alkyl is substituted with F and cases where the alkyl is not substituted with F.
By "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" is meant a salt of a compound of the invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reaction with a non-toxic inorganic or organic base.
"pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and/or one or more other therapeutic agents.
By "carrier" is meant a material that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
"excipient" refers to an inert substance that is 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, binders, and disintegrating agents.
"prodrug" means a compound of the invention which is converted into a biologically active form by in vivo metabolism. Prodrugs of the invention are prepared by modifying amino or carboxyl groups in the compounds of the invention, which modifications may be removed by conventional procedures or in vivo to give the parent compound. When the prodrugs of the invention are administered to a mammalian subject, the prodrugs are cleaved to form the free amino or carboxyl groups.
"co-crystals" refers to crystals of Active Pharmaceutical Ingredient (API) and co-crystal former (CCF) that are bound by hydrogen bonds or other non-covalent bonds, wherein the pure states of the API and CCF are both solid at room temperature and there is a fixed stoichiometric ratio between the components. A co-crystal is a multi-component crystal that includes both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.
"animal" is meant to include mammals, such as humans, companion animals, zoo animals and livestock, preferably humans, horses or dogs.
"stereoisomers" refers to isomers arising from the spatial arrangement of atoms in a molecule, and include cis-trans isomers, enantiomers and conformational isomers.
Detailed Description
The following examples illustrate the technical aspects of the present invention in detail, but the scope of the present invention is not limited thereto.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (sum) Mass Spectrometry (MS). NMR shift (. Delta.) of 10 -6 Units of (ppm) are given. NMR was performed using a (Bruker Avance III and Bruker Avance 300) magnetonuclear apparatus with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard Tetramethylsilane (TMS);
MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI));
HPLC was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18X14.6mm, 3.5. Mu.M);
the thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15mm-0.20mm, and the specification of the thin layer chromatography separation and purification product is 0.4mm-0.5mm;
Column chromatography generally uses 200-300 mesh silica gel of yellow sea of tobacco stand as carrier;
the known starting materials of the present invention may be synthesized using or according to methods known in the art, or may be purchased from the companies taitan technology, an Naiji chemistry, shanzheimer, chengdouke, shanghuan chemical technology, carbofuran technology, etc.;
SEM:
Figure PCTCN2021117545-APPB-000216
THP:
Figure PCTCN2021117545-APPB-000217
boc: a tert-butoxycarbonyl group; ms:
Figure PCTCN2021117545-APPB-000218
TBS:
Figure PCTCN2021117545-APPB-000219
MTBE methyl tert-butyl ether; bn:
Figure PCTCN2021117545-APPB-000220
intermediate I: 6-bromo-1-tetrahydropyran-2-yl-indazol-4-ol
6-bromo-1-tetrahydropyran-2-yl-indazol-4-ol
Figure PCTCN2021117545-APPB-000221
The first step: 6-bromo-4-fluoro-1H-indazole (1 b)
6-bromo-4-fluoro-1H-indazole
To a 1000mL reaction flask, 1a (84 g,380 mmol) and 80% hydrazine hydrate (170 mL) were added in this order, and 1, 4-dioxane (400 mL) was added, followed by stirring at 100℃for 7h. Cooling to room temperature, adding water (500 mL), stirring for crystallization for 30min, filtering, adding dichloromethane (160 mL), petroleum ether (800 mL), stirring and pulping for 1 hour, suction filtering, washing the filter cake with petroleum ether (100 mL) once, and drying under reduced pressure at 45 ℃ 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] +
And a second step of: 6-bromo-4-fluoro-1-tetrahydropyran-2-yl-indazole (1 c)
6-bromo-4-fluoro-1-tetrahydropyran-2-yl-indazole
1b (21.4 g,99.55 mmol), methylene chloride (220 mL) and p-toluenesulfonic acid monohydrate (1.89 g,9.95 mmol) were added to a reaction flask, 3, 4-dihydro-2H-pyran (16.75 g,199.10 mmol) was added under cooling in a water bath, the reaction was stirred at room temperature for 4 hours, TLC was monitored to complete, saturated sodium bicarbonate solution (300 mL. Times.1) was added for washing, the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 40℃to dryness, methanol 50mL was added, stirred under cooling in ice water to crystallize for 1 hour, filtered, and the cake was concentrated under reduced pressure at 40℃to give 1c as a yellowish brown solid (13 g, yield: 43.6%).
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).
And a third step of: 6-bromo-4-methoxy-1-tetrahydropyran-2-yl-indazole (1 d)
6-bromo-4-methoxy-1-tetrahydropyran-2-yl-indazole
In a 50mL reaction flask, methanol (0.48 g,15 mmol), naH (0.8 g,20mmol,60 wt%) and N, N-dimethylformamide (20 mL) were added in this order, and after the addition was completed, the mixture was stirred at 0℃for 20 minutes, 1c (2.99 g,10 mmol) was added and the reaction was stirred at room temperature for 3 hours. Ethyl acetate (100 mL) and water (100 mL) were added to the reaction solution, the solution was separated, the organic phase was washed with water (100 ml×2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (PE/ea=10/1) to give 1d as a white solid (1.76 g, yield 57%).
LCMS m/z＝311.0/313.0[M+H] +
Fourth step: 6-bromo-1H-indazol-4-ol (1 e)
6-bromo-1H-indazol-4-ol
In a 100mL reaction flask, 1d (1.76 g,5.7 mmol) and hydrobromic acid (30 mL) were added in this order, and after the addition was completed, the mixture was stirred at 140℃for 4h. The reaction solution was cooled to room temperature, then pH was adjusted to 8 with saturated sodium bicarbonate solution, then extracted with dichloromethane (100 ml×2), the combined organic layers were dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (PE/ea=5/1) to give 1e as a pale yellow solid (0.448 g, yield 37%).
LCMS m/z＝213.0/215.1[M+H] +
Fifth step: (6-bromo-1H-indazol-4-yl) oxy-tert-butyl-dimethyl-silane (1 f)
(6-bromo-1H-indazol-4-yl)oxy-tert-butyl-dimethyl-silane
In a 50mL 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 this order, and t-butyldimethylchlorosilane (0.62 g,4.13 mmol) was added after the addition was completed, and stirred at room temperature for 10 minutes. Ethyl acetate (50 mL) was added to the reaction solution, followed by washing with saturated sodium bicarbonate solution (50 ml×3), and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (PE/ea=40/1) to give 1f crude product, pale yellow oil, which was directly used for the next reaction.
Sixth step: (6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl) oxy-tert-butyl-dimethyl-silane (1 g)
(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxy-tert-butyl-dimethyl-silane
In a 50mL reaction flask, the crude 1f, p-toluenesulfonic acid monohydrate (0.038 g,0.2 mmol) and methylene chloride (20 mL) were added sequentially, after the addition was completed, 3, 4-dihydro-2H-pyran (0.52 g,6.2 mmol) was added, and after the addition was completed, stirring was performed at room temperature for 20 minutes. Ethyl acetate (50 mL) was added to the reaction solution, which was then washed with saturated sodium bicarbonate solution (50 ml×3), and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (PE/ea=20/1) to give 1g as a pale yellow oil (0.75 g, two-step yield 88%).
Seventh step: 6-bromo-1-tetrahydropyran-2-yl-indazol-4-ol (intermediate I)
6-bromo-1-tetrahydropyran-2-yl-indazol-4-ol
In a 50mL reaction flask, 1g (0.54 g,1.32 mmol) of tetrahydrofuran (20 mL) was sequentially added, and potassium hydroxide (0.22 g,3.96 mmol) was added after the addition was completed, and the mixture was stirred at room temperature for 4 hours. Saturated ammonium chloride (40 mL) was added to the reaction solution, followed by extraction with ethyl acetate (40 ml×2), and the combined organic phases were dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (PE/ea=10/1 to PE/ea=1/1) to give intermediate I as a white foam solid (0.36 g, yield 92%).
LCMS m/z＝297.0/299.0[M+H] + ；
1 H NMR(400MHz,CD 3 OD)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).
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-enamide
Figure PCTCN2021117545-APPB-000222
The first step: cis- [3- (tert-butoxycarbonylamino) cyclobutyl ] methanesulfonate (1B)
cis-[3-(tert-butoxycarbonylamino)cyclobutyl]methanesulfonate
In a 50mL reaction flask, cis-3-Boc aminocyclobutanol (0.47 g,2.5 mmol), triethylamine (0.51 g,5 mmol) and dichloromethane (20 mL) were sequentially added, and after the addition was completed, stirring was performed at 0℃for 20 minutes, methanesulfonyl chloride (0.37 g,3.25 mmol) was slowly added dropwise and the reaction was stirred at room temperature for 1h. The reaction solution was washed with water (30 mL. Times.1) and saturated brine (30 mL. Times.1), and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude 1B product as a pale yellow solid (0.647 g), which was used directly in the next reaction.
And a second step of: trans-N- [3- (6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl) oxy-cyclobutyl ] carbamic acid tert-butyl ester (1C)
trans-tert-butyl N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]carbamate
In a 50mL reaction flask, 6-bromo-1-tetrahydropyran-2-yl-indazol-4-ol (intermediate I) (0.284 g,0.97 mmol), a 1B crude product (0.33 g), cesium carbonate (1.26 g,3.87 mmol) and N, N-dimethylformamide (40 mL) were sequentially added, and after the addition was completed, the reaction was stirred at 90℃for 5 hours, ethyl acetate (50 mL) was added, followed by washing with water (50 mL. Times.3), the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 1C as a pale yellow oil (0.38 g, yield 84%).
LCMS m/z＝466.1/468.0[M+H] +
And a third step of: trans-N- [3- [6- (4-hydroxyphenyl) -1-tetrahydropyran-2-yl-indazol-4-yl ] oxetanyl ] carbamic acid tert-butyl ester (1D)
trans-tert-butyl N-[3-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclobutyl]carbamate
In a 50mL reaction flask, 1C (0.38 g,0.82 mmol), 4-hydroxyphenylboronic acid (0.136 g,0.98 mmol), potassium phosphate heptahydrate (0.83 g,2.46 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (67 mg,0.082 mmol) and dioxane/water (v/v=4/1, 10 mL) were sequentially added, and after three substitutions of nitrogen, the reaction was stirred at 90℃for 2 hours. To the reaction solution was added water (50 mL), followed by extraction with ethyl acetate (50 ml×2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (PE/ea=3/1) to give 1D as a pale yellow solid (0.28 g, yield 71%).
Fourth step: 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-enamide
In a 50mL reaction flask, 1D (0.27 g,0.56 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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. Times.3), and then concentrated to dryness under reduced pressure. To the resulting residue were successively added trans-4-dimethylaminocrotonic acid hydrochloride (0.093 g,0.56 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.216 g,1.13 mmol), 1-hydroxybenzotriazole (0.098 g,0.73 mmol) and N, N-dimethylformamide (40 mL), and after the addition, the mixture was stirred at room temperature for 10 minutes, and N, N-diisopropylethylamine (0.45 g,3.48 mmol) was added, and after the addition, the mixture was stirred at room temperature for 50 minutes. To the reaction solution was added saturated sodium hydrogencarbonate (50 mL), followed by extraction with methylene chloride/methanol (v/v=10/1) (50 ml×2), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by separation to give compound 1 (76 mg, yield 33%) by preparing a liquid phase (instrument: waters 2767, liquid phase; column: sunfire@prep C18 (19 mm×150 mM), mobile phase composition: mobile phase a: acetonitrile mobile phase B: water (containing 5mM ammonium acetate)).
LCMS m/z＝407.1[M+H] + ；
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).
Example 2: cis- (E) -4- (dimethylamino) -N- [3- [ [6- (4-hydroxyphenyl) -1H-indazol-4-yl ] oxy ] cyclobutyl ] but-2-enamide (Compound 2)
cis-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclobutyl]but-2-enamide
Figure PCTCN2021117545-APPB-000223
The first step: trans- [3- (tert-butoxycarbonylamino) cyclobutyl ] methanesulfonate (2B)
trans-[3-(tert-butoxycarbonylamino)cyclobutyl]methanesulfonate
In a 50mL reaction flask, trans-3-Boc aminocyclobutanol (0.5 g,2.6 mmol), triethylamine (0.51 g,5 mmol) and dichloromethane (10 mL) were sequentially added, and after the addition was completed, stirring was performed at 0℃for 20 minutes, methanesulfonyl chloride (0.37 g,3.25 mmol) was slowly added dropwise and the reaction was stirred at room temperature for 1h. The reaction solution was washed with water (30 mL. Times.1) and saturated brine (30 mL. Times.1), and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2B, crude product, pale yellow solid (0.67 g), which was used directly in the next reaction.
And a second step of: cis-N- [3- (6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl) oxy-cyclobutyl ] carbamic acid tert-butyl ester (2C)
cis-tert-butyl N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]carbamate
In a 50mL reaction flask, 6-bromo-1-tetrahydropyran-2-yl-indazol-4-ol (intermediate I) (0.57 g,1.96 mmol), a crude 2B product (0.67 g), cesium carbonate (2.52 g,7.6 mmol) and N, N-dimethylformamide (40 mL) were sequentially added, and after the addition was completed, the reaction was stirred at 90℃for 5 hours, ethyl acetate (50 mL) was added to the reaction mixture, followed by washing with water (50 mL. Times.3), the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2C as a pale yellow oil (0.71 g, yield 82%).
And a third step of: cis-N- [3- [6- (4-hydroxyphenyl) -1-tetrahydropyran-2-yl-indazol-4-yl ] oxetanyl ] carbamic acid tert-butyl ester (2D)
cis-tert-butyl N-[3-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclobutyl]carbamate
In a 50mL reaction flask, 2C (0.36 g,0.81 mmol), 4-hydroxyphenylboronic acid (0.136 g,0.98 mmol), potassium phosphate heptahydrate (0.83 g,2.46 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (67 mg,0.082 mmol) and dioxane/water (v/v=4/1, 10 mL) were sequentially added, and after three substitutions of nitrogen, the reaction was stirred at 90℃for 2 hours. To the reaction solution was added water (50 mL), followed by extraction with ethyl acetate (50 ml×2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and 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, yield 80%).
LCMS m/z＝480.2[M+H] +
Fourth step: cis- (E) -4- (dimethylamino) -N- [3- [ [6- (4-hydroxyphenyl) -1H-indazol-4-yl ] oxy ] cyclobutyl ] but-2-enamide (Compound 2)
cis-(E)-4-(dimethylamino)-N-[3-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclobutyl]but-2-enamide
In a 50mL reaction flask, 2D (0.31 g,0.59 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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. Times.3), and then concentrated to dryness under reduced pressure. To the resulting residue were successively added trans-4-dimethylaminocrotonic acid hydrochloride (0.093 g,0.56 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.216 g,1.13 mmol), 1-hydroxybenzotriazole (0.098 g,0.73 mmol) and N, N-dimethylformamide (40 mL), and after the addition, the mixture was stirred at room temperature for 10 minutes, and N, N-diisopropylethylamine (0.45 g,3.48 mmol) was added, and after the addition, the mixture was stirred at room temperature for 50 minutes. To the reaction solution was added saturated sodium bicarbonate (50 mL), followed by extraction with dichloromethane/methanol (v/v=10/1, 50ml×2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v=20/1-10/1)) to give compound 2 (26 mg, yield 11%).
LCMS m/z＝407.2[M+H] + ；
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).
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-enamide
Figure PCTCN2021117545-APPB-000224
Figure PCTCN2021117545-APPB-000225
The first step: trans- [3- (tert-butoxycarbonylamino) cyclobutyl ] methanesulfonic acid methyl ester (3B)
trans-[3-(tert-butoxycarbonylamino)cyclobutyl]methyl methanesulfonate
In a 50mL reaction flask, tert-butyl trans-3-hydroxymethyl cyclobutylcarbamate (0.4 g,2.0 mmol), triethylamine (0.404 g,4 mmol) and dichloromethane (10 mL) were successively added, and after the addition, the mixture was stirred at 0℃for 20 minutes, methanesulfonyl chloride (0.30 g,2.6 mmol) was slowly added dropwise and the reaction was stirred at room temperature for 1h. The reaction solution was washed with water (30 mL. Times.1) and saturated brine (30 mL. Times.1), and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 3B as a crude product, which was used as a pale yellow solid (0.51 g) for the next reaction.
And a second step of: trans-N- [3- [ (6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl) oxymethyl ] cyclobutyl ] carbamic acid tert-butyl ester (3C)
trans-tert-butyl N-[3-[(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxymethyl]cyclobutyl]carbamate
In a 100mL reaction flask, 6-bromo-1-tetrahydropyran-2-yl-indazol-4-ol (intermediate I) (0.5 g,1.69 mmol), a 3B crude product (0.51 g), cesium carbonate (1.66 g,5.07 mmol) and N, N-dimethylformamide (10 mL) were sequentially added, and after the addition was completed, the reaction was stirred at 75℃for 2 hours, ethyl acetate (100 mL) was added to the reaction solution, followed by washing with water (100 mL. Times.3), the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 3C as a pale yellow foamy solid (0.712 g, 86% yield).
And a third step of: trans-N- [3- [ [6- (4-hydroxyphenyl) -1-tetrahydropyran-2-yl-indazol-4-yl ] oxymethyl ] cyclobutyl ] carbamic acid tert-butyl ester (3D)
trans-tert-butyl N-[3-[[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxymethyl]cyclobutyl]carbamate
In a 100mL 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), a [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (119 mg,0.146 mmol) and dioxane/water (v/v=4/1, 10 mL) were sequentially added, and after three substitutions of nitrogen, the reaction was stirred at 90℃for 2 hours. To the reaction solution was added water (50 mL), followed by extraction with ethyl acetate (50 ml×2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and 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, yield 92%).
LCMS m/z＝494.2[M+H] +
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-enamide
In a 50mL reaction flask, 3D (0.3 g,0.61 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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. Times.3), and then concentrated to dryness under reduced pressure. To the resulting residue were added, in order, trans-4-dimethylaminocrotonic acid hydrochloride (0.131 g,0.79 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.232 g,1.22 mmol), 1-hydroxybenzotriazole (0.109 g,0.81 mmol) and N, N-dimethylformamide (20 mL), and after the addition, the mixture was stirred at room temperature for 10 minutes, and N, N-diisopropylethylamine (0.47 g,3.65 mmol) was added, and after the addition, the mixture was stirred at room temperature for 50 minutes. To the reaction solution was added saturated sodium hydrogencarbonate (50 mL), followed by extraction with methylene chloride/methanol (v/v=10/1, 50ml×2), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by separation to give compound 3 (81 mg, yield 32%) by preparing a liquid phase (instrument: waters 2767, liquid phase; column chromatography: sunfire@prep C18 (19 mm×150 mM), mobile phase composition: mobile phase a: acetonitrile mobile phase B: water (containing 5mM ammonium acetate)).
LCMS m/z＝421.2[M+H] + ；
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).
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-enamide
Figure PCTCN2021117545-APPB-000226
The first step: cis- [3- (tert-Butoxycarbonylamino) cyclobutyl ] methanesulfonic acid methyl ester (4B)
cis-[3-(tert-butoxycarbonylamino)cyclobutyl]methyl methanesulfonate
In a 50mL reaction flask, tert-butyl cis-3-hydroxymethylcyclobutylcarbamate (0.403 g,2.0 mmol), triethylamine (0.404 g,4 mmol) and methylene chloride (20 mL) were successively added, and after the addition, the mixture was stirred at 0℃for 20 minutes, methanesulfonyl chloride (0.30 g,2.6 mmol) was slowly added dropwise and the mixture was reacted at room temperature for 1 hour with stirring. The reaction solution was washed with water (30 mL. Times.1) and saturated brine (30 mL. Times.1), and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude 4B product as a pale yellow solid (0.677 g), which was used directly in the next reaction.
LCMS m/z＝302.1[M+Na] +
And a second step of: 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]carbamate
In a 100mL reaction flask, 6-bromo-1-tetrahydropyran-2-yl-indazol-4-ol (intermediate I) (0.6 g,2.0 mmol), a crude 4B (0.6 g), cesium carbonate (2.6 g,8.0 mmol) and N, N-dimethylformamide (40 mL) were sequentially added, and after the addition was completed, the reaction was stirred at 90℃for 5 hours, ethyl acetate (100 mL) was added to the reaction mixture, followed by washing with water (100 mL. Times.3), the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 4C as a pale yellow foamy solid (0.86 g, yield 90%).
LCMS m/z＝480.1/482.0[M+H] +
And a third step of: cis-N- [3- [ [6- (4-hydroxyphenyl) -1-tetrahydropyran-2-yl-indazol-4-yl ] oxymethyl ] cyclobutyl ] carbamic acid tert-butyl ester (4D)
cis-tert-butylN-[3-[[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxymethyl]cyclobutyl]carbamate
In a 100mL 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), a [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (126 mg,0.154 mmol) and dioxane/water (v/v=4/1, 10 mL) were sequentially added, and after three substitutions of nitrogen, the reaction was stirred at 90℃for 2 hours. To the reaction solution was added water (50 mL), followed by extraction with ethyl acetate (50 ml×2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and 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, yield 98%).
LCMS m/z＝494.2[M+H] +
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-enamide
In a 50mL reaction flask, 4D (0.37 g,0.75 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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. Times.3), and then concentrated to dryness under reduced pressure. To the resulting residue were added, in order, trans-4-dimethylaminocrotonic acid hydrochloride (0.161 g,0.97 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.284 g,1.5 mmol), 1-hydroxybenzotriazole (0.132 g,1.0 mmol) and N, N-dimethylformamide (40 mL), and after the addition, the mixture was stirred at room temperature for 10 minutes, and N, N-diisopropylethylamine (0.58 g,4.5 mmol) was added and after the addition, the mixture was stirred at room temperature for 50 minutes. To the reaction solution was added saturated sodium hydrogencarbonate (50 mL), followed by extraction with methylene chloride/methanol (v/v=10/1, 50ml×2), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by separation to give compound 4 (97 mg, yield 31%) by preparing a liquid phase (instrument: waters 2767 for preparing a liquid phase; column: xbridge@prep C18 (30 mm×150 mm); mobile phase composition: mobile phase a: acetonitrile; mobile phase B: water (containing 0.05% ammonia)).
LCMS m/z＝421.3[M+H] + ；
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).
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
Figure PCTCN2021117545-APPB-000227
The first step: [3- (tert-Butoxycarbonylamino) -1-bicyclo [1.1.1] pentyl ] methanesulfonic acid methyl ester (5B)
[3-(tert-butoxycarbonylamino)-1-bicyclo[1.1.1]pentanyl]methylmethanesulfonate
In a 50mL reaction flask, tert-butyl (3- (hydroxymethyl) bicyclo [1.1.1] pent-1-yl) carbamate (5A) (0.626 g,2.73 mmol), triethylamine (0.58 g,5.7 mmol) and dichloromethane (20 mL) were sequentially added, and after the addition, stirring was performed at 0℃for 20 minutes, methanesulfonyl chloride (0.336 g,2.93 mmol) was slowly added dropwise and the reaction was stirred at room temperature for 1h. The reaction solution was washed with water (30 mL. Times.1) and saturated brine (30 mL. Times.1), and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude 5B product as a pale yellow solid (0.72 g), which was used directly in the next reaction.
And a second step of: n- [1- [ (6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl) oxymethyl ] -3-bicyclo [1.1.1] pentyl ] carbamic acid tert-butyl ester (5C)
tert-butyl N-[1-[(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxymethyl]-3-bicyclo[1.1.1]pentanyl]carbamate
In a 100mL reaction flask, 6-bromo-1-tetrahydropyran-2-yl-indazol-4-ol (intermediate I) (0.23 g,0.774 mmol), a crude 5B product (0.6 g), cesium carbonate (1.0 g,3.06 mmol) and N, N-dimethylformamide (40 mL) were sequentially added, and after the addition was completed, the reaction was stirred at 90℃for 5 hours, ethyl acetate (100 mL) was added to the reaction mixture, followed by washing with water (100 mL. Times.3), the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a 5C, pale yellow foamy solid (0.343 g, yield 90%).
LCMS m/z＝492.1/494.1[M+H] +
And a third step of: n- [1- [ [ [6- (4-hydroxyphenyl) -1-tetrahydropyran-2-yl-indazol-4-yl ] oxymethyl ] -3-bicyclo [1.1.1] pentyl ] carbamic acid tert-butyl ester (5D)
tert-butyl N-[1-[[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxymethyl]-3-bicyclo[1.1.1]pentanyl]carbamate
In a 100mL reaction flask, 5C (0.318 g, 0.640 mmol), 4-hydroxyphenylboronic acid (0.107 g,0.775 mmol), potassium phosphate heptahydrate (0.650 g,1.938 mmol), [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (53 mg,0.065 mmol) and dioxane/water (v/v=4/1, 10 mL) were sequentially added, and after three substitutions of nitrogen, the reaction was stirred at 90℃for 2 hours. To the reaction solution was added water (50 mL), followed by extraction with ethyl acetate (50 ml×2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and 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, yield 92%).
LCMS m/z＝506.2[M+H] +
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
In a 50mL reaction flask, 5D (0.11 g,0.218 mmol) and methylene chloride/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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. Times.3), and then concentrated to dryness under reduced pressure. To the resulting residue were added, in order, trans-4-dimethylaminocrotonic acid hydrochloride (0.047 g,0.283 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.084 g,0.438 mmol), 1-hydroxybenzotriazole (0.038 g,0.283 mmol) and N, N-dimethylformamide (40 mL), and after the addition, the mixture was stirred at room temperature for 10 minutes, N-diisopropylethylamine (0.58 g,4.5 mmol) was added, and after the addition, the mixture was stirred at room temperature for 50 minutes. To the reaction solution was added saturated sodium bicarbonate (50 mL), followed by extraction with dichloromethane/methanol (v/v=10/1, 50ml×2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v=20/1-10/1)) to give compound 5 (27 mg, yield 29%).
LCMS m/z＝433.2[M+H] + ；
1 H NMR(400MHz,CD 3 OD)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).
Example 6: trans- (E) -4- (dimethylamino) -N-3- ((6- (2-ethyl-5-fluoro-4-hydroxyphenyl) -1H-indazol-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-enamide
Figure PCTCN2021117545-APPB-000228
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)carbamate
Under nitrogen, 2- (4- (benzyloxy) -2-ethyl-5-fluorophenyl) -4, 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 ] palladium dichloride dichloromethane complex (73.5 mg,0.09 mmol), each was added to a solution of trans-N- [3- (6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl) oxy cyclobutyl ] carbamic acid tert-butyl ester (1C) (420 mg,0.9 mmol), 1, 4-dioxabicyclo (40 mL) and water (10 mL), stirred for 1h at 110 ℃, saturated sodium bicarbonate solution (30 mL) quenched, ethyl acetate (30 mL x 3) was extracted, the combined organic layers were dried with anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure and the silica gel column (petroleum ether/ethyl acetate (v) =2.6 mg) was chromatographed to give 480mg of a grey solid (5.86%).
And a second step of: trans-tert-butyl (3- ((6- (2-ethyl-5-fluoro-4-hydroxyphenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole-4-ethoxy) cyclobutyl carbamate (6B)
trans-tert-butyl(3-((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)carbamate
6A (480 mg,0.78 mmol) was added. Into a reaction flask, palladium on carbon (48 mg,10 wt%) and methanol solution (30 mL) were added and the hydrogen gas was purged three times; the reaction was stirred at room temperature for 6h. The reaction solution was filtered through celite and eluted with ethyl acetate. Concentrated to dryness under reduced pressure to give crude 6B as a grey solid (410 mg) which was used directly in the next reaction.
LCMS m/z＝526.2[M+1] +
And a third step of: trifluoroacetate salt of trans-4- (4- ((3-aminocyclobutoxy) -1H-indazol-6-yl) -5-ethyl-2-fluorophenol (6C)
trans-4-(4-(3-aminocyclobutoxy)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol；trifluoroaceticacid
The crude 6B (410 mg) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (8 mL) was added and reacted at room temperature for 3 hours. The reaction solution was concentrated directly to give a crude trifluoroacetate salt of 6C as a yellow oil (355 mg).
Fourth step: trans- (E) -4- (dimethylamino) -N- (3- ((6- (2-ethyl-5-fluoro-4-hydroxyphenyl) -1H-indazol-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-enamide
In a 50mL three-necked flask, 6-chlorobenzotriazole-1, 3-tetramethylurea hexafluorophosphate (62 mg,0.15 mmol) was added to a solution of trans 4-dimethylaminocrotonic acid hydrochloride (24.8 mg,0.15 mmol) in N, N-dimethylformamide (2 mL), reacted at room temperature for 10min at 0℃to prepare a solution of 6C trifluoroacetate (59 mg) in 1mL N, N-dimethylformamide and dropwise added to the above-mentioned reaction solution, stirred at 0℃for 1min, N-diisopropylethylamine (101 mg,0.78 mmol) in 1mL N, N-dimethylformamide and dropwise added to the above-mentioned reaction solution, stirred at 0℃for 3h, quenched with saturated sodium bicarbonate solution (5 mL), extracted with ethyl acetate (20X 3 mL) and concentrated under reduced pressure, the residue was prepared by preparing a liquid phase (water 2767; column: sunFire@Prep 18X 150 mM) and a mobile phase (19 mM: mobile phase: 6 mM) was separated to obtain an aqueous phase (mobile phase: 6 mM: mobile phase) and an aqueous phase (mobile phase: 150 mM: mobile phase) was purified to obtain an aqueous phase (mobile phase: 6 mM: aqueous phase) of acetic acid solution (12 mM)
LCMS m/z＝453.3[M+1] +
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).
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-enamide
Figure PCTCN2021117545-APPB-000229
The first step: trans-N- [3- (6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl) oxy cyclobutyl ] -N-methyl-carbamic acid tert-butyl ester (7A)
trans-tert-butyl N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]-N-methyl-carbamate
In a 50mL reaction flask, 1C (0.22 g,0.47 mmol), tetrahydrofuran (15 mL), and sodium hydride (0.28 g,7.05mmol,60 wt%) were sequentially added, and after the addition was completed, stirring was performed at 25℃for 30 minutes, methyl iodide (1.33 g,9.4 mmol) was slowly added dropwise and the reaction was stirred at room temperature for 1.2h. Ethyl acetate (50 mL) was added to the reaction solution, which was then washed with water (30 ml×1) and saturated brine (30 ml×1), and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (PE/ea=9/1) to give a crude 7A product as a pale yellow oil (0.12 g) which was directly used for the next reaction.
And a second step of: trans-N- [3- [6- (4-hydroxyphenyl) -1-tetrahydropyran-2-yl-indazol-4-yl ] oxetanyl ] -N-methyl-carbamic acid tert-butyl ester (7B)
trans-tert-butyl N-[3-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclobutyl]-N-methyl-carbamate
In a 50mL reaction flask, crude 7A (0.12 g), 4-hydroxyphenylboronic acid (0.040 g,0.287 mmol), potassium phosphate heptahydrate (0.243 g,0.720 mmol), a [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (20 mg,0.024 mmol) and dioxane/water (v/v=4/1, 10 mL) were sequentially added, and after three substitutions of nitrogen, the reaction was stirred at 90℃for 2 hours. To the reaction solution was added water (50 mL), followed by extraction with ethyl acetate (50 ml×2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and 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% in two steps).
LCMS m/z＝494.2[M+H] + ；
And a third step of: 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-enamide
In a 50mL reaction flask, 7B (0.071 g,0.132 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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. Times.3), and then concentrated to dryness under reduced pressure.
In a 50mL reaction flask, trans-4-dimethylaminocrotonic acid hydrochloride (0.024 g,0.145 mmol), 6-chlorobenzotriazol-1, 3-tetramethylurea hexafluorophosphate (0.071 g,0.172 mmol) and DMF (10 mL) were added, and after the addition was completed, the solution was stirred at room temperature for 30 minutes, and then DMF (5 mL) solution of the residue obtained in the above step was added, and after the addition was completed, the solution was stirred at room temperature for 10 minutes, N-diisopropylethylamine (0.102 g,0.79 mmol) was added, and after the addition was completed, the solution was stirred at room temperature for 50 minutes. To the reaction solution was added saturated sodium bicarbonate (50 mL), followed by extraction with dichloromethane/methanol (v/v=10/1) (50 ml×2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by plate separation (dichloromethane/methanol=5/1) over silica gel to give compound 7 (18 mg, yield 32%).
LCMS m/z＝421.2[M+H] + ；
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).
Example 8: trans- (E) -4- (dimethylamino) -N- [4- [ [6- (4-hydroxyphenyl) -1H-indazol-4-yl ] oxy ] cyclohexyl ] but-2-enamide (compound 8)
trans-(E)-4-(dimethylamino)-N-[4-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclohexyl]but-2-enamide
Figure PCTCN2021117545-APPB-000230
The first step: cis- [4- (tert-butoxycarbonylamino) cyclohexyl ] methanesulfonate (8B)
cis-[4-(tert-butoxycarbonylamino)cyclohexyl]methanesulfonate
In a 50mL reaction flask, cis-4-Boc aminocyclohexanol (1.08 g,5.0 mmol), triethylamine (1.01 g,10.0 mmol) and methylene chloride (20 mL) were sequentially added, and after the addition was completed, stirring was performed at 0℃for 20 minutes, methanesulfonyl chloride (0.75 g,6.5 mmol) was slowly added dropwise and the reaction was stirred at room temperature for 1 hour. The reaction solution was washed with water (30 mL. Times.1) and saturated brine (30 mL. Times.1), and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude 8B product as a pale yellow solid (1.17 g), which was used directly in the next reaction.
And a second step of: trans-N- [4- (6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl) oxycyclohexyl ] carbamic acid tert-butyl ester (8C)
trans-tert-butyl N-[4-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclohexyl]carbamate
In a 50mL reaction flask, 6-bromo-1-tetrahydropyran-2-yl-indazol-4-ol (intermediate I) (0.294 g,1.0 mmol), crude 8B (0.38 g), cesium carbonate (1.26 g,3.87 mmol) and N, N-dimethylformamide (40 mL) were sequentially added, and after the addition was completed, the reaction was stirred at 90℃overnight, ethyl acetate (50 mL) was added to the reaction mixture, followed by washing with water (50 mL. Times.3), the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 8C as a pale yellow oil (0.43 g, yield 87%).
And a third step of: trans-N- [4- [6- (4-hydroxyphenyl) -1-tetrahydropyran-2-yl-indazol-4-yl ] oxycyclohexyl ] carbamic acid tert-butyl ester (8D)
trans-tert-butyl N-[4-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclohexyl]carbamate
In a 50mL reaction flask, 8C (0.43 g,0.87 mmol), 4-hydroxyphenylboronic acid (0.144 g,1.04 mmol), potassium phosphate heptahydrate (0.883 g,2.61 mmol), [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (71 mg,0.087 mmol) and dioxane/water (v/v=4/1, 10 mL) were sequentially added, and after three substitutions of nitrogen, the reaction was stirred at 90℃for 2 hours. To the reaction solution was added water (50 mL), followed by extraction with ethyl acetate (50 ml×2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and 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, yield 51%).
LCMS m/z＝508.3[M+H] +
Fourth step: trans- (E) -4- (dimethylamino) -N- [4- [ [6- (4-hydroxyphenyl) -1H-indazol-4-yl ] oxy ] cyclohexyl ] but-2-enamide (compound 8)
trans-(E)-4-(dimethylamino)-N-[4-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclohexyl]but-2-enamide
In a 50mL reaction flask, 8D (0.22 g,0.42 mmol) and methylene chloride/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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. Times.3), and then concentrated to dryness under reduced pressure.
In a 50mL reaction flask, trans-4-dimethylaminocrotonic acid hydrochloride (0.066 g,0.397 mmol), 6-chlorobenzotriazol-1, 3-tetramethylurea hexafluorophosphate (0.194 g,0.172 mmol) and DMF (10 mL) were added, and after the addition, a solution of the residue obtained in the above step in DMF (5 mL) was added and stirred at room temperature for 10 minutes, and N, N-diisopropylethylamine (0.28 g,2.17 mmol) was added and stirred at room temperature for 50 minutes. To the reaction solution was added saturated sodium bicarbonate (50 mL), followed by extraction with dichloromethane/methanol (v/v=10/1) (50 ml×2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by plate separation (dichloromethane/methanol=5/1) over silica gel to give compound 8 (15 mg, yield 8%).
LCMS m/z＝435.2[M+H] + ；
1 H NMR(400MHz,CD 3 OD)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).
Example 9: cis- (E) -4- (dimethylamino) -N- [4- [ [6- (4-hydroxyphenyl) -1H-indazol-4-yl ] oxy ] cyclohexyl ] but-2-enamide (compound 9)
cis-(E)-4-(dimethylamino)-N-[4-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclohexyl]but-2-enamide
Figure PCTCN2021117545-APPB-000231
The first step: trans- [4- (tert-butoxycarbonylamino) cyclohexyl ] methanesulfonate (9B)
trans-[4-(tert-butoxycarbonylamino)cyclohexyl]methanesulfonate
In a 50mL reaction flask, trans-4-Boc aminocyclohexanol (0.75 g,3.48 mmol), triethylamine (0.88 g,8.7 mmol) and dichloromethane (30 mL) were sequentially added, and after the addition was completed, stirring was performed at 0℃for 20 minutes, methanesulfonyl chloride (0.6 g,5.22 mmol) was slowly added dropwise and the reaction was stirred at room temperature for 1h. The reaction solution was washed with water (30 mL. Times.1) and saturated brine (30 mL. Times.1), and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude 9B product as a pale yellow solid (1 g), which was used directly in the next reaction.
And a second step of: 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]carbamate
In a 50mL reaction flask, 6-bromo-1-tetrahydropyran-2-yl-indazol-4-ol (intermediate I) (0.6 g,2.02 mmol), a crude 9B product (0.89 g), cesium carbonate (1.97 g,6.06 mmol) and N, N-dimethylformamide (40 mL) were sequentially added, the reaction mixture was stirred at 90℃overnight, ethyl acetate (50 mL) was added, then water (50 mL. Times.3) was used for washing, the organic layer was dried over anhydrous sodium sulfate, filtration and the filtrate was concentrated under reduced pressure to give a crude product, which was isolated and purified by a silica gel preparation plate to give 9C as a pale yellow oil (0.215 g, yield 22%).
And a third step of: 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]carbamate
In a 50mL reaction flask, 9C (0.215 g,0.43 mmol), 4-hydroxyphenylboronic acid (0.077 g,0.56 mmol), potassium phosphate heptahydrate (0.73 g,2.15 mmol), a [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (35 mg,0.043 mmol) and dioxane/water (v/v=4/1, 20 mL) were sequentially added, and after nitrogen substitution, the reaction was stirred at 110℃for 2 hours. To the reaction solution was added water (50 mL), followed by extraction with ethyl acetate (80 ml×2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and 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, yield 91%).
LCMS m/z＝508.3[M+H] +
Fourth step: cis- (E) -4- (dimethylamino) -N- [4- [ [6- (4-hydroxyphenyl) -1H-indazol-4-yl ] oxy ] cyclohexyl ] but-2-enamide (compound 9)
cis-(E)-4-(dimethylamino)-N-[4-[[6-(4-hydroxyphenyl)-1H-indazol-4-yl]oxy]cyclohexyl]but-2-enamide
In a 50mL reaction flask, 9D (0.199g, 0.39 mmol) and methylene chloride/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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. Times.3), and then concentrated to dryness under reduced pressure.
In a 50mL reaction flask, trans-4-dimethylaminocrotonic acid hydrochloride (0.05 g,0.38 mmol), 6-chlorobenzotriazol-1, 3-tetramethylurea hexafluorophosphate (0.194 g,0.172 mmol) and DMF (10 mL) were added, and after the addition, a solution of the residue obtained in the above step in DMF (5 mL) was added and stirred at room temperature for 10 minutes, and N, N-diisopropylethylamine (0.28 g,2.17 mmol) was added and after the addition, stirred at room temperature for 50 minutes. To the reaction solution was added saturated sodium bicarbonate (50 mL), followed by extraction with dichloromethane/methanol (v/v=10/1) (50 ml×2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by plate separation (dichloromethane/methanol=5/1) over silica gel to give compound 9 (14 mg, yield 10%).
LCMS m/z＝435.2[M+H] + ；
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).
Example 10: (E) -4- (dimethylamino) -N- [ (1 s,3 s) -3- [ [6- (4-hydroxyphenyl) -1H-indazol-4-yl ] oxy ] 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
Figure PCTCN2021117545-APPB-000232
The first step: [ (1R, 3S) -3- (tert-Butoxycarbonylamino) cyclopentyl ] methanesulfonate (10B)
[(1R,3S)-3-(tert-butoxycarbonylamino)cyclopentyl]methanesulfonate
In a 50mL reaction flask, tert-butyl [ (1S, 3R) -3-hydroxycyclopentyl ] carbamate (0.50 g,2.5 mmol), triethylamine (0.51 g,5.0 mmol) and dichloromethane (20 mL) were successively added, and after the addition was completed, stirring was performed at 0℃for 20 minutes, methanesulfonyl chloride (0.37 g,3.25 mmol) was slowly added dropwise and the reaction was stirred at room temperature for 1h. The reaction solution was washed with water (30 mL. Times.1) and saturated brine (30 mL. Times.1), and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude 10B product as a pale yellow solid (0.67 g) which was used directly in the next reaction.
And a second step of: n- [ (1S, 3S) -3- (6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl) oxy-cyclopentyl ] carbamic acid tert-butyl ester (10C)
tert-butyl N-[(1S,3S)-3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclopentyl]carbamate
In a 50mL reaction flask, 6-bromo-1-tetrahydropyran-2-yl-indazol-4-ol (intermediate I) (0.585 g,1.97 mmol), a crude 10B (0.66 g), cesium carbonate (2.57 g,7.88 mmol) and N, N-dimethylformamide (40 mL) were sequentially added, and after the addition was completed, the reaction was stirred at 90℃overnight, ethyl acetate (50 mL) was added to the reaction mixture, followed by washing with water (50 mL. Times.3), the organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was isolated and purified by column chromatography (PE/EA=4/1) to give 10C as a white solid (0.9 g, yield 95%).
And a third step of: n- [ (1S, 3S) -3- [6- (4-hydroxyphenyl) -1-tetrahydropyran-2-yl-indazol-4-yl ] oxocyclopentyl ] carbamic acid tert-butyl ester (10D)
tert-butyl N-[(1S,3S)-3-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclopentyl]carbamate
In a 50mL 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), a [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (69 mg,0.083 mmol) and dioxane/water (v/v=4/1, 10 mL) were sequentially added, and after three substitutions of nitrogen, the reaction was stirred at 90℃for 2 hours. To the reaction solution was added water (50 mL), followed by extraction with ethyl acetate (50 ml×2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and 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, yield 91%).
LCMS m/z＝494.3[M+H] +
Fourth step: (E) -4- (dimethylamino) -N- [ (1 s,3 s) -3- [ [6- (4-hydroxyphenyl) -1H-indazol-4-yl ] oxy ] 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
In a 50mL reaction flask, 10D (0.37 g,0.75 mmol) and methylene chloride/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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. Times.3), and then concentrated to dryness under reduced pressure. To the resulting residue were successively added trans-4-dimethylaminocrotonic acid hydrochloride (0.146 g,0.88 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.335 g,1.74 mmol), 1-hydroxybenzotriazole (0.116 g,0.86 mmol) and N, N-dimethylformamide (40 mL), and after the addition was completed, the mixture was stirred at room temperature for 10 minutes, and N, N-diisopropylethylamine (0.43 g,3.33 mmol) was added, and after the addition was completed, the mixture was stirred at room temperature for 50 minutes. To the reaction solution was added saturated sodium bicarbonate (50 mL), followed by extraction with dichloromethane/methanol (v/v=10/1, 50ml×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 (dichloromethane/methanol (v/v) =20/1 to 10/1) to give compound 10 (140 mg, yield 44%).
LCMS m/z＝421.2[M+H] + ；
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).
Example 11: (E) -4- (dimethylamino) -N- [ (1 s,3 s) -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
Figure PCTCN2021117545-APPB-000233
Figure PCTCN2021117545-APPB-000234
The first step: n- [ (1S, 3S) -3- [6- (4-benzyloxy-2-ethyl-5-fluoro-phenyl) -1-tetrahydropyran-2-yl-indazol-4-yl ] oxocyclopentyl ] carbamic acid 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]carbamate
In a 50mL reaction flask, 10C (0.49 g,1.04 mmol), 2- (4- (benzyloxy) -2-ethyl-5-fluorophenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (0.44 g,1.24 mmol), potassium phosphate heptahydrate (1.06 g,3.12 mmol), a [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (85 mg,0.106 mmol) and dioxane/water (v/v=4/1, 10 mL) were sequentially added, and after nitrogen substitution three times, the reaction was stirred at 90℃for 2 hours. To the reaction solution was added water (50 mL), followed by extraction with ethyl acetate (50 ml×2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and 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, yield 96%).
And a second step of: n- [ (1S, 3S) -3- [6- (2-ethyl-5-fluoro-4-hydroxy-phenyl) -1-tetrahydropyran-2-yl-indazol-4-yl ] oxocyclopentyl ] carbamic acid tert-butyl ester (11B)
tert-butylN-[(1S,3S)-3-[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclopentyl]carbamate
In a 50mL reaction flask, 11A (0.618 g,0.98 mmol), palladium on carbon (0.12 g,60 wt%) and methanol (50 mL) were added, and after three hydrogen substitutions, the reaction was stirred at room temperature for 3 hours. The reaction solution was filtered with celite, and the filtrate was concentrated to dryness under reduced pressure to give a crude 11B product, which was used as a white solid (0.524 g) for the next reaction.
LCMS m/z＝540.3[M+H] +
And a third step of: (E) -4- (dimethylamino) -N- [ (1 s,3 s) -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
In a 50mL reaction flask, 11B crude (0.524 g) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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. Times.3), and then concentrated to dryness under reduced pressure. To the resulting residue were successively added trans-4-dimethylaminocrotonic acid hydrochloride (0.19 g,1.15 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.604 g,3.15 mmol), 1-hydroxybenzotriazole (0.212 g,1.57 mmol) and N, N-dimethylformamide (40 mL), and after the addition, the mixture was stirred at room temperature for 10 minutes, N-diisopropylethylamine (0.814 g,6.3 mmol) was added, and after the addition, the mixture was stirred at room temperature for 50 minutes. To the reaction solution was added saturated sodium bicarbonate (50 mL), followed by extraction with dichloromethane/methanol (v/v=10/1, 50ml×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 (dichloromethane/methanol (v/v) =20/1 to 10/1) to give compound 11 (210 mg, yield 46%).
LCMS m/z＝467.2[M+H] + ；
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).
Example 12: trans- (2E) -4- (dimethylamino) -N- [3- [ (6- (3-chloro-4-hydroxyphenyl) -1H-indazol-4-yl) oxy ] 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-enamide
Figure PCTCN2021117545-APPB-000235
The first step: trans-N- [3- (6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl) oxy-cyclobutyl ] carbamic acid tert-butyl ester (12B)
trans-tert-butyl N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]carbamate
In a 50mL reaction flask, tert-butyl trans-N- [ 3-hydroxycyclobutyl ] carbamate (1.41 g,7.51 mmol) and N, N-dimethylformamide (20 mL) were added, naH (0.4 g,9.92mmol,60 wt%) was added in portions with ice water cooling, and after the addition was completed, stirring was performed at 0℃for 20 minutes, 6-bromo-4-fluoro-1-tetrahydropyran-2-yl-indazole (1 c) (1.5 g,5 mmol) was added and the reaction was stirred at room temperature for 2 hours. To the reaction solution were added a saturated ammonium chloride solution (200 mL) and water (200 mL), the reaction solution was extracted with ethyl acetate (300 ml×2), the organic phase was combined, the organic phase was washed with a saturated sodium chloride solution (300 ml×2), the organic phase 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%).
And a second step of: trans- (3- (((6- (3-chloro-4-hydroxyphenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) cyclobutyl) carbamic acid tert-butyl ester (12C)
trans-tert-butyl(3-((6-(3-chloro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)carbamate
In a 100mL reaction flask, 12B (0.8 g,1.72 mmol), 3-chloro-4-hydroxyphenylboronic acid (0.44 g,2.58 mmol), potassium phosphate heptahydrate (1.75 g,5.16 mmol), [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (210 mg,0.26 mmol) and dioxane/water (v/v=4/1, 20 mL) were sequentially added, and after three substitutions of nitrogen, the reaction was stirred at 90℃for 2 hours. To the reaction solution was added water (50 mL), followed by extraction with ethyl acetate (50 ml×2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (PE/ea=3/1) to give 12C as a pale yellow solid (0.80 g, yield 90.4%).
LCMS m/z＝514.2[M+H] +
And a third step of: trans- (2E) -4- (dimethylamino) -N- [3- [ (6- (3-chloro-4-hydroxyphenyl) -1H-indazol-4-yl) oxy ] 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-enamide
In a 50mL reaction flask, 12C (0.4 g,0.78 mmol) and methylene chloride/trifluoroacetic acid (v/v=1/1, 8 mL) were added, and then the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure. To the resulting residue were added, in order, trans-4-dimethylaminocrotonic acid hydrochloride (0.15 g,1.17 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.30 g,1.56 mmol), 1-hydroxybenzotriazole (0.16 g,1.17 mmol) and N, N-dimethylformamide (10 mL), and after the addition, the mixture was stirred at room temperature for 10 minutes, and N, N-diisopropylethylamine (0.6 g,4.68 mmol) was added and after the addition, the mixture was stirred at room temperature for 50 minutes. To the reaction solution was added saturated sodium hydrogencarbonate (50 mL), followed by extraction with methylene chloride/methanol (v/v=10/1, 50ml×4), the organic layers were combined and dried over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure, and the residue was purified by separation to give compound 12 (180 mg, yield 52.3%) by preparing a liquid phase (instrument: waters 2767, liquid phase; column: xbridge@prep C18 (30 mm×150 mm), mobile phase composition: mobile phase a: acetonitrile, mobile phase B: water (containing 0.05%) and the like.
LCMS m/z＝441.2[M+H] +
1 H NMR(400MHz,CD 3 OD)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).
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)acrylamide
Figure PCTCN2021117545-APPB-000236
The first step: ((5-bromo-3-fluoropyridin-2-yl) methyl) carbamic acid tert-butyl ester (13B)
tert-butyl((5-bromo-3-fluoropyridin-2-yl)methyl)carbamate
In a 50mL reaction flask, 5-bromo-3-fluoro-2-pyridinecarbonitrile (13A) (2.0 g,10 mmol), raney nickel (2 g), methanol (20 mL), BOC anhydride (4.36 g,20 mmol), stirring at room temperature for 48h, celite filtration, concentration under reduced pressure, silica gel column purification (petroleum ether/ethyl acetate (v/v) =10:1) to give 13B as a yellow oil (0.92 g, 30% yield)
LCMS m/z＝249.0/251.0[M-55] +
And a second step of: trifluoroacetate salt of (5-bromo-3-fluoropyridin-2-yl) methylamine (13C)
(5-bromo-3-fluoropyridin-2-yl)methanamine；2,2,2-trifluoroacetic acid
13B (0.92 g,3 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (3 mL) was added and reacted at room temperature for 1 hour. The reaction solution was concentrated directly to give a crude trifluoroacetate salt of 13C as a yellow oil (962 mg) which was used directly in the next reaction.
And a third step of: n- ((5-bromo-3-fluoropyridin-2-yl) methyl) carboxamide (13D)
N-((5-bromo-3-fluoropyridin-2-yl)methyl)formamide
In a 50mL reaction bottle, a crude trifluoroacetate (962 mg) of the (5-bromo-3-fluoropyridin-2-yl) methylamine (13C) obtained in the previous step and anhydrous formic acid (20 mL) are added in sequence under the protection of nitrogen, after stirring for 1h at 100 ℃, acetic anhydride (4 mL) is added, stirring is carried out for 48h at 100 ℃, and vacuum concentration is carried out to obtain a 13D crude product, and a black oily substance (700 mg) is directly used for the next reaction.
Fourth step: 6-bromo-8-fluoroimidazo [1,5-a ] pyridine (13E)
6-bromo-8-fluoroimidazo[1,5-a]pyridine
To a 50mL reaction flask, 13D crude product (700 mg), phosphorus oxychloride (1 mL), toluene (10 mL) were added in this order under nitrogen protection, and after the addition was completed, the mixture was stirred at 80℃for 2 hours. Concentrated under reduced pressure, quenched with saturated sodium bicarbonate solution (50 mL), extracted with dichloromethane (30 mL x 3), the combined organic layers dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give 13E as a grey solid (291 mg, 45% three step yield).
LCMS m/z＝215.0/217.0[M+1] +
1 H NMR(400MHz,CDCl 3 )δ8.32(s,1H),8.01(s,1H),7.62(s,1H),6.58(d,1H).
Fifth step 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)carbamate
Tert-butyl trans- (3-hydroxycyclobutyl) carbamate (224.5 mg,1.2 mmol) and DMF (5 mL) were added under nitrogen and chilled water sodium hydrogen (48 mg,60wt%,1.6 mmol) was added and the reaction stirred at room temperature for 30 min; cooled in ice water, 13E (215 mg,1 mmol) in DMF (5 mL) was added dropwise and the reaction was stirred at room temperature for 3 hours. TLC monitored completion of the reaction, ethyl acetate (100 mL) and water (100 mL), the layers were separated, the aqueous layer was extracted once with ethyl acetate (100 ml×1), the organic layers were combined, washed with saturated sodium chloride solution (100 ml×2), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure at 40 ℃ and the residue purified by silica gel column chromatography (eluent PE/ea=5/1) to give 13F as a white solid (340 mg, 89% yield).
Sixth step: trans-tert-butyl (3- ((6- (4- (benzyloxy) -2-ethyl-5-fluorophenyl) imidazo [1,5-a ] pyridin-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)carbamate
2- (4- (benzyloxy) -2-ethyl-5-fluorophenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (480.9 mg,1.35 mmol), potassium phosphate heptahydrate (913 mg,2.7 mmol), and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (73.5 mg,0.09 mmol) were added to a solution of 13F (340 mg,0.89 mmol) of 1, 4-dioxane (20 mL) and water (5 mL), respectively, stirred at 110 ℃ for 1h, quenched with saturated sodium bicarbonate solution (20 mL), extracted with ethyl acetate (20 mL x 3), the combined organic layers were dried over anhydrous sodium sulfate, 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, yield 87.3%).
LCMS m/z＝532.3[M+1] +
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)carbamate
13G (413 mg,0.78 mmol) was added to the reaction flask, palladium on carbon (41 mg) and methanol solution (30 mL) were added, the mixture was purged with hydrogen three times, and the reaction was stirred at room temperature for 6 hours. The reaction solution was filtered through celite and eluted with ethyl acetate. Concentrated to dryness under reduced pressure to give a crude 13H (343 mg) which was used directly in the next reaction.
Eighth step, trifluoroacetate salt of trans-4- (8- ((3-aminocyclobutoxy) imidazo [1,5-a ] pyridin-6-yl) -5-ethyl-2-fluorophenol (13I)
trans-4-(8-(3-aminocyclobutoxy)imidazo[1,5-a]pyridin-6-yl)-5-ethyl-2-fluorophenol；trifluoroacetic acid
The crude 13H (343 mg) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (3 mL) was added and reacted at room temperature for 1 hour. The reaction solution was directly concentrated to give a crude trifluoroacetate salt of 13I as a white solid (355 mg) which was directly used in the next reaction.
Ninth step 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)acrylamide
In a 50mL three-necked flask under the protection of nitrogen, 6-chlorobenzotriazole-1, 3-tetramethylurea hexafluorophosphate (62 mg,0.15 mmol) is added into an N, N-dimethylformamide (2 mL) solution of acrylic acid (10.8 mg,0.15 mmol), the mixture is reacted for 10min at room temperature, a crude trifluoroacetate of 13I (59 mg) is dissolved in 1mL of N, N-dimethylformamide and is added dropwise into the reaction solution at 0 ℃ for 1min after stirring at 0 ℃, N-diisopropylethylamine (101 mg,0.78 mmol) is dissolved in 1mL of N, N-dimethylformamide and is added dropwise into the reaction solution, stirring is carried out for 3h at 0 ℃ and saturated sodium bicarbonate solution (5 mL) is quenched, ethyl acetate (20 x 3 mL) is extracted, and the residue is concentrated under reduced pressure to prepare a liquid phase by preparing a liquid phase (instrument: watts 2767; the column was a SunFire@PrepC18 (19 mM. Times.150 mM), the mobile phase composition: mobile phase A: acetonitrile mobile phase B: water (containing 5mM ammonium acetate)) was separated and purified to give compound 13 (6.8 mg, yield 13.3%).
LCMS m/z＝396.1[M+1] +
1 H NMR(400MHz,CD 3 OD)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).
Example 14 trifluoroacetate salt of trans-2-fluoro-N- ((3- ((6- (4-hydroxyphenyl) imidazo [1,5-a ] pyridin-8-yl) oxy) cyclobutyl) acrylamide (Compound 14)
trans-2-fluoro-N-(3-((6-(4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)acrylamide；trifluoroacetic acid
Figure PCTCN2021117545-APPB-000237
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)carbamate
4-hydroxyphenylboronic acid (186 mg,1.35 mmol), potassium phosphate heptahydrate (913 mg,2.7 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (73.5 mg,0.09 mmol) were added to a solution of 1, 4-dioxane (20 mL) and water (5 mL) of 13F (34 mg,0.9 mmol), respectively, stirred at 110 ℃ for 1h, quenched with saturated sodium bicarbonate solution (20 mL), extracted with ethyl acetate (20 mL x 3), the combined organic layers were dried over anhydrous sodium sulfate, filtered with suction, and the filtrate concentrated under reduced pressure to give 14A as a yellow solid (312 mg, 87.7% yield).
And a second step of: 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 acid
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) and trifluoroacetic acid (3 mL) was added and reacted at room temperature for 1 hour. The reaction solution was concentrated directly to give crude trifluoroacetate salt of 14B as a yellow oil (323.4 mg).
And a third step of: trifluoroacetate salt of trans-2-fluoro-N- ((3- ((6- (4-hydroxyphenyl) imidazo [1,5-a ] pyridin-8-yl) oxy) cyclobutyl) acrylamide (compound 14)
trans-2-fluoro-N-(3-((6-(4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)cyclobutyl)acrylamide；trifluoroacetic acid
1-hydroxybenzotriazole (20.3 mg,0.15 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (28.8 mg,0.15 mmol) were added to a solution of 2-fluoroacrylic acid (9 mg,0.1 mmol) in N, N-dimethylformamide (2 mL) in a 50mL three-necked flask under nitrogen atmosphere, 1min at room temperature, 0 ℃, 14B crude trifluoroacetate (32.7 mg) was dissolved in 1mL N, N-dimethylformamide and added dropwise to the reaction solution, N-diisopropylethylamine (56 mg,0.39 mmol) was dissolved in 1mL N, N-dimethylformamide and added dropwise to the reaction solution, stirring was carried out at 0℃for 3h, saturated sodium bicarbonate solution (5 mL) was quenched, ethyl acetate (20×3 mL) was extracted, and concentrated under reduced pressure to prepare a liquid phase by a preparation apparatus (waters 67; chromatographic column SunFire@PrepC18 (19 mm. Times.150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid)) to obtain trifluoroacetate salt of compound 14 (5.8 mg, yield 15%)
LCMS m/z＝368.2[M+1] +
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).
Example 15: trans- (E) -4- (dimethylamino) -N- ((3- ((6- (2-ethyl-5-fluoro-4-hydroxyphenyl) imidazo [1,5-a ] pyridin-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-enamide
Figure PCTCN2021117545-APPB-000238
Under nitrogen protection, 6-chlorobenzotriazole-1, 3-tetramethylurea hexafluorophosphate (62 mg,0.15 mmol) was added to a solution of trans 4-dimethylaminocrotonic acid hydrochloride (24.8 mg,0.15 mmol) in N, N-dimethylformamide (2 mL) in a 50mL three-port flask, reacted at room temperature for 10min, at 0℃to prepare a crude trifluoroacetate 13I (59 mg) in 1mL N, N-dimethylformamide, dropwise adding the crude trifluoroacetate 13I to the reaction solution, stirred at 0℃for 1min, N-diisopropylethylamine (101 mg,0.78 mmol) in 1mL N, N-dimethylformamide, stirred at 0℃for 3h, quenched with saturated sodium bicarbonate solution (5 mL), extracted with ethyl acetate (20X 3 mL), concentrated under reduced pressure, and the residue was purified by preparing a liquid phase (instrument: water 2767; chromatographic column: sunFip 18X 18 mM; mobile phase: 150 mM: mobile phase: aqueous phase: 5 mM) to obtain an aqueous solution (10 mM), and purifying the aqueous phase (19 mM: mobile phase: 4 mM: mobile phase: 4 mM) to obtain an aqueous phase composition
LCMS m/z＝453.2[M+1] +
1H NMR(400MHz,CD 3 OD)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).
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-enamide
Figure PCTCN2021117545-APPB-000239
Figure PCTCN2021117545-APPB-000240
The first step: cis-N- [3- (6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl) oxy cyclobutyl ] -N-methyl-carbamic acid tert-butyl ester (16A)
cis-tert-butyl N-[3-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)oxycyclobutyl]-N-methyl-carbamate
In a 50mL reaction flask, cis-N- [3- (6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl) oxy-cyclobutyl ] carbamic acid tert-butyl ester (2C) (0.7 g,1.50 mmol), tetrahydrofuran (15 mL) and sodium hydride (1.2 g,30mmol,60 wt%) were successively added, and after the addition was completed, the mixture was stirred at 25℃for 30 minutes, methyl iodide (4.2 g,30 mmol) was slowly added dropwise and the reaction was stirred at room temperature for 1.2 hours. Ethyl acetate (50 mL) was added to the reaction solution, which was then washed with water (30 mL. Times.1) and saturated brine (30 mL. Times.1), and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (PE/EA=9/1) to give 16A as a white solid (0.6 g, yield: 83%).
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).
And a second step of: cis-N- [3- [6- (4-hydroxyphenyl) -1-tetrahydropyran-2-yl-indazol-4-yl ] oxetanyl ] -N-methyl-carbamic acid tert-butyl ester (16B)
cis-tert-butylN-[3-[6-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-indazol-4-yl]oxycyclobutyl]-N-methyl-carbamate
In a 50mL reaction flask, 16A (0.6 g,1.25 mmol), 4-hydroxyphenylboronic acid (0.26 g,1.88 mmol), potassium phosphate heptahydrate (1.69 g,5 mmol), a [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (102 mg,0.125 mmol) and dioxane/water (v/v=4/1, 10 mL) were sequentially placed three times, and then, the reaction was stirred at 90℃for 2 hours. To the reaction solution was added water (50 mL), followed by extraction with ethyl acetate (50 ml×2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and 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, yield 97%).
LCMS m/z＝494.2[M+H] + ；
And a third step of: 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-enamide
In a 50mL reaction flask, 16B (0.3 g,0.61 mmol) and methylene chloride/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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. Times.3), and then concentrated to dryness under reduced pressure.
In a 50mL reaction flask, trans-4-dimethylaminocrotonic acid hydrochloride (0.15 g,0.915 mmol), 6-chlorobenzotriazol-1, 3-tetramethylurea hexafluorophosphate (0.378 g,0.915 mmol) and DMF (10 mL) were added, and after the addition, the mixture was stirred at room temperature for 30 minutes, and then a DMF (5 mL) solution of the residue obtained in the above step was added, and after the addition, the mixture was stirred at room temperature for 10 minutes, N-diisopropylethylamine (0.79 g,6.1 mmol) was added, and after the addition, the mixture was stirred at room temperature overnight. To the reaction solution was added saturated sodium bicarbonate (50 mL), followed by extraction with dichloromethane/methanol (v/v=10/1) (50 ml×2), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC (apparatus: waters 2767 for preparing liquid phase; column: xbridge@prep C18 (30 mm×150 mm); mobile phase composition: mobile phase a: acetonitrile, mobile phase B: water (containing 0.05% ammonia)) to give compound 16 (60 mg, yield 24%).
LCMS m/z＝421.2[M+H] + ；
1 H NMR(400MHz,CD 3 OD)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).
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-enamide
Figure PCTCN2021117545-APPB-000241
The first step: trans-tert-butyl-3- ((6- (3-fluoro-4-hydroxyphenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) cyclobutyl) carbamic acid amino ester (17A)
trans-tert-butyl-3-((6-(3-fluoro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)carbamate
In a 100mL reaction flask, tert-butyl trans-N- [3- (6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl) oxy-cyclobutyl ] carbamate (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), a [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (210 mg,0.26 mmol) and dioxane/water (v/v=4/1, 20 mL) were sequentially added, and after three substitutions of nitrogen, the reaction was stirred at 90℃for 2 hours. To the reaction solution was added water (50 mL), followed by extraction with ethyl acetate (50 ml×2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and 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, yield 92%).
And a second step of: 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-enamide
In a 50mL reaction flask, 17A (0.039 g,0.078 mmol) and methylene chloride/trifluoroacetic acid (v/v=1/1, 8 mL) were added, and then the reaction was stirred at room temperature for 5 hours, and the reaction solution was concentrated under reduced pressure to dryness. To the resulting residue were added, in order, trans-4-dimethylaminocrotonic acid hydrochloride (0.015 g,0.117 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.030 g,0.156 mmol), 1-hydroxybenzotriazole (0.016 g,0.117 mmol) and N, N-dimethylformamide (10 mL), and after the addition, the mixture was stirred at room temperature for 10 minutes, and N, N-diisopropylethylamine (0.06 g, 0.4638 mmol) was added and after the addition, the mixture was stirred at room temperature for 50 minutes. To the reaction solution was added saturated aqueous sodium hydrogencarbonate (50 mL), followed by extraction with methylene chloride/methanol (v/v=10/1, 50ml×4), the organic layers were combined and dried over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure, and the residue was purified by separation to give compound 17 (17 mg, yield 51.5%) by preparing a liquid phase (instrument: waters 2767 for preparing a liquid phase; column: xbridge@prep C18 (30 mm×150 mm); mobile phase composition: mobile phase a: acetonitrile, mobile phase B: water (containing 0.05% aqueous ammonia)).
LCMS m/z＝425.2[M+1] +
1H NMR(400MHz,CD 3 OD)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).
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-enamide
Figure PCTCN2021117545-APPB-000242
The first step: trans-N- [3- [ (6- (2-fluoro-4-hydroxyphenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-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)carbamate
In a 50mL reaction flask, tert-butyl trans-N- [3- (6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl) oxy-cyclobutyl ] carbamate (1C) (0.293 g,0.64 mmol), 2-fluoro-4-hydroxyphenylboronic acid (0.119 g,0.76 mmol), potassium phosphate heptahydrate (0.645 g,1.91 mmol), a [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (53 mg,0.065 mmol) and dioxane/water (v/v=4/1, 10 mL) were sequentially added, and after nitrogen substitution three times, the reaction was stirred at 90℃for 2 hours. To the reaction solution was added water (50 mL), followed by extraction with ethyl acetate (50 ml×2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and 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, yield 91%).
LCMS m/z＝498.3[M+H] + ；
And a second step of: 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-enamide
In a 50mL reaction flask, 18A (0.14 g,0.28 mmol) and methylene chloride/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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. Times.3), and then concentrated to dryness under reduced pressure. To the resulting residue were added, in order, trans-4-dimethylaminocrotonic acid hydrochloride (0.062 g,0.37 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.165 g,0.858 mmol), 1-hydroxybenzotriazole (0.058 g,0.429 mmol) and N, N-dimethylformamide (20 mL), and after the addition, the mixture was stirred at room temperature for 10 minutes, and N, N-diisopropylethylamine (0.222 g,1.76 mmol) was added and after the addition, the mixture was stirred at room temperature for 50 minutes. To the reaction solution was added saturated sodium hydrogencarbonate (50 mL), followed by extraction with methylene chloride/methanol (v/v=10/1) (50 ml×2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by separation to give compound 18 (48 mg, yield 40%) by preparing a liquid phase (instrument: waters 2767, liquid phase; column chromatography: sunfire@prep C18 (19 mm×150 mM), mobile phase composition: mobile phase a: acetonitrile mobile phase B: water (containing 5mM ammonium acetate)).
LCMS m/z＝425.2[M+H] + ；
1 H NMR(400MHz,CD 3 OD)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).
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-enamide
Figure PCTCN2021117545-APPB-000243
The first step: trans-tert-butyl (3- (((6- (4-hydroxy-2-methylphenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-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)carbamate
In a 50mL reaction flask, tert-butyl trans-N- [3- (6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl) oxy-cyclobutyl ] carbamate (1C) (0.293 g,0.64 mmol), 4-hydroxy-2-methylbenzoboric acid (0.116 g,0.76 mmol), potassium phosphate heptahydrate (0.645 g,1.91 mmol), a [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (53 mg,0.065 mmol) and dioxane/water (v/v=4/1, 10 mL) were sequentially added, and after nitrogen substitution three times, the reaction was stirred at 90℃for 2 hours. To the reaction solution was added water (50 mL), followed by extraction with ethyl acetate (50 ml×2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and 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, yield 91%).
LCMS m/z＝494.3[M+H] + ；
And a second step of: 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-enamide
In a 50mL reaction flask, 19A (0.22 g,0.45 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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. Times.3), and then concentrated to dryness under reduced pressure. To the resulting residue were added, in order, trans-4-dimethylaminocrotonic acid hydrochloride (0.096 g,0.58 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.222 g,1.156 mmol), 1-hydroxybenzotriazole (0.102 g,0.75 mmol) and N, N-dimethylformamide (20 mL), and after the addition, the mixture was stirred at room temperature for 10 minutes, N-diisopropylethylamine (0.448 g, 3.4638 mmol) was added, and after the addition, the mixture was stirred at room temperature for 50 minutes. To the reaction solution was added saturated sodium hydrogencarbonate (50 mL), followed by extraction with methylene chloride/methanol (v/v=10/1) (50 ml×2), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by separation to give compound 19 as a white solid (60 mg, yield 32%) by preparing a liquid phase (instrument: waters 2767, liquid phase; column chromatography: sunfire@prep C18 (19 mm×150 mM); mobile phase composition: mobile phase a: acetonitrile mobile phase B: water (containing 5mM ammonium acetate)).
LCMS m/z＝421.1[M+H] + ；
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).
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-enamide
Figure PCTCN2021117545-APPB-000244
The first step: trans-tert-butyl-3- ((6- (2-chloro-4-hydroxyphenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) cyclobutyl) carbamic acid amino ester (20A)
trans-tert-butyl-3-((6-(2-chloro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)carbamate
In a 100mL reaction flask, tert-butyl trans-N- [3- (6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl) oxy-cyclobutyl ] carbamate (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), a [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (210 mg,0.26 mmol) and dioxane/water (v/v=4/1, 20 mL) were sequentially added, and after three substitutions of nitrogen, the reaction was stirred at 90℃for 2 hours. To the reaction solution was added water (50 mL), followed by extraction with ethyl acetate (50 ml×2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and 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, yield 90.4%).
And a second step of: 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-enamide
In a 50mL reaction flask, 20A (0.04 g,0.078 mmol) and methylene chloride/trifluoroacetic acid (v/v=1/1, 8 mL) were added, and then the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure. To the resulting residue were added, in order, trans-4-dimethylaminocrotonic acid hydrochloride (0.015 g,0.117 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.030 g,0.156 mmol), 1-hydroxybenzotriazole (0.016 g,0.117 mmol) and N, N-dimethylformamide (10 mL), and after the addition, the mixture was stirred at room temperature for 10 minutes, and N, N-diisopropylethylamine (0.06 g, 0.4638 mmol) was added and after the addition, the mixture was stirred at room temperature for 50 minutes. To the reaction solution was added saturated sodium hydrogencarbonate (50 mL), followed by extraction with methylene chloride/methanol (v/v=10/1, 50ml×4), the organic layers were combined and dried over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure, and the residue was purified by separation to give compound 20 (18 mg, yield 52.3%) by preparing a liquid phase (instrument: waters 2767, liquid phase; column: xbridge@prep C18 (30 mm×150 mm), mobile phase composition: mobile phase a: acetonitrile, mobile phase B: water (containing 0.05%) and the like.
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).
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-enamide
Figure PCTCN2021117545-APPB-000245
The first step: cis-tert-butyl (-3- ((6-bromo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) cyclobutyl) (ethyl) carbamate (21A)
cis-tert-butyl(3-((6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)(ethyl)carbamate
In a 50mL reaction flask, cis-N- [3- (6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl) oxy-cyclobutyl ] carbamic acid tert-butyl ester (2C) (0.578 g,1.20 mmol), tetrahydrofuran (15 mL) and sodium hydride (1.06 g,26.4mmol,60 wt%) were successively added, and after the addition, stirred at 25℃for 30 minutes, and ethyl iodide (2.81 g,18 mmol) was slowly added dropwise and reacted at room temperature with stirring for 2 hours. Ethyl acetate (50 mL) was added to the reaction solution, which was then washed with water (30 ml×1) and then with saturated brine (30 ml×1), and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (PE/ea=7/1) to give 21A as a white solid (0.4 g, yield: 68%).
LCMS m/z＝438.1/440.0[M-55] + ；
And a second step of: cis-N-ethyl-N- [3- [ (6- (4-hydroxyphenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy ] cyclobutyl ] carbamic acid 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]carbamate
In a 50mL reaction flask, cis-tert-butyl (-3- ((6-bromo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) cyclobutyl) (ethyl) carbamate (21A) (0.4 g,0.8 mmol), 4-hydroxyphenylboronic acid (0.13 g,0.96 mmol), potassium phosphate heptahydrate (0.81 g,2.4 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (65 mg,0.08 mmol) and dioxane/water (v/v=4/1, 10 mL) were sequentially added, and after three substitutions of nitrogen, the reaction was stirred at 90℃for 2 hours. To the reaction solution was added water (50 mL), followed by extraction with ethyl acetate (50 mL ×2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and 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, yield 79%).
LCMS m/z＝508.2[M+H] +
And a third step of: 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-enamide
In a 50mL reaction flask, tert-butyl cis-N-ethyl-N- [3- [ (6- (4-hydroxyphenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy ] cyclobutyl ] carbamate (21B) (0.31 g,0.61 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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. Times.3), and then concentrated to dryness under reduced pressure.
In a 50mL reaction flask, trans-4-dimethylaminocrotonic acid hydrochloride (0.162 g,0.98 mmol), DMF (1 drop by 5mL disposable plastic dropper) and dichloromethane (3 mL) were added, and after the addition, they were stirred at room temperature for 5 minutes, oxalyl chloride (0.25 g,1.97 mmol) was then added dropwise, and then a solution of the residue obtained in the above step in dichloromethane (5 mL) and N, N-diisopropylethylamine (0.79 g,6.1 mmol) was added, and after the addition, they were stirred at room temperature for 10 minutes. To the reaction solution was added saturated sodium bicarbonate (50 mL), followed by extraction with dichloromethane/methanol (v/v=10/1) (50 ml×2), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC (apparatus: waters 2767 for preparing liquid phase; column: xbridge@prep C18 (30 mm×150 mm); mobile phase composition: mobile phase a: acetonitrile, mobile phase B: water (containing 0.05% ammonia)) to give compound 21 (6 mg, yield 2%).
LCMS m/z＝435.3[M+H] + ；
1 H NMR(400MHz,CD 3 OD)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).
Example 22: cis- (2E) -N- (cyclopropylmethyl) -4- (dimethylamino) -N- [3- [ (6- (4-hydroxyphenyl) -1H-indazol-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-enamide
Figure PCTCN2021117545-APPB-000246
Figure PCTCN2021117545-APPB-000247
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)carbamate
In a 50mL reaction flask, cis-N- [3- (6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl) oxy-cyclobutyl ] carbamic acid tert-butyl ester (2C) (0.460 g,1.0 mmol), sodium iodide (450 mg,3.0 mmol), DMF (15 mL) and sodium hydride (0.8 g,20mmol,60 wt%) were added in this order, stirred at 25℃for 30 minutes after the addition, and bromomethylcyclopropane (2.81 g,18 mmol) was slowly added dropwise and reacted at 45℃with stirring for 2 hours. Ethyl acetate (50 mL) was added to the reaction solution, which was then washed with water (30 ml×1) and then saturated brine (30 ml×1), and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (PE/ea=7/1) to give 22A, crude product, white solid (0.57 g, yield: 100%).
LCMS m/z＝464.1/466.2[M-55] + ；
And a second step of: cis-N- (cyclopropylmethyl) -N- [3- [ (6- (4-hydroxyphenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl ] oxy ] cyclobutyl ] carbamic acid 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]carbamate
In a 50mL reaction flask, 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 ] palladium dichloride dichloromethane complex (90 mg,0.11 mmol) and dioxane/water (v/v=4/1, 10 mL) were sequentially added, and after three nitrogen substitutions, the reaction was stirred at 90℃for 2 hours. To the reaction solution was added water (50 mL), followed by extraction with ethyl acetate (50 ml×2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and 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, yield 82%).
1 H NMR(400MHz,CD 3 OD)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).
And a third step of: cis- (2E) -N- (cyclopropylmethyl) -4- (dimethylamino) -N- [3- [ (6- (4-hydroxyphenyl) -1H-indazol-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-enamide
In a 50mL reaction flask, 22B (0.3995 g,0.74 mmol) and methylene chloride/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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. Times.3), then concentrated to dryness under reduced pressure, and methylene chloride (5 mL) and N, N-diisopropylethylamine (0.574 g,4.44 mmol) were added and stirred for 10 minutes to give a solution I to be used.
To a mixed solution of trans-4-dimethylaminocrotonic acid hydrochloride (0.331 g,2.0 mmol) and diisopropylethylamine (775 mg,6.0mmol,1.0 mL) in dichloromethane (9.0 mL) and acetonitrile (1.0 mL), tripyrrolidinylphosphonium bromide hexafluorophosphate (0.932 g,2 mmol) was added and stirred at room temperature for 20min to give a reaction intermediate solution II.
Reaction intermediate solution II (4.88 mL) was slowly added dropwise to the above reaction solution I to be used, and after the addition was completed, stirred at room temperature for 60 minutes. To the reaction solution was added saturated sodium bicarbonate (50 mL), followed by extraction with dichloromethane/methanol (v/v=10/1) (50 ml×2), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol= (v/v) 30/1-25/1) to give compound 22 (90 mg, yield 26%).
LCMS m/z＝461.2[M+H] + ；
1 H NMR(400MHz,CD 3 OD)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).
Example 23: trans- (2E) -N- (2- (dimethylamino) ethyl) -N- [3- [ (6- (4-hydroxyphenyl) -1H-indazol-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-enamide
Figure PCTCN2021117545-APPB-000248
Figure PCTCN2021117545-APPB-000249
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)carbamate
In a 50mL reaction flask, tert-butyl trans-N- [3- (6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl) oxy-cyclobutyl ] carbamate (1C) (0.72 g,1.54 mmol), N-dimethylformamide (15 mL), sodium iodide (0.12 g,0.77 mmol) and sodium hydride (1.23 g,30.8mmol,60 wt%) were successively added, and after the addition, the mixture was stirred at 25℃for 10 minutes, 2-chloroethyldimethylamine (0.66 g,6.16 mmol) was added, and the mixture was heated to 50℃and reacted under stirring for 5 hours. Cooled to room temperature, quenched with 1mL of water, ethyl acetate (50 mL) was added to the reaction solution, which was then washed with water (30 ml×1) and then saturated brine (30 ml×1), the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM/MeOH (V/V) =100/0-100/5) to give 23A as a white solid (0.48 g, yield: 58%).
LCMS m/z＝537.1/539.1[M+H] +
And a second step of: 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]carbamate
In a 50mL reaction flask, the above-mentioned trans-tert-butyl (3- ((6-bromo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) cyclobutyl) (2- (dimethylamino) ethyl) carbamate (23A) (0.48 g,0.89 mmol), 4-hydroxyphenylboronic acid (0.18 g,1.33 mmol), potassium phosphate heptahydrate (0.9 g,2.67 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (73 mg,0.089 mmol) and dioxane/water (v/v=4/1, 10 mL) were sequentially added, and after three substitutions of nitrogen, the reaction was stirred at 90℃for 2 hours. Water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL. Times.2), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM/MeOH (V/V) =100/0-100/5) to give 23B as a pale yellow solid (0.49 g, yield 98%).
LCMS m/z＝551.4[M+H] +
And a third step of: trans- (2E) -N- (2- (dimethylamino) ethyl) -N- [3- [ (6- (4-hydroxyphenyl) -1H-indazol-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-enamide
In a 50mL reaction flask, compound 23B (0.14 g,0.25 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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 methyl tert-butyl ether (10 mL. Times.3), concentrated to dryness under reduced pressure, dissolved in 5mL of acetonitrile, and stirred for 10min with diisopropylethylamine (0.35 g,2.7 mmol) added.
To a mixed solution of crotonic acid (0.028 g,0.32 mmol) and diisopropylethylamine (83 mg,0.64 mmol) in dichloromethane (5 mL) and acetonitrile (5 mL), tripyrrolidinylphosphonium bromide hexafluorophosphate (0.15 g,0.32 mmol) was added and stirred at room temperature for 20 minutes. The reaction solution was slowly added dropwise to the above acetonitrile solution to be used, and stirring was continued for 1 hour. 10mL of saturated aqueous sodium bicarbonate solution was added to the mixture to alkalize the mixture, 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) =50/1/0.5-25/1/0.25) to give compound 23 (60 mg, yield: 50%).
LCMS m/z＝435.3[M+H] +
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).
Example 24: trans-N- (2- (dimethylamino) ethyl) -2-fluoro-N- (3- ((6- (4-hydroxyphenyl) -1H-indazol-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)acrylamide
Figure PCTCN2021117545-APPB-000250
In a 50mL reaction flask, compound 23B (0.14 g,0.25 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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 methyl tert-butyl ether (10 mL. Times.3), concentrated to dryness under reduced pressure, dissolved in 5mL of acetonitrile, and stirred for 10min with diisopropylethylamine (0.35 g,2.7 mmol) added.
To a mixed solution of 2-fluoroacrylic acid (0.029 g,0.32 mmol) and diisopropylethylamine (83 mg,0.64 mmol) in dichloromethane (5 mL) and acetonitrile (5 mL), tripyrrolidinylphosphonium bromide hexafluorophosphate (0.15 g,0.32 mmol) was added and stirred at room temperature for 20min. The reaction solution was slowly added dropwise to the above acetonitrile solution to be used, and stirring was continued for 1 hour. 10mL of saturated aqueous sodium bicarbonate was added, 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) =50/1/0.5-25/1/0.25) to give compound 24 (58 mg, yield: 57%).
LCMS m/z＝439.1[M+H] +
Example 25: trans- (2E) -3- [ (2R) -1-methylpyrrolidin-2-yl ] -N- [3- [ (6- (4-hydroxyphenyl) -1H-indazol-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-enamide
Figure PCTCN2021117545-APPB-000251
The first step: (2R) -2- [ ((1E) -3-ethoxy-3-oxoprop-1-en-1-yl ] pyrrolidine-1-carboxylic acid tert-butyl ester (25A)
tert-butyl(2R)-2-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]pyrrolidine-1-carboxylate
The compound triethyl phosphorylacetate (1.24 g,5.52 mmol) was dissolved in dichloromethane (10 ml), sodium hydride (60%, 0.4g,10.04 mmol) was added under ice bath, and after the addition, the mixture was naturally warmed to room temperature, stirred for 20min, cooled to 0 ℃, BOC-D-prolyl aldehyde (1 g,5.02 mmol) was added, and after the addition, the mixture was naturally warmed to room temperature and stirred for 1h. The reaction was quenched by slowly dropping 10mL of saturated aqueous ammonium chloride, and 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 give 25A as a pale yellow oil (0.62 g, yield: 46%).
1 H 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).
And a second step of: (2E) -3- [ ((2R) -1-methylpyrrolidin-2-yl ] prop-2-enoic acid ester (25B)
ethyl(2E)-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enoate
Compound 25A (0.62 g,2.30 mmol) and paraformaldehyde (0.35 g,11.5 mmol) are dissolved in anhydrous formic acid (8 mL), heated to 90℃and stirred for 2h. Cooled to room temperature, the solvent was removed under reduced pressure, 10mL of 1N hydrochloric acid was added, extraction was performed with 10mL of ethyl acetate, the organic layer was discarded, pH was adjusted to >7 with 6N aqueous sodium hydroxide solution, extraction was performed with 20mL of ethyl acetate, and the organic layer was concentrated under reduced pressure to give 25B crude product, a yellow oil (0.39 g) which was used directly in the next step.
LCMS m/z＝184.2[M+H] +
And a third step of: (2E) Hydrochloride of (2R) -1-methylpyrrolidin-2-yl ] prop-2-enoic acid (25C)
(2E)-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enoic acid；hydrochloric acid
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 2h, and ph=5-6 was adjusted with 1N diluted hydrochloric acid. The solvent was removed by concentration under reduced pressure, 20mL of a mixed solvent of DCM/MeOH (V/V=10/1) was added and stirred for 10min, the organic salt was removed by filtration, 2mL of a 3N hydrogen chloride/ethyl acetate solution was added to the filtrate, concentration was performed under reduced pressure, the residue was slurried with 5mL of acetonitrile, filtration was performed, and the cake was dried under reduced pressure to give 25C hydrochloride as a yellow solid (0.12 g, yield: 29%) which was directly used in the next reaction.
Fourth step: trans- (2E) -3- [ (2R) -1-methylpyrrolidin-2-yl ] -N- [3- [ (6- (4-hydroxyphenyl) -1H-indazol-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-enamide
In a 50mL reaction flask, tert-butyl trans-N- [3- [6- (4-hydroxyphenyl) -1-tetrahydropyran-2-yl-indazol-4-yl ] oxetan ] carbamate (1D) (0.2 g,0.42 mmol) and methylene chloride/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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. Times.3), and then concentrated to dryness under reduced pressure. To the resulting residue was added, in order, hydrochloride of compound 25C (0.107 g), 6-chlorobenzotriazole-1, 3-tetramethylurea hexafluorophosphate (231 mg,0.56 mmol) and N, N-dimethylformamide (10 mL), and after the addition was completed, stirring was carried out at room temperature for 10 minutes, N-diisopropylethylamine (0.45 g,3.48 mmol) was slowly added, and after the addition was completed, stirring was carried out at room temperature for 50 minutes. To the reaction solution was added saturated sodium hydrogencarbonate (50 mL), followed by extraction with methylene chloride/methanol (v/v=10/1) (50 ml×2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by separation to give compound 25 (50 mg, yield 23%) by preparing a liquid phase (instrument: waters 2767, liquid phase; column chromatography: sunfire@prep C18 (19 mm×150 mM), mobile phase composition: mobile phase a: acetonitrile mobile phase B: water (containing 5mM ammonium acetate)).
LCMS m/z＝433.2[M+H] + ；
1 H NMR(400MHz,CD 3 OD)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).
Example 26: trans- (2E) -3- [ (2S) -1-methylpyrrolidin-2-yl ] -N- [3- [ (6- (4-hydroxyphenyl) -1H-indazol-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
Figure PCTCN2021117545-APPB-000252
The first step: (2S) -2- [ ((1E) -3-ethoxy-3-oxoprop-1-en-1-yl ] pyrrolidine-1-carboxylic acid tert-butyl ester (26A)
tert-butyl(2S)-2-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]pyrrolidine-1-carboxylate
The compound triethyl phosphorylacetate (3.71 g,16.57 mmol) was dissolved in dichloromethane (30 ml), sodium hydride (60%, 1.2g,30.12 mmol) was added under ice bath, and after the addition, the mixture was naturally warmed to room temperature, stirred for 20min, cooled to 0 ℃, BOC-L-prolyl aldehyde (3 g,15.06 mmol) was added, and after the addition, the mixture was naturally warmed to room temperature and stirred for 1h. The reaction was quenched by slowly dropping 20mL of saturated aqueous ammonium chloride, and 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 give 26A as a pale yellow oil (1.9 g, yield: 47%).
And a second step of: (2E) -3- [ ((2S) -1-methylpyrrolidin-2-yl ] prop-2-enoic acid ester (26B)
ethyl(2E)-3-[(2S)-1-methylpyrrolidin-2-yl]prop-2-enoate
Compound 26A (1.9 g,7.05 mmol) and paraformaldehyde (1.06 g,35.25 mmol) are dissolved in anhydrous formic acid (15 ml), heated to 90℃and stirred for 2h. Cooled to room temperature, concentrated under reduced pressure to remove the solvent, 20mL of 1N hydrochloric acid was added, extracted with 10mL of ethyl acetate, the organic layer was discarded, pH was adjusted to >7 with 6N aqueous sodium hydroxide solution, 30mL of ethyl acetate was added to extract, and the organic layer was concentrated under reduced pressure to give 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] +
And a third step of: (2E) Hydrochloride of (2S) -1-methylpyrrolidin-2-yl ] prop-2-enoic acid (26C)
(2E)-3-[(2S)-1-methylpyrrolidin-2-yl]prop-2-enoic acid；chlorohydrogen
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 and stirred for 2h, and pH=5-6 was adjusted with 1N dilute hydrochloric acid. The solvent was removed by concentrating under reduced pressure, 20mL of a mixed solvent of DCM/MeOH (V/V=10/1) was added, the mixture was stirred for 10min, the organic salt was removed by filtration, 4mL of a 3N solution of hydrogen chloride/ethyl acetate was added to the filtrate, the residue was slurried with 10mL of acetonitrile under reduced pressure, the filtration was carried out, and the cake was dried under reduced pressure to give 26C as a hydrochloride salt, as a gray solid (0.4 g, yield: 35%).
1 H 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).
Fourth step: trans- (2E) -3- [ (2S) -1-methylpyrrolidin-2-yl ] -N- [3- [ (6- (4-hydroxyphenyl) -1H-indazol-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.
In a 50mL reaction flask, tert-butyl trans-N- [3- [6- (4-hydroxyphenyl) -1-tetrahydropyran-2-yl-indazol-4-yl ] oxetan ] carbamate (1D) (0.2 g,0.42 mmol) and methylene chloride/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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. Times.3), and then concentrated to dryness under reduced pressure. To the resulting residue was added 26C hydrochloride (0.107 g), 6-chlorobenzotriazole-1, 3-tetramethylurea hexafluorophosphate (231 mg,0.56 mmol) and N, N-dimethylformamide (10 mL) in this order, and after the addition, the mixture was stirred at room temperature for 10 minutes, and N, N-diisopropylethylamine (0.45 g,3.48 mmol) was slowly added, and after the addition, the mixture was stirred at room temperature for 50 minutes. To the reaction solution was added saturated sodium hydrogencarbonate (50 mL), followed by extraction with methylene chloride/methanol (v/v=10/1) (50 ml×2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by separation to give compound 26 (50 mg, yield 23%) by preparing a liquid phase (instrument: waters 2767, liquid phase; column chromatography: sunfire@prep C18 (19 mm×150 mM), mobile phase composition: mobile phase a: acetonitrile mobile phase B: water (containing 5mM ammonium acetate)).
LCMS m/z＝433.2[M+H] +
1 H NMR(400MHz,CD 3 OD)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).
Example 27: trans- (E) -4- (bis (2-methoxyethyl) amino) -N- (3- ((6- (4-hydroxyphenyl) -1H-indazol-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-enamide
Figure PCTCN2021117545-APPB-000253
The first step: (E) -4- (bis (2-methoxyethyl) amino) but-2-enoic acid ester (27B)
methyl(E)-4-(bis(2-methoxyethyl)amino)but-2-enoate
In a 100mL reaction flask, (E) -4-bromobut-2-enoic acid methyl ester (1.33 g,10 mmol) was added dropwise to a tetrahydrofuran solution (60 mL) of bis (2-methoxyethyl) amine (27A) (1.79 g,10 mmol) and triethylamine (2.02 g,20 mmol), the reaction was stirred at room temperature for 12 hours, ethyl acetate (100 mL) was added to the reaction solution, which was then washed with water (100 mL. Times.3), and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 27B as a pale yellow oil (2.31 g, yield 100%).
And a second step of: (E) Hydrochloride of 4- (bis (2-methoxyethyl) amino) but-2-enoic acid (27C)
(E)-4-(bis(2-methoxyethyl)amino)but-2-enoic acid
In a 100mL reaction flask, (E) -4- (bis (2-methoxyethyl) amino) but-2-enoate (27B) (2.31 g,10 mmol), potassium hydroxide (1.12 g,20 mmol), water (1 mL) and methanol (20 mL) were sequentially added, the reaction mixture was stirred at room temperature for 2 hours, 10% diluted hydrochloric acid (8 mL) was added, and the mixture was concentrated under reduced pressure to give 27C hydrochloride, as a white solid (2.17 g), which was directly used in the next reaction.
And a third step of: trans- (E) -4- (bis (2-methoxyethyl) amino) -N- (3- ((6- (4-hydroxyphenyl) -1H-indazol-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-enamide
In a 50mL reaction flask, tert-butyl trans-N- [3- [6- (4-hydroxyphenyl) -1-tetrahydropyran-2-yl-indazol-4-yl ] oxetan ] carbamate (1D) (0.037 g,0.077 mmol) and methylene chloride/trifluoroacetic acid (v/v=1/1, 8 mL) were added, and then the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure. To the resulting residue was added, in order, 27C hydrochloride (0.025 g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.030 g,0.156 mmol), 1-hydroxybenzotriazole (0.016 g,0.117 mmol) and N, N-dimethylformamide (10 mL), and after the addition, the mixture was stirred at room temperature for 10 minutes, N-diisopropylethylamine (0.06 g, 0.4638 mmol) was added, and after the addition, the mixture was stirred at room temperature for 50 minutes. To the reaction solution was added saturated sodium hydrogencarbonate (50 mL), followed by extraction with methylene chloride/methanol (v/v=10/1, 50ml×4), the organic layers were combined and dried over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure, and the residue was purified by separation to give compound 27 (14 mg, yield 36.8%) by preparing a liquid phase (instrument: waters 2767, liquid phase; column: xbridge@prep C18 (30 mm×150 mm), mobile phase composition: mobile phase a: acetonitrile, mobile phase B: water (containing 0.05%) and the like.
LCMS m/z＝495.4[M+1] +
1 H NMR(400MHz,CD 3 OD)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).
Example 28: trans- (E) -N- ((3- ((6- (4-hydroxyphenyl) -1H-indazol-4-yl) oxy) cyclobutyl) -4- (pyrrolidin-1-yl) but-2-enamide; acetate (compound 28)
trans-(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-000255
The first step: (E) Hydrochloride of (28A) 4- (pyrrolidinyl-1-yl) but-2-enoic acid
(E)-4-(pyrrolidin-1-yl)but-2-enoic acid
Methyl 4-bromo-2-butenoate (1.79 g,10.0 mmol) was weighed, dissolved in a 100mL single port round bottom flask with 30mL tetrahydrofuran, cooled to 0-5℃with an ice water bath, and tetrahydropyrrole (1.42 g,20 mmol) was slowly added dropwise, after the addition was completed, the reaction was slowly warmed to room temperature for 1 hour, quenched with water, extracted with 40mL diethyl ether, the organic phase was washed with 30mL saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow oily residue. The residue was added to a 250mL single neck round bottom flask, 40mL 3N HCl was added, the mixture was heated to 100deg.C and refluxed for 2 hours, the residue was concentrated under reduced pressure, isopropanol and diethyl ether mixture was added to the residue, white solid was precipitated, and suction filtration was performed to obtain 28A hydrochloride, white solid (0.708 g, yield: 46%).
LCMS m/z＝156.2[M+H] +
And a second step of: trifluoroacetate salt of trans-4- (4- ((3-aminocyclobutoxy) -1H-indazol-6-yl) phenol (28B)
trans-4-(4-(3-aminocyclobutoxy)-1H-indazol-6-yl)phenol
Trans-N- [3- [6- (4-hydroxyphenyl) -1-tetrahydropyran-2-yl-indazol-4-yl ] oxetan-yl ] carbamic acid tert-butyl ester (1D) (0.4 g,0.84 mmol) was dissolved in 50mL single neck round bottom flask with 20mL dichloromethane, 10mL trifluoroacetic acid was added, and heated to 35℃and stirred for 2 hours. Concentrated under reduced pressure to give the trifluoroacetate salt of 28B as a tan solid (0.246 g) which was used directly in the next reaction.
LCMS m/z＝296.1[M+H] +
And a third step of: trans- (E) -N- ((3- ((6- (4-hydroxyphenyl) -1H-indazol-4-yl) oxy) cyclobutyl) -4- (pyrrolidin-1-yl) but-2-enamide; acetate (compound 28)
trans-(E)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-4-(pyrrolidin-1-yl)but-2-enamide；acetic acid
(E) -4- (pyrrolidinyl-1-yl) but-2-enoic acid (28A) hydrochloride (78 mg) was weighed, dissolved in 5mL DMF in a 50mL single neck round bottom flask, 6-chlorobenzotriazole-1, 3-tetramethylurea hexafluorophosphate (210 mg,0.5 mmol) was added and stirred at room temperature for fifteen minutes. The stirred mixture was added dropwise to a solution of 28B trifluoroacetate (123 mg) in 5mL DMF, cooled to 0-5℃with an ice-water bath, N-diisopropylethylamine (270 mg,2.1 mmol) was added dropwise, and the mixture was allowed to react at room temperature for 2 hours. 30mL of water was added, 30mL of a mixed solvent of dichloromethane/methanol (v/v=10/1) was added for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by separation to obtain compound 28 (20 mg, yield: 9.67%) by preparing a liquid phase (instrument: waters 2767 for preparing a liquid phase; column: sunFire@PrepC18 (19 mM. Times.150 mM)), mobile phase composition: mobile phase A: acetonitrile mobile phase B: water (containing 5mM ammonium acetate)).
LCMS m/z＝433.3[M-CH 3 COOH+H] +
1 H NMR(400MHz,CD 3 OD)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).
Example 29: trans- (E) -4- (azetidin-1-yl) -N- ((3- ((6- (4-hydroxyphenyl) -1H-indazol-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-enamide
Figure PCTCN2021117545-APPB-000256
The first step: (E) -4- (azetidin-1-yl) but-2-enoic acid (29A) hydrochloride
(E)-4-(azetidin-1-yl)but-2-enoic acid
Methyl 4-bromo-2-butenoate (1.79 g,10.0 mmol) was weighed, dissolved in a 100mL single port round bottom flask with 30mL tetrahydrofuran, cooled to 0-5℃in an ice water bath, and azetidine (1.71 g,30.0 mmol) was slowly added dropwise, after the addition was completed, the reaction was slowly warmed to room temperature for 1 hour, quenched with water, extracted with 40mL diethyl ether, the organic phase was washed with 30mL saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a pale yellow oily residue. The residue was added to a 250mL single neck round bottom flask, 40mL 3N HCl was added, the mixture was heated to 100deg.C and refluxed for 2 hours, the residue was concentrated under reduced pressure, isopropanol and diethyl ether mixture was added to the residue, white solid was precipitated, and suction filtration was performed to obtain 29A hydrochloride, white solid (0.168 g, yield: 12%).
LCMS m/z＝142.2[M+H] +
And a second step of: trans- (E) -4- (azetidin-1-yl) -N- ((3- ((6- (4-hydroxyphenyl) -1H-indazol-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-enamide
29A (71 mg,0.5 mmol) was weighed out and dissolved in 5mL DMF in a 50mL single neck round bottom flask, 6-chlorobenzotriazole-1, 3-tetramethylurea hexafluorophosphate (210 mg,0.5 mmol) was added and stirred at room temperature for fifteen minutes. A stirred mixture of (E) -4- (pyrrolidin-1-yl) but-2-enoic acid and 6-chlorobenzotriazol-1, 3-tetramethylurea hexafluorophosphate was added dropwise to a solution of trans-4- (4- ((3-aminocyclobutoxy) -1H-indazol-6-yl) phenol (28B) hydrochloride (123 mg) in 5mL DMF, cooled to 0-5℃with an ice-water bath, N-diisopropylethylamine (270 mg,2.1 mmol) was added dropwise, the mixture was cooled down to room temperature after the addition, reacted for 2 hours at room temperature, 30mL of water was added, 30mL of a mixed solvent dichloromethane/methanol (v/v=10/1) was added, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was prepared into a liquid phase by a preparation apparatus of 2767, a chromatographic column of Sunfire Prep C18 (19 mM. Times 150 mM), a mobile phase composition of a mobile phase of acetonitrile: mobile phase B: aqueous 5mM ammonium acetate) was separated and purified (29.53 mg) to give a compound having a yield of 15.53%.
LCMS m/z＝419.1[M+H] +
EXAMPLE 30 trans- (2E) -4- (diethylamino) -N- [3- [ (6- (4-hydroxyphenyl) -1H-indazol-4-yl) oxy ] cyclobutyl ] but-2-enamide (Compound 30)
trans-(2E)-4-(diethylamino)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamide
Figure PCTCN2021117545-APPB-000257
The first step: (2E) -methyl 4- (diethylamino) but-2-enoate (30A)
methyl(2E)-4-(diethylamino)but-2-enoate
E-4-bromo-2-butenoic acid methyl ester (2 g,11.17 mmol) was dissolved in tetrahydrofuran (10 ml), diethylamine (3.27 g,44.68 mmol) was slowly added dropwise at room temperature, and the mixture was stirred at room temperature for 2 hours. 20mL of water and 20mL of ethyl acetate were added to extract, and the organic layer was washed once with 20mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude 30A product, which was used as a yellow liquid (2 g) for the next step.
LCMS m/z＝172.1[M+H] +
And a second step of: (2E) -4- (diethylamino) but-2-enoic acid (30B) hydrochloride
(2E)-4-(diethylamino)but-2-enoic acid；hydrochloric acid
Compound 30A (2 g) was dissolved in a mixed solvent of methanol (9 mL) and water (3 mL), and solid potassium hydroxide (1.31 g,23.36 mmol) was added thereto and stirred at room temperature for 2h. The pH was adjusted to 5-6 with concentrated hydrochloric acid, concentrated under reduced pressure, the residue was dissolved by adding methylene chloride/methanol (V/V=10/1, 20 mL), filtered, 3N hydrogen chloride/ethyl acetate solution was added to the filtrate 5mL, the filtrate was concentrated under reduced pressure, the residue was slurried with ethyl acetate/acetonitrile (20 mL, V/V=1/1), filtered, and the cake was dried under reduced pressure to give 30B hydrochloride salt as a white solid (1.1 g, yield: 49%).
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).
And a third step of: trans- (2E) -4- (diethylamino) -N- [3- [ (6- (4-hydroxyphenyl) -1H-indazol-4-yl) oxy ] cyclobutyl ] but-2-enamide (Compound 30)
trans-(2E)-4-(diethylamino)-N-[3-[(6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]but-2-enamide
In a 50mL reaction flask, tert-butyl trans-N- [3- [6- (4-hydroxyphenyl) -1-tetrahydropyran-2-yl-indazol-4-yl ] oxetan ] carbamate (1D) (0.2 g,0.42 mmol) and methylene chloride/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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. Times.3), and then concentrated to dryness under reduced pressure. To the resulting residue was added, in order, compound 30B hydrochloride (0.11 g), 6-chlorobenzotriazole-1, 3-tetramethylurea hexafluorophosphate (231 mg,0.56 mmol) and N, N-dimethylformamide (10 mL), followed by stirring at room temperature for 10 minutes after the completion of the addition, and N, N-diisopropylethylamine (0.45 g,3.48 mmol) was slowly added, followed by stirring at room temperature for 50 minutes after the completion of the addition. To the reaction solution was added saturated sodium hydrogencarbonate (50 mL), followed by extraction with methylene chloride/methanol (v/v=10/1) (50 ml×2), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by separation to give compound 30 (100 mg, yield 45%) by preparing a liquid phase (instrument: waters 2767, liquid phase; column chromatography: sunfire@prep C18 (19 mm×150 mM); mobile phase composition: mobile phase a: acetonitrile mobile phase B: water (containing 5mM ammonium acetate)).
LCMS m/z＝435.1[M+H] + ；
1 H NMR(400MHz,CD 3 OD)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).
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)acrylamide
Figure PCTCN2021117545-APPB-000258
In a 50mL three-necked flask, 6-chlorobenzotriazole-1, 3-tetramethylurea hexafluorophosphate (62 mg,0.15 mmol) was added to a solution of acrylic acid (10.8 mg,0.15 mmol) in N, N-dimethylformamide (2 mL), reacted at room temperature for 10min at 0℃and quenched with trifluoroacetic acid salt of trans-4- (8- ((3-aminocyclobutoxy) imidazo [1,5-a ] pyridin-6-yl) phenol (14B) (61.4 mg,0.15 mmol) in 1mL of N, N-dimethylformamide, after stirring at 0℃for 1min, N-diisopropylethylamine (101 mg,0.78 mmol) in 1mL of N-dimethylformamide, stirring at 0℃for 3h, saturated sodium bicarbonate solution (5 mL) was quenched, ethyl acetate (20X 3 mL) was extracted, concentrated, and concentrated by a water column chromatography (150 mM) to prepare a mobile phase of 35 mM aqueous 35 mM acetic acid, 35 mM, and aqueous 35 mM (150 mM) was prepared to obtain a mobile phase of 35 mM aqueous phase chromatography, which was purified to give an aqueous phase of 35 mM of 35% acetonitrile.
LCMS m/z＝350.1[M+1] +
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)acrylamide
Figure PCTCN2021117545-APPB-000259
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)carbamate
Tert-butyl cis- (3-hydroxycyclobutyl) carbamate (224.5 mg,1.2 mmol) and DMF (5 mL) were added under nitrogen and chilled water sodium hydrogen (48 mg,60wt%,1.6 mmol) was added and the reaction stirred at room temperature for 30 min; a solution of 6-bromo-8-fluoroimidazo [1,5-a ] pyridine (13E) (215 mg,1 mmol) in DMF (5 mL) was added dropwise after cooling in ice water, and the reaction was stirred at room temperature for 3 hours. TLC monitored completion of the reaction, ethyl acetate (100 mL) and water (100 mL), the layers were separated, the aqueous layer was extracted once with ethyl acetate (100 ml×1), the organic layers were combined, washed with saturated sodium chloride solution (100 ml×2), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure at 40 ℃ and the residue purified by silica gel column chromatography (eluent PE/ea=5/1) to give 32A as a white solid (340 mg, 89% yield).
And a second step of: cis-tert-butyl (3- ((6- (4- (benzyloxy) -2-ethyl-5-fluorophenyl) imidazo [1,5-a ] pyridin-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)carbamate
2- (4- (benzyloxy) -2-ethyl-5-fluorophenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (480.9 mg,1.35 mmol), potassium phosphate heptahydrate (913 mg,2.7 mmol), and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (73.5 mg,0.09 mmol) were added to a solution of 32A (340 mg,0.89 mmol) of 1, 4-dioxane (20 mL) and water (5 mL), respectively, stirred at 110 ℃ for 1h, quenched with saturated sodium bicarbonate solution (20 mL), extracted with ethyl acetate (20 mL x 3), the combined organic layers were dried over anhydrous sodium sulfate, 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, yield 87.3%).
And a third step of: 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)carbamate
32B (413 mg,0.78 mmol) was added to the flask, palladium on carbon (41 mg) and methanol solution (30 mL) were added, the mixture was purged with hydrogen three times, and the reaction was stirred at room temperature for 6 hours. The reaction solution was filtered through celite and eluted with ethyl acetate. Concentrated to dryness under reduced pressure to give 32C (343 mg) which was used directly in the next reaction.
Eighth step, trifluoroacetate salt of cis-4- (8- ((3-aminocyclobutoxy) imidazo [1,5-a ] pyridin-6-yl) -5-ethyl-2-fluorophenol (32D)
cis-4-(8-(3-aminocyclobutoxy)imidazo[1,5-a]pyridin-6-yl)-5-ethyl-2-fluorophenol；trifluoroacetic acid
The crude 32C (343 mg) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (3 mL) was added and reacted at room temperature for 1 hour. The reaction solution was concentrated directly to give 32D trifluoroacetate salt as a white solid (355 mg) which was used directly in the next reaction.
Ninth step 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)acrylamide
In a 50mL three-necked flask under nitrogen protection, 6-chlorobenzotriazole-1, 3-tetramethylurea hexafluorophosphate (62 mg,0.15 mmol) was added to a solution of acrylic acid (11 mg,0.15 mmol) in N, N-dimethylformamide (2 mL), the reaction was carried out at room temperature for 10min, then a crude trifluoroacetate (59 mg) of 32D was dissolved in 1mL of N, N-dimethylformamide and was added dropwise to the above reaction solution at 0℃for 1min, after stirring at 0℃N, N-diisopropylethylamine (101 mg,0.78 mmol) was dissolved in 1mL of N, N-dimethylformamide and was added dropwise to the above reaction solution, stirring at 0℃for 3h, saturated sodium bicarbonate solution (5 mL) was quenched, ethyl acetate (20X 3 mL) was extracted, and the residue was concentrated under reduced pressure to prepare a liquid phase by preparing a liquid phase (instrument: waters 2767); the column was SunFire@PrepC18 (19 mM. Times.150 mM.) the mobile phase composition: mobile phase A: acetonitrile mobile phase B: water (containing 5mM ammonium acetate)) was isolated and purified to give compound 32 (6.8 mg, yield 13.3%).
LCMS m/z＝396.2[M+1] +
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-fluoroacrylamide
Figure PCTCN2021117545-APPB-000260
In a 50mL three-necked flask, 6-chlorobenzotriazole-1, 3-tetramethylurea hexafluorophosphate (62 mg,0.15 mmol) was added to a solution of 2-fluoroacrylic acid (14 mg,0.15 mmol) in N, N-dimethylformamide (2 mL), reacted at room temperature for 10min at 0℃to prepare a crude trifluoroacetate 32D (68.3 mg) in 1mL of N, N-dimethylformamide, and then dropwise added to the above-mentioned reaction solution, stirred at 0℃for 1min, N-diisopropylethylamine (101 mg,0.78 mmol) in 1mL of N, N-dimethylformamide was dropwise added to the above-mentioned reaction solution, stirred at 0℃for 3h, saturated sodium bicarbonate solution (5 mL) was quenched, ethyl acetate (20X 3 mL) was extracted, and the residue was concentrated under reduced pressure to prepare a liquid phase (water 2767; chromatography column: sunFire PreC 18 @ 150 mM; mobile phase: 4 mM, aqueous phase: 33 mM) was prepared by preparing a liquid phase (19X 150 mM; mobile phase: 33 mM) and purified to obtain an aqueous phase of acetic acid (17 mM).
LCMS m/z＝414.2[M+1] +
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-enamide
Figure PCTCN2021117545-APPB-000261
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]carbamate
In a 50mL reaction flask, tert-butyl trans-N- [3- (6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl) oxy-cyclobutyl ] carbamate (1C) (0.5 g,1.07 mmol), N-dimethylformamide (15 mL), sodium iodide (0.08 g,0.54 mmol) and sodium hydride (0.85 g,21.4mmol,60 wt%) were successively added, and after the addition, the mixture was stirred at 25℃for 10 minutes, 2-bromoethylmethyl ether (0.59 g,4.28 mmol) was added, and the mixture was heated to 50℃and reacted under stirring for 5 hours. Cooled to room temperature, quenched with 1mL of water, ethyl acetate (50 mL) was added to the reaction solution, then washed with water (30 ml×1) and saturated brine (30 ml×1) in this order, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate/petroleum ether (V/V) =1/20-1/5) to give 34A as a white solid (0.4 g, yield: 71%).
LCMS m/z＝524.2/526.2[M+H] +
And a second step of: 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]carbamate
In a 50mL reaction flask, 34A (0.40 g,0.76 mmol), 4-hydroxyphenylboronic acid (0.16 g,1.14 mmol), potassium phosphate heptahydrate (0.77 g,2.28 mmol), [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (73 mg,0.089 mmol) and dioxane/water (v/v=4/1, 10 mL) of the previous step were sequentially added, and after nitrogen substitution, the reaction was stirred at 90℃for 2 hours. Water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL. Times.2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate/petroleum ether (V/V) =1/10-1/1) to give 34B as a white solid (0.4 g, yield 98%).
LCMS m/z＝538.3[M+H] +
And a third step of: 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-enamide
In a 50mL reaction flask, compound 34B (0.12 g,0.21 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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 methyl tert-butyl ether (10 mL. Times.3), concentrated to dryness under reduced pressure, dissolved in 5mL of acetonitrile, and stirred for 10min with diisopropylethylamine (0.35 g,2.7 mmol) added.
To a mixed solution of trans-4-dimethylaminocrotonic acid hydrochloride (0.041 g,0.25 mmol) and diisopropylethylamine (83 mg,0.64 mmol) in dichloromethane (5 mL) and acetonitrile (5 mL), tripyrrolidinylphosphonium bromide hexafluorophosphate (0.12 g,0.25 mmol) was added and stirred at room temperature for 20 minutes. The reaction solution was slowly added dropwise to the above acetonitrile solution to be used, and stirring was continued for 1 hour. 10mL of saturated aqueous sodium bicarbonate solution was added to the mixture to alkalize the mixture, 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) =50/1/0.5-25/1/0.25) to give compound 34 as a pale yellow solid (70 mg, yield: 71%).
LCMS m/z＝465.2[M+H] +
EXAMPLE 35 trifluoroacetate salt of trans-N-methyl-N- [3- [ [6- (2-ethyl-5-fluoro-4-hydroxyphenyl) imidazo [1,5-a ] pyridin-8-yl) oxy ] cyclobutyl ] propane-2-amide (Compound 35)
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 acid
Figure PCTCN2021117545-APPB-000262
Figure PCTCN2021117545-APPB-000263
The first step: trans-N-methyl-N- [3- [ [ 6-bromoimidazo [1,5-a ] pyridin-8-yl) oxy ] cyclobutyl ] carbamic acid tert-butyl ester (35A)
trans-tert-butyl N-methyl-N-[3-[(6-bromoimidazo[1,5-a]pyridin-8-yl)oxy]cyclobutyl]carbamate
In a 50mL reaction flask, trans-tert-butyl (3- ((6-bromoimidazo [1,5-a ] pyridin-8-yl) oxy) cyclobutyl) carbamate (13F) (0.83 g,2.17 mmol), N-dimethylformamide (30 mL) and sodium hydride (1.6 g,40mmol,60 wt%) were added sequentially, stirred at 25℃for 30 minutes after the addition was completed, methyl iodide (4.26 g,30 mmol) was slowly added dropwise and the reaction stirred at 45℃for 2 hours. Ethyl acetate (50 mL) was added to the reaction solution, which was then washed with water (30 ml×3) and saturated brine (30 ml×1), and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/ea=9/1) to give 35A as a pale yellow oil (0.4 g, yield: 46%).
LCMS m/z＝396.1/398.0[M+H] +
And a second step of: trans-N-methyl-N- [3- [ (6- (4- (benzyloxy) -2-ethyl-5-fluorophenyl) imidazo [1,5-a ] pyridin-8-yl ] oxy ] cyclobutyl ] carbamic acid 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]carbamate
In a 50mL reaction flask, 35A (0.378 g,0.95 mmol), 2- (4- (benzyloxy) -2-ethyl-5-fluorophenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (0.41 g,1.14 mmol), potassium phosphate heptahydrate (0.97 g,2.87 mmol), [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (78 mg,0.096 mmol) and dioxane/water (v/v=4/1, 10 mL) were sequentially added, and after three substitutions of nitrogen, the reaction was stirred at 90℃for 2 hours. To the reaction solution was added water (50 mL), followed by extraction with ethyl acetate (50 ml×2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (PE/ea=3/1) to give a crude 35B product, a pale yellow solid (0.32 g), which was directly used for the next reaction.
And a third step of: trans-N-methyl-N- [3- [ (6- (2-ethyl-5-fluoro-4-hydroxyphenyl) imidazo [1,5-a ] pyridin-8-yl) oxy ] cyclobutyl ] carbamic acid tert-butyl ester (35C)
trans-tert-butyl N-methyl-N-[3-[(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy]cyclobutyl]carbamate
The crude 35B (320 mg) was added to a reaction flask, and palladium on carbon (41 mg) and methanol solution (30 mL) were added, and the mixture was purged with hydrogen three times and reacted at room temperature with stirring for 6 hours. The reaction solution was filtered through celite and eluted with ethyl acetate. Concentrated to dryness under reduced pressure to give crude 35C (260 mg) which was used directly in the next reaction.
LCMS m/z＝456.2[M+H] +
Fourth step: trifluoroacetate salt of trans-N-methyl-N- [3- [ [6- (2-ethyl-5-fluoro-4-hydroxyphenyl) imidazo [1,5-a ] pyridin-8-yl) oxy ] cyclobutyl ] propane-2-amide (compound 35)
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 acid
In a 50mL reaction flask, 35C crude (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, and the residue was washed with MTBE (10 mL. Times.3), and then concentrated to dryness under reduced pressure to give a black foamy solid residue (400 mg).
In a 50mL reaction flask, the above-mentioned black foamy solid residue (0.22 g), N-diisopropylethylamine (0.29 g,2.26 mmol) and methylene chloride (10 mL) were added, and after the addition was completed, the mixture was stirred at room temperature for 5 minutes, and then acryloyl chloride (0.034 g,0.38 mmol) was added dropwise, and after the addition was completed, the mixture was stirred at room temperature for 10 minutes. To the reaction solution was added saturated sodium bicarbonate (50 mL), followed by extraction with dichloromethane/methanol (v/v=10/1) (50 ml×2), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC (apparatus: waters 2767 for preparing liquid phase; column: sunfire@prepc18 (19 mm×150 mm), mobile phase composition: mobile phase a: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid)) to give the trifluoroacetate salt of compound 35 (44 mg, yield 18%).
LCMS m/z＝410.2[M+H] +
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).
Example 36: trans- (2E) -4- (dimethylamino) -N- [ (3- [ [6- (4-hydroxyphenyl) -1H-indazol-4-yl) oxy ] -2, 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-enamide
Figure PCTCN2021117545-APPB-000264
Figure PCTCN2021117545-APPB-000265
The first step: trans-3- [ (6-bromo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy ] -2, 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-amine
The compound 6-bromo-4-fluoro-1-tetrahydropyran-2-yl-indazole (1 c) (0.3 g,1.00 mmol), t-butyl trans-N- [ 3-hydroxy-2, 4-tetramethylcyclobutyl ] carbamate (0.29 g,1.2 mmol), tetrabutylammonium bromide (0.97 g,3 mmol) and potassium hydroxide (0.56 g,10 mmol) were mixed in a mixed solvent of toluene (10 ml) and water (3 ml), and the mixture was heated to 80℃and stirred for 48 hours. Cooled to room temperature, extracted with 10mL of water and 10mL of ethyl acetate, and the organic layer was separated, concentrated under reduced pressure, and purified by column chromatography (DCM/MeOH (V/V) =100/1-20/1) to give 36A as a white solid (180 mg, yield: 43%).
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).
And a second step of: trans-4- (1- (tetrahydro-2H-pyran-2-yl) -4- [ (3-amino-2, 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)phenol
In a 50mL reaction flask, 36A (0.18 g,0.43 mmol), 4-hydroxyphenylboronic acid (0.071 g,0.52 mmol), potassium phosphate heptahydrate (0.44 g,1.29 mmol), [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (35 mg,0.043 mmol) and dioxane/water (v/v=4/1, 10 mL) of the last step were sequentially added, and after nitrogen substitution, the reaction was stirred at 90℃for 2 hours. Water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL. Times.2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate/petroleum ether (V/V) =1/10-1/1) to give 36B as a white solid (0.1 g, yield 53%).
LCMS m/z＝436.2[M+H] +
And a third step of: trans- (2E) -4- (dimethylamino) -N- [ (3- [ [6- (4-hydroxyphenyl) -1H-indazol-4-yl) oxy ] -2, 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-enamide
In a 50mL reaction flask, compound 36B (0.1 g,0.23 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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 methyl tert-butyl ether (10 mL. Times.3), concentrated to dryness under reduced pressure, dissolved in 5mL of acetonitrile, and stirred for 10min with diisopropylethylamine (0.35 g,2.7 mmol) added.
To a mixed solution of trans-4-dimethylaminocrotonic acid hydrochloride (0.041 g,0.25 mmol) and diisopropylethylamine (83 mg,0.64 mmol) in dichloromethane (5 mL) and acetonitrile (5 mL), tripyrrolidinylphosphonium bromide hexafluorophosphate (0.12 g,0.25 mmol) was added and stirred at room temperature for 20 minutes. The reaction solution was slowly added dropwise to the above acetonitrile solution to be used, and stirring was continued for 1 hour. 10mL of saturated aqueous sodium bicarbonate solution was added to the mixture to alkalize the mixture, 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) =50/1/0.5-25/1/0.25) to give compound 36 (40 mg, yield: 38%).
LCMS m/z＝463.2[M+H] +
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).
Example 37: acetate salt of trans- (E) -4- (dimethylamino) -N- (3- ((6- (2-fluoro-4-hydroxyphenyl) -1H-indazol-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-enamide；acetic acid
Figure PCTCN2021117545-APPB-000266
The first step: trans- (3- ((6- (2-fluoro-4-hydroxyphenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) cyclobutyl) (methyl) carbamic acid tert-butyl ester (37A)
trans-tert-butyl(3-((6-(2-fluoro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)(methyl)carbamate
In a 50mL reaction flask, compound 7A (0.48 g,1.00 mmol), 2-fluoro-4-hydroxyphenylboronic acid (0.19 g,1.20 mmol), potassium phosphate heptahydrate (1.02 g,3.00 mmol), [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (120 mg,0.15 mmol) and dioxane/water (v/v=4/1, 20 mL) were sequentially added, and after nitrogen substitution, the reaction was stirred at 90℃for 2 hours. Water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL. Times.2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and 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, yield 99%).
LCMS m/z＝512.2[M+H] +
And a second step of: acetate salt of trans- (E) -4- (dimethylamino) -N- (3- ((6- (2-fluoro-4-hydroxyphenyl) -1H-indazol-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-enamide；acetic acid
In a 50mL reaction flask, compound 37A (0.51 g,1.00 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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 methyl tert-butyl ether (10 mL. Times.3), concentrated to dryness under reduced pressure, dissolved in 10mL of acetonitrile, and stirred for 10min with diisopropylethylamine (0.37 g,2.84 mmol) added.
To a solution of trans-4-dimethylaminocrotonic acid hydrochloride (0.165 g,1.00 mmol) and diisopropylethylamine (0.367 mg,2.84 mmol) in a mixture of dichloromethane (10 mL) and acetonitrile (10 mL), tripyrrolidinylphosphonium bromide hexafluorophosphate (0.463 g,1.00 mmol) was added and stirred at room temperature for 20 minutes. The reaction solution was slowly added dropwise to the acetonitrile solution for the previous operation, and stirring was continued for 1 hour. After adding 20mL of saturated aqueous sodium hydrogencarbonate solution and separating the solution, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by separating and freeze-drying the prepared liquid phase (instrument: waters 2767 for preparing liquid phase; column: sunFire@PrepC18 (19 mM. Times.150 mM); mobile phase composition: mobile phase A: acetonitrile mobile phase B: water (containing 5mM ammonium acetate)), to obtain acetate of Compound 37 (56 mg, yield: 11.82%).
LCMS m/z＝439.3[M+H] +
1 H NMR(400MHz,CD 3 OD)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).
Example 37-1: trans- (E) -4- (dimethylamino) -N- (3- ((6- (2-fluoro-4-hydroxyphenyl) -1H-indazol-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-enamide
In a 100mL single neck round bottom flask, the acetate salt of Compound 37 (47 mg) was added, followed by dichloromethane (20 mL) and saturated sodium bicarbonate solution (15 mL) and stirred for half an hour. The layers were left to stand and the aqueous phase was extracted with dichloromethane/methanol (v/v=4/1; 20ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and compound 37 (20 mg) concentrated under reduced pressure.
LCMS m/z＝439.2[M+H] +
1 H NMR(400MHz,CD 3 OD)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).
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-enamide
Figure PCTCN2021117545-APPB-000267
The first step: trans- (3- ((6- (4-hydroxy-2-methylphenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) cyclobutyl) (methyl) carbamic acid tert-butyl ester (38A)
trans-tert-butyl(3-((6-(4-hydroxy-2-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)(methyl)carbamate
In a 50mL 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 (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (120 mg,0.15 mmol) and dioxane/water (v/v=4/1, 20 mL) were sequentially added, and after three substitutions of nitrogen, the reaction was stirred at 90℃for 2 hours. Water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL. Times.2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and 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, yield 99%).
LCMS m/z＝508.2[M+H] +
And a second step of: 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-enamide
In a 50mL reaction flask, compound 38A (0.507 g,1.00 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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 methyl tert-butyl ether (10 mL. Times.3), concentrated to dryness under reduced pressure, dissolved in 10mL of acetonitrile, and stirred for 10min with diisopropylethylamine (0.367 g,2.84 mmol) added.
To a solution of trans-4-dimethylaminocrotonic acid hydrochloride (0.165 g,1.00 mmol) and diisopropylethylamine (0.367 mg,2.84 mmol) in a mixture of dichloromethane (10 mL) and acetonitrile (10 mL), tripyrrolidinylphosphonium bromide hexafluorophosphate (0.463 g,1.00 mmol) was added and stirred at room temperature for 20 minutes. The reaction solution was slowly added dropwise to the acetonitrile solution for use in the previous step, and stirring was continued for 1 hour. After addition of 20mL of saturated aqueous sodium bicarbonate, 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) =50/1/0.5-25/1/0.25) to give compound 38 (62 mg, yield: 25.24%).
LCMS m/z＝435.3[M+H] +
1 H NMR(400MHz,CD 3 OD)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).
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-enamide
Figure PCTCN2021117545-APPB-000268
Figure PCTCN2021117545-APPB-000269
The first step: cis- (3- ((6- (4-hydroxy-2-methylphenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) cyclobutyl) (methyl) carbamic acid tert-butyl ester (39A)
cis-tert-butyl(3-((6-(4-hydroxy-2-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)(methyl)carbamate
In a 100mL reaction flask, cis-N- [3- (6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl) oxy cyclobutyl ] -N-methyl-carbamic acid tert-butyl ester (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 ] palladium dichloride dichloromethane complex (82 mg,0.1 mmol) and dioxane/water (v/v=4/1, 10 mL) were sequentially added, and after nitrogen substitution three times, the reaction was stirred at 90℃for 2 hours. Water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL. Times.2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (PE/EA=3/1) to give 39A (0.47 g, yield 92%).
LCMS m/z＝508.3[M+H] +
And a second step of: 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-enamide
In a 50mL reaction flask, compound 39A (0.3 g,0.59 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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 methyl tert-butyl ether (10 mL. Times.3), concentrated to dryness under reduced pressure, dissolved in 5mL of acetonitrile, and stirred for 10min with diisopropylethylamine (0.46 g,3.54 mmol) added.
To a mixed solution of trans-4-dimethylaminocrotonic acid hydrochloride (0.098 g,0.59 mmol) and diisopropylethylamine (229 mg,1.77 mmol) in dichloromethane (15 mL) and acetonitrile (5 mL), tripyrrolidinylphosphonium bromide hexafluorophosphate (0.275 g,0.59 mmol) was added and stirred at room temperature for 20 minutes. The reaction solution was slowly added dropwise to the above acetonitrile solution to be used, and stirring was continued for 1 hour. 30mL of saturated aqueous sodium bicarbonate solution was added to the mixture to alkalize the mixture, 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) =50/1/0.5-25/1/0.25) to give compound 39 (148 mg, yield: 57.6%).
LCMS m/z＝435.2[M+H] +
1 H NMR(400MHz,CD 3 OD)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).
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-enamide
Figure PCTCN2021117545-APPB-000270
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)carbamate
In a 50mL reaction flask, tert-butyl trans-N- [3- (6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl) oxy-cyclobutyl ] carbamate (1C) (0.70 g,1.50 mmol), iodoethane (4.68 g,30 mmol) and DMF (20 mL) were added sequentially, sodium hydride (1.2 g,30 mmol) was added with stirring at room temperature, the reaction was stirred for 3 hours at 50℃with an oil bath, and TLC monitored for completion. Ethyl acetate (100 mL) was added under ice-water cooling, saturated aqueous ammonium chloride (50 mL) and water (50 mL) were added, and the organic layer was washed with saturated aqueous sodium chloride (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate (V/V) =5/1) to give 40B (0.65 g, yield: 87.6%).
And a second step of: trans-tert-butylethyl (3- ((6- (4-hydroxyphenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-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)carbamate
In a 50mL reaction flask, the above-mentioned 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 (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (160 mg,0.19 mmol) and dioxane/water (v/v=4/1, 15 mL) were sequentially added, and after three substitutions of nitrogen, the reaction was stirred at 90℃for 2 hours. Water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL. Times.2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate (V/V) =5/1-1/1) to give 40C (0.33 g, yield 49.4%).
And a third step of: 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-enamide
In a 50mL reaction flask, compound 40C (0.30 g,0.59 mmol) from the previous step, dichloromethane (3 mL), trifluoroacetic acid (3 mL) were added, the reaction was stirred at room temperature for 5 hours, TLC monitored for completion, concentrated to dryness under reduced pressure, dichloromethane (3 mL), N, N-diisopropylethylamine (0.22 g,1.77 mmol) was added, and stirred for dissolution.
Into a 50mL reaction flask, 4-N, N-dimethylaminocrotonic acid hydrochloride (0.13 g,0.82 mmol), methylene chloride (4 mL) and tripyrrolidinyl phosphonium bromide hexafluorophosphate (0.35 g,0.76 mmol) were added, N-diisopropylethylamine (0.22 g,1.77 mmol) was added dropwise, and the mixture was stirred at room temperature for 30 minutes; adding the solution into the reaction solution of the previous operation under the cooling of ice water, and stirring at room temperature for reaction for 4 hours; TLC monitoring the completion of the reaction through adding 10mL of methylene chloride, washing the reaction solution with saturated sodium hydrogen carbonate (20 mL. Times.3), drying the organic layer over anhydrous sodium sulfate, filtering, concentrating the dried under reduced pressure, separating and purifying the residue by silica gel column chromatography (methylene chloride/methanol (V/V) =20/1) to give compound 40 (0.13 g, yield: 50.2%).
LCMS m/z＝435.2[M+H] +
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).
Example 41: trifluoroacetate salt of trans- (E) -N- (cyclopropylmethyl) -4- (dimethylamino) -N- (3- ((6- (4-hydroxyphenyl) -1H-indazol-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 acid
Figure PCTCN2021117545-APPB-000271
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)carbamate
In a 50mL reaction flask, tert-butyl trans-N- [3- (6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl) oxy-cyclobutyl ] carbamate (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) were added in sequence, sodium hydride (1.2 g,30 mmol) was added under stirring at room temperature, the reaction was stirred at 50℃for 3 hours after completion of the oil bath, and TLC monitored for completion of the reaction. Ethyl acetate (100 mL) was added under ice-water cooling, saturated aqueous ammonium chloride (50 mL) and water (50 mL) were added, and the organic layer was washed with saturated aqueous sodium chloride (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate (V/V) =5/1) to give 41B (0.75 g, yield: 96.1%).
And a second step of: 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)carbamate
In a 50mL 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 (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (171 mg,0.21 mmol) and dioxane/water (v/v=4/1, 15 mL) of the previous step were sequentially added, and after nitrogen substitution, the reaction was stirred at 90℃for 2 hours. Water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL. Times.2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate (V/V) =5/1-1/1) to give 41C (0.65 g, yield 84.5%).
And a third step of: trifluoroacetate salt of trans- (E) -N- (cyclopropylmethyl) -4- (dimethylamino) -N- (3- ((6- (4-hydroxyphenyl) -1H-indazol-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 acid
In a 50mL reaction flask, compound 41C (0.30 g,0.56 mmol) of the previous step, dichloromethane (3 mL), trifluoroacetic acid (3 mL) were added, the reaction was stirred at room temperature for 5 hours, TLC was monitored to complete the reaction, concentrated to dryness under reduced pressure, dichloromethane (3 mL), N, N-diisopropylethylamine (0.22 g,1.68 mmol) was added, and stirred for dissolution for use.
In a 50mL reaction flask, 4-N, N-dimethylaminocrotonic acid hydrochloride (0.13 g,0.78 mmol), methylene chloride (4 mL), and tripyrrolidinylphosphonium bromide hexafluorophosphate (0.34 g,0.73 mmol) were added dropwise to N, N-diisopropylethylamine (0.22 g,1.68 mmol), and the reaction was stirred at room temperature for 30 minutes; adding the reaction solution into the reaction solution of the previous operation under the cooling of ice water, and stirring at room temperature for reaction for 4 hours; TLC was monitored to completion, methylene chloride 10mL was added, the reaction solution was washed with saturated sodium hydrogencarbonate (20 mL. Times.3), the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (methylene chloride/methanol (V/V) =20/1), and the resulting compound was subjected to preparative HPLC (apparatus: waters 2767 preparation liquid phase; chromatographic column: sunFire@PrepC 18 (19 mm. Times.150 mm)), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid)) purification and lyophilized to give trifluoroacetate (51 mg, yield: 13.1%) of compound 41.
LCMS m/z＝461.3[M+H] +
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).
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-enamide
Figure PCTCN2021117545-APPB-000272
Figure PCTCN2021117545-APPB-000273
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]carbamate
In a 50mL reaction flask, tert-butyl trans-N- [3- (6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl) oxy-cyclobutyl ] carbamate (1C) (0.4 g,0.86 mmol), dimethyl sulfoxide (10 mL) and sodium hydride (0.17 g,4.3mmol,60 wt%) were successively added, and after the addition, the mixture was stirred at 25℃for 10 minutes, 2-bromoethylbenzyl ether (0.55 g,2.58 mmol) was added, and the mixture was heated to 50℃and reacted for 2 hours with stirring. Cooled to room temperature, quenched with 1mL of water, ethyl acetate (50 mL) was added to the reaction solution, which was then washed with water (30 ml×1) and then saturated brine (30 ml×1), the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether (V/V) =1/20-1/5) to give 42A crude product (0.53 g).
And a second step of: trans-tert-butyl N- (2- (benzyloxy) ethyl) -N- [3- [ (6- (4-hydroxyphenyl) -1- (tetrahydro-2H-pyran-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]carbamate
In a 50mL reaction flask, 42A (0.53 g), 4-hydroxyphenylboronic acid (0.16 g,1.14 mmol), potassium phosphate heptahydrate (0.77 g,2.28 mmol), a [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (73 mg,0.089 mmol) and dioxane/water (v/v=4/1, 10 mL) of the above-mentioned were successively added, and after three substitutions of nitrogen, the reaction was stirred at 90℃for 2 hours. Water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL. Times.2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate/petroleum ether (V/V) =1/10-1/1) to give 42B (0.4 g, two-step yield 74%).
LCMS m/z＝614.4[M+H] +
And a third step of: 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]carbamate
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 stirred overnight at room temperature. Filtration and concentration of the filtrate under reduced pressure gave 42C (0.3 g, 88% yield).
LCMS m/z＝524.3[M+H] +
Fourth step: 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-enamide
In a 50mL reaction flask, compound 42C (0.14 g,0.27 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 4 mL) were added, and then the reaction was stirred at 35℃for 3 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was washed with methyl tert-butyl ether (10 mL. Times.3), concentrated to dryness under reduced pressure, dissolved in 5mL of acetonitrile, and stirred for 10min with diisopropylethylamine (0.35 g,2.7 mmol) added.
To a mixed solution of trans-4-dimethylaminocrotonic acid hydrochloride (0.044 g,0.27 mmol) and diisopropylethylamine (83 mg,0.64 mmol) in dichloromethane (5 mL) and acetonitrile (5 mL), tripyrrolidinylphosphonium bromide hexafluorophosphate (0.126 g,0.27 mmol) was added and stirred at room temperature for 20 minutes. The reaction solution was slowly added dropwise to the acetonitrile solution for use in the previous step, and stirring was continued for 1 hour. 10mL of saturated aqueous sodium bicarbonate was added, 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) =50/1/0.5-25/1/0.25) to give compound 42 (15 mg, yield: 13%).
LCMS m/z＝451.3[M+H] +
1 H NMR(400MHz,CD 3 OD)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).
Example 43: trans- (E) -4- (dimethylamino) -N- (3- ((6- (4-hydroxyphenyl) -1H-indazol-4-yl) oxy) cyclobutyl) -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-enamide
Figure PCTCN2021117545-APPB-000274
Figure PCTCN2021117545-APPB-000275
The first step: trans- (3- ((6-bromo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) cyclobutyl) (3-methoxypropyl) carbamic acid tert-butyl ester (43A)
trans-tert-butyl(3-((6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)(3-methoxypropyl)carbamate
Compound 1C (0.600 g,1.29 mmol) was weighed and dissolved in a 100mL single neck round bottom flask with dimethyl sulfoxide (25 mL), sodium hydride (155 mg,3.87 mmol) was weighed and added to the reaction flask, 3-bromopropyl methyl ether (0.328 g,2.14 mmol) and anhydrous sodium iodide (16 mg,0.11 mmol) were added, and the mixture was heated to 50℃and stirred for reaction for 1 hour. The reaction solution was added dropwise to a 250mL single neck round bottom flask containing saturated aqueous ammonium chloride (60 mL), water (30 mL) was added after the addition, extraction was performed with ethyl acetate (50 ml×3), and the organic phases were combined, washed once with water (50 mL) and saturated brine (50 mL) in this order, 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] +
And a second step of: trans- (3- ((6-bromo- (4-hydroxyphenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) cyclobutyl) (3-methoxypropyl) carbamic acid tert-butyl ester (43B)
trans-tert-butyl(3-((6-(4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)(3-methoxypropyl)carbamate
43A (0.675 g,1.25 mmol), 4-hydroxy-2-methylphenylboronic acid (0.26 g,1.88 mmol), potassium phosphate heptahydrate (2.457 g,6.25 mmol), [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (152 mg,0.188 mmol) and dioxane/water (v/v=4/1, 25 mL) were sequentially added to a 50mL reaction flask, and after three nitrogen substitutions, the reaction was stirred at 90℃for 2 hours. Water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL. Times.2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography to give 43B (0.64 g, yield 92.81%).
LCMS m/z＝552.3[M+H] +
And a third step of: trans- (E) -4- (dimethylamino) -N- (3- ((6- (4-hydroxyphenyl) -1H-indazol-4-yl) oxy) cyclobutyl) -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-enamide
In a 50mL reaction flask, compound 43B (0.64 g,1.16 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 14 mL) were added, and then 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 methyl tert-butyl ether (10 mL. Times.3), concentrated to dryness under reduced pressure, dissolved in 10mL of acetonitrile, and stirred for 10min with diisopropylethylamine (0.367 g,2.84 mmol) added.
To a mixed solution of trans-4-dimethylaminocrotonic acid hydrochloride (0.193 g,1.16 mmol) and diisopropylethylamine (0.367 mg,2.84 mmol) in dichloromethane (10 mL) and acetonitrile (10 mL), tripyrrolidinylphosphonium bromide hexafluorophosphate (0.541 g,1.16 mmol) was added and stirred at room temperature for 20 minutes. The reaction solution is slowly dropped into the last oneAnd (3) in the acetonitrile solution to be used, stirring for 1h. After addition of 20mL of saturated aqueous sodium bicarbonate, 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) =50/1/0.5-25/1/0.25) to give compound 43 (284 mg, yield: 51.16%).
LCMS m/z＝479.3[M+H] +
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).
Example 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-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-enamide
Figure PCTCN2021117545-APPB-000276
The first step: trans- (3- ((6- (2-ethyl-5-fluoro-4-hydroxyphenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) cyclobutyl) (2-methoxyethyl) carbamic acid tert-butyl ester (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)carbamate
In a 100mL reaction flask, compound 34A (0.52 g,1.0 mmol), 5-ethyl-2-fluoro-4- (4, 5-tetramethyl-1, 3-dioxolan-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 complex (82 mg,0.1 mmol) and dioxane/water (v/v=4/1, 10 mL) were sequentially added, and after three substitutions of nitrogen, the reaction was stirred at 90℃for 2 hours. Water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL. Times.2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and 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, yield 77%).
LCMS m/z＝584.3[M+H] +
And a second step of: trans- (E) -4- (dimethylamino) -N- ((3- ((6- (2-ethyl-5-fluoro-4-hydroxyphenyl) -1H-indazol-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-enamide
In a 50mL reaction flask, compound 44A (0.2 g,0.34 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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 methyl tert-butyl ether (10 mL. Times.3), concentrated to dryness under reduced pressure, dissolved in 5mL of acetonitrile, and stirred for 10min with diisopropylethylamine (0.266 g,2.06 mmol) added.
To a solution of trans-4-dimethylaminocrotonic acid hydrochloride (0.057 g,0.34 mmol) and diisopropylethylamine (132 mg,1.02 mmol) in a mixture of dichloromethane (15 mL) and acetonitrile (5 mL), tripyrrolidinylphosphonium bromide hexafluorophosphate (0.1599 g,0.34 mmol) was added and stirred at room temperature for 20 minutes. The reaction solution was slowly added dropwise to the above acetonitrile solution to be used, and stirring was continued for 1 hour. 30mL of saturated aqueous sodium bicarbonate solution was added to the mixture to alkalize the mixture, 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) =50/1/0.5-25/1/0.25) to give compound 44 (60 mg, yield: 35%).
LCMS m/z＝511.3[M+H] +
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).
Example 45: acetate salt of 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)
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 acid
Figure PCTCN2021117545-APPB-000277
Figure PCTCN2021117545-APPB-000278
The first step: 5- (chloromethyl) -1-methyl-1H-imidazole (45B)
5-(chloromethyl)-1-methyl-1H-imidazole
In a 50mL reaction flask, (1-methyl-1H-imidazol-5-yl) methanol (45A) (112 mg,1 mmol) and thionyl chloride (10 mL) were sequentially added, and the mixture was stirred at 60℃for 2 hours, and concentrated under reduced pressure to give a 45B crude product (130 mg) which was directly used in the next reaction.
1 H NMR(400MHz,DMSO-d6)δ9.26(s,1H),7.84(s,1H),5.04(s,2H),3.89(s,3H).
And a second step of: trans-tert-butyl (-3- ((6-bromo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) cyclobutyl) ((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)carbamate
In a 50mL reaction flask, tert-butyl trans-N- [3- (6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl) oxy-cyclobutyl ] carbamate (1C) (0.3 g,0.65 mmol), tetrahydrofuran (50 mL) and sodium hydride (0.28 g,7.05mmol,60 wt%) were successively added, and after the addition, the mixture was stirred at 25℃for 30 minutes, 5- (chloromethyl) -1-methyl-1H-imidazole (45B) (130 mg) was slowly added dropwise and the mixture was stirred at room temperature for 1.2H. Ethyl acetate (50 mL) was added to the reaction solution, which was then washed with water (30 ml×1) and then with saturated brine (30 ml×1), and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (PE/ea=1/1) to give 45C (0.26 g, yield 72%).
And a third step of: 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)carbamate
In a 50mL 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), a [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (20 mg,0.024 mmol) and dioxane/water (v/v=4/1, 10 mL) were sequentially added, and after three substitutions of nitrogen, the reaction was stirred at 90℃for 2 hours. To the reaction solution was added water (50 mL), followed by extraction with ethyl acetate (50 ml×2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and 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, yield 56.7%).
LCMS m/z＝574.3[M+H] +
Fourth step: acetate salt of 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)
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 acid
In a 50mL reaction flask, 45D (0.12 g,0.21 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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 methyl tert-butyl ether (10 mL. Times.3), concentrated to dryness under reduced pressure, dissolved in 5mL of acetonitrile, and stirred for 10min with diisopropylethylamine (0.35 g,2.7 mmol) added.
To a mixed solution of trans-4-dimethylaminocrotonic acid hydrochloride (0.041 g,0.25 mmol) and diisopropylethylamine (83 mg,0.64 mmol) in dichloromethane (5 mL) and acetonitrile (5 mL), tripyrrolidinylphosphonium bromide hexafluorophosphate (0.12 g,0.25 mmol) was added and stirred at room temperature for 20 minutes. The reaction solution was slowly added dropwise to the above acetonitrile solution to be used, and stirring was continued for 1 hour. 10mL of saturated aqueous sodium bicarbonate solution was added to the mixture to alkalize the mixture, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by separation to give a liquid phase (apparatus: waters 2767; column: sunFire@PrepC18 (19 mM. Times.150 mM)), a mobile phase (mobile phase A: acetonitrile mobile phase B: water (containing 5mM ammonium acetate)), and then lyophilized to give an acetate salt of Compound 45 (23 mg, yield 19.6%).
LCMS m/z＝501.2[M+H] +
Example 46: cis-N- (2- (dimethylamino) ethyl) -2-fluoro-N- (3- ((6- (4-hydroxyphenyl) -1H-indazol-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)acrylamide
Figure PCTCN2021117545-APPB-000279
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)carbamate
In a 50mL reaction flask, cis-N- [3- (6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl) oxy-cyclobutyl ] carbamic acid tert-butyl ester (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,30.8mmol,60 wt%) were successively added, and after the addition, the mixture was stirred at 25℃for 10 minutes, 2-chloroethyl dimethylamine (0.66 g,6.16 mmol) was added, and the temperature was raised to 50℃and the mixture was stirred for 3 hours. Cooled to room temperature, quenched with 1mL of water, ethyl acetate (50 mL) was added to the reaction solution, which was then washed with water (30 ml×1) and then saturated brine (30 ml×1), the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM/MeOH (V/V) =100/0-100/5) to give 46A (0.48 g, yield: 58%).
LCMS m/z＝537.1/539.1[M+H] +
And a second step of: 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]carbamate
In a 50mL reaction flask, 46A (0.48 g,0.89 mmol), 4-hydroxyphenylboronic acid (0.18 g,1.33 mmol), potassium phosphate heptahydrate (0.9 g,2.67 mmol), a [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (73 mg,0.089 mmol) and dioxane/water (v/v=4/1, 10 mL) were successively added, and after three substitutions of nitrogen, the reaction was stirred at 90℃for 2 hours. Water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL. Times.2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM/MeOH (V/V) =100/0-100/5) to give 46B (0.49 g, yield 98%).
LCMS m/z＝551.4[M+H] +
And a third step of: cis-N- (2- (dimethylamino) ethyl) -2-fluoro-N- (3- ((6- (4-hydroxyphenyl) -1H-indazol-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)acrylamide
In a 50mL reaction flask, compound 46B (0.14 g,0.25 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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 methyl tert-butyl ether (10 mL. Times.3), concentrated to dryness under reduced pressure, dissolved in 5mL of acetonitrile, and stirred for 10min with diisopropylethylamine (0.35 g,2.7 mmol) added.
To a mixed solution of 2-fluoroacrylic acid (0.029 g,0.32 mmol) and diisopropylethylamine (83 mg,0.64 mmol) in dichloromethane (5 mL) and acetonitrile (5 mL), tripyrrolidinylphosphonium bromide hexafluorophosphate (0.15 g,0.32 mmol) was added and stirred at room temperature for 20min. The reaction solution was slowly added dropwise to the above acetonitrile solution to be used, and stirring was continued for 1 hour. 10mL of saturated aqueous sodium bicarbonate was added, 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) =50/1/0.5-25/1/0.25) to give compound 46 (58 mg, yield: 57%).
LCMS m/z＝439.1[M+H] +
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).
Example 47: trifluoroacetate salt of 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 (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-enamide；trifluoroacetic acid
Figure PCTCN2021117545-APPB-000280
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]carbamate
In a 50mL reaction flask, 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-dioxaborolan-2-yl) phenol (0.17 g,0.65 mmol), potassium phosphate heptahydrate (0.55 g,1.62 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (44 mg,0.054 mmol) and dioxane/water (v/v=4/1, 10 mL) were sequentially added, and after three substitutions of nitrogen, the reaction was stirred at 90℃for 2 hours. Water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL. Times.2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM/MeOH (V/V) =100/0-100/5) to give 47A (0.3 g, yield 98%).
LCMS m/z＝597.3[M+H] +
And a second step of: trifluoroacetate salt of 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 (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-enamide；trifluoroacetic acid
In a 50mL reaction flask, compound 47A (0.14 g,0.23 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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 methyl tert-butyl ether (10 mL. Times.3), concentrated to dryness under reduced pressure, dissolved in 5mL of acetonitrile, and stirred for 10min with diisopropylethylamine (0.35 g,2.7 mmol) added.
To a mixed solution of 2-fluoroacrylic acid (0.021 g,0.23 mmol) and diisopropylethylamine (60 mg,0.46 mmol) in dichloromethane (5 mL) and acetonitrile (5 mL), tripyrrolidinylphosphonium bromide hexafluorophosphate (0.11 g,0.24 mmol) was added and stirred at room temperature for 20min. The reaction solution was slowly added dropwise to the above acetonitrile solution to be used, and stirring was continued for 1 hour. 10mL of saturated aqueous sodium hydrogencarbonate solution was added, the organic layer was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative HPLC (instrument: waters 2767 for preparing liquid phase; column: sunFire@PrepC18 (19 mm. Times.150 mm)), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid)) to obtain trifluoroacetate salt of compound 47 (20 mg, yield: 12%) by freeze-drying.
LCMS m/z＝485.2[M+H] +
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).
Example 47-1: 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 (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-enamide
In a 50mL reaction flask, 47A (0.18 g,0.30 mmol) and methylene chloride/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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 methyl tert-butyl ether (10 mL. Times.3), concentrated to dryness under reduced pressure, dissolved in 5mL of acetonitrile, and stirred for 10min with diisopropylethylamine (0.35 g,2.7 mmol) added.
To a mixed solution of 2-fluoroacrylic acid (0.027 g,0.30 mmol) and diisopropylethylamine (77 mg,0.60 mmol) in dichloromethane (5 mL) and acetonitrile (5 mL), tripyrrolidinylphosphonium bromide hexafluorophosphate (0.14 g,0.30 mmol) was added and stirred at room temperature for 20min. The reaction solution was slowly added dropwise to the above acetonitrile solution to be used, and stirring was continued for 1 hour. 10mL of saturated aqueous sodium bicarbonate was added, 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)，Compound 47 (35 mg, yield: 24%) was obtained.
LCMS m/z＝485.2[M+H] +
1 H 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).
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)acrylamide
Figure PCTCN2021117545-APPB-000281
The first step: 4-nitrophenyl-2-fluoroacrylate (48A)
4-nitrophenyl 2-fluoroacrylate
In a 100mL reaction flask, 2-fluoroacrylic acid (1.00 g,11.10 mmol) was dissolved in N, N-dimethylformamide (15 mL), 4-nitrophenol (1.85 g,13.33 mmol) and 1-hydroxybenzotriazole (1.50 g,11.10 mmol) were added, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3.20 g,16.64 mmol) was added at room temperature, and stirred for 4 hours. Water (30 mL) and methylene chloride (40 mL. Times.2) were added to extract, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to give 48A (1.5 g, yield: 64.10%).
LCMS m/z＝212.1[M+H] +
And a second step of: 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)acrylamide
In a 50mL reaction flask, 1D (0.401 g,0.84 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 20 mL) were added, and then the reaction was stirred at room temperature for 5 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was washed with methyl tert-butyl ether (10 mL. Times.3), concentrated to dryness under reduced pressure, dissolved in 20mL of acetonitrile, and reacted with 48A (0.282 g,1.34 mmol) and triethylamine (0.282 g,5.76 mmol) at room temperature under stirring for 1 hour. Saturated aqueous sodium hydrogencarbonate (20 mL) was added to quench, ethyl acetate (20 mL) was added to extract, and the aqueous phase was extracted with dichloromethane (40X 2 mL), and the organic phases 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 give compound 48 (130 mg, yield: 39.76%).
LCMS m/z＝368.1[M+H] +
1 H NMR(400MHz,CD 3 OD)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).
Example 49: trifluoroacetate salt of trans-2-fluoro-N- (2-hydroxyethyl) -N- [3- [ (6- (4-hydroxyphenyl) -1H-indazol-4-yl) oxy ] 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 acid
Figure PCTCN2021117545-APPB-000282
In a 50mL reaction flask, compound 42C (0.18 g,0.34 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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 methyl tert-butyl ether (10 mL. Times.3), concentrated to dryness under reduced pressure, dissolved in 5mL of acetonitrile, and stirred for 10min with diisopropylethylamine (0.35 g,2.7 mmol) added.
To a mixed solution of 2-fluoroacrylic acid (0.030 g,0.34 mmol) and diisopropylethylamine (83 mg,0.68 mmol) in dichloromethane (5 mL) and acetonitrile (5 mL), tripyrrolidinylphosphonium bromide hexafluorophosphate (0.16 g,0.34 mmol) was added and stirred at room temperature for 20min. The reaction solution was slowly added dropwise to the above acetonitrile solution to be used, and stirring was continued for 1 hour. 10mL of saturated aqueous sodium hydrogencarbonate solution was added, the organic layer was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative HPLC (instrument: waters 2767 for preparing liquid phase; column: sunFire@PrepC18 (19 mm. Times.150 mm)), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid)), and lyophilized to give trifluoroacetate salt of compound 49 (9 mg, yield: 5%).
LCMS m/z＝412.2[M+H] +
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).
Example 50: acetate salt of trans- (E) -N- ((3- ((6- (4-hydroxyphenyl) -1H-indazol-4-yl) oxy) cyclobutyl) -4- ((2-methoxyethyl) (methyl) amino) -2-enamide (Compound 50)
trans-(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
The first step: (E) -4- (((2-methoxyethyl) (methyl) amino) but-2-enoic acid ester (50B)
methyl(E)-4-((2-methoxyethyl)(methyl)amino)but-2-enoate
E-4-bromo-2-butenoic acid methyl ester (1.8 g,10 mmol), triethylamine (1.01 g,10 mmol) were dissolved in tetrahydrofuran (50 ml), and 2-methoxy-N-methylethyl-1-amine (780 mg,10 mmol) was slowly added dropwise at room temperature, and the mixture was stirred at room temperature for 2 hours. 20mL of water and 20mL of ethyl acetate were added to extract, and the organic layer was washed once with 20mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude 50B product (1.87 g) which was used directly in the next step.
And a second step of: (E) Hydrochloride of 4- (((2-methoxyethyl) (methyl) amino) but-2-enoic acid (50C)
(E)-4-((2-methoxyethyl)(methyl)amino)but-2-enoic acid；hydrochloric acid
Compound 50B (1.8 g) was dissolved in a mixed solvent of methanol (9 mL) and water (3 mL), and solid potassium hydroxide (1.31 g,23.36 mmol) was added thereto and stirred at room temperature for 2h. The pH was adjusted to 5-6 with concentrated hydrochloric acid, concentrated under reduced pressure, the residue was dissolved by adding methylene chloride/methanol (V/V=10/1, 20 mL), filtered, 3N hydrogen chloride/ethyl acetate solution was added to the filtrate 5mL, the filtrate was concentrated under reduced pressure, the residue was slurried with ethyl acetate/acetonitrile (20 mL, V/V=1/1), filtered, and the cake was dried under reduced pressure to give 50C hydrochloride (1.05 g, yield: 50%).
And a third step of: acetate salt of trans- (E) -N- ((3- ((6- (4-hydroxyphenyl) -1H-indazol-4-yl) oxy) cyclobutyl) -4- ((2-methoxyethyl) (methyl) amino) -2-enamide (Compound 50)
trans-(E)-N-(3-((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)cyclobutyl)-4-((2-methoxyethyl)(methyl)amino)but-2-enamide；acetic acid
In a 50mL reaction flask, tert-butyl trans-N- [3- [6- (4-hydroxyphenyl) -1-tetrahydropyran-2-yl-indazol-4-yl ] oxetan ] carbamate (1D) (0.27 g,0.56 mmol) and methylene chloride/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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. Times.3), and then concentrated to dryness under reduced pressure. To the resulting residue was added sequentially 50C hydrochloride (117 mg,0.56 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.216 g,1.13 mmol), 1-hydroxybenzotriazole (0.098 g,0.73 mmol) and N, N-dimethylformamide (40 mL), and after the addition was completed, the mixture was stirred at room temperature for 10 minutes, and N, N-diisopropylethylamine (0.45 g,3.48 mmol) was added, and after the addition was completed, the mixture was stirred at room temperature for 50 minutes. To the reaction solution was added saturated sodium hydrogencarbonate (50 mL), followed by extraction with methylene chloride/methanol (v/v=10/1) (50 ml×2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by separation to give acetate (53 mg, yield 18.5%) of compound 50 by preparing a liquid phase (instrument: waters 2767, liquid phase; column: sunfire@prep C18 (19 mm×150 mM), mobile phase composition: mobile phase a: acetonitrile mobile phase B: water (containing 5mM ammonium acetate)).
LCMS m/z＝451.3[M+H] + ；
1 H NMR(400MHz,CD 3 OD)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).
Example 51: acetate salt of trans- (E) -N- ((3- ((6- (4-hydroxyphenyl) -1H-indazol-4-yl) oxy) cyclobutyl) -N-methyl-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 acid
Figure PCTCN2021117545-APPB-000284
In a 50mL reaction flask, trans-N- [3- [6- (4-hydroxyphenyl) -1-tetrahydropyran-2-yl-indazol-4-yl ] oxetanyl ] -N-methyl-carbamic acid tert-butyl ester (7B) (0.071 g,0.132 mmol) and methylene chloride/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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. Times.3), and then concentrated to dryness under reduced pressure.
In a 50mL reaction flask, (2E) -3- [ ((2S) -1-methylpyrrolidin-2-yl ] prop-2-enoic acid (26C) hydrochloride (22.5 mg,0.145 mmol), 6-chlorobenzotriazol-1, 3-tetramethylurea hexafluorophosphate (0.071 g,0.172 mmol) and DMF (10 mL) were added, after the addition was completed, stirring at room temperature for 30 minutes, then DMF (5 mL) of the residue obtained from the previous operation was added, after the addition was stirred at room temperature for 10 minutes, N-diisopropylethylamine (0.102 g,0.79 mmol) was added, after the addition was completed, stirring at room temperature for 50 minutes the reaction mixture was added with saturated sodium bicarbonate (50 mL), then extracted with dichloromethane/methanol (50 mL. Times.2), the combined organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was passed through to prepare a liquid phase (instrument: waters 2767; chromatography column SunFire@PrepC18 (19 mM. Times.150 mM), mobile phase composition: mobile phase A: acetonitrile mobile phase B: water (5 mM ammonium acetate)), separation and purification followed by lyophilization afforded the acetate salt of compound 51 (15.3 mg, 21% yield).
LCMS m/z＝447.1[M+H] + ；
1 H NMR(400MHz,CD 3 OD)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).
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-enamide
Figure PCTCN2021117545-APPB-000285
The first step: (E) -methyl 4- (pyrrolidin-1-yl) but-2-enoate (52A)
methyl(E)-4-(pyrrolidin-1-yl)but-2-enoate
Into a 50mL reaction flask, tetrahydropyrrole (1.4 g,20 mmol) and methylene chloride (20 mL) were added in this order, 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, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol (V/V) =20/1) to give 52A (1.1 g, yield 65.0%).
And a second step of: (E) Hydrochloride of (E) -4- (pyrrolidin-1-yl) but-2-enoic acid (52B)
(E)-4-(pyrrolidin-1-yl)but-2-enoic acid；HCl
In a 50mL reaction flask, (E) -methyl 4- (pyrrolidin-1-yl) but-2-enoate (52A) (1.1 g,6.50 mmol) and tetrahydrofuran (10 mL) were added sequentially, lithium hydroxide monohydrate (0.55 g,13 mmol) and water (2 mL) were added with stirring, and the reaction was stirred at room temperature for 2 hours. The reaction solution is dripped into 1N hydrochloric acid to adjust the pH value to 2-3, and the reaction solution is concentrated to dryness under reduced pressure and directly used for the next step.
And a third step of: 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-enamide
In a 50mL reaction flask, tert-butyl trans-N- [3- [6- (4-hydroxyphenyl) -1-tetrahydropyran-2-yl-indazol-4-yl ] oxetanyl ] -N-methyl-carbamate (7B) (0.30 g,0.61 mmol), methylene chloride (3 mL), trifluoroacetic acid (3 mL) were added, the reaction was stirred at room temperature for 5 hours, TLC was monitored for completion, concentrated to dryness under reduced pressure, methylene chloride (3 mL) and N, N-diisopropylethylamine (0.23 g,1.83 mmol) were added, and stirred for dissolution for use.
In a 50mL reaction flask, hydrochloride (0.13 g) of (E) -4- (pyrrolidin-1-yl) but-2-enoic acid (52B), methylene chloride (4 mL), and tripyrrolidinyl phosphonium bromide hexafluorophosphate (0.37 g,0.79 mmol) were added dropwise to N, N-diisopropylethylamine (0.23 g,1.83 mmol), and the reaction was stirred at room temperature for 30 minutes; adding the reaction solution into the reaction solution of the previous operation under the cooling of ice water, and stirring at room temperature for reaction for 4 hours; TLC was monitored to completion, methylene chloride 10mL was added, the reaction solution was washed with saturated sodium hydrogencarbonate (20 mL. Times.3), the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (methylene chloride/methanol (V/V) =20/1), the resulting compound was prepared by HPLC (apparatus: waters 2767 preparation liquid phase; chromatographic column: sunFire@PrepC 18 (19 mm. Times.150 mm)), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid)) was purified, the preparation was treated with saturated aqueous sodium hydrogencarbonate solution, methylene chloride was extracted, and after concentrating the organic phase, a small amount of water and methanol was added to freeze-dry to give compound 52 (40 mg, yield: 14.7%).
LCMS m/z＝447.1[M+H] +
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).
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-enamide
Figure PCTCN2021117545-APPB-000286
The first step: trans-N-methyl-N- [3- [ (6- (4-hydroxyphenyl) imidazo [1,5-a ] pyridin-8-yl) oxy ] cyclobutyl ] carbamic acid tert-butyl ester (53A)
trans-tert-butyl N-methyl-N-[-3-[(6-(4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy]cyclobutyl]carbamate
In a 50mL 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), a [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (82 mg,0.1 mmol) and dioxane/water (v/v=4/1, 10 mL) were sequentially added, and after three substitutions of nitrogen, the reaction was stirred at 90℃for 2 hours. Water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL. Times.2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and 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, yield 98%).
And a second step of: 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-enamide
In a 50mL reaction flask, compound 53A (0.15 g,0.37 mmol) and dichloromethane/trifluoroacetic acid (v/v=2/1, 10 mL) were added, and then the reaction was stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, 5mL of dichloromethane was added to dissolve, diisopropylethylamine (0.35 g,2.7 mmol) and acryloyl chloride (33 mg,0.37 mmol) were added sequentially under ice-bath, after stirring at this temperature for 30min, 10mL of saturated aqueous sodium bicarbonate solution and 10mL of dichloromethane were added to extract, and 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 give compound 53 (0.3 g, yield 23%).
LCMS m/z＝364.2[M+H]+
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).
Example 54: trifluoroacetate salt of trans- (E) -4- (dimethylamino) -N- (3- ((6- (2-chloro-4-hydroxyphenyl) -1H-indazol-4-yl) 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 acid
Figure PCTCN2021117545-APPB-000287
The first step: trans- (3- ((6- (2-chloro-4-hydroxyphenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) cyclobutyl) (methyl) carbamic acid tert-butyl ester (54A)
trans-tert-butyl(3-((6-(2-chloro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)cyclobutyl)(methyl)carbamate
In a 50mL reaction flask, 7A (0.48 g,1.00 mmol), 2-chloro-4-hydroxyphenylboronic acid (0.19 g,1.10 mmol), potassium phosphate heptahydrate (1.02 g,3.00 mmol), [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (120 mg,0.15 mmol) and dioxane/water (v/v=4/1, 20 mL) were sequentially added, and after three substitutions of nitrogen, the reaction was stirred at 90℃for 2 hours. Water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL. Times.2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and 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, yield 96.58%).
LCMS m/z＝528.2[M+H] +
And a second step of: trifluoroacetate salt of trans- (E) -4- (dimethylamino) -N- (3- ((6- (2-chloro-4-hydroxyphenyl) -1H-indazol-4-yl) 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 acid
In a 50mL reaction flask, compound 54A (0.51 g,0.97 mmol) and dichloromethane/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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 methyl tert-butyl ether (10 mL. Times.3), concentrated to dryness under reduced pressure, dissolved in 10mL of acetonitrile, and stirred for 10min with diisopropylethylamine (0.367 g,2.84 mmol) added.
To a solution of trans-4-dimethylaminocrotonic acid hydrochloride (0.165 g,1.00 mmol) and diisopropylethylamine (0.367 mg,2.84 mmol) in a mixture of dichloromethane (10 mL) and acetonitrile (10 mL), tripyrrolidinylphosphonium bromide hexafluorophosphate (0.463 g,1.00 mmol) was added and stirred at room temperature for 20 minutes. The reaction solution was slowly added dropwise to the acetonitrile solution for use in the previous step, and stirring was continued for 1 hour. 20mL of saturated aqueous sodium hydrogencarbonate solution was added to the mixture to alkalize the mixture, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to preparative HPLC (apparatus: waters 2767 for preparing a liquid phase; column: sunFire@PrepC18 (19 mm. Times.150 mm)), and the mobile phase consisted of mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid)) to purify the mixture, followed by lyophilization to give trifluoroacetate of compound 54 (81 mg, yield: 14.99%).
LCMS m/z＝455.2[M+H] +
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).
Example 55: trifluoroacetate salt of 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)
trans-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
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]carbamate
In a 50mL reaction flask, 23A (0.29 g,0.54 mmol), 3-methyl-4- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol (0.15 g,0.65 mmol), potassium phosphate heptahydrate (0.55 g,1.62 mmol), [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (44 mg,0.054 mmol) and dioxane/water (v/v=4/1, 10 mL) were sequentially added, and after three substitutions of nitrogen, the reaction was stirred at 90℃for 2 hours. Water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL. Times.2), and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM/MeOH (V/V) =100/0-100/5) to give 55A (0.29 g, yield 98%).
LCMS m/z＝565.3[M+H] +
And a second step of: trifluoroacetate salt of 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)
trans-N-(2-(dimethylamino)ethyl)-2-fluoro-N-[3-[(6-(4-hydroxy-2-methylphenyl)-1H-indazol-4-yl)oxy]cyclobutyl]prop-2-enamide；trifluoroacetic acid
In a 50mL reaction flask, 55A (0.14 g,0.25 mmol) and methylene chloride/trifluoroacetic acid (v/v=1/1, 10 mL) were added, and then 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 methyl tert-butyl ether (10 mL. Times.3), concentrated to dryness under reduced pressure, dissolved in 5mL of acetonitrile, and stirred for 10min with diisopropylethylamine (0.35 g,2.7 mmol) added.
To a mixed solution of 2-fluoroacrylic acid (0.023 g,0.25 mmol) and diisopropylethylamine (60 mg,0.46 mmol) in dichloromethane (5 mL) and acetonitrile (5 mL), tripyrrolidinylphosphonium bromide hexafluorophosphate (0.12 g,0.25 mmol) was added and stirred at room temperature for 20min. The reaction solution was slowly added dropwise to the above acetonitrile solution to be used, and stirring was continued for 1 hour. 10mL of saturated aqueous sodium hydrogencarbonate solution was added, the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by preparative HPLC (instrument: waters 2767 for preparing a liquid phase; column: sunFire@PrepC18 (19 mm. Times.150 mm)), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid)), to give trifluoroacetate salt of compound 55 (30 mg, yield: 27%).
LCMS m/z＝453.3[M+H] +
1 H NMR(400MHz,CD 3 OD)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).
Biological test case
Test example 1: inhibitory Activity against JAK1, JAK2, JAK3, TYK2 kinases
Detection was performed using the HTRF KinEASE-TK kit (cat# 62TK0 PEC) from Cisbio, as follows:
diluting the compound with 1 Xkinase buffer to a final concentration of 2.5 times; enzymes JAK1, JAK2, JAK3 and Tyk2 (Carna; 08-144, 08-045, 08-046 and 08-147) were diluted to 15. Mu.g/mL, 0.185. Mu.g/mL, 1.665. Mu.g/mL and 5. Mu.g/mL, respectively; ATP was diluted to 19.6. Mu.M (JAK 1), 19.8. Mu.M (JAK 2), 7.15. Mu.M (JAK 3) and 25.3. Mu.M (Tyk 2), respectively; TK Substrate-biotin stock was diluted to 10. Mu.M.
10. Mu.L kinase reaction was performed with 1 Xkinase buffer: after incubation at room temperature for 2 hours (JAK 1), 30 minutes (JAK 2 and JAK 3) or 50 minutes (Tyk 2) after addition of 5 μl of strepavidin-XL 665 (500 nM) and 5 μl of TK anti-cryptate (1×) for 1 hour, 5 μl of test compounds or positive 4 μl+tk Substrate-biotin 2 μl+enzyme 2 μl+atp 2 μl was mixed. The fluorescence values at 665nm and 620nm were measured by a microplate reader (PHERAstar FSX). Calculating a signal Ratio according to formula (1), calculating and analyzing IC using origin 9.2 50 。
Ratio＝[Signal 665]/[Signal 620]×10 4 (1)
The inhibitory activities of the compounds of the present invention, JAK1, JAK2, JAK3 and Tyk2 kinase, were measured by the above experiments, and the measured IC 50 The values are shown in Table 1 below.
TABLE 1 results of testing the inhibitory Activity of Compounds JAK1, JAK2, JAK3 and Tyk2 kinases
Figure PCTCN2021117545-APPB-000289
Figure PCTCN2021117545-APPB-000290
Figure PCTCN2021117545-APPB-000291
Conclusion: the compound provided by the invention has a selective inhibition effect on a JAK kinase family, has a good inhibition effect on JAK3 kinase, and has high selectivity on JAK3 kinase. Compounds 1, 6, 7, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19, 20, 24, 28, 29, 31Active IC for JAK3 of 32, 34, 35, 36, 37, 38, 39, 40, 41, 42, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 55 50 0.1-5 nM, active IC of Compounds 2, 3, 5, 14, 22, 23, 25, 26, 27, 30, 43, 54 against JAK3 50 5-10 nM.
Test example 2: IL-2 and anti-CD3 stimulation of hBMC secretion IFNgamma experiment
Peripheral blood of healthy volunteers was taken into an anticoagulant tube containing heparin sodium, and an equal volume of sterile PBS was added and thoroughly mixed to reduce blood viscosity and reduce erythrocyte aggregation. Ficoll (GE Healthcare; 17-1440-02) with a density of 1.077 was added to a 50mL centrifuge tube, and the diluted blood was then aspirated with a pipette and slowly added to the stratified liquid surface along the tube wall 1 cm above the stratified liquid surface (final volume ratio of peripheral blood, PBS to Ficoll 1:1). 400g, and centrifuging for 30min at room temperature, wherein the lifting rate is adjusted to be 1 during centrifugation. The mononuclear cells are inserted into a mononuclear cell layer along the periphery of the tube wall by a liquid-transferring gun, the mononuclear cells are sucked into another centrifuge tube, PBS with more than 5 times of volume is added, the mixture is centrifuged for 10min at 300g and room temperature (the lifting speed is adjusted to be 9), and the cells are washed twice. The supernatant was discarded, 1mL of complete medium (RPMI 1640+10% foetal calf serum+1×penicillin-streptomycin solution) was added to resuspend the cells and counted, and the cell density was adjusted to 4×10 6 /mL。
At 2X 10 per well 5 Individual cells (50. Mu.L) were plated in 96-well plates at 37℃with 5% CO 2 Incubation for 1h at 37℃and 5% CO was continued by adding 100. Mu.L/well of compound 2 Incubate for 1h under conditions. 50. Mu.L of IL-2 (R) was added to each well at a final concentration of 100ng/mL&D Systems; 202-IL-050) with anti-CD3 (BD Pharmingen;555329 At 37℃with 5% CO 2 Incubate under conditions for 24h. Centrifuge at 500g for 5min at 4℃and take 150. Mu.L of supernatant. Human ifnγ Quantikine ELISA kit (R&D Systems; SIF 50C) detects ifnγ concentration in supernatant and fits and calculates IC of compound using Origin 2019b 50 Values.
TABLE 2 results of Compounds for the inhibition of the secretion of IFNgamma by hBMC stimulated by IL-2 and anti-CD3
Numbering of compounds IC 50 (nM)
Compound 6 <100
Compound 13 11.7
Compound 24 <100
Compound 31 3.09
Acetate salt of Compound 37 10.8
Compound 38 <100
Trifluoroacetate salt of Compound 47 <100
Acetate salt of compound 50 <100
Compound 52 <100
Compound 53 19.7
Conclusion: the compound has good inhibition effect on hBMC secretion IFN gamma stimulated by IL-2 and anti-CD3, and the compound of the embodiment has inhibition effect IC on hBMC secretion IFN gamma stimulated by IL-2 and anti-CD3 50 <IC of 1. Mu.M, e.g., compounds 13, 31, 37 and 53 50 See table 2.
Test example 3: rat intestinal blood ratio experiment
3.1. Test animals: SD rats, 200-250g, male, 6-8 weeks old, 42 purchased from Chengdu laboratory animals Inc., production license number: SCXK 2020-030.
3.2. Experiment design:
Figure PCTCN2021117545-APPB-000292
intravenous administration vehicle: 5% DMA (N, N-dimethylacetamide) +5% Solutol (polyethylene glycol-15-hydroxystearate) +90% Saline (physiological saline); gastric lavage dosing vehicle: 0.5% MC (methyl cellulose)
Before and after administration, 0.1mL of isoflurane was anesthetized and collected via orbit, placed in an EDTAK2 centrifuge tube, centrifuged at 5000rpm at 4℃for 10min, and plasma was collected. Intravenous set blood collection time point: 0min,5min,0.25h,0.5h,1h,2h,4h,6h,8h and 24h; time point of blood collection for the lavage group: 1h,2h,4h,6h,8h and 24h; all plasma samples were stored at-80 ℃ prior to analytical testing.
Time point of collection of colonic tissue samples of the lavage group: 1h,2h,4h,6h,8h and 24h. The colon tissue is taken after the animal is bled and euthanized, the colon tissue is washed clean by normal saline, homogenized by 50% ice methanol according to the ratio of m/v=1:10, and stored in a refrigerator of-80 degrees for analysis.
TABLE 3 results of test compound rat intestinal blood ratio
Figure PCTCN2021117545-APPB-000293
Figure PCTCN2021117545-APPB-000294
Conclusion: the inventive example compounds showed good exposure in the rat colon, a high colon/plasma drug concentration (exposure) ratio, and the exposure and colon/plasma drug concentration (exposure) ratio were significantly better than WO 2019027960-compound 1.
Test example 4: intestinal blood ratio experiment in mice
4.1. Test animals: BALB/c mice, 25g, male, 6-8 weeks old, 90 purchased from Chengdu laboratory animals Inc., production license number: SCXK 2020-030.
4.2. Experiment design:
Figure PCTCN2021117545-APPB-000295
gastric lavage dosing vehicle: 0.5% MC (methyl cellulose)
Isoflurane was anesthetized before and after dosing to obtain 0.06mL of blood through the orbit, placed in an EDTAK2 centrifuge tube, centrifuged at 5000rpm at 4 ℃ for 10min, and plasma was collected. Blood collection time point: 2h,6h,8h,10h and 16h. All plasma samples were stored at-80 ℃ prior to analytical testing.
Time point of colon tissue sample collection in dosing group: 2h,6h,8h,10h and 16h. The colon tissue is taken after the animal is bled and euthanized, and the colon tissue is preserved by a refrigerator of-80 degrees after being homogenized by 50 percent methanol according to the ratio of m/v=1:9 after being cleaned by normal saline.
TABLE 4 results of test compound mice intestinal blood ratio
Figure PCTCN2021117545-APPB-000296
Conclusion: the inventive example compounds showed good exposure in the colon of mice and a high colon/plasma drug concentration (exposure) ratio.
Test example 5: IL-2/anti-CD3 induces STAT5 phosphorylation experiments in human PBMC cells
Peripheral blood of healthy volunteers was taken into an anticoagulant tube, which was thoroughly mixed with PBS and diluted 1:1. A proper amount of Ficoll is added to the bottom of a 10mL centrifuge tube (Greiner bio, cat # 163290), diluted blood is slowly added along the tube wall, centrifuged at 400 Xg for 30 minutes at room temperature, and after centrifugation, the mononuclear cells are aspirated and placed into another centrifuge tube, and 5 volumes of PBS are added. After centrifugation at 300 Xg for 10min at room temperature, the cells were washed twice. After the last centrifugation, the supernatant was discarded, and 1mL HBSS was added to resuspend the cells and counted. Dissolving the compound with DMSO to prepare a 10mM mother solution, and diluting with HBSS to 3 times of final concentration for standby; 4. Mu.L of cell fluid and 2. Mu.L of compound were added to each well of 384 well plates at 37℃with 5% CO 2 Incubation was carried out for 1 hour (blank wells and negative control wells plus 2. Mu.L of HBSS with 3% DMSO). mu.L of IL-2 (R) containing 400ng/mL was added&D, cat#202-IL-050) and 4. Mu.g/mL anti-CD3 (BD, cat# 555329) at 37℃with 5% CO 2 Incubate for 0.5 hours under conditions. The subsequent use of the p-STAT5 AlphaLisa kit (PE, cat#ALSU-PST5-B500) was tested as follows: 2 mu L of 5 Xlysate is added into each hole, the plates are sealed, and the mixture is vibrated for 10 minutes at a low speed; preparing a receptor mixed solution (comprising a reaction buffer solution 1, a reaction buffer solution 2, an activation buffer solution and receptor microbeads), adding 2.5 mu L of the receptor mixed solution into each hole, sealing a plate, vibrating for 2 minutes at a low speed in a dark place, and incubating for 1.5 hours at room temperature; preparing donor mixed solution (comprising dilution buffer and acceptor microbeads), adding 2.5 μl of donor mixed solution into each well, sealing plate, and shaking at low speed for 2 min under dark conditionIncubate at temperature for 1.5 hours. After detection with a BMG microplate reader (PHERAstar FSX), IC was obtained using a DoseResp function fit in Origin 9.2 software 50 Values.
TABLE 5 inhibitory Activity of Compounds IC for IL-2/anti-CD3 induction of STAT5 phosphorylation in human PBMC cells 50 Value of
Compounds of formula (I) IC 50 (nM)
Compound 37 <500
Conclusion: the compounds of the examples of the present invention have inhibitory activity against IL-2/anti-CD3 inducing STAT5 phosphorylation in human PBMC cells.

Claims (12)

  1. A compound selected from the group consisting of a compound of formula (I) or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
    Figure PCTCN2021117545-APPB-100001
    Y 1 、Y 2 、Y 3 Each independently selected from CH or N;
    ring A is selected from 5 to 6 membered heterocyclic or heteroaromatic rings optionally further substituted with 0 to 3R a Substituted by substituents, said heterocyclic or heteroaromatic ring containingFrom 1 to 4 heteroatoms selected from O, S, N;
    R a 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 Carbocycle or- (CH) 2 ) q -3 to 12 membered heterocycle, said CH 2 Optionally further substituted with 0 to 4 groups selected from H, halogen, CF 3 OH, cyano, COOH, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with an alkoxy substituent, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
    ring B is selected from C 3-10 Carbocycles, said carbocycles optionally being further substituted with 0 to 4R b Substitution;
    R b each independently selected from H, halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0 to 4 groups selected from H, halogen, CF 3 OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy or C 3-8 Substituted cycloalkyl;
    L 1 selected from the group consisting of 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 is 1c Each independently selected from H, C 1-4 Alkyl or- (CH) 2 ) p -C 3-6 Carbocycles, said alkyl or carbocycle optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, CF 3 Cyano, C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
    alternatively, R 1b 、R 1c Together with the carbon atom to which it is directly attached, form a 3-membered carbocyclic ring;
    ring C is selected from 5-6 membered heteroaryl or phenyl, optionally further substituted with 0 to 4R c Substitution;
    R c 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, carbonThe ring or heterocycle is optionally further substituted with 0 to 4 groups selected from H, halogen, CF 3 (n), = O, OH, cyano, COOH, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy, -C 1-4 Alkylene-hydroxy, C 3-6 A carbocyclyl or a 3-to 8-membered heterocyclyl substituted with 1 to 3 heteroatoms selected from O, S, N;
    R a1 、R a2 、R 3a 、R 3b 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 being further substituted with 0 to 4 groups selected from H, halogen, CF 3 OH, cyano, COOH, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with an alkoxy substituent, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;
    R 5 selected from the group consisting of
    Figure PCTCN2021117545-APPB-100002
    R 5a 、R 5b 、R 5c 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, said alkyl, alkoxy, carbocyclyl or heterocyclyl optionally being further substituted with 0 to 4 groups selected from H, halogen, CF 3 (n), = O, OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-4 Alkyl, C 1-4 Alkoxy radicalBase or-SC 1-4 A substituent of an alkyl group, said heterocyclic group containing 1 to 3 heteroatoms selected from O, S, N;
    alternatively, R 5b And R is R 5c Chemical bonds may be formed;
    R 5d 、R 5e each independently selected from H, C 1-6 Alkyl, C 3-8 Carbocyclyl or 3-to 10-membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl optionally being further substituted with 0 to 4 groups selected from H, halogen, CF 3 (n), = O, OH, cyano, NH 2 、-NH(C 1- 4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-4 Alkyl, C 1-4 Alkoxy or-SC 1-4 A substituent of an alkyl group, said heterocyclic group containing 1 to 3 heteroatoms selected from O, S, N;
    alternatively, R 5d 、R 5e Together with the nitrogen atom to which it is directly attached, form a 4 to 8 membered heterocyclic group, said heterocyclic group optionally being further substituted with 0 to 4 groups selected from H, halogen, CF 3 (v), = O, OH, cyano, C 1-4 Alkyl, C 1-4 Alkoxy or-C 1-4 alkylene-C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 3 heteroatoms selected from O, S, N;
    R 5f 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 Cycloalkyl, said alkyl, cycloalkyl or heterocyclyl optionally being further substituted with 0 to 4 substituents selected from H, halogen, CF 3 (v), = 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 group 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl), a 3 to 8 membered heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;
    n, s are selected from 0, 1 or 2;
    m, p, q are each independently selected from 0, 1, 2, 3 or 4.
  2. The compound of claim 1, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
    Figure PCTCN2021117545-APPB-100003
    selected from the group consisting of
    Figure PCTCN2021117545-APPB-100004
    Right side and L 1 Directly connecting;
    Figure PCTCN2021117545-APPB-100005
    selected from the group consisting of
    Figure PCTCN2021117545-APPB-100006
    X 1 Selected from N or CR a ；
    R a 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, said CH 2 Optionally further substituted with 0 to 4 groups selected from H, halogen, CF 3 OH, cyano, COOH, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with an alkoxy substituent, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
    ring B is selected from C 3-6 Carbocycles, C, of saturated or unsaturated monocyclic rings 5-10 Saturated or unsaturated spiro carbocyclic ring, C 5-10 Saturated or unsaturated carbocyclic ring, C 5-10 A saturated or unsaturated bridged carbocyclic ring, optionally further substituted with 0 to 4R b Substitution;
    R b each independently selected from H, halogen, cyano, C 1-4 Alkyl or C 1-4 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0 to 4 groups selected from H, halogen, CF 3 OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy or C 3-8 Substituted cycloalkyl;
    L 1 selected from the group consisting of 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 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 Carbocycles, said CH 2 Optionally further substituted with 0 to 4 groups selected from H, halogen, CF 3 (n), = O, OH, cyano, COOH, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy, -C 1-4 Alkylene-hydroxy, C 3-6 Cycloalkyl or a substituent of a 3 to 8 membered heterocyclic group, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
    R a1 、R a2 、R 3a 、R 3b 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 being further substituted with 0 to 4 groups selected from H, halogen, CF 3 OH, cyano, COOH, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with an alkoxy substituent, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;
    R 5a 、R 5b 、R 5c 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, said alkyl, alkoxy, carbocyclyl or heterocyclyl optionally being further substituted with 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 A substituent of an alkyl group, said heterocyclic group containing 1 to 3 heteroatoms selected from O, S, N;
    alternatively, R 5b And R is R 5c Chemical bonds may be formed;
    R 5d 、R 5e 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 optionally being further substituted with 0 to 4 groups selected from H, halogen, CF 3 (n), = O, OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-4 Alkyl, C 1-4 Alkoxy or-SC 1-4 Alkyl, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
    alternatively, R 5d 、R 5e Together with the nitrogen atom to which it is directly attached, form a 4 to 6 membered heterocyclic ring, said heterocyclic ring optionally being further substituted with 0 to 4 groups selected from H, halogen, CF 3 (v), = O, OH, cyano, C 1-4 Alkyl, C 1-4 Alkoxy or-C 1-4 alkylene-C 1- 4 A substituent of an alkoxy group, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
    R 5f 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 Cycloalkyl or C 3-6 Cycloalkyl, said alkyl, cycloalkyl or heterocyclyl optionally being further substituted with 0 to 4 substituents selected from H, halogen, CF 3 (v), = 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 group 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl), 3-to 8-membered heterocyclyl, C 3-6 A substituent of cycloalkyl, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N.
  3. The compound of claim 2, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein
    L 1 Selected from bonds, -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 )-；
    Ring B is selected from one of the following substituted or unsubstituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, bicyclo [1.1.1 ]Pentanyl and bicyclo [2.2.1]Heptyl, cubanyl, bicyclo [3.1.0]Hexalkyl and bicyclo [3.2.0]Heptyl, cyclopentyl, and bicyclo [4.2.0]Octyl and bicyclo [2.2.2]Octyl, cyclobutylspirobutyl, cyclobutylspiropentyl, cyclobutylspirohexyl, cyclopentylpspirohexyl, optionally further substituted with 0 to 4R when substituted b Substitution;
    R b each independently selected from H, F, cl, br, I, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy, said methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy optionally further being 0 to 4 selected from H, halogen, CF 3 OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted cycloalkyl;
    R a 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 Optionally further 0 to 4 are selected from H, halogen, CF, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl or cyclopentyl 3 OH, cyano, COOH, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
    R 1 、R 2 、R 3 、R 4 each independently selected from H, F, cl, br, I, OH, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, ethenyl, 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 Azacyclobutyl, - (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 Optionally further 0 to 4 groups selected from H, halogen, CF, from methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, ethenyl, propenyl, ethynyl, propynyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl or azepanyl 3 (n), = O, OH, cyano, COOH, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy, -C 1-4 Alkylene-hydroxy, C 3-6 Cycloalkyl or a 3 to 8 membered heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;
    R a1 、R a2 、R 3a 、R 3b Each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl, said methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl optionally being further substituted with 0 to 4 moieties selected from H, halogen, CF 3 OH, cyano, COOH, C 1-4 Alkyl or C 1-4 Taking alkoxy groupsSubstituted by substituents;
    R 5 selected from the group consisting of
    Figure PCTCN2021117545-APPB-100007
    R 5a 、R 5b 、R 5c Each independently selected from H, F, cl, br, I, cyano, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl, said methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl optionally being further substituted with 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 Substituted by alkyl;
    Alternatively, R 5b And R is R 5c Chemical bonds may be formed;
    R 5d 、R 5e each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl or morpholinyl, said methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl or morpholinyl optionally being further substituted with 0 to 4 groups selected from H, halogen, CF 3 (n), = O, OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-4 Alkyl, C 1-4 Alkoxy or-SC 1-4 Substituted by alkyl;
    alternatively, R 5d 、R 5e Together with the nitrogen atom to which it is directly attached, forms an azetidinyl, pyrrolyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl or thiomorpholinyl group, which is optionally further substituted with 0 to 4 groups selected from H, halogen, CF 3 (v), = O, OH, cyano, C 1- 4 Alkyl, C 1-4 Alkoxy or-C 1-4 alkylene-C 1-4 Substitution of the substituent of the alkoxy group;
    R 5f selected from H or one of the following substituted or unsubstituted groups: methyl, ethyl, propyl, butyl, isopropyl, isobutyl, azetidinyl, piperazinyl, oxetanyl, oxolanyl, morpholinyl, -CH 2 -azetidinyl, -CH 2 Azacyclopentyl, -CH 2 -azacyclyl, -CH 2 Piperazine, -CH 2 -oxetanyl, -CH 2 -oxacyclopentyl, -CH 2 -oxacyclohexanyl, -CH 2 -morpholine, -CH 2 CH 2 -azetidinyl, -CH 2 CH 2 Azacyclopentyl, -CH 2 CH 2 -azacyclyl, -CH 2 CH 2 Piperazine, -CH 2 CH 2 -oxetanyl, -CH 2 CH 2 -oxacyclopentyl, -CH 2 CH 2 -oxacyclohexanyl, -CH 2 CH 2 -morpholine, -CH 2 -thiazole, -CH 2 Thiophene, -CH 2 -pyrrole, -CH 2 -pyrazole, -CH 2 -imidazole, -CH 2 -furan, -CH 2 -oxazole, -CH 2 -pyrrole, -CH 2 -pyridine,
    Figure PCTCN2021117545-APPB-100008
    Figure PCTCN2021117545-APPB-100009
    When substituted, optionally further substituted with 0 to 4 groups selected from H, halogen, CF 3 (v), = 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 group 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl), 3-to 8-membered heterocyclyl, C 3-6 A substituent of cycloalkyl, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N.
  4. The compound of claim 3, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein
    Ring B is selected from one of the following substituted or unsubstituted groups:
    Figure PCTCN2021117545-APPB-100010
    Figure PCTCN2021117545-APPB-100011
    Figure PCTCN2021117545-APPB-100012
    when substituted, optionally further substituted with 0 to 4R b Substituted, left side and L 1 Are connected;
    R b each independently selected from H, F, cl, br, I, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy, saidOptionally further 0 to 4 methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy 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 A methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, or cyclopentyl substituent;
    R a 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) CH 3 、-NHC(O)CH 2 CH 3 -NHC (O) -cyclopropyl, -NHC (O) -cyclobutyl, -NHC (O) -cyclopentyl, -NHC (O) -cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 Cyclopentyl or CH 2 -a cyclohexyl group;
    R 1 、R 2 、R 3 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 Optionally further substituted with 0 to 4 groups selected from H, F, CF, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy 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 A substituent of OH;
    R 3a 、R 3b each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl, said methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl optionally being further selected from H, F, CF by from 0 to 4 3 Substituted with OH, cyano, COOH, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, or propoxy substituents;
    R 4 selected from H, F, cl, br, I, OH, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, ethenyl, 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 Azacyclobutyl, - (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 Optionally further 0 to 4 groups selected from H, F, = O, OH, cyano, CF, and methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, vinyl, propenyl, ethynyl, propynyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl or azepanyl 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, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl or azepanyl;
    R 5 selected from the group consisting of
    Figure PCTCN2021117545-APPB-100013
    Figure PCTCN2021117545-APPB-100014
    Figure PCTCN2021117545-APPB-100015
    Or R is 5 Selected from the group consisting of
    Figure PCTCN2021117545-APPB-100016
    Figure PCTCN2021117545-APPB-100017
    Or R is 5 Selected from the group consisting of
    Figure PCTCN2021117545-APPB-100018
    Figure PCTCN2021117545-APPB-100019
    Figure PCTCN2021117545-APPB-100020
    Or R is 5 Selected from the group consisting of
    Figure PCTCN2021117545-APPB-100021
    Figure PCTCN2021117545-APPB-100022
    Figure PCTCN2021117545-APPB-100023
  5. The compound of claim 4, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein
    L 1 Selected from-O-, -NH-, -OCH 2 -、-OC(CH 3 ) 2 -、-CH 2 O-or-NHCH 2 -；
    R b Are independently selected from H, F, cl and cyanogenA group, methyl, ethyl, isopropyl, propyl, methoxy or ethoxy, said methyl, ethyl, isopropyl, propyl, methoxy or ethoxy optionally being further substituted with 0 to 4 groups selected from H, F, CF 3 OH, cyano, NH 2 、-N(CH 3 ) 2 、-N(CH 2 CH 3 ) 2 A methyl, ethyl, isopropyl, propyl, cyclopropyl or cyclobutyl substituent;
    X 1 selected from N or CH;
    R 1 、R 2 each independently selected from H, F, cl, OH, CF 3 Cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy;
    R 3 selected from H, F, cl, OH, CF 3 、-CN、-CH 2 CN、-CH 2 CH 2 CN、NH 2 、-N(CH 3 ) 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, propyl, butyl, methoxy, ethoxy or propoxy;
    R 4 selected from H, F, OH, CF 3 、NH 2 、-CN、-CH 2 CN、-CH 2 CH 2 CN、-NHCH 3 、-N(CH 3 ) 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)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, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl or piperazinyl;
    R 5 selected from the group consisting of
    Figure PCTCN2021117545-APPB-100024
    Figure PCTCN2021117545-APPB-100025
    Or R is 5 Selected from the group consisting of
    Figure PCTCN2021117545-APPB-100026
    Figure PCTCN2021117545-APPB-100027
    Or R is 5 Selected from the group consisting of
    Figure PCTCN2021117545-APPB-100028
    Figure PCTCN2021117545-APPB-100029
    Figure PCTCN2021117545-APPB-100030
    Or R is 5 Selected from the group consisting of
    Figure PCTCN2021117545-APPB-100031
    Figure PCTCN2021117545-APPB-100032
    Figure PCTCN2021117545-APPB-100033
  6. The compound of claim 5, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein
    L 1 Selected from-O-, -OCH 2 -、-OC(CH 3 ) 2 -or-CH 2 O-；
    Ring B is selected from
    Figure PCTCN2021117545-APPB-100034
    Figure PCTCN2021117545-APPB-100035
    Left side and L 1 Are connected;
    Figure PCTCN2021117545-APPB-100036
    selected from the group consisting of
    Figure PCTCN2021117545-APPB-100037
    Right side and L 1 Directly connecting;
    R 5 selected from the group consisting of
    Figure PCTCN2021117545-APPB-100038
    Figure PCTCN2021117545-APPB-100039
    Or R is 5 Selected from the group consisting of
    Figure PCTCN2021117545-APPB-100040
    Figure PCTCN2021117545-APPB-100041
    Or R is 5 Selected from the group consisting of
    Figure PCTCN2021117545-APPB-100042
    Figure PCTCN2021117545-APPB-100043
    Figure PCTCN2021117545-APPB-100044
    Or R is 5 Selected from the group consisting of
    Figure PCTCN2021117545-APPB-100045
    Figure PCTCN2021117545-APPB-100046
    Figure PCTCN2021117545-APPB-100047
    R 1 Selected from H, F, cl, cyano, CF 3 Methyl, ethyl or methoxy;
    R 2 selected from H, F, cl, cyano, CF 3 Methyl, ethylA radical or methoxy;
    R 3 selected from H, F, cl, cyano, CF 3 Methyl, ethyl or methoxy;
    R 4 selected from H, F, cl, cyano, CF 3 Methyl, ethyl or methoxy.
  7. The compound of claim 3, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein
    R 5 Selected from the group consisting of
    Figure PCTCN2021117545-APPB-100048
    Figure PCTCN2021117545-APPB-100049
    R 5f Selected from H or one of the following substituted or unsubstituted groups: methyl, ethyl, propyl, butyl, isopropyl, isobutyl, azetidinyl, piperazinyl, oxetanyl, oxolanyl, morpholinyl, -CH 2 -azetidinyl, -CH 2 Azacyclopentyl, -CH 2 -azacyclyl, -CH 2 Piperazine, -CH 2 -oxetanyl, -CH 2 -oxacyclopentyl, -CH 2 -oxacyclohexanyl, -CH 2 -morpholine, -CH 2 CH 2 -azetidinyl, -CH 2 CH 2 Azacyclopentyl, -CH 2 CH 2 -azacyclyl, -CH 2 CH 2 Piperazine, -CH 2 CH 2 -oxetanyl, -CH 2 CH 2 -oxacyclopentyl, -CH 2 CH 2 -oxacyclohexanyl, -CH 2 CH 2 -morpholine, -CH 2 -thiazole, -CH 2 Thiophene, -CH 2 -pyrrole, -CH 2 -pyrazole, -CH 2 -imidazole, -CH 2 -furan, -CH 2 -oxazole, -CH 2 -pyrrole, -CH 2 -pyridine,
    Figure PCTCN2021117545-APPB-100050
    Figure PCTCN2021117545-APPB-100051
    When substituted, optionally further substituted with 0, 1, 2, 3 or 4 members selected from H, F, CF 3 (n) = 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(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), azetidinyl, piperazinyl, oxetanyl, oxolanyl, morpholinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, pyrrolyl, pyridyl.
  8. The compound of claim 7, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein
    L 1 Selected from-O-, -OCH 2 -、-OC(CH 3 ) 2 -or-CH 2 O-；
    Ring B is selected from
    Figure PCTCN2021117545-APPB-100052
    Figure PCTCN2021117545-APPB-100053
    Left side and L 1 Are connected;
    Figure PCTCN2021117545-APPB-100054
    selected from the group consisting of
    Figure PCTCN2021117545-APPB-100055
    Right side and L 1 Directly connecting;
    R 1 selected from H, F, cl, cyano, CF 3 Methyl, ethyl or methoxy;
    R 2 selected from H, F, cl, cyano, CF 3 Methyl, ethyl or methoxy;
    R 3 selected from H, F, cl, cyano, CF 3 Methyl, ethyl or methoxy;
    R 4 selected from H, F, cl, cyano, CF 3 Methyl, ethyl or methoxy.
  9. The compound of claim 1, or a stereoisomer, deuterate, 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-100057
    Figure PCTCN2021117545-APPB-100058
    Figure PCTCN2021117545-APPB-100059
    Figure PCTCN2021117545-APPB-100060
    Figure PCTCN2021117545-APPB-100061
    Figure PCTCN2021117545-APPB-100062
    Figure PCTCN2021117545-APPB-100063
    Figure PCTCN2021117545-APPB-100064
    Figure PCTCN2021117545-APPB-100065
    Figure PCTCN2021117545-APPB-100066
    Figure PCTCN2021117545-APPB-100067
    Figure PCTCN2021117545-APPB-100068
    Figure PCTCN2021117545-APPB-100069
    Figure PCTCN2021117545-APPB-100070
    Figure PCTCN2021117545-APPB-100071
    Figure PCTCN2021117545-APPB-100072
    Figure PCTCN2021117545-APPB-100073
  10. a pharmaceutical composition comprising a compound of any one of claims 1-9, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier.
  11. Use of a compound according to any one of claims 1-9, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, for the manufacture of a medicament for the prevention or treatment of a disease associated with JAK3 kinase activity or expression level.
  12. The use according to claim 11, wherein the disease is selected from immune system related diseases.
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