WO2017128896A1 - Fxr agonist and preparation method and use thereof - Google Patents

Fxr agonist and preparation method and use thereof Download PDF

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WO2017128896A1
WO2017128896A1 PCT/CN2016/111652 CN2016111652W WO2017128896A1 WO 2017128896 A1 WO2017128896 A1 WO 2017128896A1 CN 2016111652 W CN2016111652 W CN 2016111652W WO 2017128896 A1 WO2017128896 A1 WO 2017128896A1
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group
membered
compound
substituted
mmol
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PCT/CN2016/111652
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French (fr)
Chinese (zh)
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黄梦林
包如迪
李元念
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江苏豪森药业集团有限公司
上海翰森生物医药科技有限公司
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Priority claimed from CN201610575260.0A external-priority patent/CN106995416A/en
Application filed by 江苏豪森药业集团有限公司, 上海翰森生物医药科技有限公司 filed Critical 江苏豪森药业集团有限公司
Priority to CN201680079972.1A priority Critical patent/CN109071470B/en
Publication of WO2017128896A1 publication Critical patent/WO2017128896A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • 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
    • A61K31/425—Thiazoles
    • 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
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the invention belongs to the field of drug synthesis, and particularly relates to a 3-(2,6-dichlorophenyl)isothiazole/isoxazole series compound having FXR agonistic activity, a preparation method and application thereof.
  • the farnesyl ester derivative X receptor is a member of the hormone nuclear receptor superfamily, which is mainly expressed in the liver, small intestine, kidney, and adrenal gland, and less expressed in adipose tissue and heart. Farnesol was originally thought to be its ligand and was named after it.
  • FXR ligand binds directly to the FXR carboxy terminal ligand binding region (LBD)
  • LBD FXR carboxy terminal ligand binding region
  • RXR retinoid receptor
  • the binding of FXR DNA response elements to regulate the transcription of target genes and participate in the regulation of sugar and lipid metabolism is an important energy regulator.
  • Primary bile acid chenodeoxycholic acid is the most potent ligand for FXR, and secondary bile acid bile acid and deoxycholic acid can also activate FXR.
  • FXR ligands such as 6-ECDCA, GW4064, etc.
  • the main target genes of FXR include bile salt export pump (BSEP), bile acid binding protein (IBABP) and small heterodimeric chaperone receptor (SHP), etc., FXR and FXR response elements on these gene promoters (FXRE) Binding to regulate the expression of these genes.
  • FXR agonists can both reduce bile acid-dependent bile flow by stimulating the bile salt output pump (BSEP) and also stimulate MRP2 to increase non-biliary acid-dependent bile flow to reduce cholestasis.
  • BSEP bile salt output pump
  • MRP2 biliary acid-dependent bile flow to reduce cholestasis.
  • FXR is expected to be a new drug target for screening and treating other metabolic diseases including cholestatic diseases and nonalcoholic steatohepatitis.
  • FXR agonists may have therapeutic and research value in the following diseases, including atherosclerosis, cholestatic disease caused by bile acid disorders, liver fibrosis, cirrhosis, cancer, etc. (see Table 1).
  • the inventors discovered a class of compounds having the structure of formula (I) during the course of the study. These compounds have significant agonistic effects on FXR activity and can be used to treat FXR-mediated diseases including cardiovascular disease, atherosclerosis, arteriosclerosis, hypercholesterolemia, hyperlipidemia, chronic hepatitis disease, chronic Liver diseases, gastrointestinal diseases, kidney diseases, cardiovascular diseases, metabolic diseases, cancers (such as colorectal cancer) or nerve signs such as stroke, have a wide range of medical applications, and are expected to be developed into a new generation of FXR modulators.
  • FXR-mediated diseases including cardiovascular disease, atherosclerosis, arteriosclerosis, hypercholesterolemia, hyperlipidemia, chronic hepatitis disease, chronic Liver diseases, gastrointestinal diseases, kidney diseases, cardiovascular diseases, metabolic diseases, cancers (such as colorectal cancer) or nerve signs such as stroke.
  • the invention provides a compound having the structure of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • X is selected from S or O;
  • Y is selected from CR 6 or N;
  • Z is selected from CR 6 , N or NO;
  • Ar is selected from C 5-10 aryl or 5-10 membered heteroaryl, optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, azide, C 1-8 alkyl, C 2 - 8 -alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylsulfide Base, -C 0-8 -S(O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -C(O)R 8 , -C 0-8 -OC(O)R 9 ,
  • R is selected from C 3-8 cycloalkyl or 3-8 membered heterocyclyl, optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, azide, C 1-8 alkyl, C 2 8 -alkenyl, C 2-8 alkynyl, halogen-substituted C 1-8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3 -8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy Base, 5-10 membered heteroarylthio group, -C 0-8 -S(O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -C(O)R 8
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen, hydrazine, halogen, cyano, nitro, azide, C 1-8 alkyl, C 2-8 chain.
  • R 7 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 2-8 alkenyl, C 3-8 cycloalkyl, halogen substituted C 1-8 alkyl, phenyl, p-methylphenyl, amino , a mono C 1-8 alkylamino group, a di C 1-8 alkylamino group or a C 1-8 alkanoylamino group;
  • R 8 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 3-8 cycloalkyl, halogen substituted C 1-8 alkyl or hydroxy substituted C 1-8 alkyl;
  • R 9 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, halogen substituted C 1-8 alkyl, halogen Substituting a C 1-8 alkoxy group, a hydroxy-substituted C 1-8 alkyl group or a hydroxy-substituted C 1-8 alkoxy group;
  • R 10 and R 11 are each independently selected from the group consisting of hydrogen, hydrazine, hydroxy, amino, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3 -8 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group or C 1-8 alkanoyl group,
  • substituents selected from halo, hydroxy, mercapto, cyano, nitro, acetamido, azido, a sulfonyl group, mesyl group, C 1-8 alkyl, trifluoromethyl, C 2 8 -alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 1-8 alkoxy, C 1-8 alkoxycarbonyl, C 1-8 Alkylcarbonyl, C 1-8 alkylcarbonyloxy, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, amino, mono C 1-8 alkylamino or di C Substituted by a substituent of a 1
  • n 0, 1 or 2;
  • r 0, 1, or 2.
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, Y is selected from CR 6 ;
  • Ar is selected from a C 6-10 aryl group or a 6-10 membered heteroaryl group, optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl group, C 2-8 alkynyl group, C 3-8 cycloalkyl group, 3-8 membered heterocyclic group, 3-8 membered heterocyclic oxy group, 3-8 membered heterocyclic thio group , C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroaryl Thiothio group, -C 0-8 -S(O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -C(O) R 8, -C 0-8 -OC
  • R is selected from C 3-6 cycloalkyl or 3-6 membered heterocyclyl, optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, azide, C 1-8 alkyl, C 2 8 -alkenyl, C 2-8 alkynyl, halogen-substituted C 1-8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3 -8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy Base, 5-10 membered heteroarylthio group, -C 0-8 -S(O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -C(O)R 8
  • R 1 , R 2 , R 4 , R 5 , R 6 are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-8 alkyl, halo-substituted C 1-8 alkyl Halogen substituted C 1-8 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, halogen substituted C 3-8 cycloalkyl, 3-8 membered Cyclo, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5- 10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 7 , -C 0-8 -OR 8 ,- C 0-8 -C(O)OR 8 ,
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, Y is selected from CR 6 ;
  • Ar is selected from the following structures:
  • R is selected from the following structures:
  • R 1 , R 2 , R 4 , R 5 and R 6 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-4 alkyl, halo-substituted C 1-4 alkyl, halo-substituted C 1-8 alkoxy.
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of the compound of the formula (II):
  • Ar is selected from the following structures:
  • R is selected from the following structures:
  • R 1 is selected from the group consisting of hydrogen, hydrazine, methyl, ethyl, isopropyl, trifluoromethyl, allyl, ethynyl, cyclopropyl, methoxy, ethoxy, isopropoxy or amino;
  • R 2 is selected from the group consisting of hydrogen, hydrazine, fluorine, chlorine, hydroxy, decyl, methyl, ethyl, isopropyl, trifluoromethyl, allyl, ethynyl, cyclopropyl, cyclobutyl, methoxy, Ethoxy, isopropoxy or amino.
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, methoxy or ethoxy.
  • the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of the compound of the formula (III):
  • Ar is selected from the following structures:
  • R is selected from the following structures:
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-4 alkyl, halo-substituted C 1-4 alkyl, halo-substituted C 1-8 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halogen substituted C 3-6 cycloalkyl, 3-6 membered heterocyclic, 3-6 membered heterocyclyloxy, 3-6 membered heterocyclic ring Thiothio group, -C 0-4 -S(O) r R 7 , -C 0-4 -OR 8 , -C 0-4 -C(O)OR 8 , -C 0-4 -C(O) R 8 , -C 0-4 -OC(O)R 9 , -C 0-4 -NR 10 R 11 , -C 0-4 -C(O)NR 10 R 11 , -
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of the compound of the formula (IIIa), (IIIb), (IIIc) or (IIId):
  • Ar is selected from the following structures:
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl, methoxy. Or ethoxylated.
  • the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
  • Another aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the above formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a compound of the above formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above in the manufacture of a medicament for preventing or treating a FXR-mediated disease or condition
  • the FXR-mediated disease or condition is preferably selected from cardiovascular disease, atherosclerosis, arteriosclerosis, hypercholesterolemia, hyperlipidemia, chronic hepatitis disease, chronic liver disease, gastrointestinal disease, kidney disease, cardiovascular disease, Metabolic disease, cancer (such as colorectal cancer) or nerve signs such as stroke.
  • the chronic liver disease is selected from the group consisting of hepatitis B, primary sclerosis (PBC), cerebral xanthoma (CTX), primary sclerosing cholecystitis (PSC), drug-induced cholestasis, pregnancy Intrahepatic cholestasis, extraintestinal absorption-related cholestasis (PNAC), bacterial overgrowth or sepsis cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), Nonalcoholic steatohepatitis (NASH), liver graft-related graft-versus-host disease, live donor liver transplant regeneration, congenital liver fibrosis, common bile duct stones, granulomatous liver disease, intrahepatic or extraneous malignancy, Sjogren syndrome , sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis or alpha
  • Another aspect of the invention provides a method of preventing or treating a FXR-mediated disease or condition comprising administering a therapeutically effective amount of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or The aforementioned pharmaceutical composition.
  • C 1-8 alkyl means a straight-chain alkyl group having 1 to 8 carbon atoms and a branched alkyl group, the alkyl group means a saturated aliphatic hydrocarbon group, and C 0-8 means no carbon atom or C.
  • 1-8 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 , 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl , 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhex
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from the group consisting of halogen, cyano, and nitrate.
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and "C 3-8 cycloalkyl” refers to a cycloalkyl group of 3 to 8 carbon atoms, "5-10 membered ring.”
  • Alkyl means a cycloalkyl group of 5 to 10 carbon atoms, for example:
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptene Alkenyl, cyclooctyl and the like.
  • Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
  • “Spirocycloalkyl” refers to a polycyclic group that shares a carbon atom (called a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system.
  • the spirocycloalkyl group is divided into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group according to the number of shared spiro atoms between the ring and the ring.
  • Non-limiting examples of spirocycloalkyl groups include:
  • fused cycloalkyl refers to an all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but None of the rings have a fully conjugated ⁇ -electron system. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl groups, and non-limiting examples of fused cycloalkyl groups include:
  • Bridge cycloalkyl refers to an all-carbon polycyclic group in which two rings share two carbon atoms that are not directly bonded, which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system . Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. Non-limiting examples of bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydrogen Naphthyl, benzocycloheptyl and the like.
  • Cycloalkyl may optionally be substituted or unsubstituted.
  • the substituent is preferably one or more groups independently selected from halogen, cyano, nitro, azido, C 1- 8- alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclic oxy, 3-8 Heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5 -10-membered heteroarylthio, -C 0-8 -S(O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -C(O)R 8 , -C 0-8 -OC(O)R 9 , -C —
  • Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O) r (wherein r is an integer of 0, 1, 2 a hetero atom, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • the "5-10 membered heterocyclic group” means a ring group containing 5 to 10 ring atoms
  • the "3-8 membered heterocyclic group” means a ring group containing 3 to 8 ring atoms.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • “Spiroheterocyclyl” refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer) The heteroatoms of 0, 1, 2), and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system.
  • the spirocycloalkyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspiroheterocyclic group depending on the number of common spiro atoms between the ring and the ring.
  • Non-limiting examples of spirocycloalkyl groups include:
  • fused heterocyclyl refers to a polycyclic heterocyclic group in which each ring of the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bonds, but none
  • the ring has a fully conjugated pi-electron system in which one or more ring atoms are selected from the group consisting of nitrogen, oxygen or S(O) r (wherein r is an integer of 0, 1, 2) heteroatoms, the remaining ring atoms being carbon.
  • r is an integer of 0, 1, 2
  • it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups, and non-limiting examples of fused heterocyclic groups include:
  • Bridge heterocyclyl refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly bonded, and these may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system, One or more of the ring atoms are selected from the group consisting of nitrogen, oxygen or S(O) r (wherein r is an integer of 0, 1, 2) heteroatoms, and the remaining ring atoms are carbon. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups.
  • Non-limiting examples of bridged cycloalkyl groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples comprising:
  • the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, cyano, nitro, azide, C 1- 8- alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclic oxy, 3-8 a heterocyclic thio group, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryl group, 5 -10-membered heteroarylthio, -C 0-8 -S(O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -C(O)R 8 , -C 0-8 -OC(O)R 9
  • Aryl means an all-carbon monocyclic or fused polycyclic (ie, a ring that shares a pair of adjacent carbon atoms) groups having a polycyclic ring of a conjugated ⁇ -electron system (ie, having a ring adjacent to a carbon atom) a group
  • C 5-10 aryl means an all-carbon aryl group having 5 to 10 carbons
  • 5-10 membered aryl group means an all-carbon aryl group having 5 to 10 carbons, such as phenyl and Naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, cyano, nitro, azide, C 1-8 alkyl. , C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclic oxy, 3-8 membered heterocyclic Thio group, C 5-10 aryl group, C 5-10 aryloxy group, C 5-10 arylthio group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group, 5-10 yuan Heteroarylthio, -C 0-8 -S(O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -C( O) R 8 , -C 0-8 -OC(
  • Heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms including nitrogen, oxygen and a hetero atom of S(O) r (where r is an integer 0, 1, 2), 5-
  • a 7-membered heteroaryl group means a heteroaromatic system having 5 to 7 ring atoms
  • a 5-10 membered heteroaryl group means a heteroaromatic system having 5 to 10 ring atoms, such as furyl, thienyl, pyridyl, Pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples comprising:
  • Heteroaryl may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more groups independently selected from halogen, cyano, nitro, azido, C 1- 8- alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclic oxy, 3-8 Heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5 -10-membered heteroarylthio, -C 0-8 -S(O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -C(O)R 8 , -C 0-8 -OC(O)R 9 , -C —
  • Alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, and a C 2-8 alkenyl group means a straight or branched olefin containing from 2 to 8 carbons base.
  • alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond
  • a C 2-8 alkenyl group means a straight or branched olefin containing from 2 to 8 carbons base.
  • vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like are examples of the alkenyl group.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, cyano, nitro, azide, C 1-8 alkyl. , C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclic oxy, 3-8 membered heterocyclic Thio group, C 5-10 aryl group, C 5-10 aryloxy group, C 5-10 arylthio group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group, 5-10 yuan Heteroarylthio, -C 0-8 -S(O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -C( O) R 8 , -C 0-8 -OC
  • Alkynyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond
  • C2-8 alkynyl refers to a straight or branched alkynyl group containing from 2 to 8 carbons.
  • ethynyl 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.
  • the alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, cyano, nitro, azide, C 1-8 alkyl. , C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclyl Thio group, C 5-10 aryl group, C 5-10 aryloxy group, C 5-10 arylthio group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group, 5-10 yuan Heteroarylthio, -C 0-8 -S(O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -C( O) R 8 , -C 0-8
  • Alkoxy means -O-(alkyl) wherein alkyl is as defined above.
  • the C 1-8 alkoxy group means an alkyloxy group having 1-8 carbons, and the non-limiting examples include a methoxy group, an ethoxy group, a propoxy group, a butoxy group and the like.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent, preferably one or more of the following groups, independently selected from the group consisting of halogen, cyano, nitro, azide, C 1 -8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 Aroheterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, -C 0-8 -S(O) r R 7 , -C 0-8 -OR 8 , -C 0- 8 -C(O)OR 8 , -C 0-8 -C(O)R 8 , -C 0-8 -OC(O)R 9 , -C 0-8 -NR 10 R 11 , -C 0- Substituted with a substituent of 8 -
  • Halogen means fluoro, chloro, bromo or iodo.
  • PE petroleum ether
  • THF tetrahydrofuran
  • EA means ethyl acetate
  • BINAP means ( ⁇ )-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl.
  • CDI N,N-carbonyldiimidazole.
  • DMF N,N-dimethylformamide
  • DMAP means 4-dimethylaminopyridine.
  • DIPEA N,N-diisopropylethylamine
  • EDCI refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
  • IBX 2-iodobenzoic acid
  • Pd(dppf)Cl 2 means [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.
  • Pd 2 (dba) 3 refers to tris(dibenzylideneacetone) dipalladium.
  • TBAF means tetrabutylammonium fluoride
  • X-phos refers to 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl.
  • NCS N-chlorosuccinimide
  • BPin refers to a terpenyl borate
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted means that one or more hydrogen atoms in the group are each independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS).
  • NMR chemical shift ( ⁇ ) is given in parts per million (ppm).
  • the NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ).
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • LC-MS was determined by LC-MS using an Agilent 1200 Infinity Series mass spectrometer.
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
  • the thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification for TLC is 0.15mm ⁇ 0.20mm, and the specification for separation and purification of thin layer chromatography is 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the solution in the examples means an aqueous solution unless otherwise specified.
  • the temperature of the reaction is room temperature.
  • the room temperature is an optimum reaction temperature of 20 ° C to 30 ° C.
  • TLC thin layer chromatography
  • LC-MS liquid chromatography-mass spectrometry
  • Column chromatography eluent system includes: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: dichloromethane and ethyl acetate system, D: ethyl acetate and methanol, solvent
  • A dichloromethane and methanol system
  • B n-hexane and ethyl acetate system
  • C dichloromethane and ethyl acetate system
  • D ethyl acetate and methanol
  • solvent The volume ratio is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of ammonia water and acetic acid.
  • the first step Compound I-2-a (10 g, 57.1 mmol) and sodium hydroxide (2.7 g, 68.5 mmol) were dissolved in ethanol (100 mL) and water (50 mL), and hydroxylamine hydrochloride (4.7 g, 68.5 mmol) was added. After stirring at 90 ° C for 2 h, the reaction was completely cooled, diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and dried to give compound I-2-b (10.5 g).
  • the second step the compound I-2-b (10g, 52.6mmol) and NCS (9.2g, 69.0mmol) were dissolved in DMF, stirred at room temperature for 2h, extracted with water and methyl tert-butyl ether, the organic phase was washed with water After drying it over sodium sulfate and dried to give compound I-2-c (10.5 g).
  • Second step The above compound I-3-b was dissolved in toluene (20 mL), and tetrachlorophenylhydrazine (0.87 g) and phosphorus pentasulfide (2.4 g) were successively added. The reaction was refluxed for 30 min. The reaction solution was cooled and filtered. The filtrate was concentrated and purified by column chromatography to yield compound I-3-c (0.76 g, yield: 58%)
  • the third step the above compound I-3-c was dissolved in dry THF (8 mL), cooled in an ice-water bath, and lithium tetrahydroaluminum (93 mg) was added in portions. Stir at room temperature for 30 min. The reaction was quenched with sodium sulfate decahydrate. Filtration, the filtrate was concentrated, and the crude product was purified by column chromatography to yield Compound I-3-d (475 mg, yield: 70%).
  • the second step Weighed compound I-4-c (3.6g, 22.20mmol) in a 500mL three-necked flask, added dry ether (108mL), then added zinc powder (4.4g, 66.60mmol), ultrasonic for half an hour under nitrogen atmosphere . After that, ultrasonically, a solution of trichloroacetyl chloride (10.1 g, 55.49 mmol) in diethyl ether (36 mL) was slowly added dropwise. After the addition was completed, the ultrasound was refluxed for 2 h. After the reaction liquid was cooled, water (40 mL) was added dropwise to quench. The reaction mixture was stirred for 15 min.
  • the second step Weighed compound I-8-b (5886mg, 21.6mmol) and I-4-b (4980mg, 32.3mmol) dissolved in 1,4-dioxane (100mL), added Pd under nitrogen protection Dppf)Cl 2 (1577 mg, 2.16 mmol) and Cs 2 CO 3 (14.0 g, 43.1 mmol), and then reacted to 100 ° C overnight. After the reaction was completed, it was cooled to room temperature, filtered and washed with EtOAc. The filtrate was concentrated and the crude was purified eluted elut elut elut
  • the first step the compound 3-fluoro-4-nitrobenzoic acid methyl ester I-9-a (3983 mg, 20 mmol) was dissolved in 40 mL EtOAc / MeOH (1:1) mixture, and Pd/C (400 mg) was added. Hydrogenation at normal temperature and atmospheric pressure, and overnight reaction. The reaction was completed by LC-MS. Filtration and concentration of the filtrate gave crude product I-9-b directly to the next step.
  • the first step the compound I-10-a (10 mmol) and NaSCN (3243 mg, 40 mmol) were added to acetic acid (10 mL) and cooled in an ice water bath; Br 2 (0.5 mL, 10.0 mmol) dissolved in acetic acid (5 mL), and then transferred to the reaction system Slowly add in the middle, add about 5 minutes. The reaction was heated at 40 ° C overnight, monitored by LC-MS, and the reaction was completed. Cool to room temperature, dilute with water (20 mL), and neutralize with aqueous ammonia. Filtration, washing with water and drying in vacuo gave compound I-10-b (2100 mg, quantitative).
  • Step Two A solution of Compound I-11-b (1.0g, 4.2mmol) in H 3 PO 4 (8mL) was added to a 50mL three-necked flask. A solution of NaNO 2 (0.9 g, 12.6 mmol) in water (10 mL) was added dropwise at 0 °C. The obtained solution was stirred at 0 ° C for 1 h. Then, CuSO 4 (3.4 g, 21.0 mmol) was added portionwise at 0 ° C, followed by dropwise addition of a solution of NaCl (3.7 g, 63.0 mmol) in water (10 mL) at 0 °C. The resulting solution was stirred at room temperature for 1 h then diluted with water (20 mL). The aqueous solution was extracted with dichloromethane, and the combined organic layers were concentrated. The crude product was subjected to silica gel column chromatography to afford Compound I-11 (250 mg, yield 23%).
  • the second step methanol (60 mL) was placed in a 250 mL single-mouth bottle, and acetyl chloride (6.2 g) was slowly added dropwise under ice-cooling. After the dropwise addition, the compound I-12-b (6.2 g, 26 mmol) was added and refluxed for 16 h. It was cooled, filtered, washed and dried to give Compound I-12-c (4.9 g, yield: 75.0%).
  • the first step Compound I-13-a (150 mg, 0.75 mmol) was dissolved in dichloromethane (3 mL), and a solution of boron tribromide (4N) was slowly added dropwise at -78 ° C, and the mixture was stirred at room temperature for 20 min. The mixture was stirred and stirred for 30 min. Filtered, concentrated, and the crude product was used directly in the lower portion.
  • the second step the above crude product was placed in a 100 mL single-necked flask, and dichloromethane (5 mL), triethylamine (0.8 mL) and di-tert-butyl dicarbonate (180 mg) were successively added and stirred at room temperature for 2 h. Extract, dry, concentrate, and proceed to the next step without purification.
  • the third step The above compound was placed in a 50 mL single-mouth flask, and Compound I-2, DMF (3 mL) and potassium carbonate (414 mg) were successively added, and the mixture was stirred at 50 ° C overnight, and the reaction was completed. After concentration and column chromatography, Compound I-13 (180 mg, yield 43%).
  • the first step Compound I-14-a (1.17 g, 5.0 mmol) was dissolved in ethanol (15 ml), and activated iron powder (1.68 g, 30.0 mmol) and 1M HCl (5 ml) were added and refluxed for 2 h. After cooling to room temperature, it was filtered. The filtrate was concentrated, dissolved in ethyl acetate, and washed successively with saturated aqueous sodium carbonate, water and brine. The organic layer was dried and concentrated, and then purified, mjjjjjj
  • the first step Compound 1-a (468 mg, 1.45 mmol) was dissolved in dry THF (6 mL) and stirred under nitrogen, and n-butyl lithium (1.6 M, 1.0 mL) was added dropwise at -70 to -78 °C. ). After the addition was completed, the mixture was stirred at this temperature for 45 minutes. Then, a dry THF solution (0.5 mL) in which Compound I-4 (270 mg, 1.32 mmol) was dissolved was dissolved. After the addition was completed, the mixture was stirred at this temperature for 1 h. Was slowly warmed to room temperature, and washed with saturated NH 4 Cl (5mL) was quenched, extracted with ethyl acetate. The organic phase was dried, concentrated and purified by column chromatography (EtOAc/EtOAc, EtOAc: EtOAc
  • the first step the compound 1-a (160 mg, 0.50 mmol) was dissolved in dry tetrahydrofuran (2 mL), and the mixture was filtered under nitrogen, and n-butyl lithium (1.6 M in tetrahydrofuran solution, 0.38 mL) was added dropwise at -70 to 78 °C. Stir for 45 min. A solution of the compound I-5 (102 mg, 0.50 mmol) in THF was evaporated. The reaction solution was warmed to room temperature, brine (EtOAc) The organic phase was dried, concentrated and purified by column chromatography (EtOAc/EtOAc: EtOAc:EtOAc:
  • the second step the compound 9-a (120 mg, 0.27 mmol) was dissolved in tetrahydrofuran (1.5 mL) and added dropwise with stirring. A solution of TBAF in tetrahydrofuran (0.54 mL, 1 M, 0.54 mmol). Stir at room temperature for 20 min. After the reaction is completed, a small amount of water is added, and the mixture is extracted with ethyl acetate (2 ⁇ 10 mL). The organic phase is combined, washed with brine, dried over anhydrous sodium sulfate, filtered, %) Compound 9-b (50 mg, yield: 55%).
  • the fourth step Compound 9-c (50 mg, 0.08 mmol) was dissolved in methanol (1 mL) and (1 mL) water, and sodium hydroxide (10 mg, 0.24 mmol). The reaction was stirred at 40 ° C for 2 h. After the reaction was completed, it was acidified to pH 5-6 with 1N hydrochloric acid, and a solid precipitated. After filtration and drying, a crude product was obtained, which was purified by column chromatography to afford compound 9 (25 mg, yield: 51%).
  • the second step Compound 10-a (20 mg, 0.03 mmol) was dissolved in methanol (1 mL) and (1 mL) water, and sodium hydroxide (13 mg, 0.3 mmol). The reaction was stirred at 40 ° C for 2 h. After the reaction was completed, it was acidified to pH 5-6 with 1N hydrochloric acid, and a solid precipitated. After filtration and drying, a crude product was obtained, which was purified by column chromatography to afford compound 10 (9 mg, yield: 46%).
  • the second step Compound 12-a (10 mg, 0.015 mmol) was dissolved in methanol (1 mL) and (1 mL) water and sodium hydroxide (6 mg, 0.15 mmol). The reaction was stirred at 40 ° C for 2 h. After the reaction was completed, it was acidified to pH 5-6 with 1N hydrochloric acid, and a solid precipitated. After filtration and drying, a crude product was obtained, which was purified by column chromatography to afford compound 12 (6 mg, yield: 61%).
  • the third step Compound 14-b (30 mg, 0.07 mmol) was dissolved in dry DMF (3 mL). After the reaction mixture was cooled, ethyl acetate (20 mL) was added, and then washed with water and brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE/EA: 10 ⁇ 25%) c (30 mg, yield: 64%).
  • the second step the compound 17-a (13 mg, 0.020 mmol) was dissolved in tetrahydrofuran (2 mL) and 1N hydrogen was added. An aqueous solution of sodium oxide (2 mL) was reacted at 50 ° C for 2 h. The reaction was completed, the mixture was acidified with EtOAc (EtOAc)EtOAc. Filtration, concentration and crude product were purified by EtOAc EtOAc (EtOAc)
  • the first step Compound 20-a (2215 mg, 10.0 mmol) was dissolved in dry THF (20 mL), cooled in a dry ice-ethanol bath, and BuLi (6.9 mL, 11.0 mmol, 1.6 M n-hexane solution) was added dropwise and reacted at low temperature for 30 min.
  • Ketone 20-b (856 mg, 5.0 mmol) was dissolved in dry THF (10 mL). Slowly warm to near 0 ° C for 2 h. After completion of the reaction was added saturated aqueous NH 4 Cl was quenched, extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate. Filtration, concentration and column chromatography (PE/EA3: 1) gave Compound 20-c (1040 mg, yield: 66%).
  • Step Two Compound 20-c (1040mg, 3.31mmol) was dissolved in dry CH 2 Cl 2 (20mL, ice-water bath, followed by addition of Et 3 SiH (5.3mL, 33.1mmol) and BF 3 ⁇ Et 2 O (5.0 mL, 39.8 mmol). Keep the temperature at low temperature for 2 h. After the reaction is complete, add NaOH aqueous solution to adjust the pH to weakly alkaline. Concentrate, add crude ethyl acetate, stir vigorously to dissolve the product. Filter, wash with ethyl acetate. The crude compound 20-d (955 mg, yield: 100%) was obtained.
  • the third step adding compound 20-d (89 mg, 0.45 mmol), 20-e (70 mg, 0.30 mmol), X-phos (29 mg, 0.06 mmol) and Cs 2 CO 3 (195 mg, 0.60 mmol) to dioxane ring (4 mL), ring gas pump, under nitrogen was added Pd 2 (dba) 3 (27mg, 0.03mmol), 100 °C overnight. The reaction was completed, cooled to room temperature, washed with saturated brine and evaporated. After concentration, the crude product was separated by chromatography to afford compound 20-f (80mg, yield: 76%).
  • the fourth step the compound 20-f (80 mg, 0.23 mmol) was dissolved in dichloromethane (2 mL), cooled in ice water, BBr 3 /CH 2 Cl 2 (0.9 mL, 0.91 mmol, 1 M) . It was quenched by the addition of methanol and extracted with dichloromethane. The crude compound 20-g was used directly in the next step.
  • the third step the compound 1-a (300 mg, 0.93 mmol) was dissolved in dry tetrahydrofuran (5 mL), and the mixture was filtered under nitrogen, and n-butyl lithium (1.6 M in tetrahydrofuran solution, 0.7 mL) was added dropwise at -70 to 78 °C. . Stir for 45 min. A solution of compound 22-d (175 mg, 0.85 mmol) in THF was evaporated. The reaction mixture was warmed to room temperature and then brined The organic layer was dried, concentrated and purified by column chromatography to afford Compound 22-e (30mg, yield: 7%).
  • the fifth step Compound 24-e (47 mg, 0.20 mmol) was dissolved in dry 1,4-dioxane (5 mL), followed by compound 24-f (127 mg, 0.27 mmol), Cs 2 CO 3 (205 mg) , 0.63 mmol), X-phos (30 mg, 0.06 mmol) and Pd 2 (dba) 3 (29 mg, 0.03 mmol). The reaction was stirred with nitrogen and stirred at 105 ° C overnight. After cooling the reaction, the celite was filtered and washed three times with ethyl acetate. After the filtrate was extracted, the organic layer was dried (MgSO4)
  • the third step Compound 24-a (60 mg, 0.23 mmol) was dissolved in dry THF (3 mL), and then, i-PrMgCl (2.0M, 0.13mL) was added dropwise at -70 to 78 °C. After the addition was completed, the mixture was stirred at this temperature for 1 h. A dry THF solution (1 mL) in which compound 25-b (60 mg, 0.20 mmol) was dissolved was dissolved at -70 °C. After the addition was completed, the mixture was stirred at this temperature for 1 h. The reaction solution was allowed to warm to room temperature and stirred for 1 h. 4 Cl (5mL) was quenched with saturated NH, extracted with ethyl acetate. The organic layer was dried and concentrated, and then purified by column chromatography to afford Compound 25-c (35 mg, yield: 40%).
  • Step Two Compound 29-b (10mg, 0.026mmol) was dissolved in dichloromethane (2 mL), ice-water bath, was added BBr 3 / CH 2 Cl 2 ( 13 ⁇ L, 0.053mmol, 4M), 0 °C reaction 1h. It was quenched by the addition of methanol and extracted with dichloromethane. The crude product was isolated by PTLC to afford compound 29-c (5mg).
  • Compound 31-a was synthesized in the first to second steps of Reference Example 30.
  • Compound 32-a was synthesized in the first to second steps of Reference Example 30.
  • Compound 33-a was synthesized in the first to second steps of Reference Example 30.
  • Compound 34-a was synthesized in the first to second steps of Reference Example 30.
  • Compound 35-a was synthesized in the first to second steps of Reference Example 30.
  • Compound 36-a was synthesized in the first to second steps of Reference Example 30.
  • the first step dichloroethane (30 mL) was placed in a 250 mL three-necked flask, and compound I-12-c (760 mg, 3.0 mmol), cyclopropylboronic acid (516 mg, 6.0 mmol) and sodium carbonate (640 mg, 6.0 mmol) were added. ). Copper acetate (600 mg, 3.0 mmol) and 2,2-bipyridine (470 mg, 3.0 mmol) were placed in a solution of dichloroethane (15 mL), heated to a suspension, and the suspension was added dropwise to the above reaction solution. Stir at 70 ° C for 5 h. The reaction was completed, cooled, added with aq. EtOAc, EtOAc (EtOAc)EtOAc.
  • the second step weighed compound 38-a (450 mg, 1.5 mmol) in a 100 mL single-mouth bottle, added 1,4-dioxane solution (15 mL), followed by 20-d (300 mg, 1.5 mmol), carbonic acid ⁇ (1476 mg, 4.5 mmol), Pd 2 (dba) 3 (140 mg, 0.15 mmol) and X-phos (143 mg, 0.3 mmol) were replaced with nitrogen three times and heated to reflux overnight. After cooling the reaction, it was filtered through celite and washed three times with EA. The filtrate was extracted, dried over sodium sulfate, filtered, concentrated, and then evaporated
  • the second step Weighing compound 39-b (200 mg, 0.75 mmol) in a 100 mL single-mouth bottle, adding 1,4-dioxane solution (15 mL), followed by 20-d (150 mg, 0.75 mmol), carbonic acid ⁇ (740 mg, 2.25 mmol), Pd 2 (dba) 3 (70 mg, 0.075 mmol) and X-phos (70 mg, 0.15 mmol) were replaced with nitrogen three times. Heat to reflux and react overnight. After cooling the reaction, it was filtered through celite and washed three times with EA. The filtrate was extracted and the organic layer was dried (MgSO4)
  • Step 2 To the above crude product, compound I-14 (45 mg, 0.17 mmol), Pd 2 (dba) 3 (17 mg, 0.02 mmol) and X-Phos (18 mg, 0.04 mmol) were dissolved in toluene (6 mL) . Pumping gas, nitrogen protection. Heat to 100 ° C for 6 h. The reaction mixture was cooled and extracted with EtOAc EtOAc EtOAc.
  • Compound 41-a was prepared in the first to second steps of Reference Example 40.
  • Compound 42-a was prepared in the first to second steps of Reference Example 40.
  • Compound 43-a was prepared in the first to second steps of Reference Example 40.
  • Compound 44-a was prepared in the first to second steps of Reference Example 40.
  • the second step Compound 45-c (5.0 g, 26.4 mmol) was dissolved in anhydrous dichloromethane (30 mL) and EtOAc (11.0 g, 79. The reaction was stirred at room temperature for 16 hours. The reaction solution was dried to give Compound 45-d. The solid was dissolved in carbon disulfide (10 mL) and anhydrous aluminum trichloride (10.0 g, 79.34 mmol) was slowly portionwise added at room temperature. The reaction mixture was dark red with the addition of aluminum trichloride, and the reaction was stirred at room temperature for 16 hours. After the reaction was quenched into EtOAc (EtOAc)EtOAc. The crude compound 45-e (3.0 g) was obtained. The product was used directly in the next step without further purification.
  • EtOAc EtOAc
  • the third step 45-e (3.0 g) was dissolved in methanol (20 mL), and aqueous ammonia (25-28%, 10 mL) was added. The reaction mixture became pale yellow, and the mixture was stirred at room temperature for 16 hr. then H 2 O 2 (30%, 3 mL) was added, and the reaction mixture was immediately whited, and the mixture was stirred at room temperature for 2 hours. Filtration and washing of the filter cake with water to give a crude white solid, 45-f (2.0 g). The product was used directly in the next step without further purification.
  • the first step sodium hydroxide (273 mg, 6.825 mmol) was dissolved in water (5 ml), cooled to 0 ° C, and a solution of hydroxylamine hydrochloride (459 mg, 6.650 mmol) in water (5 ml) was added and stirred for 10 min.
  • the third step potassium carbonate (815 mg, 5.897 mmol) and THF (10 ml) were cooled to -10 ° C, and ethyl 3-cyclopropyl-3-oxopropanoate (895 mg, 5.731 mmol) / THF (5 ml). Stir for 30 min. A 47-c (1.907 g) / THF (5 ml) solution was added dropwise and stirred at room temperature for 1 h. Triethylamine (5 ml) was added and stirred overnight. Water was added, ethyl acetate was extracted, brine was evaporated, dried and concentrated to dryness to afford compound 47-d (1.722 g, yield: 98.0%).
  • the fourth step lithium tetrahydrogen aluminum (600 mg) was added to dry THF (10 ml), cooled to -10 ° C under nitrogen atmosphere, and a solution of 47-d (1.722 g) / THF (10 ml) was added dropwise, and the mixture was stirred for 30 min. .
  • Step 6 47-f (200 mg, 0.6629 mmol), 47-g (170 mg, 0.5991 mmol), carbonic acid Potassium (166 mg, 1.201 mmol) and DMF (5 ml) were stirred at 50 ° C for 1 h under nitrogen.
  • Step 8 47-i (180 mg, 0.3709 mmol), 47-j (130 mg, 0.5578 mmol), Pd 2 (dba) 3 (35 mg, 0.0382 mmol), X-Phos (36 mg, 0.0756 mmol), cesium carbonate (485 mg, 1.4886 mmol) and toluene (20 ml) were mixed, stirred at 100 ° C for 6 h under nitrogen atmosphere, cooled to room temperature, filtered, washed with toluene, and purified by column chromatography to give compound 47-k.
  • the ninth step mixing the 47-k, 5N sodium hydroxide (2ml) solution obtained in the previous step, THF (3ml) and methanol (3ml), stirring at 60 ° C for 3h, cooling, adding water and dichloromethane, 2N hydrochloric acid adjustment The pH was 5-6, partitioned, extracted with dichloromethane, dried and purified to give compound 47 (137 mg, yield: 62.9%).
  • the first step mixing 47-i (80 mg, 0.165 mmol), I-9 (53 mg, 0.183 mmol), cesium carbonate (160 mg, 0.491 mmol) and DMA (5 ml), and stirring under nitrogen for 60 h at 6 ° C, adding water Dichloromethane extraction, drying and purification gave compound 48-a (70 mg, yield: 64.5%).
  • the second step mixing 48-a (70 mg, 0.1064 mmol), 5N sodium hydroxide (2 ml), THF (3 ml) and methanol (3 ml), stirring at 60 ° C for 2 h, adding water and dichloromethane, 2N hydrochloric acid The pH was 5-6, separated, extracted with dichloromethane, dried and purified to give Compound 48 (46 mg, yield: 67.1%).
  • the second step Compound 49-c (3.0 g) was dissolved in methanol (20 mL) and aqueous ammonia (25 to 28%, 10 mL) was added. The reaction mixture became light yellow. After the mixture was stirred at room temperature for 16 hrs, H 2 O 2 (30%, 3 mL) was added, and the reaction mixture was immediately whited, and the mixture was stirred at room temperature for 2 hours. Filtration and washing of the filter cake with water afforded crude product 49-d (2.0 g). The product was used directly in the next step without further purification.
  • the second step Compound 51-a (1.0 g, 3.17 mmol) was dissolved in dry THF (20 mL), and stirred under nitrogen atmosphere, i-PrMgCl. LiCl (1.3 M, 3.1 mL) was added dropwise at 0 °C. After the addition was completed, stirring was continued at this temperature for 1 h. A solution of the compound tert-butyl-3-carbonylazetidine-1-carboxylate (815 mg, 4.76 mmol) in dry THF (3 mL) was evaporated. After the addition was completed, the reaction solution was stirred at 0 ° C for 30 minutes, and the mixture was stirred at room temperature overnight.
  • the third step at 0 ° C, boron trifluoride etherate (4.4 mL) was added dropwise to 10 mL of a solution containing compound 51-b (500 mg, 1.39 mmol) and triethylsilylhydrogen (2.2 mL) in dichloromethane After the completion of the solution, the solution was stirred at room temperature overnight. The solution is extracted once with water, and the organic phase is basified with aqueous ammonia and then concentrated. The crude product is purified by reverse phase purification to afford crude product, which is purified by normal phase column chromatography to afford compound 51-c (260 mg).
  • the fourth step Compound 51-c (24 mg, 0.10 mmol) was placed in a 10 mL microwave tube, and dry 1,4-dioxane (2 mL) was added, followed by the addition of compound 24-f (62 mg, 0.13 mmol), carbonic acid. ⁇ (66 mg, 0.20 mmol), X-phos (14 mg, 0.03 mmol) and Pd 2 (dba) 3 (14 mg, 0.015 mmol). The air was ventilated for 1 minute under a nitrogen atmosphere, and then microwaved at 100 ° C for 2 hours. After cooling the reaction, the celite was filtered and washed three times with EA. The filtrate was extracted and dried (MgSO4)
  • the fifth step Compound 51-d (20 mg, 0.03 mmol) was dissolved in dioxane (2 mL). Aqueous NaOH (5.0 M, 1 mL) and methanol (1 mL) were added to the solution. The reaction solution was stirred at reflux for 72 hours. After cooling, it was acidified with EtOAc (3 mL).
  • FXR receptor binding activity assay kit to test the effect of compounds on FXR and its binding protein fragments (LBD domain binds to SRC1 fragment) (kit supplier) Lifetechnology Invitrogen Catalog: PV4835; cisbioCatalog: 610 SAXLA and 61 GSTKLA). See the kit instructions for specific methods. The operation is as follows:
  • ⁇ X represents the value of 665/615 for each concentration
  • ⁇ Min represents the 665/615 value of the unadded compound
  • ⁇ Max represents the 665/615 value of the reference compound.
  • biochemical activity of the compounds of the present invention was determined by the above test, and the EC 50 values were measured as shown in the following table.
  • the transfection reagent is FugeneHD (Promega#E231A)
  • Firefly luciferase and Renilla luciferase signals were detected by Promega's dual luciferase assay system (Promega #E1980).
  • the value obtained was determined by dividing the firefly luciferase signal (F) by the Renilla luciferase signal (R), ie F/R. This data processing eliminates the difference in cell number and transfection efficiency.
  • ⁇ X represents the F/R value for each concentration
  • ⁇ Min represents the F/R value of the unadded compound
  • ⁇ Max represents the F/R value of the reference compound.
  • biochemical activity of the compounds of the present invention was determined by the above test, and the measured EC 50 values are shown in the following table.

Abstract

Disclosed are an FXR agonist and a preparation method and use thereof, in particular relating to the compound having the structure of formula (I), a stereisomer or a pharmaceutically acceptable salt thereof. The series of compounds can be used to treat FXR mediated diseases, comprising cardiovascular disease, atherosclerosis, arteriosclerosis, hypercholesterolemia, hyperlipidemia and chronic hepatitis, chronic liver disease, gastrointestinal diseases, kidney diseases, metabolic diseases, cancers (such as colorectal cancer) or neurological conditions such as strokes etc., have a wide medical application, and have a promising future for being developed into a new generation of FXR regulating agents.

Description

FXR激动剂及其制备方法和应用FXR agonist and preparation method and application thereof 技术领域Technical field
本发明属于药物合成领域，具体涉及一种具有FXR激动活性的3-(2,6-二氯苯基)异噻唑/异惡唑系列化合物及其制备方法和应用。The invention belongs to the field of drug synthesis, and particularly relates to a 3-(2,6-dichlorophenyl)isothiazole/isoxazole series compound having FXR agonistic activity, a preparation method and application thereof.
背景技术Background technique
法尼酯衍生物X受体(FXR)属于激素核受体超家族的一员，其主要在肝脏、小肠、肾脏和肾上腺表达，在脂肪组织和心脏中较少表达。最初认为法尼醇是其配体，并由此得名。当FXR配体与FXR羧基末端配体结合区(LBD)直接结合后，核受体空间构象发生改变并与视黄醛衍生物受体(RXR)形成异源二聚体，最后与靶基因特定FXRDNA反应元件结合从而调节靶基因的转录，参与糖、脂代谢的调控，是重要的能量调节器。初级胆汁酸鹅脱氧胆酸是FXR最有效的配体，次级胆汁酸石胆酸和脱氧胆酸也可以激活FXR。目前还有合成FXR配体(如6-ECDCA、GW4064等)，其与FXR结合力比天然配体强数倍。FXR的主要靶基因包括胆盐输出泵(BSEP)、胆酸结合蛋白(IBABP)和小异源二聚体伴侣受体(SHP)等，FXR通过和这些基因启动子上的FXR反应元件(FXRE)结合从而调控这些基因的表达。但如胆固醇7α羟化酶(CYP7α1)等主要FXR调控基因的启动子序列中没有典型FXR结合反应序列，FXR则是间接通过诱导转录抑制因子SHP表达，然后SHP与CYP7α1启动子肝受体同源物(LRH-1)形成抑制性复合物，从而阻断CYP7α1和其它LRH-1靶基因转录。由于FXR在胆汁酸及胆固醇代谢中的重要作用，这将使其和肝脏相关疾病关系日益受到关注。寻找FXR新型激动剂成了治疗包括胆汁淤积综合症等肝脏疾病的研究热点，6-乙炔鹅脱氧胆酸(奥贝胆酸)作为治疗原发性胆汁性肝硬化(PBC)已经完成III期临床试验，最早将于2015年上市，而且该化合物在非酒精性脂肪性肝炎患者中也表现出令人满意的治疗效果。FXR激动剂既可以通过刺激胆盐输出泵(BSEP)增加胆汁酸依赖性胆流和也可以刺激MRP2增加非胆汁酸依赖性胆流以减轻胆汁淤积。FXR有望成为筛选治疗包括胆汁淤积性疾病和非酒精性脂肪性肝炎等其它代谢疾病的新的药物靶点。不仅如此，目前的研究已经表明，FXR激动剂可能在以下疾病中具有治疗和研究价值，包括动脉粥样硬化，胆汁酸紊乱引起的胆汁淤积性疾病、肝纤维化、肝硬化，癌症等(见表1)。The farnesyl ester derivative X receptor (FXR) is a member of the hormone nuclear receptor superfamily, which is mainly expressed in the liver, small intestine, kidney, and adrenal gland, and less expressed in adipose tissue and heart. Farnesol was originally thought to be its ligand and was named after it. When the FXR ligand binds directly to the FXR carboxy terminal ligand binding region (LBD), the nuclear receptor spatial conformation changes and forms a heterodimer with the retinoid receptor (RXR), and finally with the target gene specific The binding of FXR DNA response elements to regulate the transcription of target genes and participate in the regulation of sugar and lipid metabolism is an important energy regulator. Primary bile acid chenodeoxycholic acid is the most potent ligand for FXR, and secondary bile acid bile acid and deoxycholic acid can also activate FXR. There are also synthetic FXR ligands (such as 6-ECDCA, GW4064, etc.) which bind to FXR several times more strongly than natural ligands. The main target genes of FXR include bile salt export pump (BSEP), bile acid binding protein (IBABP) and small heterodimeric chaperone receptor (SHP), etc., FXR and FXR response elements on these gene promoters (FXRE) Binding to regulate the expression of these genes. However, there is no typical FXR binding reaction sequence in the promoter sequence of major FXR regulatory genes such as cholesterol 7α hydroxylase (CYP7α1), and FXR is indirectly through the induction of transcriptional repressor SHP expression, and then SHP is homologous to the CYP7α1 promoter liver receptor. (LRH-1) forms an inhibitory complex that blocks CYP7α1 and other LRH-1 target gene transcription. Due to the important role of FXR in bile acid and cholesterol metabolism, this will increasingly attract attention to liver-related diseases. The search for new FXR agonists has become a research hotspot for the treatment of liver diseases including cholestasis syndrome. 6-acetylene chenodeoxycholic acid (obeyolic acid) has been completed as a treatment for primary biliary cirrhosis (PBC). The trial, which will be available as early as 2015, and the compound also shows satisfactory therapeutic effects in patients with nonalcoholic steatohepatitis. FXR agonists can both reduce bile acid-dependent bile flow by stimulating the bile salt output pump (BSEP) and also stimulate MRP2 to increase non-biliary acid-dependent bile flow to reduce cholestasis. FXR is expected to be a new drug target for screening and treating other metabolic diseases including cholestatic diseases and nonalcoholic steatohepatitis. Moreover, current research has shown that FXR agonists may have therapeutic and research value in the following diseases, including atherosclerosis, cholestatic disease caused by bile acid disorders, liver fibrosis, cirrhosis, cancer, etc. (see Table 1).
表1.FXR激动剂可以对治疗有所帮助的疾病Table 1. Diseases that FXR agonists can help with treatment
Figure PCTCN2016111652-appb-000001
Figure PCTCN2016111652-appb-000001
Figure PCTCN2016111652-appb-000002
Figure PCTCN2016111652-appb-000002
发明内容Summary of the invention
发明人在研究过程中发现一类具有式(I)结构的化合物。该类化合物对FXR活性具有明显地激动作用，可以用来治疗用于治疗FXR介导的疾病，包括心血管疾病、动脉粥样硬化、动脉硬化、高胆甾醇血、高血脂慢性肝炎疾病、慢性肝病、胃肠疾病、肾病、心血管疾病、代谢疾病、癌症(例如结直肠癌)或神经迹象如中风等疾病，具有广泛医学应用，有望开发成新一代FXR调控剂。The inventors discovered a class of compounds having the structure of formula (I) during the course of the study. These compounds have significant agonistic effects on FXR activity and can be used to treat FXR-mediated diseases including cardiovascular disease, atherosclerosis, arteriosclerosis, hypercholesterolemia, hyperlipidemia, chronic hepatitis disease, chronic Liver diseases, gastrointestinal diseases, kidney diseases, cardiovascular diseases, metabolic diseases, cancers (such as colorectal cancer) or nerve signs such as stroke, have a wide range of medical applications, and are expected to be developed into a new generation of FXR modulators.
本发明一方面提供了一种具有如下式(I)结构的化合物、其立体异构体或其药学上可接受盐：In one aspect, the invention provides a compound having the structure of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
Figure PCTCN2016111652-appb-000003
Figure PCTCN2016111652-appb-000003
其中，among them,
X选自S或O；X is selected from S or O;
Y选自CR6或N；Y is selected from CR 6 or N;
Z选自CR6、N或NO；Z is selected from CR 6 , N or NO;
Ar选自C5-10芳基或5-10元杂芳基，任选进一步被一个或多个选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10 芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR7、-C0-8-O-R8、-C0-8-C(O)OR8、-C0-8-C(O)R8、-C0-8-O-C(O)R9、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R9或-N(R10)-C(O)OR8的取代基所取代，Ar is selected from C 5-10 aryl or 5-10 membered heteroaryl, optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, azide, C 1-8 alkyl, C 2 - 8 -alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylsulfide Base, -C 0-8 -S(O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -C(O)R 8 , -C 0-8 -OC(O)R 9 , -C 0-8 -NR 10 R 11 , -C 0-8 -C(O)NR 10 R 11 , -N(R 10 )-C(O Substituting a substituent of R 9 or -N(R 10 )-C(O)OR 8 ,
再任选进一步被一个或多个选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR7、-C0-8-O-R8、-C0-8-C(O)OR8、-C0-8-C(O)R8、-C0-8-O-C(O)R9、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R9或-N(R10)-C(O)OR8的取代基所取代；Then optionally further substituted with one or more groups selected from halo, cyano, nitro, azido, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, a halogen substituted C 1 to -8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5 -10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 - S(O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -C(O)R 8 , -C 0-8 -OC (O)R 9 , -C 0-8 -NR 10 R 11 , -C 0-8 -C(O)NR 10 R 11 , -N(R 10 )-C(O)R 9 or -N(R Substituted by a substituent of 10 )-C(O)OR 8 ;
R选自C3-8环烷基或3-8元杂环基，任选进一步被一个或多个选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR7、-C0-8-O-R8、-C0-8-C(O)OR8、-C0-8-C(O)R8、-C0-8-O-C(O)R9、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R9或-N(R10)-C(O)OR8的取代基所取代；R is selected from C 3-8 cycloalkyl or 3-8 membered heterocyclyl, optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, azide, C 1-8 alkyl, C 2 8 -alkenyl, C 2-8 alkynyl, halogen-substituted C 1-8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3 -8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy Base, 5-10 membered heteroarylthio group, -C 0-8 -S(O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -C(O)R 8 , -C 0-8 -OC(O)R 9 , -C 0-8 -NR 10 R 11 , -C 0-8 -C(O)NR 10 R 11 , Substituted with a substituent of -N(R 10 )-C(O)R 9 or -N(R 10 )-C(O)OR 8 ;
R1、R2、R3、R4、R5、R6各自独立的选自氢、氘、卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR7、-C0-8-O-R8、-C0-8-C(O)OR8、-C0-8-C(O)R8、-C0-8-O-C(O)R9、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R9或-N(R10)-C(O)OR8，R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen, hydrazine, halogen, cyano, nitro, azide, C 1-8 alkyl, C 2-8 chain. Alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5 10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -C(O)R 8 ,- C 0-8 -OC(O)R 9 , -C 0-8 -NR 10 R 11 , -C 0-8 -C(O)NR 10 R 11 , -N(R 10 )-C(O)R 9 or -N(R 10 )-C(O)OR 8 ,
任选进一步被一个或多个选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR7、-C0-8-O-R8、-C0-8-C(O)OR8、-C0-8-C(O)R8、-C0-8-O-C(O)R9、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R9或-N(R10)-C(O)OR8的取代基所取代；Optionally further substituted with one or more groups selected from halo, cyano, nitro, azido, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, a halogen substituted C 1- 8- alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5 - 10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S (O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -C(O)R 8 , -C 0-8 -OC( O) R 9 , -C 0-8 -NR 10 R 11 , -C 0-8 -C(O)NR 10 R 11 , -N(R 10 )-C(O)R 9 or -N(R 10 Substituted by a substituent of -C(O)OR 8 ;
R7选自氢、氘、C1-8烷基、C2-8链烯基、C3-8环烷基、卤取代C1-8烷基、苯基、对甲基苯基、氨基、单C1-8烷基氨基、二C1-8烷基氨基或C1-8烷酰氨基；R 7 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 2-8 alkenyl, C 3-8 cycloalkyl, halogen substituted C 1-8 alkyl, phenyl, p-methylphenyl, amino , a mono C 1-8 alkylamino group, a di C 1-8 alkylamino group or a C 1-8 alkanoylamino group;
R8选自氢、氘、C1-8烷基、C3-8环烷基、卤取代C1-8烷基或羟取代C1-8烷基；R 8 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 3-8 cycloalkyl, halogen substituted C 1-8 alkyl or hydroxy substituted C 1-8 alkyl;
R9选自氢、氘、C1-8烷基、C1-8烷氧基、C3-8环烷基、C3-8环烷氧基、卤取代C1-8烷基、卤取代C1-8烷氧基、羟取代C1-8烷基或羟取代C1-8烷氧基；R 9 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, halogen substituted C 1-8 alkyl, halogen Substituting a C 1-8 alkoxy group, a hydroxy-substituted C 1-8 alkyl group or a hydroxy-substituted C 1-8 alkoxy group;
R10、R11各自独立的选自氢、氘、羟基、氨基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、C5-10芳基、5-10元杂芳基或C1-8烷酰基，R 10 and R 11 are each independently selected from the group consisting of hydrogen, hydrazine, hydroxy, amino, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3 -8 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group or C 1-8 alkanoyl group,
任选进一步被一个或多个选自卤素、羟基、巯基、氰基、硝基、乙酰氨基、 叠氮基、磺酰基、甲磺酰基、C1-8烷基、三氟甲基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、C1-8烷氧基、C1-8烷氧羰基、C1-8烷基羰基、C1-8烷基羰基氧基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、氨基、单C1-8烷基氨基或二C1-8烷基氨基的取代基所取代；Optionally further substituted with one or more substituents selected from halo, hydroxy, mercapto, cyano, nitro, acetamido, azido, a sulfonyl group, mesyl group, C 1-8 alkyl, trifluoromethyl, C 2 8 -alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 1-8 alkoxy, C 1-8 alkoxycarbonyl, C 1-8 Alkylcarbonyl, C 1-8 alkylcarbonyloxy, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, amino, mono C 1-8 alkylamino or di C Substituted by a substituent of a 1-8 alkylamino group;
m为0、1或2；m is 0, 1 or 2;
r为0、1或2。r is 0, 1, or 2.
作为进一步优选的方案，所述式(I)化合物、其立体异构体或其药学上可接受盐，Y选自CR6；As a further preferred embodiment, the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, Y is selected from CR 6 ;
Ar选自选自C6-10芳基或6-10元杂芳基，任选进一步被一个或多个选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR7、-C0-8-O-R8、-C0-8-C(O)OR8、-C0-8-C(O)R8、-C0-8-O-C(O)R9、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R9或-N(R10)-C(O)OR8的取代基所取代，Ar is selected from a C 6-10 aryl group or a 6-10 membered heteroaryl group, optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl group, C 2-8 alkynyl group, C 3-8 cycloalkyl group, 3-8 membered heterocyclic group, 3-8 membered heterocyclic oxy group, 3-8 membered heterocyclic thio group , C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroaryl Thiothio group, -C 0-8 -S(O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -C(O) R 8, -C 0-8 -OC (O ) R 9, -C 0-8 -NR 10 R 11, -C 0-8 -C (O) NR 10 R 11, -N (R 10) -C Substituted by a substituent of (O)R 9 or -N(R 10 )-C(O)OR 8 ,
再任选进一步被一个或多个选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR7、-C0-8-O-R8、-C0-8-C(O)OR8、-C0-8-C(O)R8、-C0-8-O-C(O)R9、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R9或-N(R10)-C(O)OR8的取代基所取代；Then optionally further substituted with one or more groups selected from halo, cyano, nitro, azido, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, a halogen substituted C 1 to -8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5 -10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 - S(O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -C(O)R 8 , -C 0-8 -OC (O)R 9 , -C 0-8 -NR 10 R 11 , -C 0-8 -C(O)NR 10 R 11 , -N(R 10 )-C(O)R 9 or -N(R Substituted by a substituent of 10 )-C(O)OR 8 ;
R选自C3-6环烷基或3-6元杂环基，任选进一步被一个或多个选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR7、-C0-8-O-R8、-C0-8-C(O)OR8、-C0-8-C(O)R8、-C0-8-O-C(O)R9、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R9或-N(R10)-C(O)OR8的取代基所取代；R is selected from C 3-6 cycloalkyl or 3-6 membered heterocyclyl, optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, azide, C 1-8 alkyl, C 2 8 -alkenyl, C 2-8 alkynyl, halogen-substituted C 1-8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3 -8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy Base, 5-10 membered heteroarylthio group, -C 0-8 -S(O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -C(O)R 8 , -C 0-8 -OC(O)R 9 , -C 0-8 -NR 10 R 11 , -C 0-8 -C(O)NR 10 R 11 , Substituted with a substituent of -N(R 10 )-C(O)R 9 or -N(R 10 )-C(O)OR 8 ;
R1、R2、R4、R5、R6各自独立的选自氢、氘、卤素、氰基、硝基、叠氮基、C1-8烷基、卤取代C1-8烷基、卤取代C1-8烷氧基、C2-8链烯基、C2-8链炔基、C3-8环烷基、卤取代C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR7、-C0-8-O-R8、-C0-8-C(O)OR8、-C0-8-C(O)R8、-C0-8-O-C(O)R9、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R9或-N(R10)-C(O)OR8；R 1 , R 2 , R 4 , R 5 , R 6 are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-8 alkyl, halo-substituted C 1-8 alkyl Halogen substituted C 1-8 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, halogen substituted C 3-8 cycloalkyl, 3-8 membered Cyclo, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5- 10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 7 , -C 0-8 -OR 8 ,- C 0-8 -C(O)OR 8 , -C 0-8 -C(O)R 8 , -C 0-8 -OC(O)R 9 , -C 0-8 -NR 10 R 11 ,- C 0-8 -C(O)NR 10 R 11 , -N(R 10 )-C(O)R 9 or -N(R 10 )-C(O)OR 8 ;
m为0。 m is 0.
作为进一步优选的方案，所述式(I)化合物、其立体异构体或其药学上可接受盐，Y选自CR6；As a further preferred embodiment, the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, Y is selected from CR 6 ;
Ar选自如下结构：Ar is selected from the following structures:
Figure PCTCN2016111652-appb-000004
Figure PCTCN2016111652-appb-000004
任选进一步被一个或多个选自卤素、C5-10芳基、5-10元杂芳基、-C0-8-O-R8、-C0-4-S(O)rR7、-C0-4-C(O)OR8、-C0-4-C(O)R8、-C0-4-O-C(O)R9或-C0-4-C(O)NR10R11的取代基所取代，再任选进一步被一个或多个选自卤素、C5-10芳基、5-10元杂芳基、-C0-4-S(O)rR7、-C0-4-C(O)OR8、-C0-4-C(O)R8、-C0-4-O-C(O)R9或-C0-4-C(O)NR10R11的取代基所取代；Optionally further selected from one or more selected from the group consisting of halogen, C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -OR 8 , -C 0-4 -S(O) r R 7 , -C 0-4 -C(O)OR 8 , -C 0-4 -C(O)R 8 , -C 0-4 -OC(O)R 9 or -C 0-4 -C(O)NR Substituted by a substituent of 10 R 11 , optionally further selected from one or more selected from the group consisting of halogen, C 5-10 aryl, 5-10 membered heteroaryl, -C 0-4 -S(O) r R 7 , -C 0-4 -C(O)OR 8 , -C 0-4 -C(O)R 8 , -C 0-4 -OC(O)R 9 or -C 0-4 -C(O) Substituted by a substituent of NR 10 R 11 ;
R选自如下结构：
Figure PCTCN2016111652-appb-000005
R is selected from the following structures:
Figure PCTCN2016111652-appb-000005
任选进一步被一个或多个选自卤素、巯基、-C0-4-O-R8或-C0-4-NR10R11的取代基所取代；Optionally further substituted with one or more substituents selected from halogen, fluorenyl, -C 0-4 -OR 8 or -C 0-4 -NR 10 R 11 ;
R1、R2、R4、R5、R6各自独立的选自氢、氘、卤素、C1-4烷基、卤取代C1-4烷基、卤取代C1-8烷氧基、C2-4链烯基、C2-4链炔基、C3-6环烷基、卤取代C3-6环烷基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、-C0-4-S(O)rR7、-C0-4-O-R8、-C0-4-C(O)OR8、-C0-4-C(O)R8、-C0-4-O-C(O)R9、-C0-4-NR10R11、-C0-4-C(O)NR10R11、-N(R10)-C(O)R9或-N(R10)-C(O)OR8；R 1 , R 2 , R 4 , R 5 and R 6 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-4 alkyl, halo-substituted C 1-4 alkyl, halo-substituted C 1-8 alkoxy. , C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halogen substituted C 3-6 cycloalkyl, 3-6 membered heterocyclic, 3-6 membered heterocyclic Oxy, 3-6 membered heterocyclylthio, -C 0-4 -S(O) r R 7 , -C 0-4 -OR 8 , -C 0-4 -C(O)OR 8 ,- C 0-4 -C(O)R 8 , -C 0-4 -OC(O)R 9 , -C 0-4 -NR 10 R 11 , -C 0-4 -C(O)NR 10 R 11 , -N(R 10 )-C(O)R 9 or -N(R 10 )-C(O)OR 8 ;
m为0。m is 0.
作为进一步优选的方案，所述式(I)化合物、其立体异构体或其药学上可接受盐，选自式(Ⅱ)化合物：As a further preferred embodiment, the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is selected from the group consisting of the compound of the formula (II):
Figure PCTCN2016111652-appb-000006
Figure PCTCN2016111652-appb-000006
其中，Ar选自如下结构：Wherein Ar is selected from the following structures:
Figure PCTCN2016111652-appb-000007
Figure PCTCN2016111652-appb-000007
任选进一步被一个或多个选自氟、氯、羧基、磺酰基、甲磺酰基、异丙磺酰基、甲氧羰基、乙氧羰基、异丙氧羰基、乙酰基或选自如下结构的取代基所取代；Optionally further substituted by one or more selected from the group consisting of fluorine, chlorine, carboxyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, acetyl or a structure selected from Substituted by
Figure PCTCN2016111652-appb-000008
Figure PCTCN2016111652-appb-000008
R选自如下结构：
Figure PCTCN2016111652-appb-000009
R is selected from the following structures:
Figure PCTCN2016111652-appb-000009
任选进一步被一个或多个选自羟基、巯基、甲氧基、乙氧基或氨基的取代基所取代；Optionally further substituted with one or more substituents selected from hydroxy, thiol, methoxy, ethoxy or amino;
R1选自氢、氘、甲基、乙基、异丙基、三氟甲基、烯丙基、乙炔基、环丙基、甲氧基、乙氧基、异丙氧基或氨基；R 1 is selected from the group consisting of hydrogen, hydrazine, methyl, ethyl, isopropyl, trifluoromethyl, allyl, ethynyl, cyclopropyl, methoxy, ethoxy, isopropoxy or amino;
R2选自氢、氘、氟、氯、羟基、巯基、甲基、乙基、异丙基、三氟甲基、烯丙基、乙炔基、环丙基、环丁基、甲氧基、乙氧基、异丙氧基或氨基。R 2 is selected from the group consisting of hydrogen, hydrazine, fluorine, chlorine, hydroxy, decyl, methyl, ethyl, isopropyl, trifluoromethyl, allyl, ethynyl, cyclopropyl, cyclobutyl, methoxy, Ethoxy, isopropoxy or amino.
R4、R5各自独立的选自氢、氟、氯、甲基、乙基、异丙基、三氟甲基、环丙基、甲氧基或乙氧基。R 4 and R 5 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, methoxy or ethoxy.
作为最优方案，所述式(I)化合物、其立体异构体或其药学上可接受盐，选自如下化合物：Preferably, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
Figure PCTCN2016111652-appb-000010
Figure PCTCN2016111652-appb-000010
Figure PCTCN2016111652-appb-000011
Figure PCTCN2016111652-appb-000011
作为进一步优选的方案，所述式(I)化合物、其立体异构体或其药学上可接受盐，选自式(Ⅲ)化合物：As a further preferred embodiment, the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is selected from the group consisting of the compound of the formula (III):
Figure PCTCN2016111652-appb-000012
Figure PCTCN2016111652-appb-000012
其中，among them,
Ar选自如下结构：Ar is selected from the following structures:
Figure PCTCN2016111652-appb-000013
Figure PCTCN2016111652-appb-000013
任选进一步被一个或多个选自卤素、苯基、-C0-8-O-R8、-C0-4-S(O)rR7、-C0-4-C(O)OR8、-C0-4-C(O)R8、-C0-4-O-C(O)R9、-C0-4-C(O)NR10R11或选自如下结构的取代基所取代； Optionally further selected from one or more selected from the group consisting of halogen, phenyl, -C 0-8 -OR 8 , -C 0-4 -S(O) r R 7 , -C 0-4 -C(O)OR 8 , -C 0-4 -C(O)R 8 , -C 0-4 -OC(O)R 9 , -C 0-4 -C(O)NR 10 R 11 or a substituent selected from the following structures Replace
Figure PCTCN2016111652-appb-000014
Figure PCTCN2016111652-appb-000014
R选自如下结构：
Figure PCTCN2016111652-appb-000015
R is selected from the following structures:
Figure PCTCN2016111652-appb-000015
任选进一步被一个或多个选自卤素、巯基、-C0-4-O-R8或-C0-4-NR10R11的取代基所取代；Optionally further substituted with one or more substituents selected from halogen, fluorenyl, -C 0-4 -OR 8 or -C 0-4 -NR 10 R 11 ;
R4、R5各自独立的选自氢、氘、卤素、C1-4烷基、卤取代C1-4烷基、卤取代C1-8烷氧基、C2-4链烯基、C2-4链炔基、C3-6环烷基、卤取代C3-6环烷基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、-C0-4-S(O)rR7、-C0-4-O-R8、-C0-4-C(O)OR8、-C0-4-C(O)R8、-C0-4-O-C(O)R9、-C0-4-NR10R11、-C0-4-C(O)NR10R11、-N(R10)-C(O)R9或-N(R10)-C(O)OR8。R 4 and R 5 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-4 alkyl, halo-substituted C 1-4 alkyl, halo-substituted C 1-8 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halogen substituted C 3-6 cycloalkyl, 3-6 membered heterocyclic, 3-6 membered heterocyclyloxy, 3-6 membered heterocyclic ring Thiothio group, -C 0-4 -S(O) r R 7 , -C 0-4 -OR 8 , -C 0-4 -C(O)OR 8 , -C 0-4 -C(O) R 8 , -C 0-4 -OC(O)R 9 , -C 0-4 -NR 10 R 11 , -C 0-4 -C(O)NR 10 R 11 , -N(R 10 )-C (O) R 9 or -N(R 10 )-C(O)OR 8 .
作为更进一步优选的方案，所述所述式(I)化合物、其立体异构体或其药学上可接受盐，选自式(Ⅲa)、(Ⅲb)、(Ⅲc)或(Ⅲd)化合物：As a still further preferred embodiment, the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is selected from the group consisting of the compound of the formula (IIIa), (IIIb), (IIIc) or (IIId):
Figure PCTCN2016111652-appb-000016
Figure PCTCN2016111652-appb-000016
其中，Ar选自如下结构：Wherein Ar is selected from the following structures:
Figure PCTCN2016111652-appb-000017
Figure PCTCN2016111652-appb-000017
任选进一步被一个或多个选自氟、氯、甲氧基、乙氧基、羧基、磺酰基、甲磺酰基、异丙磺酰基、甲氧羰基、乙氧羰基、异丙氧羰基、乙酰基或选自如下结构的取代基所取代；Optionally further one or more selected from the group consisting of fluorine, chlorine, methoxy, ethoxy, carboxy, sulfonyl, methylsulfonyl, isopropylsulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, acetyl Substituted or substituted with a substituent selected from the following structures;
Figure PCTCN2016111652-appb-000018
Figure PCTCN2016111652-appb-000018
R4、R5各自独立的选自氢、氟、氯、甲基、乙基、异丙基、三氟甲基、三氟甲氧基、二氟甲氧基、环丙基、甲氧基或乙氧基。R 4 and R 5 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl, methoxy. Or ethoxylated.
最为最优方案，所述式(I)化合物、其立体异构体或其药学上可接受盐，选自如下化合物： Most preferably, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
Figure PCTCN2016111652-appb-000019
Figure PCTCN2016111652-appb-000019
Figure PCTCN2016111652-appb-000020
Figure PCTCN2016111652-appb-000020
Figure PCTCN2016111652-appb-000021
Figure PCTCN2016111652-appb-000021
本发明另一方面提供药物组合物，其包括治疗有效剂量的前述的式(I)化合物、其立体异构体或其药学上可接受盐及可药用的载体。Another aspect of the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the above formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
本发明另一方面提供了前述式(I)化合物、其立体异构体或其药学上可接受盐，或前述的药物组合物在制备用于预防或治疗FXR介导的疾病或状况的药物中的应用；所述FXR介导的疾病或状况优选自心血管疾病、动脉粥样硬化、动脉硬化、高胆甾醇血、高血脂慢性肝炎疾病、慢性肝病、胃肠疾病、肾病、心血管疾病、代谢疾病、癌症(例如结直肠癌)或神经迹象如中风。According to another aspect of the present invention, there is provided a compound of the above formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, in the manufacture of a medicament for preventing or treating a FXR-mediated disease or condition The FXR-mediated disease or condition is preferably selected from cardiovascular disease, atherosclerosis, arteriosclerosis, hypercholesterolemia, hyperlipidemia, chronic hepatitis disease, chronic liver disease, gastrointestinal disease, kidney disease, cardiovascular disease, Metabolic disease, cancer (such as colorectal cancer) or nerve signs such as stroke.
作为进一步优选的方案，所述慢性肝病选自乙肝、原发性硬化(PBC)、脑脏性黄瘤症(CTX)、原发性硬化性胆囊炎(PSC)、药物导致的胆汁郁积、妊娠肝内胆汁淤积症、肠外吸收相关胆汁郁积(PNAC)、细菌过度生长或脓血症胆汁郁积、自身免疫肝炎、慢性病毒性肝炎、酒精性肝病、非酒精性脂肪肝疾病(NAFLD)、 非酒精性脂肪性肝炎(NASH)、肝移植相关移植物抗宿主病、活供体肝移植再生、先天性肝纤维化、胆总管结石、肉芽性肝病、肝内或外恶性肿瘤、Sjogren综合征、结节病、Wilson's疾病、Gaucher's疾病、血色病或α1一抗膜蛋白酶缺乏症；所述胃肠疾病优选自炎症性肠病(IBD)(包括Crohn's疾病和溃病性肠炎)、肠易激综合征(IBS)、细菌过度生长、营养吸收不良、反射后结肠炎或微小性结肠炎；所述肾病优选自糖尿病肾病、局灶节段性肾小球硬化症(FSGS)、高血压肾病、慢性肾小球炎、慢性移植性肾小球病、慢性间质性肾炎或多囊肾病；所述心血管疾病优选自动脉硬化症、动脉硬化、血脂障碍、高胆固醇血症或高甘油三酯血症；所述代谢疾病优选自胰岛素抗性、I型糖尿病、II型糖尿病或肥胖。As a further preferred embodiment, the chronic liver disease is selected from the group consisting of hepatitis B, primary sclerosis (PBC), cerebral xanthoma (CTX), primary sclerosing cholecystitis (PSC), drug-induced cholestasis, pregnancy Intrahepatic cholestasis, extraintestinal absorption-related cholestasis (PNAC), bacterial overgrowth or sepsis cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), Nonalcoholic steatohepatitis (NASH), liver graft-related graft-versus-host disease, live donor liver transplant regeneration, congenital liver fibrosis, common bile duct stones, granulomatous liver disease, intrahepatic or extraneous malignancy, Sjogren syndrome , sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis or alpha 1 anti-membrane protein deficiency; the gastrointestinal disease is preferably from inflammatory bowel disease (IBD) (including Crohn's disease and ulcerative enteritis), irritable bowel Syndrome (IBS), bacterial overgrowth, malnutrition, post-reflex colitis or microcolitis; the kidney disease is preferably from diabetic nephropathy, focal segmental glomerulosclerosis (FSGS), hypertensive nephropathy, Chronic glomerulitis, chronic allograft glomerulopathy, chronic interstitial nephritis or polycystic kidney disease; the cardiovascular disease is preferably from arteriosclerosis, arteriosclerosis, dyslipidemia, hypercholesterolemia or hypertriglyceridemia The metabolic disease is preferably selected from insulin resistance, type I diabetes, type II diabetes or obesity.
本发明另一方面提供了一种预防或治疗FXR介导的疾病或状况的方法，包括施用治疗有效量的前述的式(I)化合物、其立体异构体或其药学上可接受盐，或前述的药物组合物。Another aspect of the invention provides a method of preventing or treating a FXR-mediated disease or condition comprising administering a therapeutically effective amount of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or The aforementioned pharmaceutical composition.
具体实施方式detailed description
详细说明：除非有相反陈述，下列用在说明书和权利要求书中的术语具有下述含义。DETAILED DESCRIPTION: Unless otherwise stated, the following terms used in the specification and claims have the following meanings.
“C1-8烷基”指包括1至8个碳原子的直链烷基和含支链烷基，烷基指饱和的脂族烃基团，C0-8是指不含碳原子或者C1-8烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1，1-二甲基丙基、1，2-二甲基丙基、2，2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1，1，2-三甲基丙基、1，1-二甲基丁基、1，2-二甲基丁基、2，2-二甲基丁基、1，3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2，3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2，3-二甲基戊基、2，4-二甲基戊基、2，2-二甲基戊基、3，3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2，3-二甲基己基、2，4-二甲基己基、2，5-二甲基己基、2，2-二甲基己基、3，3-二甲基己基、4，4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基或其各种支链异构体等。"C 1-8 alkyl" means a straight-chain alkyl group having 1 to 8 carbon atoms and a branched alkyl group, the alkyl group means a saturated aliphatic hydrocarbon group, and C 0-8 means no carbon atom or C. 1-8 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 , 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl , 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-di Methylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl , 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethyl Hexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branches thereof Isomers, etc.
烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选为一个或多个以下基团，独立地选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR7、-C0-8-O-R8、-C0-8-C(O)OR8、-C0-8-C(O)R8、-C0-8-O-C(O)R9、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R9或-N(R10)-C(O)OR8的取代基所取代；The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from the group consisting of halogen, cyano, and nitrate. Base, azido, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered Cyclooxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5- 10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O )OR 8 , -C 0-8 -C(O)R 8 , -C 0-8 -OC(O)R 9 , -C 0-8 -NR 10 R 11 , -C 0-8 -C(O Substituting a substituent of NR 10 R 11 , -N(R 10 )-C(O)R 9 or -N(R 10 )-C(O)OR 8 ;
“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，“C3-8环烷基”指包 括3至8个碳原子的环烷基，“5-10元环烷基”指包括5至10个碳原子的环烷基，例如："Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and "C 3-8 cycloalkyl" refers to a cycloalkyl group of 3 to 8 carbon atoms, "5-10 membered ring.""Alkyl" means a cycloalkyl group of 5 to 10 carbon atoms, for example:
单环环烷基的非限制性实施例包含环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等。Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptene Alkenyl, cyclooctyl and the like.
多环环烷基包括螺环、稠环和桥环的环烷基。“螺环烷基”指单环之间共用一个碳原子(称螺原子)的多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基基或多螺环烷基，螺环烷基的非限制性实施例包含：Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups. "Spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (called a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. The spirocycloalkyl group is divided into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group according to the number of shared spiro atoms between the ring and the ring. Non-limiting examples of spirocycloalkyl groups include:
Figure PCTCN2016111652-appb-000022
Figure PCTCN2016111652-appb-000022
“稠环烷基”指***中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，稠环烷基的非限制性实施例包含："Fused cycloalkyl" refers to an all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but None of the rings have a fully conjugated π-electron system. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl groups, and non-limiting examples of fused cycloalkyl groups include:
Figure PCTCN2016111652-appb-000023
Figure PCTCN2016111652-appb-000023
“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，桥环烷基的非限制性实施例包含："Bridge cycloalkyl" refers to an all-carbon polycyclic group in which two rings share two carbon atoms that are not directly bonded, which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system . Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. Non-limiting examples of bridged cycloalkyl groups include:
Figure PCTCN2016111652-appb-000024
Figure PCTCN2016111652-appb-000024
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实施例包括茚满基、四氢萘基、苯并环庚烷基等。The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydrogen Naphthyl, benzocycloheptyl and the like.
环烷基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR7、-C0-8-O-R8、-C0-8-C(O)OR8、-C0-8-C(O)R8、-C0-8-O-C(O)R9、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R9或-N(R10)-C(O)OR8 Cycloalkyl may optionally be substituted or unsubstituted. When substituted, the substituent is preferably one or more groups independently selected from halogen, cyano, nitro, azido, C 1- 8- alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclic oxy, 3-8 Heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5 -10-membered heteroarylthio, -C 0-8 -S(O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -C(O)R 8 , -C 0-8 -OC(O)R 9 , -C 0-8 -NR 10 R 11 , -C 0-8 -C(O)NR 10 R 11 , -N( R 10 )-C(O)R 9 or -N(R 10 )-C(O)OR 8
“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其中一个或多个环 原子选自氮、氧或S(O)r(其中r是整数0、1、2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。“5-10元杂环基”指包含5至10个环原子的环基，“3-8元杂环基”指包含3至8个环原子的环基。"Heterocyclyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O) r (wherein r is an integer of 0, 1, 2 a hetero atom, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. The "5-10 membered heterocyclic group" means a ring group containing 5 to 10 ring atoms, and the "3-8 membered heterocyclic group" means a ring group containing 3 to 8 ring atoms.
单环杂环基的非限制性实施例包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like.
多环杂环基包括螺环、稠环和桥环的杂环基。“螺杂环基”指单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子选自氮、氧或S(O)r(其中r是整数0、1、2)的杂原子，其余环原子为碳。这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。根据环与环之间共用螺原子的数目将螺环烷基分为单螺杂环基、双螺杂环基或多螺杂环基。螺环烷基的非限制性实施例包含：Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups. "Spiroheterocyclyl" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer) The heteroatoms of 0, 1, 2), and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. The spirocycloalkyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspiroheterocyclic group depending on the number of common spiro atoms between the ring and the ring. Non-limiting examples of spirocycloalkyl groups include:
Figure PCTCN2016111652-appb-000025
Figure PCTCN2016111652-appb-000025
“稠杂环基”指***中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***，其中一个或多个环原子选自氮、氧或S(O)r(其中r是整数0、1、2)的杂原子，其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环稠杂环烷基，稠杂环基的非限制性实施例包含："Fused heterocyclyl" refers to a polycyclic heterocyclic group in which each ring of the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bonds, but none The ring has a fully conjugated pi-electron system in which one or more ring atoms are selected from the group consisting of nitrogen, oxygen or S(O) r (wherein r is an integer of 0, 1, 2) heteroatoms, the remaining ring atoms being carbon. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups, and non-limiting examples of fused heterocyclic groups include:
Figure PCTCN2016111652-appb-000026
Figure PCTCN2016111652-appb-000026
“桥杂环基”指任意两个环共用两个不直接连接的原子的多环杂环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***，其中一个或多个环原子选自氮、氧或S(O)r(其中r是整数0、1、2)的杂原子，其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，桥环烷基的非限制性实施例包含："Bridge heterocyclyl" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly bonded, and these may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system, One or more of the ring atoms are selected from the group consisting of nitrogen, oxygen or S(O) r (wherein r is an integer of 0, 1, 2) heteroatoms, and the remaining ring atoms are carbon. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. Non-limiting examples of bridged cycloalkyl groups include:
Figure PCTCN2016111652-appb-000027
Figure PCTCN2016111652-appb-000027
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，非限制性实施例包含： The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples comprising:
Figure PCTCN2016111652-appb-000028
Figure PCTCN2016111652-appb-000028
杂环基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR7、-C0-8-O-R8、-C0-8-C(O)OR8、-C0-8-C(O)R8、-C0-8-O-C(O)R9、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R9或-N(R10)-C(O)OR8的取代基所取代；The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, cyano, nitro, azide, C 1- 8- alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclic oxy, 3-8 a heterocyclic thio group, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryl group, 5 -10-membered heteroarylthio, -C 0-8 -S(O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -C(O)R 8 , -C 0-8 -OC(O)R 9 , -C 0-8 -NR 10 R 11 , -C 0-8 -C(O)NR 10 R 11 , -N( Substituted by a substituent of R 10 )-C(O)R 9 or -N(R 10 )-C(O)OR 8 ;
“芳基”指全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，具有共轭的π电子体系的多环(即其带有相邻对碳原子的环)基团，“C5-10芳基”指含有5-10个碳的全碳芳基，“5-10元芳基”指含有5-10个碳的全碳芳基，例如苯基和萘基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，非限制性实施例包含："Aryl" means an all-carbon monocyclic or fused polycyclic (ie, a ring that shares a pair of adjacent carbon atoms) groups having a polycyclic ring of a conjugated π-electron system (ie, having a ring adjacent to a carbon atom) a group, "C 5-10 aryl" means an all-carbon aryl group having 5 to 10 carbons, and "5-10 membered aryl group" means an all-carbon aryl group having 5 to 10 carbons, such as phenyl and Naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising:
Figure PCTCN2016111652-appb-000029
Figure PCTCN2016111652-appb-000029
芳基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR7、-C0-8-O-R8、-C0-8-C(O)OR8、-C0-8-C(O)R8、-C0-8-O-C(O)R9、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R9或-N(R10)-C(O)OR8的取代基所取代；The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, cyano, nitro, azide, C 1-8 alkyl. , C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclic oxy, 3-8 membered heterocyclic Thio group, C 5-10 aryl group, C 5-10 aryloxy group, C 5-10 arylthio group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group, 5-10 yuan Heteroarylthio, -C 0-8 -S(O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -C( O) R 8 , -C 0-8 -OC(O)R 9 , -C 0-8 -NR 10 R 11 , -C 0-8 -C(O)NR 10 R 11 , -N(R 10 ) Substituted with a substituent of -C(O)R 9 or -N(R 10 )-C(O)OR 8 ;
“杂芳基”指包含1至4个杂原子的杂芳族体系，所述杂原子包括氮、氧和S(O)r(其中r是整数0、1、2)的杂原子，5-7元杂芳基指含有5-7个环原子的杂芳族体系，5-10元杂芳基指含有5-10个环原子的杂芳族体系，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一 起的环为杂芳基环，非限制性实施例包含："Heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms including nitrogen, oxygen and a hetero atom of S(O) r (where r is an integer 0, 1, 2), 5- A 7-membered heteroaryl group means a heteroaromatic system having 5 to 7 ring atoms, and a 5-10 membered heteroaryl group means a heteroaromatic system having 5 to 10 ring atoms, such as furyl, thienyl, pyridyl, Pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples comprising:
Figure PCTCN2016111652-appb-000030
Figure PCTCN2016111652-appb-000030
杂芳基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR7、-C0-8-O-R8、-C0-8-C(O)OR8、-C0-8-C(O)R8、-C0-8-O-C(O)R9、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R9或-N(R10)-C(O)OR8的取代基所取代；Heteroaryl may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more groups independently selected from halogen, cyano, nitro, azido, C 1- 8- alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclic oxy, 3-8 Heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5 -10-membered heteroarylthio, -C 0-8 -S(O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -C(O)R 8 , -C 0-8 -OC(O)R 9 , -C 0-8 -NR 10 R 11 , -C 0-8 -C(O)NR 10 R 11 , -N( Substituted by a substituent of R 10 )-C(O)R 9 or -N(R 10 )-C(O)OR 8 ;
“烯基”指由至少两个碳原子和至少一个碳-碳双键组成的如上述定义的烷基，C2-8链烯基指含有2-8个碳的直链或含支链烯基。例如乙烯基、1-丙烯基、2-丙烯基、1-，2-或3-丁烯基等。"Alkenyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, and a C 2-8 alkenyl group means a straight or branched olefin containing from 2 to 8 carbons base. For example, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.
烯基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR7、-C0-8-O-R8、-C0-8-C(O)OR8、-C0-8-C(O)R8、-C0-8-O-C(O)R9、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R9或-N(R10)-C(O)OR8的取代基所取代；The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, cyano, nitro, azide, C 1-8 alkyl. , C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclic oxy, 3-8 membered heterocyclic Thio group, C 5-10 aryl group, C 5-10 aryloxy group, C 5-10 arylthio group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group, 5-10 yuan Heteroarylthio, -C 0-8 -S(O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -C( O) R 8 , -C 0-8 -OC(O)R 9 , -C 0-8 -NR 10 R 11 , -C 0-8 -C(O)NR 10 R 11 , -N(R 10 ) Substituted with a substituent of -C(O)R 9 or -N(R 10 )-C(O)OR 8 ;
“炔基”指至少两个碳原子和至少一个碳-碳三键组成的如上所定义的烷基，C2-8链炔基指含有2-8个碳的直链或含支链炔基。例如乙炔基、1-丙炔基、2-丙炔基、1-，2-或3-丁炔基等。"Alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, and C2-8 alkynyl refers to a straight or branched alkynyl group containing from 2 to 8 carbons. . For example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.
炔基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR7、-C0-8-O-R8、-C0-8-C(O)OR8、-C0-8-C(O)R8、-C0-8-O-C(O)R9、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R9或-N(R10)-C(O)OR8的取代基所取代；The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, cyano, nitro, azide, C 1-8 alkyl. , C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclyl Thio group, C 5-10 aryl group, C 5-10 aryloxy group, C 5-10 arylthio group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group, 5-10 yuan Heteroarylthio, -C 0-8 -S(O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -C( O) R 8 , -C 0-8 -OC(O)R 9 , -C 0-8 -NR 10 R 11 , -C 0-8 -C(O)NR 10 R 11 , -N(R 10 ) Substituted with a substituent of -C(O)R 9 or -N(R 10 )-C(O)OR 8 ;
“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。C1-8烷氧基指含1-8个碳的烷基氧基，非限制性实施例包含甲氧基、乙氧基、丙氧基、丁氧基等。 "Alkoxy" means -O-(alkyl) wherein alkyl is as defined above. The C 1-8 alkoxy group means an alkyloxy group having 1-8 carbons, and the non-limiting examples include a methoxy group, an ethoxy group, a propoxy group, a butoxy group and the like.
烷氧基可以是任选取代的或未取代的，当被取代时，取代基，优选为一个或多个以下基团，独立地选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、-C0-8-S(O)rR7、-C0-8-O-R8、-C0-8-C(O)OR8、-C0-8-C(O)R8、-C0-8-O-C(O)R9、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R9或-N(R10)-C(O)OR8的取代基所取代；The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent, preferably one or more of the following groups, independently selected from the group consisting of halogen, cyano, nitro, azide, C 1 -8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 Aroheterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, -C 0-8 -S(O) r R 7 , -C 0-8 -OR 8 , -C 0- 8 -C(O)OR 8 , -C 0-8 -C(O)R 8 , -C 0-8 -OC(O)R 9 , -C 0-8 -NR 10 R 11 , -C 0- Substituted with a substituent of 8 -C(O)NR 10 R 11 , -N(R 10 )-C(O)R 9 or -N(R 10 )-C(O)OR 8 ;
“卤素”指氟、氯、溴或碘。"Halogen" means fluoro, chloro, bromo or iodo.
“PE”指石油醚。"PE" means petroleum ether.
“THF”指四氢呋喃。"THF" refers to tetrahydrofuran.
“EA”指乙酸乙酯。"EA" means ethyl acetate.
“BINAP”指(±)-2,2'-双-(二苯膦基)-1,1'-联萘。"BINAP" means (±)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl.
“CDI”指N，N-羰基二咪唑。"CDI" means N,N-carbonyldiimidazole.
“DMF”指N，N-二甲基甲酰胺。"DMF" means N,N-dimethylformamide.
“DMAP”指4-二甲氨基吡啶。"DMAP" means 4-dimethylaminopyridine.
“DIPEA”指N，N-二异丙基乙胺。"DIPEA" refers to N,N-diisopropylethylamine.
“EDCI”指1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐。"EDCI" refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
“IBX”指2-碘酰基苯甲酸。"IBX" means 2-iodobenzoic acid.
“Pd(dppf)Cl2”指[1,1'-双(二苯基磷)二茂铁]二氯化钯。"Pd(dppf)Cl 2 "" means [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.
“Pd2(dba)3”指三(二亚苄基丙酮)二钯。"Pd 2 (dba) 3 " refers to tris(dibenzylideneacetone) dipalladium.
“TBAF”指四丁基氟化铵。"TBAF" means tetrabutylammonium fluoride.
“X-phos”指2-二环己基磷-2,4,6-三异丙基联苯。"X-phos" refers to 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl.
“NCS”指N-氯代丁二酰亚胺。"NCS" means N-chlorosuccinimide.
“BPin”指嚬哪醇硼酸酯。"BPin" refers to a terpenyl borate.
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group. .
“取代的”指基团中的一个或多个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。"Substituted" means that one or more hydrogen atoms in the group are each independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。"Pharmaceutical composition" means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients. The purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
下面结合实施例对本发明做进一步详细、完整地说明，但决非限制本发明， 本发明也并非仅局限于实施例的内容。The present invention will be further described in detail and in conjunction with the embodiments, but without restricting the invention. The present invention is also not limited to the contents of the embodiments.
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用BrukerAVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代甲醇(CD3OD)和氘代氯仿(CDCl3)内标为四甲基硅烷(TMS)。The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in parts per million (ppm). The NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ). The deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ) were internally labeled as tetramethyl. Silane (TMS).
液质联用色谱LC-MS的测定用Agilent1200InfinitySeries质谱仪。HPLC的测定使用安捷伦1200DAD高压液相色谱仪(SunfireC18150×4.6mm色谱柱)和Waters2695-2996高压液相色谱仪(GiminiC18150×4.6mm色谱柱)。LC-MS was determined by LC-MS using an Agilent 1200 Infinity Series mass spectrometer. The HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，TLC采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。The thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The specification for TLC is 0.15mm~0.20mm, and the specification for separation and purification of thin layer chromatography is 0.4mm~0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.
本发明实施例中的起始原料是已知的并且可以在市场上买到，或者可以采用或按照本领域已知的方法来合成。Starting materials in the examples of the invention are known and commercially available or can be synthesized or synthesized according to methods known in the art.
在无特殊说明的情况下，本发明的所有反应均在连续的磁力搅拌下，在干燥氮气或氩气氛下进行，溶剂为干燥溶剂。Unless otherwise stated, all reactions of the present invention were carried out under continuous magnetic stirring under a dry nitrogen or argon atmosphere, and the solvent was a dry solvent.
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。氢气氛是指反应瓶连接一个约1L容积的氢气气球。An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L. The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
在无特殊说明的情况下，实施例中的溶液是指水溶液。反应的温度为室温。室温为最适宜的反应温度，为20℃～30℃。The solution in the examples means an aqueous solution unless otherwise specified. The temperature of the reaction is room temperature. The room temperature is an optimum reaction temperature of 20 ° C to 30 ° C.
实施例中的反应进程的监测采用薄层色谱法(TLC)或液质联用色谱(LC-MS)反应所使用的展开剂体系有：二氯甲烷和甲醇体系，正己烷和乙酸乙酯体系，石油醚和乙酸乙酯体系，丙酮，溶剂的体积比可根据化合物的极性不同而进行调节。柱层析的洗脱剂的体系包括：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：二氯甲烷和乙酸乙酯体系，D：乙酸乙酯和甲醇，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的氨水和醋酸等进行调节。Monitoring of the progress of the reaction in the examples using the thin layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS) reaction using the developer system: dichloromethane and methanol system, n-hexane and ethyl acetate system The volume ratio of the petroleum ether and ethyl acetate systems, acetone, and solvent can be adjusted depending on the polarity of the compound. Column chromatography eluent system includes: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: dichloromethane and ethyl acetate system, D: ethyl acetate and methanol, solvent The volume ratio is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of ammonia water and acetic acid.
一、中间体的合成First, the synthesis of intermediates
1、4-(氯甲基)-5-环丙基-3-(2,6-二氯苯基)异噻唑I-1的合成Synthesis of 1, 4-(chloromethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazole I-1
Figure PCTCN2016111652-appb-000031
Figure PCTCN2016111652-appb-000031
第一步：2,6-二氯苯腈I-1-a(10.0g，58mmol)与环丙甲酰乙酸乙酯I-1-b(9.2g,58mmol)溶于甲苯(200mL)，氮气保护下滴加SnCl4(7mL,58mmol)，室温搅拌1h，80℃继续反应2h。反应完全后用饱和碳酸氢钠水溶液淬灭，乙酸乙酯萃取两次，有机相用无水硫酸钠干燥，过滤，浓缩，柱层析纯化，得化合物I-1-c(13.0g,产率：68％)。First step: 2,6-dichlorobenzonitrile I-1-a (10.0 g, 58 mmol) and ethyl cyanoacetate I-1-b (9.2 g, 58 mmol) dissolved in toluene (200 mL), nitrogen Under the protection, SnCl 4 (7 mL, 58 mmol) was added dropwise, stirred at room temperature for 1 h, and the reaction was continued at 80 ° C for 2 h. After completion of the reaction, the mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ :68%).
LC-MS:tR＝2.76min,[M+H]+＝328.0。 LC-MS: t R = 2.76min , [M + H] + = 328.0.
第二步：化合物I-1-c(13.0g,40mmol)与四氯苯醌(9.8g,40mmol)溶于甲苯(150mL)，搅拌下加入P2S5(26.6g,120mmol)，加热回流1h。TLC监测反应完全，过滤，浓缩，柱层析纯化，得化合物I-1-d(5.8g,产率：42％)。The second step: Compound I-1-c (13.0 g, 40 mmol) and tetrachlorophenyl hydrazine (9.8 g, 40 mmol) were dissolved in toluene (150 mL), and then added to a solution of P 2 S 5 (26.6 g, 120 mmol) and heated to reflux. 1h. The reaction was completely monitored by TLC, filtered, concentrated, and purified by column chromatography to afford compound I-1-d (5.8 g, yield: 42%).
LC-MS:tR＝3.27min,[M+H]+＝342.0。 LC-MS: t R = 3.27min , [M + H] + = 342.0.
第三步：化合物I-1-d(2.8g，8.2mmol)溶于无水四氢呋喃(30mL)，冰水浴冷却，向体系加四氢铝锂(0.4g,10.6mmol)，室温反应1h。TLC监测反应完全，分别加水(0.4mL)，氢氧化钠水溶液(0.4mL,15％)和水(1.2mL)，然后加无水硫酸镁搅拌0.5h，过滤，浓缩得化合物I-1-e(2.4g,产率：97％)。The third step: Compound I-1-d (2.8 g, 8.2 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), cooled in ice-water bath, and then evaporated toluene (0.4 g, 10.6 mmol). The reaction was completely monitored by TLC, and water (0.4 mL), aqueous sodium hydroxide (0.4 mL, 15%) and water (1.2 mL) were added, and then stirred with anhydrous magnesium sulfate for 0.5h, filtered and concentrated to give compound I-1-e (2.4 g, yield: 97%).
LC-MS:tR＝2.67min,[M+H]+＝300.0。 LC-MS: t R = 2.67min , [M + H] + = 300.0.
第四步：化合物I-1-e(2.4g,8.0mmol)溶于二氯甲烷(20mL)，冰水浴下向体系加入二氯亚砜(1.7mL,24mmol)，室温反应1h。TLC监测反应完全。浓缩，柱层析纯化，得4-(氯甲基)-5-环丙基-3-(2,6-二氯苯基)异噻唑I-1(1.4g,产率：55％)。The fourth step: Compound I-1-e (2.4 g, 8.0 mmol) was dissolved in dichloromethane (20 mL), and then chlorosulfoxide (1.7 mL, 24 mmol) was added to the system, and the mixture was reacted at room temperature for 1 h. TLC monitored the reaction completely. Concentration and purification by column chromatography gave 4-(chloromethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazole I-1 (1.4 g, yield: 55%).
LC-MS:tR＝3.23min,[M+H]+＝318.0。 LC-MS: t R = 3.23min , [M + H] + = 318.0.
2、4-(氯甲基)-5-环丙基-3-(2,6-二氯苯基)异恶唑I-2的合成2. Synthesis of 4-(chloromethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole I-2
Figure PCTCN2016111652-appb-000032
Figure PCTCN2016111652-appb-000032
第一步：化合物I-2-a(10g,57.1mmol)和氢氧化钠(2.7g,68.5mmol)溶解在乙醇(100mL)和水(50mL)中，加入盐酸羟胺(4.7g,68.5mmol)，90℃下搅拌2h，反应完全后冷却，加水稀释，乙酸乙酯萃取。有机相硫酸钠干燥，旋干，得化合物I-2-b(10.5g)。The first step: Compound I-2-a (10 g, 57.1 mmol) and sodium hydroxide (2.7 g, 68.5 mmol) were dissolved in ethanol (100 mL) and water (50 mL), and hydroxylamine hydrochloride (4.7 g, 68.5 mmol) was added. After stirring at 90 ° C for 2 h, the reaction was completely cooled, diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and dried to give compound I-2-b (10.5 g).
第二步：将化合物I-2-b(10g,52.6mmol)和NCS(9.2g,69.0mmol)溶于DMF中，室温搅拌2h，加水和甲基叔丁基醚萃取，有机相用水洗两次后硫酸钠干燥，旋干，得化合物I-2-c(10.5g)。 The second step: the compound I-2-b (10g, 52.6mmol) and NCS (9.2g, 69.0mmol) were dissolved in DMF, stirred at room temperature for 2h, extracted with water and methyl tert-butyl ether, the organic phase was washed with water After drying it over sodium sulfate and dried to give compound I-2-c (10.5 g).
第三步：化合物I-2-c(10.5g,47.8mmol)和I-1-b(10.3g,71.7mmol)混合在三乙胺(40mL)中，室温搅拌过夜。加入水和乙酸乙酯萃取，有机相硫酸钠干燥，旋干，乙酸乙酯(20m)打浆，过滤，得白色固体I-2-d(7.5g)。The third step: Compound I-2-c (10.5 g, 47.8 mmol) and I-1-b (10.3 g, 71.7 mmol) were mixed in triethylamine (40 mL) and stirred at room temperature overnight. After addition of water and ethyl acetate, EtOAc (EtOAc m.
第四步：化合物I-2-d(0.5g,1.53mmol)溶解在四氢呋喃中，加入氢化铝锂(65mg,1.68mmol)，室温搅拌2h。加入水淬灭后乙酸乙酯提取，有机相旋干，得化合物I-2-e(0.5g)。The fourth step: Compound I-2-d (0.5 g, 1.53 mmol) was dissolved in tetrahydrofuran, and lithium aluminum hydride (65 mg, 1.68 mmol) was added and stirred at room temperature for 2 h. After adding water and quenching, ethyl acetate was extracted and the organic phase was dried to give compound I-2-e (0.5 g).
第五步：化合物I-2-e(0.5g,1.75mmol)溶解在二氯甲烷中，加入二氯亚砜(0.16mL)，室温下搅拌2h，然后加入水淬灭，乙酸乙酯提取，旋干，得化合物I-2(0.6g)。The fifth step: Compound I-2-e (0.5 g, 1.75 mmol) was dissolved in dichloromethane, and then added with chlorosulfoxide (0.16 mL), stirred at room temperature for 2 h, then quenched with water and ethyl acetate. Spin dry to give compound I-2 (0.6 g).
3、4-(氯甲基)-3-(2,6-二氯苯基)-5-(三氟甲基)异噻唑I-3的合成Synthesis of 3-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(trifluoromethyl)isothiazole I-3
Figure PCTCN2016111652-appb-000033
Figure PCTCN2016111652-appb-000033
第一步：称取2,6-二氯苯腈I-3-a(1.72g，10mmol)于100mL三口瓶中，加入干燥THF(13mL)。氮气氛下使溶液回流，然后分批加入活化锌粉(1.3g)。于回流状态下缓慢滴加溴乙酸乙酯(1.7mL)，回流反应1h。溶液冷却到0℃，依次滴加正丁基锂(6.8mL,1.6M)和三氟乙酸酐(1.8mL)。滴加完毕升至室温搅拌过夜。饱和氯化铵溶液淬灭反应后，乙酸乙酯萃取出有机层，有机相浓缩，柱层析分离，得到化合物I-3-b(1.25g，产率：35％，顺反异构体比例约为1:3)。First step: 2,6-Dichlorobenzonitrile I-3-a (1.72 g, 10 mmol) was weighed into a 100 mL three-necked flask, and dry THF (13 mL) was added. The solution was refluxed under a nitrogen atmosphere, and then activated zinc powder (1.3 g) was added portionwise. Ethyl bromoacetate (1.7 mL) was slowly added dropwise under reflux and refluxed for 1 h. The solution was cooled to 0 ° C, and n-butyllithium (6.8 mL, 1.6 M) and trifluoroacetic acid anhydride (1. After the dropwise addition was completed, the mixture was stirred at room temperature overnight. After quenching the saturated ammonium chloride solution, the organic layer was extracted with ethyl acetate. The organic phase was concentrated and purified by column chromatography to give compound I-3-b (1.25 g, yield: 35%, cis-trans isomer ratio About 1:3).
LC-MS:tR＝2.826min，2.926min。 LC-MS: t R = 2.826min , 2.926min.
第二步：将上述化合物I-3-b溶于甲苯(20mL)中，依次加入四氯苯醌(0.87g)和五硫化二磷(2.4g)。回流反应30min。反应液冷却后过滤。滤液浓缩，柱层析分离，得到化合物I-3-c(0.76g，产率：58％)Second step: The above compound I-3-b was dissolved in toluene (20 mL), and tetrachlorophenylhydrazine (0.87 g) and phosphorus pentasulfide (2.4 g) were successively added. The reaction was refluxed for 30 min. The reaction solution was cooled and filtered. The filtrate was concentrated and purified by column chromatography to yield compound I-3-c (0.76 g, yield: 58%)
LC-MS:tR＝3.410min； LC-MS: t R = 3.410min ;
1HNMR(400MHz,CDCl3)δ7.44-7.39(m,2H),7.35(dd,J＝9.3,6.5Hz,1H),4.22(q,J＝7.1Hz,2H),1.12(t,J＝7.1Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.44 - 7.39 (m, 2H), 7.35 (dd, J = 9.3, 6.5 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 1.12 (t, J) =7.1 Hz, 3H).
第三步：上述化合物I-3-c溶于干燥THF(8mL)中，冰水浴冷却，分批加完四氢铝锂(93mg)。室温搅拌30min。反应液用十水硫酸钠淬灭。过滤，滤液浓缩，粗产品经柱层析分离，得到化合物I-3-d(475mg，产率：70％)。The third step: the above compound I-3-c was dissolved in dry THF (8 mL), cooled in an ice-water bath, and lithium tetrahydroaluminum (93 mg) was added in portions. Stir at room temperature for 30 min. The reaction was quenched with sodium sulfate decahydrate. Filtration, the filtrate was concentrated, and the crude product was purified by column chromatography to yield Compound I-3-d (475 mg, yield: 70%).
LC-MS:tR＝2.929min； LC-MS: t R = 2.929min ;
1HNMR(400MHz,CDCl3)δ7.45(dd,J＝7.9,1.2Hz,2H),7.38(dd,J＝9.3,6.6Hz,1H),4. 60(d,J＝0.7Hz,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.45 (dd, J = 7.9, 1.2 Hz, 2H), 7.38 (dd, J = 9.3, 6.6 Hz, 1H), 4. 60 (d, J = 0.7 Hz, 2H) ).
第四步：上述化合物I-3-d溶于干燥CH2Cl2(5mL)，依次加入SOCl2(1.2mL)和DMAP(21mg)。回流反应4h。冷却，浓缩，柱层析分离，得化合物I-3(425mg，产率：85％)。Fourth step: The above compound I-3-d was dissolved in dry CH 2 Cl 2 (5 mL), and then SOCI 2 (1.2 mL) and DMAP (21 mg). The reaction was refluxed for 4 h. The mixture was cooled, concentrated, and purified tojjjjjjjj
LC-MS:tR＝3.428min； LC-MS: t R = 3.428min ;
1HNMR(400MHz,CDCl3)δ7.46(dd,J＝7.9,1.4Hz,2H),7.41(dd,J＝9.5,6.3Hz,1H),4.48(s,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.46 (dd, J = 7.9, 1.4 Hz, 2H), 7.41 (dd, J = 9.5, 6.3 Hz, 1H), 4.48 (s, 2H).
4、4-(3-羰基环丁基)苯甲酸甲酯I-4的合成Synthesis of methyl 4-(3-carbonylcyclobutyl)benzoate I-4
Figure PCTCN2016111652-appb-000034
Figure PCTCN2016111652-appb-000034
第一步：称取I-4-b(5.6g，36.64mmol)于250mL单口瓶中，加入混合溶剂THF/H2O(80mL,v/v＝9:1),依次加入间碘苯甲酸甲酯I-4-a(8.0g,30.53mmol)，碳酸铯(29.8g,91.59mmol)，三苯基膦(1.68g,6.41mmol),二氯化钯(379mg,2.14mmol)。抽换气，氮气保护下加热回流，搅拌过夜。待反应冷却后通过硅藻土过滤，并用乙酸乙酯洗涤3次，滤液经萃取后取有机层用硫酸钠干燥，浓缩，柱层析分离，得到化合物I-4-c(4.3g,产率87％)。The first step: weigh I-4-b (5.6g, 36.64mmol) in a 250mL single-mouth bottle, add the mixed solvent THF / H 2 O (80mL, v / v = 9:1), followed by the addition of m-iodobenzoic acid Methyl ester I-4-a (8.0 g, 30.53 mmol), cesium carbonate (29.8 g, 91.59 mmol), triphenylphosphine (1.68 g, 6.41 mmol), palladium chloride (379 mg, 2.14 mmol). The gas was exchanged, heated under reflux with nitrogen and stirred overnight. After the reaction was cooled, it was filtered through celite and washed with EtOAc EtOAc (EtOAc)EtOAc. 87%).
LC-MS:tR＝2.799min； LC-MS: t R = 2.799min ;
1HNMR(400MHz,CDCl3)δ8.08(t,J＝1.7Hz,1H),7.97-7.89(m,1H),7.63-7.57(m,1H),7.40(t,J＝7.7Hz,1H),6.75(dd,J＝17.6,10.9Hz,1H),5.83(dd,J＝17.6,0.6Hz,1H),5.33(d,J＝10.9Hz,1H),3.93(s,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.08 (t, J = 1.7 Hz, 1H), 7.97-7.89 (m, 1H), 7.63 - 7.57 (m, 1H), 7.40 (t, J = 7.7 Hz, 1H) ), 6.75 (dd, J = 17.6, 10.9 Hz, 1H), 5.83 (dd, J = 17.6, 0.6 Hz, 1H), 5.33 (d, J = 10.9 Hz, 1H), 3.93 (s, 3H).
第二步：称取化合物I-4-c(3.6g，22.20mmol)于500mL三口瓶中，加入干燥***(108mL)，之后加入锌粉(4.4g,66.60mmol),氮气氛下超声半小时。之后超声同时缓慢滴加溶有三氯乙酰氯(10.1g,55.49mmol)的***溶液(36mL)。加完之后，回流下超声2h。待反应液冷却后滴加水(40mL)淬灭。反应液搅拌15min后经硅藻土过滤，并用少量***洗滤。滤液有机相依次用水(40mL)，饱和碳酸氢钠溶液(40mL)，饱和食盐水洗涤，硫酸钠干燥。过滤，浓缩，得油状物(6.2g)。将此油状物溶于乙酸(40mL)，再加入锌粉(3.3g)。氮气氛下120℃加热4h。冷却后用乙酸乙酯(40mL)稀释。稀释液经硅藻土过滤后浓缩。浓缩后得油状物溶于乙酸乙酯(50mL)，依次用水(50mL)，饱和碳酸氢钠溶液(50mL)，饱和食盐水洗涤，硫酸钠干燥。过滤，浓缩，柱层析分离(PE/EA,EA:0～15％)，得化合物I-4(2.3g,产率：55％)。The second step: Weighed compound I-4-c (3.6g, 22.20mmol) in a 500mL three-necked flask, added dry ether (108mL), then added zinc powder (4.4g, 66.60mmol), ultrasonic for half an hour under nitrogen atmosphere . After that, ultrasonically, a solution of trichloroacetyl chloride (10.1 g, 55.49 mmol) in diethyl ether (36 mL) was slowly added dropwise. After the addition was completed, the ultrasound was refluxed for 2 h. After the reaction liquid was cooled, water (40 mL) was added dropwise to quench. The reaction mixture was stirred for 15 min. The organic phase of the filtrate was washed with water (40 mL) EtOAc. Filtration and concentration gave an oil (6.2 g). This oil was dissolved in acetic acid (40 mL) and then zinc powder (3.3 g). Heated at 120 ° C for 4 h under a nitrogen atmosphere. After cooling, it was diluted with ethyl acetate (40 mL). The dilution was filtered through celite and concentrated. After concentrating, the oil was evaporated, evaporated, evaporated, evaporated Filtration, concentration and column chromatography (PE/EA, EA: 0 to 15%) afforded Compound I-4 (2.3 g, yield: 55%).
LC-MS:tR＝2.453min；LC-MS: t R = 2.453 min;
1HNMR(400MHz,CDCl3)δ7.99(s,1H),7.93(d,J＝7.6Hz,1H),7.50(d,J＝7.8Hz,1H),7.43(t,J＝7.6Hz,1H),3.93(s,3H),3.79-3.69(m,1H),3.59-3.48(m,2H),3.33-3.23(m,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.99 (s, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 3.93 (s, 3H), 3.79-3.69 (m, 1H), 3.59-3.48 (m, 2H), 3.33 - 3.23 (m, 2H).
5、4-(3-羰基环丁基)苯甲酸甲酯I-5的合成 Synthesis of methyl 4-(3-carbonylcyclobutyl)benzoate I-5
Figure PCTCN2016111652-appb-000035
Figure PCTCN2016111652-appb-000035
4-(3-羰基环丁基)苯甲酸甲酯I-5的合成参照化合物I-4的制备方法。Synthesis of methyl 4-(3-carbonylcyclobutyl)benzoate I-5 Refer to the preparation method of Compound I-4.
LC-MS:tR＝2.437min；LC-MS: t R = 2.437 min;
1HNMR(400MHz,CDCl3)δ8.06-7.98(m,2H),7.37(d,J＝8.1Hz,2H),3.92(s,3H),3.80-3.67(m,1H),3.60-3.49(m,2H),3.34-3.22(m,2H)。 1 HNMR (400MHz, CDCl 3) δ8.06-7.98 (m, 2H), 7.37 (d, J = 8.1Hz, 2H), 3.92 (s, 3H), 3.80-3.67 (m, 1H), 3.60-3.49 (m, 2H), 3.34 - 3.22 (m, 2H).
6、2-氟-5-(3-羰基环丁基)苯甲酸甲酯I-6的合成。6. Synthesis of methyl 2-fluoro-5-(3-carbonylcyclobutyl)benzoate I-6.
Figure PCTCN2016111652-appb-000036
Figure PCTCN2016111652-appb-000036
2-氟-5-(3-羰基环丁基)苯甲酸甲酯I-6的合成参照化合物I-4的制备方法。Synthesis of methyl 2-fluoro-5-(3-carbonylcyclobutyl)benzoate I-6 Refer to the preparation method of Compound I-4.
1HNMR(400MHz,CDCl3)δ7.79(dd,J＝6.7,2.5Hz,1H),7.42-7.34(m,1H),7.07(dd,J＝10.3,8.6Hz,1H),3.87(s,3H),3.62(m,1H),3.52-3.39(m,2H),3.24-3.10(m,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.79 (dd, J = 6.7, 2.5 Hz, 1H), 7.42 - 7.34 (m, 1H), 7.07 (dd, J = 10.3, 8.6 Hz, 1H), 3.87 (s , 3H), 3.62 (m, 1H), 3.52-3.39 (m, 2H), 3.24-3.10 (m, 2H).
7、3-氟-5-(3-羰基环丁基)苯甲酸甲酯I-7的合成Synthesis of methyl 3-fluoro-5-(3-carbonylcyclobutyl)benzoate I-7
Figure PCTCN2016111652-appb-000037
Figure PCTCN2016111652-appb-000037
3-氟-5-(3-羰基环丁基)苯甲酸甲酯I-7的合成参照化合物I-4的制备方法。Synthesis of methyl 3-fluoro-5-(3-carbonylcyclobutyl)benzoate I-7 Refer to the preparation method of Compound I-4.
1HNMR(400MHz,CDCl3)δ7.78(s,1H),7.61(ddd,J＝8.9,2.4,1.4Hz,1H),7.20(ddd,J＝9.2,2.9,1.2Hz,1H),3.94(s,3H),3.73(dt,J＝16.2,8.3Hz,1H),3.59-3.50(m,2H),3.31-3.23(m,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.78 (s, 1H), 7.61 (ddd, J = 8.9, 2.4, 1.4 Hz, 1H), 7.20 (ddd, J = 9.2, 2.9, 1.2 Hz, 1H), 3.94 (s, 3H), 3.73 (dt, J = 16.2, 8.3 Hz, 1H), 3.59-3.50 (m, 2H), 3.31-3.23 (m, 2H).
8、4-(3-羰基环丁基)邻苯二甲酸二甲酯I-8的合成Synthesis of dimethyl 4-(3-carbonylcyclobutyl) phthalate I-8
Figure PCTCN2016111652-appb-000038
Figure PCTCN2016111652-appb-000038
第一步：3-溴苯甲酸酐I-8-a(5675mg，25.0mmol)溶于H2SO4/MeOH(100mL，1％)，加热回流，反应过夜。冷却至室温，加入NaOH水溶液中和。浓缩，除去甲醇，乙酸乙酯萃取。过滤，浓缩，得化合物I-8-b(5886mg，产率：86％)。The first step: 3-bromobenzoic anhydride I-8-a (5675 mg, 25.0 mmol) was dissolved in H 2 SO 4 /MeOH (100 mL, 1%). It was cooled to room temperature and neutralized by adding an aqueous NaOH solution. Concentrate, remove methanol and extract with ethyl acetate. Filtration and concentration gave Compound I-8-b (5886mg, yield: 86%).
1HNMR(400MHz,CDCl3)δ7.84(d,J＝1.9Hz,1H),7.67(dd,J＝8.3,1.9Hz,1H),7.62(d,J＝8.3Hz,1H),3.92(s,3H),3.90(s,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.84 (d, J = 1.9 Hz, 1H), 7.67 (dd, J = 8.3, 1.9 Hz, 1H), 7.62 (d, J = 8.3 Hz, 1H), 3.92 ( s, 3H), 3.90 (s, 3H).
第二步：称取化合物I-8-b(5886mg，21.6mmol)以及I-4-b(4980mg，32.3mmol)溶于1,4-二氧六环(100mL)，氮气保护下加入Pd(dppf)Cl2(1577mg，2.16mmol)和Cs2CO3(14.0g，43.1mmol)，加热到100℃反应过夜。反应完全后冷却至室温，过 滤，EtOAc洗涤。滤液浓缩，粗品经柱层析分离，得化合物I-8-c(4.3g，90％)。The second step: Weighed compound I-8-b (5886mg, 21.6mmol) and I-4-b (4980mg, 32.3mmol) dissolved in 1,4-dioxane (100mL), added Pd under nitrogen protection Dppf)Cl 2 (1577 mg, 2.16 mmol) and Cs 2 CO 3 (14.0 g, 43.1 mmol), and then reacted to 100 ° C overnight. After the reaction was completed, it was cooled to room temperature, filtered and washed with EtOAc. The filtrate was concentrated and the crude was purified eluted elut elut elut
1HNMR(400MHz,CDCl3)δ7.73(d,J＝8.0Hz,1H),7.70(d,J＝1.8Hz,1H),7.54(dd,J＝8.0,1.8Hz,1H),6.73(dd,J＝17.6,10.9Hz,1H),5.88(d,J＝17.6Hz,1H),5.42(d,J＝11.0Hz,1H),3.92(s,3H),3.90(s,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.73 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 1.8 Hz, 1H), 7.54 (dd, J = 8.0, 1.8 Hz, 1H), 6.73 ( Dd, J = 17.6, 10.9 Hz, 1H), 5.88 (d, J = 17.6 Hz, 1H), 5.42 (d, J = 11.0 Hz, 1H), 3.92 (s, 3H), 3.90 (s, 3H).
第三步：化合物I-8-c(1101mg，5.0mmol)溶于干燥***(25mL)，再加入Zn(981mg，15.0mmol)，超声搅拌30min。溶于干燥***(10mL)的Cl3COCl(2273mg，12.5mmol)滴加入反应体系，10min加完。继续超声，回流反应5h。加水淬灭，EtOAc萃取。有机相浓缩，粗品溶于乙酸(10mL)，再加入Zn(719mg，11.0mmol)。加热120℃反应2h。冷却至室温。EtOAc萃取，依次用水、饱和NaHCO3和饱和NaCl水溶液洗涤。有机相浓缩，粗品经柱层析分离，得化合物I-8(580mg，产率：44％)。The third step: Compound I-8-c (1101 mg, 5.0 mmol) was dissolved in dry diethyl ether (25mL), then Zn (981mg, 15.0mmol). Cl 3 COCl (2273 mg, 12.5 mmol) dissolved in dry diethyl ether (10 mL) was added dropwise to the reaction mixture and the mixture was applied over 10 min. The ultrasound was continued and the reaction was refluxed for 5 h. It was quenched with water and extracted with EtOAc. The organic phase was concentrated, the crude was dissolved in EtOAc (EtOAc) (EtOAc) The reaction was heated at 120 ° C for 2 h. Cool to room temperature. Extracted with EtOAc, washed successively with water, washed with saturated NaHCO 3 and saturated aqueous NaCl. The organic phase was concentrated and the crude was purifiedjjjjjjjjj
LC-MS:tR＝2.336min,[M+H]+＝263.2。LC-MS: t R = 2.336 min, [M+H] + = 263.2.
9、2-溴-4-氟苯并[d]噻唑-6-羧酸甲酯I-9合成Synthesis of methyl 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylate I-9
Figure PCTCN2016111652-appb-000039
Figure PCTCN2016111652-appb-000039
第一步：化合物3-氟-4-硝基苯甲酸甲酯I-9-a(3983mg，20mmol)溶于40mL EtOAc/MeOH(1:1)混合液中，加入Pd/C(400mg)，常温常压氢化，反应过夜。LC-MS监测，反应完全。过滤，滤液浓缩，得粗产品I-9-b直接用于下步反应。The first step: the compound 3-fluoro-4-nitrobenzoic acid methyl ester I-9-a (3983 mg, 20 mmol) was dissolved in 40 mL EtOAc / MeOH (1:1) mixture, and Pd/C (400 mg) was added. Hydrogenation at normal temperature and atmospheric pressure, and overnight reaction. The reaction was completed by LC-MS. Filtration and concentration of the filtrate gave crude product I-9-b directly to the next step.
LC-MS：tR＝2.226min,[M+H]+＝170.2。LC-MS: t R = 2.262 min, [M+H] + = 170.2.
第二步：化合物I-9-b(20mmol)和NaSCN(6486mg，80mmol)加入20mL乙酸，冰水浴冷却；Br2(1mL，20.0mmol)溶于乙酸(10mL)，再向反应体系中缓慢滴加，约20分钟加完。加热40℃反应5小时，LC-MS监测，反应完全。冷却至室温，加入50mL水稀释。过滤，水洗，真空干燥，得化合物I-9-c(4090mg，90％)。The second step: Compound I-9-b (20 mmol) and NaSCN (6486 mg, 80 mmol) were added to 20 mL of acetic acid, and cooled in an ice water bath; Br 2 (1 mL, 20.0 mmol) was dissolved in acetic acid (10 mL), and then slowly dropped into the reaction system. Plus, add about 20 minutes. The reaction was heated at 40 ° C for 5 hours, and the reaction was completed by LC-MS. Cool to room temperature and dilute with 50 mL of water. Filtration, washing with water and drying in vacuo gave compound I-9-c (4090mg, 90%).
LC-MS：tR＝2.161min,[M+H]+＝227.1。 LC-MS: t R = 2.161min , [M + H] + = 227.1.
第三步：CuBr2固体(1340mg，6.0mmol)加入乙腈(20mL)，冰水浴冷却下滴加tBuONO(1.1mL，9.2mmol)，再加入化合物I-9-c(905mg，4.0mmol)。恢复室温，反应过夜。加入乙酸乙酯萃取，水洗，饱和NaCl水溶液洗涤，无水Na2SO4干燥，过滤，浓缩，粗品经柱层析分离(PE/EA10:1)，得化合物I-9(230mg，20％)。The third step: CuBr 2 solid (1340 mg, 6.0 mmol) was added to acetonitrile (20 mL), tBuONO (1.1 mL, 9.2 mmol) was added dropwise under ice-cooling, and then compound I-9-c (905 mg, 4.0 mmol) was added. Return to room temperature and react overnight. Was added and extracted with ethyl acetate, washed with water, washed with saturated aqueous NaCl, dried over anhydrous Na 2 SO 4, filtered, concentrated and the crude product purified by column chromatography (PE / EA10: 1), Compound I-9 (230mg, 20% ) .
LC-MS：tR＝2.904min。 LC-MS: t R = 2.904min .
10、2-溴苯并[d]噻唑-6-羧酸甲酯I-10合成Synthesis of methyl 2-bromobenzo[d]thiazole-6-carboxylate I-10
Figure PCTCN2016111652-appb-000040
Figure PCTCN2016111652-appb-000040
第一步：化合物I-10-a(10mmol)和NaSCN(3243mg，40mmol)加入乙酸(10mL)，冰水浴冷却；Br2(0.5mL，10.0mmol)溶于乙酸(5mL)，再向反应体系中缓慢滴加，约5分钟加完。加热40℃反应过夜，LC-MS监测，反应完全。冷却至室温，加入水(20mL)稀释，氨水中和。过滤，水洗，真空干燥，得化合物I-10-b(2100mg，定量)。The first step: the compound I-10-a (10 mmol) and NaSCN (3243 mg, 40 mmol) were added to acetic acid (10 mL) and cooled in an ice water bath; Br 2 (0.5 mL, 10.0 mmol) dissolved in acetic acid (5 mL), and then transferred to the reaction system Slowly add in the middle, add about 5 minutes. The reaction was heated at 40 ° C overnight, monitored by LC-MS, and the reaction was completed. Cool to room temperature, dilute with water (20 mL), and neutralize with aqueous ammonia. Filtration, washing with water and drying in vacuo gave compound I-10-b (2100 mg, quantitative).
LC-MS：tR＝1.966min,[M+H]+＝209.1。 LC-MS: t R = 1.966min , [M + H] + = 209.1.
第二步：CuBr2固体(1340mg，6.0mmol)加入乙腈(20mL)，冰水浴冷却下滴加tBuONO(1.1mL，9.2mmol)，再分批加入化合物I-10-b(833mg，4.0mmol)。恢复室温，反应过夜。加入乙酸乙酯萃取，水洗，饱和NaCl水溶液洗涤，无水Na2SO4干燥，过滤，浓缩，粗品经柱层析分离(PE/EA10:1)，得化合物I-10(865mg，79％)。The second step: CuBr 2 solid (1340 mg, 6.0 mmol) was added to acetonitrile (20 mL), tBuONO (1.1 mL, 9.2 mmol) was added dropwise under ice-cooling, and then compound I-10-b (833 mg, 4.0 mmol) was added portionwise. . Return to room temperature and react overnight. Was added and extracted with ethyl acetate, washed with water, washed with saturated aqueous NaCl, dried over anhydrous Na 2 SO 4, filtered, concentrated and the crude product was purified by column chromatography (PE / EA10: 1), Compound I-10 (865mg, 79% ) .
LC-MS：tR＝2.871min。 LC-MS: t R = 2.871min .
11、2-氯-4-甲氧基苯并[d]噻唑-6-羧酸甲酯I-11合成11. Synthesis of methyl 2-chloro-4-methoxybenzo[d]thiazole-6-carboxylate I-11
Figure PCTCN2016111652-appb-000041
Figure PCTCN2016111652-appb-000041
第一步：在50mL三颈瓶中制备NaSCN(1.62g，20.0mmol)的HOAc(4mL)溶液。于0℃下滴加4-氨基-3-甲氧基苯甲酸甲酯I-11-a(0.9g，5.0mmol)的HOAc(4mL)溶液，再滴加Br2(0.88g,5.5mmol)的HOAc(1.2mL)溶液。将获得的溶液于室温下搅拌1小时，50℃搅拌过夜，然后用水(20mL)稀释。采用碳酸钠将溶液的pH调节至pH＝8。过滤收集固体，在减压下于温热的烘箱中干燥，First step: A solution of NaSCN (1.62 g, 20.0 mmol) in HOAc (4 mL) was prepared in a 50 mL 3-neck flask. A solution of methyl 4-amino-3-methoxybenzoate I-11-a (0.9 g, 5.0 mmol) in HOAc (4 mL) was added dropwise at 0 ° C, then Br 2 (0.88 g, 5.5 mmol) HOAc (1.2 mL) solution. The obtained solution was stirred at room temperature for 1 hour, at 50 ° C overnight, and then diluted with water (20 mL). The pH of the solution was adjusted to pH = 8 using sodium carbonate. The solid was collected by filtration and dried under a reduced pressure in a warm oven.
获得化合物I-11-b(1.0g)，收率84％。Compound I-11-b (1.0 g) was obtained in a yield of 84%.
LC-MS:tR＝2.012min,[M+H]+＝239.1。 LC-MS: t R = 2.012min , [M + H] + = 239.1.
第二步：向50mL三颈瓶中加入溶有化合物I-11-b(1.0g,4.2mmol)的H3PO4(8mL)溶液。于0℃向其中滴加NaNO2(0.9g,12.6mmol)的水(10mL)溶液。将获得的溶液于0℃搅拌1h。然后于0℃分批加入CuSO4(3.4g,21.0mmol)，随后于0℃滴加NaCl(3.7g,63.0mmol)的水(10mL)溶液。将获得的溶液于室温下搅拌1h，然后用水(20mL)稀释。水溶液用二氯甲烷萃取，合并有机相，浓缩。粗产品经硅胶柱层析分离，得化合物I-11(250mg,收率为23％)。Step Two: A solution of Compound I-11-b (1.0g, 4.2mmol) in H 3 PO 4 (8mL) was added to a 50mL three-necked flask. A solution of NaNO 2 (0.9 g, 12.6 mmol) in water (10 mL) was added dropwise at 0 °C. The obtained solution was stirred at 0 ° C for 1 h. Then, CuSO 4 (3.4 g, 21.0 mmol) was added portionwise at 0 ° C, followed by dropwise addition of a solution of NaCl (3.7 g, 63.0 mmol) in water (10 mL) at 0 °C. The resulting solution was stirred at room temperature for 1 h then diluted with water (20 mL). The aqueous solution was extracted with dichloromethane, and the combined organic layers were concentrated. The crude product was subjected to silica gel column chromatography to afford Compound I-11 (250 mg, yield 23%).
LC-MS:tR＝2.764min； LC-MS: t R = 2.764min ;
1H NMR(400MHz,CDCl3)δ8.11(d,J＝1.3Hz,1H),7.59(d,J＝1.3Hz,1H),4.09(s,3H),3.97(s,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.11 (d, J = 1.3 Hz, 1H), 7.59 (d, J = 1.3 Hz, 1H), 4.09 (s, 3H), 3.97 (s, 3H).
12、6-溴-1-甲基-1H-吲哚-3-羧酸甲酯I-12合成 Synthesis of 12,6-bromo-1-methyl-1H-indole-3-carboxylic acid methyl ester I-12
Figure PCTCN2016111652-appb-000042
Figure PCTCN2016111652-appb-000042
第一步：化合物I-12-a(8g,50mmol)溶于醋酸(100mL)，室温下缓慢滴加溴(8.4g)的醋酸溶液，滴完搅拌反应过夜。过滤，洗涤，干燥得化合物I-12-b(6.2g,产率：51.2％)。First step: Compound I-12-a (8 g, 50 mmol) was dissolved in acetic acid (100 mL), and a solution of bromine (8.4 g) in acetic acid was slowly added dropwise at room temperature, and the reaction was stirred overnight. Filtration, washing and drying gave Compound I-12-b (6.2 g, yield: 51.2%).
LC-MS:tR＝2.25min,[M-H]-＝238.0。 LC-MS: t R = 2.25min , [MH] - = 238.0.
第二步：甲醇(60mL)置于250mL单口瓶中，冰水浴冷却下缓慢滴加乙酰氯(6.2g)，滴完后加入化合物I-12-b(6.2g，26mmol)，回流反应16h。冷却，过滤，洗涤，干燥得化合物I-12-c(4.9g,产率：75.0％)。The second step: methanol (60 mL) was placed in a 250 mL single-mouth bottle, and acetyl chloride (6.2 g) was slowly added dropwise under ice-cooling. After the dropwise addition, the compound I-12-b (6.2 g, 26 mmol) was added and refluxed for 16 h. It was cooled, filtered, washed and dried to give Compound I-12-c (4.9 g, yield: 75.0%).
LC-MS:tR＝2.66min,[M-H]-＝251.9。 LC-MS: t R = 2.66min , [MH] - = 251.9.
第三步：化合物I-12-c(2.13g，8.4mmol)溶于乙腈(30mL)，加入碳酸钾(2.3g，16.8mmol)和MeI(2.1mL,33.7mmol)，于50℃下搅拌反应3h。待反应液冷却后用水(20mL)稀释，乙酸乙酯萃取3次后合并有机相。合并后的有机相用饱和食盐水洗一次，硫酸钠干燥。过滤，浓缩，柱层析分离(PE/EA 5～15％)，得化合物I-12(2.1g，产率：93％)。The third step: Compound I-12-c (2.13 g, 8.4 mmol) was dissolved in acetonitrile (30 mL), potassium carbonate (2.3 g, 16.8 mmol) and MeI (2.1 mL, 33.7 mmol) were added and stirred at 50 ° C 3h. After the reaction solution was cooled, it was diluted with water (20 mL), and extracted with ethyl acetate three times. The combined organic phases were washed once with saturated brine and dried over sodium sulfate. Filtration, concentration and column chromatography (PE/EA 5 to 15%) gave Compound I-12 (2.1 g, yield: 93%).
LC-MS:tR＝2.88min。 LC-MS: t R = 2.88min .
13、3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噻唑-4-基)甲氧基)苯基)吖丁啶-1-羧酸叔丁酯I-1313, 3-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)phenyl)azetidine-1 -carboxylic acid tert-butyl ester I-13
Figure PCTCN2016111652-appb-000043
Figure PCTCN2016111652-appb-000043
第一步：化合物I-13-a(150mg,0.75mmol)溶于二氯甲烷(3mL)，-78℃下缓慢滴加三溴化硼(4N)溶液，滴毕升至室温搅拌20min。冰水浴下加甲醇淬灭并搅拌30min，乙酸乙酯萃取，有机相合并用饱和食盐水洗一次，硫酸钠干燥。过滤，浓缩，粗产品直接用于下部反应。The first step: Compound I-13-a (150 mg, 0.75 mmol) was dissolved in dichloromethane (3 mL), and a solution of boron tribromide (4N) was slowly added dropwise at -78 ° C, and the mixture was stirred at room temperature for 20 min. The mixture was stirred and stirred for 30 min. Filtered, concentrated, and the crude product was used directly in the lower portion.
第二步：上述粗产品置于100mL单口瓶中，依次加二氯甲烷(5mL)、三乙胺(0.8mL)和二碳酸二叔丁酯(180mg)，室温搅拌2h。萃取，干燥，浓缩，无需纯化直接投下一步。The second step: the above crude product was placed in a 100 mL single-necked flask, and dichloromethane (5 mL), triethylamine (0.8 mL) and di-tert-butyl dicarbonate (180 mg) were successively added and stirred at room temperature for 2 h. Extract, dry, concentrate, and proceed to the next step without purification.
第三步：将上述化合物置于50mL单口瓶中，依次加化合物I-2、DMF(3mL)和碳酸钾(414mg)，50℃搅拌反应过夜，反应完全。浓缩后柱层析分离，得化合物I-13(180mg，产率43％)。The third step: The above compound was placed in a 50 mL single-mouth flask, and Compound I-2, DMF (3 mL) and potassium carbonate (414 mg) were successively added, and the mixture was stirred at 50 ° C overnight, and the reaction was completed. After concentration and column chromatography, Compound I-13 (180 mg, yield 43%).
LC-MS:tR＝3.59min，[M-100]+＝449.0。 LC-MS: t R = 3.59min , [M-100] + = 449.0.
14、7-溴喹啉-3-羧酸乙酯I-14 14, 7-bromoquinoline-3-carboxylic acid ethyl ester I-14
Figure PCTCN2016111652-appb-000044
Figure PCTCN2016111652-appb-000044
第一步：化合物I-14-a(1.17g,5.0mmol)溶于乙醇(15ml)，加入活化铁粉(1.68g,30.0mmol)和1M HCl(5ml)，回流反应2h。冷却至室温后过滤。滤液浓缩后经乙酸乙酯溶解，并依次用饱和碳酸钠水溶液、水、食盐水洗涤。有机层干燥后浓缩，残留物经硅胶柱层析分离，得化合物I-14-b(760mg，收率：76％)。The first step: Compound I-14-a (1.17 g, 5.0 mmol) was dissolved in ethanol (15 ml), and activated iron powder (1.68 g, 30.0 mmol) and 1M HCl (5 ml) were added and refluxed for 2 h. After cooling to room temperature, it was filtered. The filtrate was concentrated, dissolved in ethyl acetate, and washed successively with saturated aqueous sodium carbonate, water and brine. The organic layer was dried and concentrated, and then purified, mjjjjjj
LC-MS:tR＝2.512min,[M+H]+＝200.0；LC-MS: t R = 2.512 min, [M+H] + = 200.0;
1H NMR(400MHz,DMSO)δ9.79(s,1H),7.48(d,J＝8.3Hz,1H),7.26(s,2H),6.99(d,J＝1.8Hz,1H),6.79(dd,J＝8.3,1.9Hz,1H)。 1 H NMR (400MHz, DMSO) δ9.79 (s, 1H), 7.48 (d, J = 8.3Hz, 1H), 7.26 (s, 2H), 6.99 (d, J = 1.8Hz, 1H), 6.79 ( Dd, J = 8.3, 1.9 Hz, 1H).
第二步：化合物I-14-b(560mg,2.8mmol)溶于甲苯(14ml)，再加入3-乙氧基丙烯酸乙酯I-14-c(484mg,3.4mmol)、—水合对甲苯磺酸(53mg,0.28mmol)和MgSO4(560mg)。混合液回流搅拌5.5h。冷却至常温后乙酸乙酯稀释并过滤。滤液浓缩后经硅胶色谱纯化得到化合物I-14(478mg，收率：61％)。The second step: Compound I-14-b (560 mg, 2.8 mmol) was dissolved in toluene (14 ml), followed by ethyl 3-ethoxyethyl acrylate I-14-c (484 mg, 3.4 mmol), p-toluene acid (53mg, 0.28mmol) and MgSO 4 (560mg). The mixture was stirred at reflux for 5.5 h. After cooling to normal temperature, the ethyl acetate was diluted and filtered. The filtrate was concentrated and purified by silica gel chromatography to afford Compound I-14 (478 mg, yield: 61%).
LC-MS:tR＝2.962min,[M+H]+＝280.0；LC-MS: t R = 2.962 min, [M+H] + = 280.0;
1H NMR(400MHz,CDCl3)δ9.46(d,J＝2.0Hz,1H),8.85(d,J＝1.4Hz,1H),8.40(s,1H),7.83(d,J＝8.7Hz,1H),7.74(dd,J＝8.7,1.8Hz,1H),4.49(q,J＝7.1Hz,2H),1.46(t,J＝7.1Hz,3H)。 1 H NMR (400MHz, CDCl 3 ) δ9.46 (d, J = 2.0Hz, 1H), 8.85 (d, J = 1.4Hz, 1H), 8.40 (s, 1H), 7.83 (d, J = 8.7Hz , 1H), 7.74 (dd, J = 8.7, 1.8 Hz, 1H), 4.49 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H).
二、具体实施例化合物的合成Second, the synthesis of specific examples of compounds
实施例1 3-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噻唑-4-基)甲氧基)苯基)-3-羟基环丁基)苯甲酸(1)Example 1 3-(3-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)phenyl)- 3-hydroxycyclobutyl)benzoic acid (1)
Figure PCTCN2016111652-appb-000045
Figure PCTCN2016111652-appb-000045
第一步：将化合物1-a(468mg,1.45mmol)溶于干燥THF(6mL)，并在氮气氛下搅拌，于-70～-78℃下滴加正丁基锂(1.6M，1.0mL)。加完在此温度下搅拌45min。然后滴加溶有化合物I-4(270mg，1.32mmol)的干燥THF溶液(0.5mL)。加完后于此温度搅拌1h。缓慢升至室温，并用饱和NH4Cl(5mL)淬灭，乙酸乙酯萃取。有机相干燥，浓缩，柱层析分离(PE/EA,EA:0～15％)，得化合物1-b(246mg,产率：42％)。 The first step: Compound 1-a (468 mg, 1.45 mmol) was dissolved in dry THF (6 mL) and stirred under nitrogen, and n-butyl lithium (1.6 M, 1.0 mL) was added dropwise at -70 to -78 °C. ). After the addition was completed, the mixture was stirred at this temperature for 45 minutes. Then, a dry THF solution (0.5 mL) in which Compound I-4 (270 mg, 1.32 mmol) was dissolved was dissolved. After the addition was completed, the mixture was stirred at this temperature for 1 h. Was slowly warmed to room temperature, and washed with saturated NH 4 Cl (5mL) was quenched, extracted with ethyl acetate. The organic phase was dried, concentrated and purified by column chromatography (EtOAc/EtOAc, EtOAc: EtOAc
LC-MS:tR＝3.825min,[M-OH]+＝429.1；LC-MS: t R = 3.825 min, [M-OH] + = 429.1;
1HNMR(400MHz,CDCl3)δ7.97(s,1H),7.88(d,J＝7.7Hz,1H),7.48(dd,J＝16.4,8.1Hz,2H),7.39(t,J＝7.7Hz,1H),6.96(d,J＝2.5Hz,1H),6.78(dd,J＝8.5,2.5Hz,1H),3.92(s,3H),3.25-3.17(m,2H),3.04(dt,J＝17.7,9.1Hz,1H),2.59(td,J＝9.7,2.7Hz,2H),0.99(s,9H),0.23(s,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.97 (s, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.48 (dd, J = 16.4, 8.1 Hz, 2H), 7.39 (t, J = 7.7) Hz, 1H), 6.96 (d, J = 2.5 Hz, 1H), 6.78 (dd, J = 8.5, 2.5 Hz, 1H), 3.92 (s, 3H), 3.25-3.17 (m, 2H), 3.04 (dt , J = 17.7, 9.1 Hz, 1H), 2.59 (td, J = 9.7, 2.7 Hz, 2H), 0.99 (s, 9H), 0.23 (s, 6H).
第二步：将化合物1-b(246mg,0.55mmol)溶于THF(2.5mL)，加入TBAF(1.1mL,1.10mmol,1.0MinTHF)。室温搅拌15min。加入饱和碳酸氢钠溶液(2mL)淬灭，乙酸乙酯萃取，分层后水相再用乙酸乙酯萃取2次，有机相合并用饱和食盐水洗，硫酸钠干燥。过滤，浓缩，柱层析分离(PE/EA,EA:20～30％)，得化合物1-c(160mg,产率：87％)。The second step: Compound 1-b (246 mg, 0.55 mmol) was dissolved in THF (2.5 mL) and TBAF (1.1mL, 1.10mmol, 1.0MinTHF) was added. Stir at room temperature for 15 min. The mixture was stirred with EtOAc EtOAc. Filtration, concentration and column chromatography (PE/EA, EA: 20 to 30%) gave Compound 1-c (160 mg, yield: 87%).
LC-MS:tR＝2.578min,[M-OH]+＝315.1；LC-MS: t R =2.578 min, [M-OH] + = 315.1;
1HNMR(400MHz,CDCl3)δ7.97(s,1H),7.88(d,J＝7.7Hz,1H),7.48(t,J＝9.2Hz,2H),7.39(t,J＝7.7Hz,1H),6.98(d,J＝2.6Hz,1H),6.78(dd,J＝8.5,2.6Hz,1H),5.43(s,1H),3.92(s,3H),3.26-3.16(m,2H),3.09-2.98(m,1H),2.59(td,J＝9.7,2.7Hz,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.97 (s, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.48 (t, J = 9.2 Hz, 2H), 7.39 (t, J = 7.7 Hz, 1H), 6.98 (d, J = 2.6 Hz, 1H), 6.78 (dd, J = 8.5, 2.6 Hz, 1H), 5.43 (s, 1H), 3.92 (s, 3H), 3.26-3.16 (m, 2H) ), 3.09-2.98 (m, 1H), 2.59 (td, J = 9.7, 2.7 Hz, 2H).
第三步：化合物1-c(160mg,0.48mmol)溶于干燥DMF(2.5mL)。加入中间体I-1(184mg,0.57mmol)和碳酸钾(133mg,0.96mmol)。氮气氛下于60℃搅拌过夜。待反应液冷却后用水(15mL)稀释，乙酸乙酯萃取3次后合并有机相。有机相用饱和食盐水洗一次，硫酸钠干燥。过滤，浓缩，柱层析分离(PE/EA,EA:10～25％)，得化合物1-d(178mg,产率：60％)。The third step: Compound 1-c (160 mg, 0.48 mmol) was dissolved in dry DMF (2.5 mL). Intermediate I-1 (184 mg, 0.57 mmol) and potassium carbonate (133 mg, 0.96 mmol). Stir at 60 ° C overnight under a nitrogen atmosphere. After the reaction solution was cooled, it was diluted with water (15 mL), and the mixture was extracted three times with ethyl acetate. The organic phase was washed once with saturated brine and dried over sodium sulfate. Filtration, concentration and column chromatography (PE/EA, EA: 10 to 25%) gave Compound 1-d (178 mg, yield: 60%).
LC-MS:tR＝3.528min,[M+H]+＝614.0。 LC-MS: t R = 3.528min , [M + H] + = 614.0.
第四步：化合物1-d(178mg,0.29mmol)溶于甲醇(2mL)。加入NaOH水溶液(2mL，1.0M)。60℃反应3h。冷却后用1N的盐酸酸化至pH＝4，乙酸乙酯萃取3次，有机层干燥。过滤，浓缩，柱层析纯化后得化合物1(117mg)。The fourth step: Compound 1-d (178 mg, 0.29 mmol) was dissolved in methanol (2 mL). Aqueous NaOH (2 mL, 1.0 M) was added. The reaction was carried out at 60 ° C for 3 h. After cooling, it was acidified to pH = 4 with 1N hydrochloric acid and extracted three times with ethyl acetate. Filtration, concentration and purification by column chromatography gave Compound 1 (117 mg).
LC-MS:tR＝3.218min,[M+H]+＝600.0； LC-MS: t R = 3.218min , [M + H] + = 600.0;
1HNMR(400MHz,CDCl3)δ8.02(s,1H),7.95(d,J＝7.6Hz,1H),7.55(d,J＝7.4Hz,1H),7.50-7.34(m,4H),7.32-7.26(m,1H),6.91(d,J＝2.4Hz,1H),6.75(dd,J＝8.6,2.5Hz,1H),4.91(d,J＝16.0Hz,2H),3.30-3.10(m,2H),3.08-2.95(m,1H),2.59(dd,J＝12.0,9.6Hz,2H),2.28(ddd,J＝13.4,8.3,5.0Hz,1H),1.26(t,J＝6.2Hz,2H),1.00-0.88(m,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.02 (s, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 7.4 Hz, 1H), 7.50-7.34 (m, 4H), 7.32-7.26(m,1H), 6.91 (d, J=2.4Hz, 1H), 6.75 (dd, J=8.6, 2.5Hz, 1H), 4.91 (d, J=16.0Hz, 2H), 3.30-3.10 (m, 2H), 3.08-2.95 (m, 1H), 2.59 (dd, J = 12.00, 9.6 Hz, 2H), 2.28 (ddd, J = 13.4, 8.3, 5.0 Hz, 1H), 1.26 (t, J) = 6.2 Hz, 2H), 1.00-0.88 (m, 2H).
实施例2 3-(3-(4-((5-环丙基-3-(2,6-二氯苯基)异噻唑-4-基)甲氧基)-2-甲氧苯基)-3-羟基环丁基)苯甲酸(2)Example 2 3-(3-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)-2-methoxyphenyl) -3-hydroxycyclobutyl)benzoic acid (2)
Figure PCTCN2016111652-appb-000046
Figure PCTCN2016111652-appb-000046
第一步：化合物2-a的合成参照实施例1第一步～第三步的制备方法。 First step: Synthesis of compound 2-a Referring to the preparation methods of the first to third steps of Example 1.
LC-MS:tR＝3.465min,[M-OH]+＝592.0；LC-MS: t R = 3.465 min, [M-OH] + = 592.0;
1HNMR(400MHz,CDCl3)δ7.98-7.93(m,1H),7.89-7.84(m,1H),7.53-7.44(m,1H),7.41-7.35(m,3H),7.33-7.27(m,2H),6.48-6.35(m,2H),4.92(s,2H),3.91(s,3H),3.85(s,3H),3.05-2.89(m,3H),2.54-2.47(m,2H),2.34-2.25(m,1H),1.33-1.26(m,2H),0.98-0.92(m,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.98-7.93 (m, 1H), 7.89-7.84 (m, 1H), 7.53-7.44 (m, 1H), 7.41-7.35 (m, 3H), 7.33-7.27 ( m, 2H), 6.48-6.35 (m, 2H), 4.92 (s, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 3.05-2.89 (m, 3H), 2.54-2.47 (m, 2H), 2.34 - 2.25 (m, 1H), 1.33-1.26 (m, 2H), 0.98 - 0.92 (m, 2H).
第二步：将化合物2-a(30mg,0.05mmol)溶于THF/MeOH(1mL,1:1)。加入NaOH水溶液(1.0M,1mL)。反应液于60℃搅拌过夜。冷却后用3NHCl酸化至pH＝5，然后乙酸乙酯萃取2次。有机相干燥，浓缩，PTLC纯化，得化合物2(3.0mg)；The second step: Compound 2-a (30 mg, 0.05 mmol) was dissolved in THF / MeOH (1 mL, 1:1). Aqueous NaOH (1.0 M, 1 mL) was added. The reaction solution was stirred at 60 ° C overnight. After cooling, it was acidified to pH = 5 with 3N HCl and then extracted twice with ethyl acetate. The organic phase was dried, concentrated and purified by EtOAc EtOAc.
LC-MS:tR＝3.139min,[M-OH]+＝578.0；LC-MS: t R = 3. 39 min, [M-OH] + = 578.0;
1HNMR(400MHz,MeOD)δ7.95(s,1H),7.84(d,J＝7.6Hz,1H),7.55-7.32(m,6H),6.44(d,J＝8.0Hz,2H),5.00(s,2H),3.80(s,3H),3.09(d,J＝9.4Hz,2H),2.97(dd,J＝16.8,8.9Hz,1H),2.41(ddd,J＝9.9,8.9,3.4Hz,3H),1.31(dd,J＝5.5,2.8Hz,2H),0.95-0.89(m,2H)。 1 H NMR (400 MHz, MeOD) δ 7.95 (s, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.55-7.32 (m, 6H), 6.44 (d, J = 8.0 Hz, 2H), 5.00 (s, 2H), 3.80 (s, 3H), 3.09 (d, J = 9.4 Hz, 2H), 2.97 (dd, J = 16.8, 8.9 Hz, 1H), 2.41 (ddd, J = 9.9, 8.9, 3.4 Hz, 3H), 1.31 (dd, J = 5.5, 2.8 Hz, 2H), 0.95-0.89 (m, 2H).
实施例3 3-(3-(4-((5-环丙基-3-(2,6-二氯苯基)异噻唑-4-基)甲氧基)-2-甲基苯基)-3-羟基环丁基)苯甲酸(3)Example 3 3-(3-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)-2-methylphenyl) -3-hydroxycyclobutyl)benzoic acid (3)
Figure PCTCN2016111652-appb-000047
Figure PCTCN2016111652-appb-000047
第一步：化合物3-a的合成参照实施例1第一步～第三步的制备方法。First step: Synthesis of Compound 3-a Referring to the preparation methods of the first to third steps of Example 1.
LC-MS:tR＝3.514min,[M+H]+＝594.1。 LC-MS: t R = 3.514min , [M + H] + = 594.1.
第二步：将化合物3-a(8mg，0.013mmol)溶于四氢呋喃(1mL)，加入氢氧化钠水溶液(1mL,1N)，60℃反应4h。反应完全后加入稀盐酸酸化至弱酸性，乙酸乙酯萃取。有机相干燥，浓缩，PTLC分离，得化合物3(4mg，53％)。The second step: Compound 3-a (8 mg, 0.013 mmol) was dissolved in tetrahydrofuran (1 mL), and aqueous sodium hydroxide (1 mL, 1 N) was added and reacted at 60 ° C for 4 h. After the reaction was completed, it was acidified to dilute hydrochloric acid with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was dried <RTI ID=0.0>
LC-MS:tR＝3.2min,[M-OH]+＝580.0,582.1； LC-MS: t R = 3.2min , [M-OH] + = 580.0,582.1;
1HNMR(400MHz,CDCl3)δ7.95(s,1H),7.87(d,J＝7.8Hz,1H),7.48-7.44(m,1H),7.35(d,J＝7.7Hz,1H),7.33-7.28(m,3H),7.25-7.21(m,1H),6.65(d,J＝2.5Hz,1H),6.58(dd,J＝8.5,2.7Hz,1H),4.85(s,2H),3.16-3.05(m,2H),3.01-2.89(m,1H),2.54-2.43(m,2H),2.36(s,3H),2.28-2.20(m,1H),1.20-1.12(m),0.90-0.80(m)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.95 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.48-7.44 (m, 1H), 7.35 (d, J = 7.7 Hz, 1H), 7.33-7.28 (m, 3H), 7.25-7.21 (m, 1H), 6.65 (d, J = 2.5 Hz, 1H), 6.58 (dd, J = 8.5, 2.7 Hz, 1H), 4.85 (s, 2H) , 3.16-3.05 (m, 2H), 3.01-2.89 (m, 1H), 2.54-2.43 (m, 2H), 2.36 (s, 3H), 2.28-2.20 (m, 1H), 1.20-1.12 (m) , 0.90-0.80 (m).
实施例4 3-(3-(4-((5-环丙基-3-(2,6-二氯苯基)异噻唑-4-基)甲氧基)-2-三氟甲基苯基)-3-羟基环丁基)苯甲酸(4)Example 4 3-(3-(4-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)-2-trifluoromethylbenzene (3-hydroxycyclobutyl)benzoic acid (4)
Figure PCTCN2016111652-appb-000048
Figure PCTCN2016111652-appb-000048
第一步：化合物4-a的合成参照实施例1第一步～第三步的制备方法。First step: Synthesis of compound 4-a Referring to the preparation methods of the first to third steps of Example 1.
LC-MS:tR＝3.544min,[M+H]+＝648.1；LC-MS: t R = 3.544 min, [M+H] + =648.1;
1HNMR(400MHz,CDCl3)δ7.90(s,1H),7.81(d,J＝7.7Hz,1H),7.50-7.42(m,2H),7.37-7.27(m,2H),7.24-7.21(m,1H),7.11(d,J＝2.7Hz,1H),6.89(dd,J＝8.7,2.7Hz,1H),4.91(s,2H),3.85(s,3H),3.18-3.00(m,2H),2.56(dd,J＝11.4,7.8Hz,2H),2.20(ddd,J＝8.3,5.0,3.3Hz,1H),1.24-1.15(m,2H),0.92-0.84(m,2H)； 1 H NMR (400 MHz, CDCl 3 ) δ 7.90 (s, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.50-7.42 (m, 2H), 7.37-7.27 (m, 2H), 7.24-7.21 (m, 1H), 7.11 (d, J = 2.7 Hz, 1H), 6.89 (dd, J = 8.7, 2.7 Hz, 1H), 4.91 (s, 2H), 3.85 (s, 3H), 3.18-3.00 ( m, 2H), 2.56 (dd, J = 11.4, 7.8 Hz, 2H), 2.20 (ddd, J = 8.3, 5.0, 3.3 Hz, 1H), 1.24-1.15 (m, 2H), 0.92-0.84 (m, 2H);
19FNMR(376MHz,CDCl3)δ-56.74。 19 F NMR (376 MHz, CDCl 3 ) δ - 56.74.
第二步：将化合物4-a(8mg，0.013mmol)溶于甲醇(1mL)，加入氢氧化钠水溶液(1mL,1N)，60℃反应6h。反应完全后加入稀盐酸酸化至弱酸性，乙酸乙酯萃取。有机相干燥，浓缩，PTLC分离，得化合物4(4mg，53％)。The second step: Compound 4-a (8 mg, 0.013 mmol) was dissolved in methanol (1 mL), and aqueous sodium hydroxide (1 mL, 1 N) was added and reacted at 60 ° C for 6 h. After the reaction was completed, it was acidified to dilute hydrochloric acid with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was dried <RTI ID=0.0>
LC-MS:tR＝3.2min,[M-OH]+＝634.0,636.0；LC-MS: t R = 3.2 min, [M-OH] + = 634.0, 636.0;
1HNMR(400MHz,CDCl3)δ7.97(s,1H),7.88(d,J＝7.8Hz,1H),7.50(d,J＝7.7Hz,1H),7.46(d,J＝8.7Hz,1H),7.36(t,J＝7.7Hz,1H),7.33-7.28(m,2H),7.24-7.21(m,1H),7.11(d,J＝2.7Hz,1H),6.89(dd,J＝8.7,2.6Hz,1H),4.91(s,2H),3.19-3.03(m,3H),2.62-2.50(m,2H),2.22-2.13(m,1H),1.33-1.05(m),0.95-0.72(m)； 1 H NMR (400 MHz, CDCl 3 ) δ 7.97 (s, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1H), 7.36 (t, J = 7.7 Hz, 1H), 7.33 - 7.28 (m, 2H), 7.24 - 7.21 (m, 1H), 7.11 (d, J = 2.7 Hz, 1H), 6.89 (dd, J =8.7, 2.6 Hz, 1H), 4.91 (s, 2H), 3.19-3.03 (m, 3H), 2.62-2.50 (m, 2H), 2.22-2.13 (m, 1H), 1.33-1.05 (m), 0.95-0.72(m);
19FNMR(376MHz,CDCl3)δ-56.74。 19 F NMR (376 MHz, CDCl 3 ) δ - 56.74.
实施例5 3-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噻唑-4-基)甲氧基)苯基)-3-羟基环丁基)-5-氟苯甲酸(5)Example 5 3-(3-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)phenyl)- 3-hydroxycyclobutyl)-5-fluorobenzoic acid (5)
Figure PCTCN2016111652-appb-000049
Figure PCTCN2016111652-appb-000049
第一步：化合物5-a的合成参照实施例1第一步～第三步的制备方法。First step: Synthesis of compound 5-a Referring to the preparation methods of the first to third steps of Example 1.
LC-MS:tR＝3.581min,[M+H]+＝631.9；LC-MS: t R = 3.581 min, [M+H] + = 631.9;
1HNMR(400MHz,CDCl3)δ7.74(s,1H),7.55(ddd,J＝8.9,2.4,1.4Hz,1H),7.45-7.36(m,3H),7.29(dd,J＝8.9,7.1Hz,1H),7.24-7.18(m,1H),6.91(d,J＝2.6Hz,1H),6.74(dd,J＝8.6,2.6Hz,1H),4.93(s,2H),3.92(s,3H),3.25-3.13(m,2H),3.06-2.95(m,1H),2.60-2.51(m,2H),2.27(ddt,J＝12.0,8.8,4.4Hz,1H),1.26(dd,J＝4.5,2.1Hz,2H),0.94(dt,J＝6.7,4.9Hz,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.74 (s, 1H), 7.55 (ddd, J = 8.9, 2.4, 1.4 Hz, 1H), 7.45-7.36 (m, 3H), 7.29 (dd, J = 8.9, 7.1 Hz, 1H), 7.24-7.18 (m, 1H), 6.91 (d, J = 2.6 Hz, 1H), 6.74 (dd, J = 8.6, 2.6 Hz, 1H), 4.93 (s, 2H), 3.92 ( s, 3H), 3.25-3.13 (m, 2H), 3.06-2.95 (m, 1H), 2.60-2.51 (m, 2H), 2.27 (ddt, J = 12.0, 8.8, 4.4 Hz, 1H), 1.26 ( Dd, J = 4.5, 2.1 Hz, 2H), 0.94 (dt, J = 6.7, 4.9 Hz, 2H).
第二步：将化合物5-a(53mg,0.08mmol)溶于THF/MeOH(2mL,1:1)，加入NaOH水溶液(1.0M,1mL)。60℃搅拌反应3h。溶液冷却后用3NHCl酸化至pH＝4，乙酸乙酯萃取2次。有机相干燥，浓缩，PTLC分离，纯化得化合物5(11.2mg)。The second step: Compound 5-a (53 mg, 0.08 mmol) was dissolved in THF / MeOH (2 mL, 1:1). The reaction was stirred at 60 ° C for 3 h. The solution was cooled and acidified to pH = 4 with 3N HCl and extracted twice with ethyl acetate. The organic phase was dried, concentrated, purified by EtOAc EtOAc (EtOAc)
LC-MS:tR＝3.270min,[M+H]+＝618.0；LC-MS: t R = 3. </RTI><RTIgt;
1HNMR(400MHz,MeOD)δ7.73(s,1H),7.47(t,J＝20.3Hz,5H),7.20(s,1H),6.89(s,1H),6.79(s,1H),5.00(s,2H),3.27-3.18(m,2H),2.94(s,1H),2.44(d,J＝32.8Hz,3H),1.31(s,2H),0.92(s,2H)。 1 H NMR (400 MHz, MeOD) δ 7.73 (s, 1H), 7.47 (t, J = 20.3 Hz, 5H), 7.20 (s, 1H), 6.89 (s, 1H), 6.79 (s, 1H), 5.00 (s, 2H), 3.27-3.18 (m, 2H), 2.94 (s, 1H), 2.44 (d, J = 32.8 Hz, 3H), 1.31 (s, 2H), 0.92 (s, 2H).
实施例6 3-(3-(4-((5-环丙基-3-(2,6-二氯苯基)异噻唑-4-基)甲氧基)-2-(三氟甲基)苯基)-3-羟基环丁基)-5-氟苯甲酸(6)Example 6 3-(3-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)-2-(trifluoromethyl) Phenyl)-3-hydroxycyclobutyl)-5-fluorobenzoic acid (6)
第一步：化合物6-a的合成参照实施例1第一步～第三步的制备方法。First step: Synthesis of compound 6-a Referring to the preparation methods of the first to third steps of Example 1.
LC-MS:tR＝3.584min,[M+H]+＝666.0。 LC-MS: t R = 3.584min , [M + H] + = 666.0.
第二步：将化合物6-a(60mg,0.08mmol)溶于THF/MeOH(2mL,1:1)，加入NaOH水溶液(1.0M,2mL)。60℃搅拌反应3h。溶液冷却后用3NHCl酸化至pH＝4，乙酸乙酯萃取2次。有机相干燥，浓缩，PTLC分离，纯化得化合物6(40.8mg)。The second step: Compound 6-a (60 mg, 0.08 mmol) was dissolved in THF / MeOH (2 mL, 1:1). The reaction was stirred at 60 ° C for 3 h. The solution was cooled and acidified to pH = 4 with 3N HCl and extracted twice with ethyl acetate. The organic phase was dried, concentrated, purified by EtOAc EtOAc EtOAc
LC-MS:tR＝3.305min,[M+H]+＝651.8； LC-MS: t R = 3.305min , [M + H] + = 651.8;
1HNMR(400MHz,CDCl3)δ7.83(s,1H),7.64-7.59(m,1H),7.50(d,J＝8.7Hz,1H),7.39(d,J＝1.1Hz,2H),7.29(dt,J＝8.0,5.6Hz,2H),7.17(d,J＝2.7Hz,1H),6.96(dd,J＝8.7,2.7Hz,1H),4.98(s,2H),3.18(dq,J＝24.7,8.5Hz,3H),2.63(dd,J＝10.8,6.3Hz,2H),2.27(tt,J＝8.3,5.1Hz,1H),1.29-1.22(m,2H),0.94(dt,J＝6.7,4.9Hz,2H)； 1 H NMR (400 MHz, CDCl 3 ) δ 7.83 (s, 1H), 7.64 - 7.59 (m, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.39 (d, J = 1.1 Hz, 2H), 7.29 (dt, J = 8.0, 5.6 Hz, 2H), 7.17 (d, J = 2.7 Hz, 1H), 6.96 (dd, J = 8.7, 2.7 Hz, 1H), 4.98 (s, 2H), 3.18 (dq) , J = 24.7, 8.5 Hz, 3H), 2.63 (dd, J = 10.8, 6.3 Hz, 2H), 2.27 (tt, J = 8.3, 5.1 Hz, 1H), 1.29-1.22 (m, 2H), 0.94 ( Dt, J = 6.7, 4.9 Hz, 2H);
19FNMR(376MHz,CDCl3)δ-56.78(s),-112.27(s)。 19 F NMR (376 MHz, CDCl 3 ) δ - 56.78 (s), - 112.27 (s).
实施例7 5-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噻唑-4-基)甲氧基)苯基)-3-羟基环丁基)-2-氟苯甲酸(7)Example 7 5-(3-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)phenyl)- 3-hydroxycyclobutyl)-2-fluorobenzoic acid (7)
Figure PCTCN2016111652-appb-000051
Figure PCTCN2016111652-appb-000051
第一步：化合物7-a的合成参照实施例1第一步～第三步的制备方法。First step: Synthesis of compound 7-a Referring to the preparation methods of the first to third steps of Example 1.
LC-MS:tR＝3.50min,[M+H]+＝631.9。 LC-MS: t R = 3.50min , [M + H] + = 631.9.
第二步：将化合物7-a(67mg,0.1mmol)溶于甲醇(1mL)和水(1mL)，加入氢氧化钠(16mg,0.4mmol)。40℃搅拌2h。待反应完毕，用1N的盐酸酸化至pH为5～6，有固体析出。过滤干燥后得粗产物，粗产物经柱层析纯化，得化合物7(20mg,产率：30％)。The second step: Compound 7-a (67 mg, 0.1 mmol) was dissolved in methanol (1 mL) and water (1 mL). Stir at 40 ° C for 2 h. After the reaction was completed, it was acidified to pH 5-6 with 1N hydrochloric acid, and a solid precipitated. After filtration and drying, a crude product was obtained, which was purified by column chromatography to afford compound 7 (20 mg, yield: 30%).
LC-MS:tR＝3.20min,[M+H]+＝618.0； LC-MS: t R = 3.20min , [M + H] + = 618.0;
1HNMR(400MHz,MeOD-d4)δ7.79(dd,J＝6.9,2.3Hz,1H),7.54(d,J＝8.7Hz,1H),7.51-7.38(m,4H),7.10(dd,J＝10.5,8.5Hz,1H),6.91(d,J＝2.6Hz,1H),6.79(dd,J＝8.6,2.6Hz,1H),5.02(s,2H),3.29-3.19(m,2H),2.98-2.84(m,1H),2.53-2.33(m,3H),1.34-1.29(m,2H),0.96-0.89(m,2H)； 1 H NMR (400 MHz, MeOD-d 4 ) δ 7.79 (dd, J = 6.9, 2.3 Hz, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.51 - 7.38 (m, 4H), 7.10 (dd) , J = 10.5, 8.5 Hz, 1H), 6.91 (d, J = 2.6 Hz, 1H), 6.79 (dd, J = 8.6, 2.6 Hz, 1H), 5.02 (s, 2H), 3.29-3.19 (m, 2H), 2.98-2.84 (m, 1H), 2.53-2.33 (m, 3H), 1.34-1.29 (m, 2H), 0.96-0.89 (m, 2H);
19FNMR(400MHz,MeOD-d4)δ-117.2。 19 F NMR (400 MHz, MeOD-d 4 ) δ -117.2.
实施例8 5-(3-(4-((5-环丙基-3-(2,6-二氯苯基)异噻唑-4-基)甲氧基)-2-(三氟甲基)苯基)-3-羟基环丁基)-2-氟苯甲酸(8)Example 8 5-(3-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)-2-(trifluoromethyl) Phenyl)-3-hydroxycyclobutyl)-2-fluorobenzoic acid (8)
Figure PCTCN2016111652-appb-000052
Figure PCTCN2016111652-appb-000052
第一步：化合物8-a的合成参照实施例1第一步～第三步的制备方法。First step: Synthesis of Compound 8-a Referring to the preparation methods of the first to third steps of Example 1.
LC-MS:tR＝3.51min,[M+H]+＝666.0。 LC-MS: t R = 3.51min , [M + H] + = 666.0.
第二步：将化合物8-a(66mg,0.1mmol)溶于甲醇(1mL)和(1mL)水，加入氢氧化钠(16mg,0.4mmol)。反应液于40℃搅拌2h。待反应完毕，用1N的盐酸酸化至pH为5～6，有固体析出。过滤干燥后得粗产物，粗产物经柱层析纯化后得化合物8(20mg,产率：31％)。The second step: Compound 8-a (66 mg, 0.1 mmol) was dissolved in methanol (1 mL) and (1 mL) water and sodium hydroxide (16 mg, 0.4 mmol). The reaction was stirred at 40 ° C for 2 h. After the reaction was completed, it was acidified to pH 5-6 with 1N hydrochloric acid, and a solid precipitated. After filtration and drying, a crude product was obtained, which was purified by column chromatography to afford compound 8 (20 mg, yield: 31%).
LC-MS:tR＝3.25min,[M+H]+＝652.0；LC-MS: t R = 3.25 min, [M+H] + = 652.0;
1HNMR(400MHz,MeOD-d4)δ7.80(d,J＝5.1Hz,1H),7.67(d,J＝8.7Hz,1H),7.54-7.28(m,4H),7.10(dd,J＝17.8,8.8Hz,3H),5.09(s,2H),3.17-2.92(m,3H),2.53(m,2H),2.47-2.31(m,1H),1.30(m,2H),0.93(m,2H)； 1 H NMR (400 MHz, MeOD-d 4 ) δ 7.80 (d, J = 5.1 Hz, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.54 - 7.28 (m, 4H), 7.10 (dd, J =17.8, 8.8 Hz, 3H), 5.09 (s, 2H), 3.17-2.92 (m, 3H), 2.53 (m, 2H), 2.47-2.31 (m, 1H), 1.30 (m, 2H), 0.93 ( m, 2H);
19FNMR(400MHz,MeOD-d4)δ-57.9,-117.1。 19 F NMR (400 MHz, MeOD-d 4 ) δ -57.9, -117.1.
实施例9 4-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噻唑-4-基)甲氧基)苯基)-3-羟基环丁基)苯甲酸(9)Example 9 4-(3-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)phenyl)- 3-hydroxycyclobutyl)benzoic acid (9)
Figure PCTCN2016111652-appb-000053
Figure PCTCN2016111652-appb-000053
第一步：将化合物1-a(160mg，0.50mmol)溶于干燥四氢呋喃(2mL)，氮气保护，于-70～78℃下滴加正丁基锂(1.6M的四氢呋喃溶液，0.38mL)，搅拌45min。滴加化合物I-5(102mg，0.50mmol)的四氢呋喃溶液，搅拌1h。反应液升至室温，饱和氯化铵溶液(5mL)淬灭，乙酸乙酯萃取。有机相干燥，浓缩，柱层析分离纯化(EA/PE:0～15％)，得到化合物9-a(120mg，产率：53％)。The first step: the compound 1-a (160 mg, 0.50 mmol) was dissolved in dry tetrahydrofuran (2 mL), and the mixture was filtered under nitrogen, and n-butyl lithium (1.6 M in tetrahydrofuran solution, 0.38 mL) was added dropwise at -70 to 78 °C. Stir for 45 min. A solution of the compound I-5 (102 mg, 0.50 mmol) in THF was evaporated. The reaction solution was warmed to room temperature, brine (EtOAc) The organic phase was dried, concentrated and purified by column chromatography (EtOAc/EtOAc: EtOAc:EtOAc:
LC-MS:tR＝3.82min,[M-OH]+＝429.1。 LC-MS: t R = 3.82min , [M-OH] + = 429.1.
第二步：将化合物9-a(120mg,0.27mmol)溶于四氢呋喃(1.5mL)，搅拌下滴加 TBAF的四氢呋喃溶液(0.54mL,1M,0.54mmol)。室温搅拌20min。反应完全后加少量水，并用乙酸乙酯(2×10mL)萃取，有机相合并后用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析纯化(EA/PE:20～30％)得化合物9-b(50mg，产率：55％)。The second step: the compound 9-a (120 mg, 0.27 mmol) was dissolved in tetrahydrofuran (1.5 mL) and added dropwise with stirring. A solution of TBAF in tetrahydrofuran (0.54 mL, 1 M, 0.54 mmol). Stir at room temperature for 20 min. After the reaction is completed, a small amount of water is added, and the mixture is extracted with ethyl acetate (2×10 mL). The organic phase is combined, washed with brine, dried over anhydrous sodium sulfate, filtered, %) Compound 9-b (50 mg, yield: 55%).
LC-MS:tR＝2.58min,[M-OH]+＝315.1。 LC-MS: t R = 2.58min , [M-OH] + = 315.1.
第三步：将化合物9-b(50mg,0.15mmol)与I-1(52mg,0.165mmol)溶于干燥DMF(1mL)，加入碳酸钾(28mg,0.20mmol)，于60℃搅拌过夜。待反应液冷却后加乙酸乙酯(20mL)，依次用水和饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，柱层析纯化(PE/EA:10～25％)，得化合物9-c(50mg,产率：54％)。The third step: Compound 9-b (50 mg, 0.15 mmol) was dissolved in dry DMF (1 mL). After the reaction mixture was cooled, ethyl acetate (20 mL) was added, and then washed with water and brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE/EA: 10~25%) to give compound 9-c (50 mg, yield: 54%).
LC-MS:tR＝3.53min,[M+H]+＝614.0。 LC-MS: t R = 3.53min , [M + H] + = 614.0.
第四步：将化合物9-c(50mg,0.08mmol)溶于甲醇(1mL)和(1mL)水，加入氢氧化钠(10mg,0.24mmol)。反应液于40℃搅拌2h。待反应完毕，用1N的盐酸酸化至pH为5～6，有固体析出。过滤干燥后得粗产物，粗产物经柱层析纯化后得化合物9(25mg,产率：51％)。The fourth step: Compound 9-c (50 mg, 0.08 mmol) was dissolved in methanol (1 mL) and (1 mL) water, and sodium hydroxide (10 mg, 0.24 mmol). The reaction was stirred at 40 ° C for 2 h. After the reaction was completed, it was acidified to pH 5-6 with 1N hydrochloric acid, and a solid precipitated. After filtration and drying, a crude product was obtained, which was purified by column chromatography to afford compound 9 (25 mg, yield: 51%).
LC-MS:tR＝3.19min,[M+H]+＝600.0； LC-MS: t R = 3.19min , [M + H] + = 600.0;
1HNMR(400MHz,CDCl3):δ7.97(d,J＝8.2Hz,2H),7.37(d,J＝8.7Hz,1H),7.30(m,4H),7.20(dd,J＝9.3,1.9Hz,1H),6.84(d,J＝2.5Hz,1H),6.67(dd,J＝8.6,2.5Hz,1H),4.86(s,2H),3.16-3.04(m,2H),3.00-2.88(m,1H),2.55-2.46(m,2H),2.20(m,1H),1.17-1.10(m,2H),0.87-0.82(m,2H)。 1 H NMR (400 MHz, CDCl 3 ): δ 7.97 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.7 Hz, 1H), 7.30 (m, 4H), 7.20 (dd, J = 9.3, 1.9 Hz, 1H), 6.84 (d, J = 2.5 Hz, 1H), 6.67 (dd, J = 8.6, 2.5 Hz, 1H), 4.86 (s, 2H), 3.16-3.04 (m, 2H), 3.00- 2.88 (m, 1H), 2.55-2.46 (m, 2H), 2.20 (m, 1H), 1.17-1.10 (m, 2H), 0.87-0.82 (m, 2H).
实施例10 4-(3-(4-((5-环丙基-3-(2,6-二氯苯基)异噻唑-4-基)甲氧基)-2-甲基苯基)-3-羟基环丁基)苯甲酸(10)Example 10 4-(3-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)-2-methylphenyl) -3-hydroxycyclobutyl)benzoic acid (10)
Figure PCTCN2016111652-appb-000054
Figure PCTCN2016111652-appb-000054
第一步：化合物10-a的合成参照实施例9第一步～第三步的制备方法。First step: Synthesis of compound 10-a Referring to the preparation methods of the first to third steps of Example 9.
LC-MS:tR＝3.49min,[M+H]+＝594.0。 LC-MS: t R = 3.49min , [M + H] + = 594.0.
第二步：将化合物10-a(20mg,0.03mmol)溶于甲醇(1mL)和(1mL)水，加入氢氧化钠(13mg,0.3mmol)。反应液于40℃搅拌2h。待反应完毕，用1N的盐酸酸化至pH为5～6，有固体析出。过滤干燥后得粗产物，粗产物经柱层析纯化后得化合物10(9mg,产率：46％)。The second step: Compound 10-a (20 mg, 0.03 mmol) was dissolved in methanol (1 mL) and (1 mL) water, and sodium hydroxide (13 mg, 0.3 mmol). The reaction was stirred at 40 ° C for 2 h. After the reaction was completed, it was acidified to pH 5-6 with 1N hydrochloric acid, and a solid precipitated. After filtration and drying, a crude product was obtained, which was purified by column chromatography to afford compound 10 (9 mg, yield: 46%).
LC-MS:tR＝3.16min,[M+H]+＝580.0； LC-MS: t R = 3.16min , [M + H] + = 580.0;
1HNMR(400MHz,MeOD-d4)δ7.97(d,J＝8.3Hz,2H),7.48(dd,J＝8.0,1.0Hz,2H),7.44-7.37(m,4H),6.68(d,J＝2.5Hz,1H),6.64(dd,J＝8.4,2.7Hz,1H),4.98(s,2H),3.19-3.08(m,2 H),2.97(d,J＝8.2Hz,1H),2.49(td,J＝10.0,2.6Hz,2H),2.41-2.39(m,4H),1.32-1.29(m,2H),0.95-0.89(m,2H)。 1 H NMR (400 MHz, MeOD-d 4 ) δ 7.97 (d, J = 8.3 Hz, 2H), 7.48 (dd, J = 8.0, 1.0 Hz, 2H), 7.44 - 7.37 (m, 4H), 6.68 (d) , J=2.5 Hz, 1H), 6.64 (dd, J=8.4, 2.7 Hz, 1H), 4.98 (s, 2H), 3.19-3.08 (m, 2 H), 2.97 (d, J = 8.2 Hz, 1H) ), 2.49 (td, J = 10.0, 2.6 Hz, 2H), 2.41-2.39 (m, 4H), 1.32-1.29 (m, 2H), 0.95-0.89 (m, 2H).
实施例11 4-(3-(4-((5-环丙基-3-(2,6-二氯苯基)异噻唑-4-基)甲氧基)-2-(三氟甲基)苯基)-3-羟基环丁基)苯甲酸(11)Example 11 4-(3-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)-2-(trifluoromethyl) Phenyl)-3-hydroxycyclobutyl)benzoic acid (11)
Figure PCTCN2016111652-appb-000055
Figure PCTCN2016111652-appb-000055
第一步：化合物11-a的合成参照实施例9第一步～第三步的制备方法。First step: Synthesis of compound 11-a Referring to the preparation methods of the first to third steps of Example 9.
LC-MS:tR＝3.52min,[M+H]+＝648.1。 LC-MS: t R = 3.52min , [M + H] + = 648.1.
第二步：化合物11-a(80mg,0.12mmol)溶于甲醇(1mL)和(1mL)水，加入氢氧化钠(15mg,0.36mmol)。反应液于40℃搅拌2h。待反应完毕，用1N的盐酸酸化至pH为5～6，有固体析出。过滤干燥后得粗产物，粗产物经柱层析纯化后得化合物11(10mg,产率：13％)。The second step: Compound 11-a (80 mg, 0.12 mmol) was dissolved in methanol (1 mL) and (1 mL) water. The reaction was stirred at 40 ° C for 2 h. After the reaction was completed, it was acidified to pH 5-6 with 1N hydrochloric acid, and a solid precipitated. After filtration and drying, a crude product was obtained, which was purified by column chromatography to afford compound 11 (10 mg, yield: 13%).
LC-MS:tR＝3.23min,[M+H]+＝634.0；LC-MS: t R = 3.23 min, [M+H] + = 634.0;
1HNMR(400MHz,DMSO-d6)δ12.80(bs，1H)，7.88(d,J＝8.0Hz,2H),7.65(d,J＝7.7Hz,1H),7.56(m,2H),7.46(m,3H),7.10(d,J＝8.7Hz,2H),5.64(s,1H),5.05(s,2H),3.00(m,3H),2.48-2.39(m,3H),1.35-1.22(m,2H),0.87(m,2H)； 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.80 (bs, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 7.7 Hz, 1H), 7.56 (m, 2H), 7.46 (m, 3H), 7.10 (d, J = 8.7 Hz, 2H), 5.64 (s, 1H), 5.05 (s, 2H), 3.00 (m, 3H), 2.48-2.39 (m, 3H), 1.35 -1.22 (m, 2H), 0.87 (m, 2H);
19FNMR(400MHz,DMSO-d6)δ-55.3。 19 F NMR (400 MHz, DMSO-d 6 ) δ - 55.3.
实施例12 3-(3-(2-氯-4-((3-(2,6-二氯苯基)-5-异丙基异噻唑-4-基)甲氧基)苯基)-3-羟基环丁基)-5-氟苯甲酸(12)Example 12 3-(3-(2-Chloro-4-((3-(2,6-dichlorophenyl)-5-isopropylisothiazol-4-yl)methoxy)phenyl)- 3-hydroxycyclobutyl)-5-fluorobenzoic acid (12)
Figure PCTCN2016111652-appb-000056
Figure PCTCN2016111652-appb-000056
第一步：化合物12-a的合成参照实施例1第一步～第三步的制备方法。First step: Synthesis of compound 12-a Referring to the preparation methods of the first to third steps of Example 1.
LC-MS:tR＝3.65min,[M+H]+＝634.0。 LC-MS: t R = 3.65min , [M + H] + = 634.0.
第二步：将化合物12-a(10mg,0.015mmol)溶于甲醇(1mL)和(1mL)水，加入氢氧化钠(6mg,0.15mmol)。反应液于40℃搅拌2h。待反应完毕，用1N的盐酸酸化至pH为5～6，有固体析出。过滤干燥后得粗产物，粗产物经柱层析纯化后得化合物12(6mg,产率：61％)。The second step: Compound 12-a (10 mg, 0.015 mmol) was dissolved in methanol (1 mL) and (1 mL) water and sodium hydroxide (6 mg, 0.15 mmol). The reaction was stirred at 40 ° C for 2 h. After the reaction was completed, it was acidified to pH 5-6 with 1N hydrochloric acid, and a solid precipitated. After filtration and drying, a crude product was obtained, which was purified by column chromatography to afford compound 12 (6 mg, yield: 61%).
LC-MS:tR＝3.34min,[M+H]+＝619.9；LC-MS: t R = 3.34 min, [M+H] + = 619.9;
1HNMR(400MHz,MeOD-d4)δ7.77(s,1H),7.55(d,J＝8.7Hz,1H),7.50(ddd,J＝9.1,4. 9,0.9Hz,3H),7.41(dd,J＝9.2,6.8Hz,1H),7.25(d,J＝9.6Hz,1H),6.89(d,J＝2.6Hz,1H),6.79(dd,J＝8.6,2.6Hz,1H),4.94(s,2H),3.61(dt,J＝13.7,6.9Hz,1H),3.31-3.19(m,2H),3.04-2.82(m,1H),2.51(td,J＝9.8,2.7Hz,2H),1.53-1.43(m,6H)； 1 H NMR (400 MHz, MeOD-d 4 ) δ 7.77 (s, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.50 (ddd, J = 9.1, 4. 9.0.9 Hz, 3H), 7.41 (dd, J = 9.2, 6.8 Hz, 1H), 7.25 (d, J = 9.6 Hz, 1H), 6.89 (d, J = 2.6 Hz, 1H), 6.79 (dd, J = 8.6, 2.6 Hz, 1H) , 4.94 (s, 2H), 3.61 (dt, J = 13.7, 6.9 Hz, 1H), 3.31-3.19 (m, 2H), 3.04-2.82 (m, 1H), 2.51 (td, J = 9.8, 2.7 Hz , 2H), 1.53-1.43 (m, 6H);
19FNMR(400MHz,MeOD-d4)δ-115.8。 19 F NMR (400 MHz, MeOD-d 4 ) δ-115.8.
实施例13 3-(3-(2-氯-4-((3-(2,6-二氯苯基)-5-(三氟甲基)异噻唑-4-基)甲氧基)苯基)-3-羟基环丁基)-5-氟苯甲酸(13)Example 13 3-(3-(2-Chloro-4-((3-(2,6-dichlorophenyl)-5-(trifluoromethyl)isothiazol-4-yl)methoxy)benzene 3-hydroxycyclobutyl)-5-fluorobenzoic acid (13)
Figure PCTCN2016111652-appb-000057
Figure PCTCN2016111652-appb-000057
第一步：化合物13-a的合成参照实施例1第一步～第三步的制备方法。First step: Synthesis of compound 13-a Referring to the preparation methods of the first to third steps of Example 1.
LC-MS:tR＝3.729min,[M-OH]+＝642.1；LC-MS: t R =3.729 min, [M-OH] + =642.1;
1HNMR(400MHz,CDCl3)δ7.74(s,1H),7.55(ddd,J＝8.9,2.4,1.4Hz,1H),7.38(ddd,J＝15.9,8.9,4.2Hz,4H),7.21(dd,J＝9.4,1.7Hz,1H),6.80(d,J＝2.6Hz,1H),6.68(dd,J＝8.6,2.6Hz,1H),5.01(s,2H),3.92(s,3H),3.23-3.12(m,2H),3.06-2.95(m,1H),2.61-2.50(m,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.74 (s, 1H), 7.55 (ddd, J = 8.9, 2.4, 1.4 Hz, 1H), 7.38 (ddd, J = 15.9, 8.9, 4.2 Hz, 4H), 7.21. (dd, J = 9.4, 1.7 Hz, 1H), 6.80 (d, J = 2.6 Hz, 1H), 6.68 (dd, J = 8.6, 2.6 Hz, 1H), 5.01 (s, 2H), 3.92 (s, 3H), 3.23 - 3.12 (m, 2H), 3.06 - 2.95 (m, 1H), 2.61-2.50 (m, 2H).
第二步：化合物13-a(50mg,.08mmol)溶于MeOH(1mL)和THF(1mL)。加入NaOH水溶液(1.0M,1mL)。60℃搅拌反应2h。冷却后用1N的盐酸酸化至pH＝4，乙酸乙酯萃取3次，有机相干燥，过滤，浓缩，柱层析分离，纯化后得白色固体化合物13(14.9mg)。The second step: Compound 13-a (50 mg, .08 mmol) was dissolved in MeOH (1 mL) Aqueous NaOH (1.0 M, 1 mL) was added. The reaction was stirred at 60 ° C for 2 h. After cooling, it was acidified to pH = 4 with EtOAc (EtOAc)EtOAc.
LC-MS:tR＝3.443min,[M-H]-＝644.0；LC-MS: t R =3.443 min, [MH] - = 644.0;
1HNMR(400MHz,MeOD)δ7.77(s,1H),7.66-7.40(m,5H),7.24(d,J＝9.8Hz,1H),6.85(s,1H),6.78(d,J＝8.6Hz,1H),5.10(s,2H),3.31-3.22(m,2H),3.03-2.93(m,1H),2.51(t,J＝10.4Hz,2H)； 1 H NMR (400 MHz, MeOD) δ 7.77 (s, 1H), 7.66-7.40 (m, 5H), 7.24 (d, J = 9.8 Hz, 1H), 6.85 (s, 1H), 6.78 (d, J = 8.6 Hz, 1H), 5.10 (s, 2H), 3.31-3.22 (m, 2H), 3.03-2.93 (m, 1H), 2.51 (t, J = 10.4 Hz, 2H);
19FNMR(376MHz,MeOD)δ-56.76(s),-115.96(s)。 19 F NMR (376 MHz, MeOD) δ - 56.76 (s), -115.96 (s).
实施例14 4-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噻唑-4-基)甲氧基)苯基)-3-羟基环丁基)酞酸(14)Example 14 4-(3-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)phenyl)- 3-hydroxycyclobutyl)decanoic acid (14)
Figure PCTCN2016111652-appb-000058
Figure PCTCN2016111652-appb-000058
第一步：将化合物1-a(320mg，0.55mmol)溶于干燥四氢呋喃(10mL)，氮气保护，于-70～78℃下滴加正丁基锂(1.6M的四氢呋喃溶液，0.4mL)。加完搅拌45min。滴加化合物I-8(131mg，0.50mmol)的四氢呋喃溶液。加完搅拌1h。反应液升至室温，并用饱和氯化铵溶液淬灭，乙酸乙酯萃取。有机层干燥浓缩后柱层析纯化(EA/PE:0～15％)，得化合物14-a(40mg，产率：20％)。The first step: Compound 1-a (320 mg, 0.55 mmol) was dissolved in dry tetrahydrofuran (10 mL), and then evaporated, and then n-butyl lithium (1.6 M in tetrahydrofuran, 0.4 mL) was added dropwise at -70 to 78 °C. Stirring was added for 45 min. A solution of compound I-8 (131 mg, 0.50 mmol) in tetrahydrofuran was added dropwise. Stirring was completed for 1 h. The reaction mixture was warmed to room temperature and then brined The organic layer was dried and concentrated, and purified by column chromatography (EA/PE: 0 to 15%) to afford compound 14-a (40 mg, yield: 20%).
LC-MS:tR＝3.64min,[M-OH]+＝487.0。 LC-MS: t R = 3.64min , [M-OH] + = 487.0.
第二步：将化合物14-a(40mg,0.08mmol)溶于四氢呋喃(1mL)，搅拌下滴加TBAF的四氢呋喃溶液(1M,0.24mL,0.24mmol)。室温搅拌20min后，体系加少量水，用乙酸乙酯(2×210mL)萃取，有机相合并后用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析纯化(EA/PE:20～30％)得化合物14-b(120mg，产率：62％)。The second step: Compound 14-a (40 mg, 0.08 mmol) was dissolved in tetrahydrofuran (1 mL) and THF (THF) (1M, After stirring at room temperature for 20 min, a little water was added and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated 20 to 30%) Compound 14-b (120 mg, yield: 62%).
LC-MS:tR＝2.46min,[M-OH]+＝373.0。 LC-MS: t R = 2.46min , [M-OH] + = 373.0.
第三步：将化合物14-b(30mg,0.07mmol)与I-1(30mg,0.09mmol)溶于干燥DMF(3mL)，加入碳酸钾(50mg,0.35mmol)，于60℃搅拌过夜。待反应液冷却后加乙酸乙酯(20mL)，依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析纯化(PE/EA:10～25％)，得化合物14-c(30mg,产率：64％)。The third step: Compound 14-b (30 mg, 0.07 mmol) was dissolved in dry DMF (3 mL). After the reaction mixture was cooled, ethyl acetate (20 mL) was added, and then washed with water and brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE/EA: 10~25%) c (30 mg, yield: 64%).
LC-MS:tR＝3.41min,[M+H]+＝672.1。 LC-MS: t R = 3.41min , [M + H] + = 672.1.
第四步：将化合物14-c(10mg,0.015mmol)溶于甲醇(1mL)和水(1mL)，加入氢氧化钠(3mg,0.075mmol)。40℃搅拌2h。待反应完毕用1N的盐酸酸化至pH为5～6，有白色固体析出。过滤干燥后得粗产物，粗产物经柱层析纯化后得化合物14(4mg,产率：40％)。The fourth step: Compound 14-c (10 mg, 0.015 mmol) was dissolved in methanol (1 mL) and water (1 mL). Stir at 40 ° C for 2 h. After the reaction was completed, it was acidified with 1N hydrochloric acid to pH 5-6, and a white solid precipitated. After filtration and drying, a crude product was obtained, which was purified by column chromatography to afford compound 14 (4 mg, yield: 40%).
LC-MS:tR＝2.91min,[M-OH]+＝626.0； LC-MS: t R = 2.91min , [M-OH] + = 626.0;
1HNMR(400MHz,MeOD-d4)δ8.04(d,J＝8.1Hz,1H),8.00(d,J＝1.6Hz,1H),7.45(d,J＝8.7Hz,1H),7.39(m,3H),7.30(dd,J＝9.2,6.7Hz,1H),6.79(d,J＝2.6Hz,1H),6.68(dd,J＝8.6,2.6Hz,1H),5.03(s,2H),3.19-3.07(m,2H),2.93-2.79(m,1H),2.43(td,J＝9.8,2.7Hz,2H),2.30(tt,J＝8.3,5.1Hz,1H),1.24-1.17(m,2H),0.83-0.76(m,2H)。 1 H NMR (400 MHz, MeOD-d 4 ) δ 8.04 (d, J = 8.1 Hz, 1H), 8.00 (d, J = 1.6 Hz, 1H), 7.45 (d, J = 8.7 Hz, 1H), 7.39 ( m, 3H), 7.30 (dd, J = 9.2, 6.7 Hz, 1H), 6.79 (d, J = 2.6 Hz, 1H), 6.68 (dd, J = 8.6, 2.6 Hz, 1H), 5.03 (s, 2H) ), 3.19-3.07 (m, 2H), 2.93-2.79 (m, 1H), 2.43 (td, J = 9.8, 2.7 Hz, 2H), 2.30 (tt, J = 8.3, 5.1 Hz, 1H), 1.24 1.17 (m, 2H), 0.83-0.76 (m, 2H).
实施例15 5-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噻唑-4-基)甲氧基)苯基)-3-羟基环丁基)-2-羟基异二氢吲哚-1,3-二酮(15)Example 15 5-(3-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)phenyl)- 3-hydroxycyclobutyl)-2-hydroxyisoindoline-1,3-dione (15)
Figure PCTCN2016111652-appb-000059
Figure PCTCN2016111652-appb-000059
第一步：将化合物14(64mg，0.1mmol)与EDCI(38mg，0.2mmol)溶于DMF(5mL)，并在氮气保护下搅拌2h。TLC监测反应完全后向体系中加乙酸乙酯(30mL)，依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得化合物15-a(50mg,产率：80％)。 The first step: Compound 14 (64 mg, 0.1 mmol) was obtained eluted with EtOAc EtOAc EtOAc After the reaction was completed by TLC, ethyl acetate (30 mL) was added, and then washed successively with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to give compound 15-a (50 mg, yield: 80%).
LC-MS:tR＝3.38min,[M+H]+＝625.9。 LC-MS: t R = 3.38min , [M + H] + = 625.9.
第二步：将化合物15-a(50mg,0.08mmol)和盐酸羟胺(200mg)溶于吡啶(6mL)，回流反应3h。TLC监测反应完全。向体系中加乙酸乙酯(30mL)，依次用水和饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，柱层析纯化，得化合物15(13mg,产率：30.7％)。The second step: Compound 15-a (50 mg, 0.08 mmol) and hydroxylamine hydrochloride (200 mg) were dissolved in pyridine (6 mL) and refluxed for 3 h. TLC monitored the reaction completely. Ethyl acetate (30 mL) was added to the mixture, and the mixture was evaporated.
LC-MS:tR＝3.12min,[M+H]+＝640.9； LC-MS: t R = 3.12min , [M + H] + = 640.9;
1HNMR(400MHz,DMSO-d6)δ10.76(s,1H),7.87(s,1H),7.74(q,J＝7.7Hz,2H),7.62-7.54(m,2H),7.54-7.44(m,2H),6.94(d,J＝2.6Hz,1H),6.79(dd,J＝8.6,2.6Hz,1H),5.54(s,1H),4.97(s,2H),3.23-3.11(m,2H),3.09-2.94(m,1H),2.50-2.37(m,3H),1.29(dt,J＝6.5,4.6Hz,2H),0.87(dt,J＝6.8,4.7Hz,2H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.76 (s, 1H), 7.87 (s, 1H), 7.74 (q, J = 7.7 Hz, 2H), 7.62-7.54 (m, 2H), 7.54-7.44 (m, 2H), 6.94 (d, J = 2.6 Hz, 1H), 6.79 (dd, J = 8.6, 2.6 Hz, 1H), 5.54 (s, 1H), 4.97 (s, 2H), 3.23 - 3.11 ( m, 2H), 3.09-2.94 (m, 1H), 2.50-2.37 (m, 3H), 1.29 (dt, J = 6.5, 4.6 Hz, 2H), 0.87 (dt, J = 6.8, 4.7 Hz, 2H) .
实施例16 5-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噻唑-4-基)甲氧基)苯基)-3-羟基环丁基)异二氢吲哚-1,3-二酮(16)Example 16 5-(3-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)phenyl)- 3-hydroxycyclobutyl)isoindoline-1,3-dione (16)
Figure PCTCN2016111652-appb-000060
Figure PCTCN2016111652-appb-000060
将化合物15-a(50mg,0.08mmol)和NH4OAc(200mg)置于50mL圆底烧瓶中，搅拌下加热到熔融状态反应2h。TLC监测反应完全后向体系中加乙酸乙酯(30mL)，依次用水和饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，柱层析纯化，得化合物16(15mg,产率：30％)。Compound 15-a (50 mg, 0.08 mmol) and NH 4 OAc (200 mg) were placed in a 50 mL round bottom flask and heated to a molten state for 2 h under stirring. After the reaction was completed by TLC, ethyl acetate (30 mL) was added, and the mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound 16 (15 mg, yield: 30%) .
LC-MS:tR＝3.20min,[M+H]+＝624.8； LC-MS: t R = 3.20min , [M + H] + = 624.8;
1HNMR(400MHz,DMSO-d6)δ11.25(s,1H),7.84(s,1H),7.74(s,2H),7.59(d,J＝8.3Hz,2H),7.55-7.43(m,2H),6.94(s,1H),6.79(d,J＝8.6Hz,1H),5.54(s,1H),4.97(s,2H),3.17(d,J＝10.4Hz,2H),3.10-2.97(m,1H),2.44(m,3H),1.29(m,2H),0.88(m,2H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.25 (s, 1H), 7.84 (s, 1H), 7.74 (s, 2H), 7.59 (d, J = 8.3 Hz, 2H), 7.55-7.43 (m) , 2H), 6.94 (s, 1H), 6.79 (d, J = 8.6 Hz, 1H), 5.54 (s, 1H), 4.97 (s, 2H), 3.17 (d, J = 10.4 Hz, 2H), 3.10 - 2.97 (m, 1H), 2.44 (m, 3H), 1.29 (m, 2H), 0.88 (m, 2H).
实施例17 4-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)-3-羟基环丁基)酞酸(17)Example 17 4-(3-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) -3-hydroxycyclobutyl)decanoic acid (17)
Figure PCTCN2016111652-appb-000061
Figure PCTCN2016111652-appb-000061
第一步：化合物17-a的合成参照实施例14第一步～第三步的制备方法。First step: Synthesis of compound 17-a Referring to the preparation methods of the first to third steps of Example 14.
LC-MS:tR＝3.298min,[M-OH]+＝638.0,640.0。LC-MS: t R = 3.298 min, [M-OH] + = 638.0, 640.0.
第二步：将化合物17-a(13mg，0.020mmol)溶于四氢呋喃(2mL)，加入1N氢 氧化钠水溶液(2mL)，50℃反应2h。反应完全，加入稀盐酸酸化，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，浓缩，粗品经PTLC分离，得化合物17(9mg，产率：73％)。The second step: the compound 17-a (13 mg, 0.020 mmol) was dissolved in tetrahydrofuran (2 mL) and 1N hydrogen was added. An aqueous solution of sodium oxide (2 mL) was reacted at 50 ° C for 2 h. The reaction was completed, the mixture was acidified with EtOAc (EtOAc)EtOAc. Filtration, concentration and crude product were purified by EtOAc EtOAc (EtOAc)
LC-MS:tR＝2.82min,[M+H]+＝626.0,628.0；LC-MS: t R = 2.82 min, [M+H] + = 626.0, 628.0;
1HNMR(400MHz,MeOD)δ8.06(d,J＝7.9Hz,1H),8.01(s,1H),7.44-7.29(m,5H),6.81(d,J＝2.5Hz,1H),6.66(dd,J＝8.6,2.5Hz,1H),4.79(s,2H),3.16(t,J＝10.1Hz,2H),2.97-2.84(m,1H),2.46(dd,J＝12.0,9.9Hz,2H),2.22-2.08(m,1H),1.21-1.07(m,4H)。 1 HNMR (400MHz, MeOD) δ8.06 (d, J = 7.9Hz, 1H), 8.01 (s, 1H), 7.44-7.29 (m, 5H), 6.81 (d, J = 2.5Hz, 1H), 6.66 (dd, J=8.6, 2.5 Hz, 1H), 4.79 (s, 2H), 3.16 (t, J = 10.1 Hz, 2H), 2.97-2.84 (m, 1H), 2.46 (dd, J = 12.0, 9.9 Hz, 2H), 2.22-2.08 (m, 1H), 1.21-1.07 (m, 4H).
实施例18 5-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)-3-羟基环丁基)-2-羟基异二氢吲哚-1,3-二酮(18)Example 18 5-(3-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) -3-hydroxycyclobutyl)-2-hydroxyisoindoline-1,3-dione (18)
Figure PCTCN2016111652-appb-000062
Figure PCTCN2016111652-appb-000062
第一步：将化合物17(80mg，0.127mmol)溶于干燥DMF(1.5mL)，搅拌下加入EDCI(38mg)。室温搅拌反应3h。用水稀释，乙酸乙酯萃取3次。合并有机相，再用饱和食盐水洗涤，干燥，浓缩，得粗产物18-a(68mg，产率：88％)。First step: Compound 17 (80 mg, 0.127 mmol) was dissolved in dry DMF (1.5 mL). The reaction was stirred at room temperature for 3 h. It was diluted with water and extracted with ethyl acetate three times. The organic phase was combined, washed with brine, dried and evaporated]]]]
LC-MS:tR＝3.275min,[M+H]+＝不出峰。 LC-MS: t R = 3.275min , [M + H] + = no peak.
第二步：将化合物18-a(34mg，0.056mmol)溶于吡啶(2mL)，加入盐酸羟胺(40mg)。回流搅拌2h。反应液冷却至室温，用乙酸乙酯稀释，依次水洗和食盐水洗后干燥浓缩，纯化后得到化合物18(14.6mg，产率：42％)。The second step: Compound 18-a (34 mg, 0.056 mmol) was dissolved in pyridine (2 mL) and hydroxylamine hydrochloride (40 mg). Stir under reflux for 2 h. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, and then dried and concentrated to afford compound 18 (14.6 mg, yield: 42%).
LC-MS:tR＝2.999min.[M-OH]+＝606.8；LC-MS: t R = 2.99 min. [M-OH] + = 606.8;
1HNMR(400MHz,DMSO)δ10.86(s,1H),7.86(s,1H),7.73(q,J＝7.8Hz,2H),7.66-7.61(m,2H),7.59-7.49(m,2H),6.92(d,J＝2.6Hz,1H),6.77(dd,J＝8.6,2.6Hz,1H),5.55(s,1H),4.92(s,2H),3.23-3.14(m,2H),3.02(dt,J＝17.2,8.7Hz,1H),2.45(t,J＝9.9Hz,3H),1.19(dd,J＝7.8,2.9Hz,2H),1.16-1.11(m,2H)。 1 H NMR (400 MHz, DMSO) δ 10.86 (s, 1H), 7.86 (s, 1H), 7.73 (q, J = 7.8 Hz, 2H), 7.66-7.61 (m, 2H), 7.59-7.49 (m, 2H), 6.92 (d, J = 2.6 Hz, 1H), 6.77 (dd, J = 8.6, 2.6 Hz, 1H), 5.55 (s, 1H), 4.92 (s, 2H), 3.23 - 3.14 (m, 2H) ), 3.02 (dt, J = 17.2, 8.7 Hz, 1H), 2.45 (t, J = 9.9 Hz, 3H), 1.19 (dd, J = 7.8, 2.9 Hz, 2H), 1.16.11.11 (m, 2H) .
实施例19 5-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)-3-羟基环丁基)异二氢吲哚-1,3-二酮(19)Example 19 5-(3-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) -3-hydroxycyclobutyl)isoindoline-1,3-dione (19)
Figure PCTCN2016111652-appb-000063
Figure PCTCN2016111652-appb-000063
将化合物18-a(34mg，0.056mmol)和乙酸铵(1.0g)加热至130℃反应2h。冷却至室温后用水稀释，乙酸乙酯萃取2次。合并有机相，干燥，浓缩，经柱层析分离纯化，得化合物19(9mg，26％)。Compound 18-a (34 mg, 0.056 mmol) and ammonium acetate (1.0 g) were heated to 130 ° C for 2 h. After cooling to room temperature, it was diluted with water and extracted twice with ethyl acetate. The combined organic layers were dried, concentrated and purified elut elut
LC-MS:tR＝3.081min.[M-OH]+＝591.0； LC-MS: t R = 3.081 min. [M-OH] + = 591.0;
1HNMR(400MHz,DMSO)δ11.25(s,1H),7.84(s,1H),7.74(d,J＝8.0Hz,2H),7.68-7.60(m,2H),7.59-7.49(m,2H),6.92(d,J＝2.5Hz,1H),6.77(dd,J＝8.7,2.5Hz,1H),5.54(s,1H),4.92(s,2H),3.18(t,J＝10.0Hz,2H),3.03(dd,J＝17.3,8.8Hz,1H),2.45(dd,J＝15.1,6.8Hz,3H),1.16(ddd,J＝17.5,6.8,3.7Hz,4H)。 1 H NMR (400 MHz, DMSO) δ 11.25 (s, 1H), 7.84 (s, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.68-7.60 (m, 2H), 7.59-7.49 (m, 2H), 6.92 (d, J = 2.5 Hz, 1H), 6.77 (dd, J = 8.7, 2.5 Hz, 1H), 5.54 (s, 1H), 4.92 (s, 2H), 3.18 (t, J = 10.0) Hz, 2H), 3.03 (dd, J = 17.3, 8.8 Hz, 1H), 2.45 (dd, J = 15.1, 6.8 Hz, 3H), 1.16 (ddd, J = 17.5, 6.8, 3.7 Hz, 4H).
实施例20 3-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯基)吖丁啶-1-基)-5-氟苯甲酸(20)Example 20 3-(3-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Azetidin-1-yl)-5-fluorobenzoic acid (20)
Figure PCTCN2016111652-appb-000064
Figure PCTCN2016111652-appb-000064
第一步：将化合物20-a(2215mg，10.0mmol)溶于干燥THF(20mL)，干冰-乙醇浴冷却，滴加BuLi(6.9mL，11.0mmol，1.6M正己烷溶液)，低温反应30min。酮20-b(856mg，5.0mmol)溶于干燥THF(10mL)，加入反应体系。缓慢升温至接近0℃反应2h。反应完全后加入饱和NH4Cl水溶液淬灭，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥。过滤，浓缩，柱层析分离(PE/EA3:1)，得化合物20-c(1040mg，产率：66％)。The first step: Compound 20-a (2215 mg, 10.0 mmol) was dissolved in dry THF (20 mL), cooled in a dry ice-ethanol bath, and BuLi (6.9 mL, 11.0 mmol, 1.6 M n-hexane solution) was added dropwise and reacted at low temperature for 30 min. Ketone 20-b (856 mg, 5.0 mmol) was dissolved in dry THF (10 mL). Slowly warm to near 0 ° C for 2 h. After completion of the reaction was added saturated aqueous NH 4 Cl was quenched, extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate. Filtration, concentration and column chromatography (PE/EA3: 1) gave Compound 20-c (1040 mg, yield: 66%).
LC-MS:tR＝2.69min,[M+H-Boc]+＝214.1。 LC-MS: t R = 2.69min , [M + H-Boc] + = 214.1.
第二步：将化合物20-c(1040mg，3.31mmol)溶于干燥CH2Cl2(20mL，冰水浴冷却，依次加入Et3SiH(5.3mL，33.1mmol)和BF3·Et2O(5.0mL，39.8mmol)。保持低温，反应2h。反应完全后加入NaOH水溶液调节pH至弱碱性。浓缩，粗品加入乙酸乙酯，剧烈搅拌使产物充分溶解。过滤，乙酸乙酯洗涤。滤液浓缩，得粗品化合物20-d(955mg，产率：100％)。Step Two: Compound 20-c (1040mg, 3.31mmol) was dissolved in dry CH 2 Cl 2 (20mL, ice-water bath, followed by addition of Et 3 SiH (5.3mL, 33.1mmol) and BF 3 · Et 2 O (5.0 mL, 39.8 mmol). Keep the temperature at low temperature for 2 h. After the reaction is complete, add NaOH aqueous solution to adjust the pH to weakly alkaline. Concentrate, add crude ethyl acetate, stir vigorously to dissolve the product. Filter, wash with ethyl acetate. The crude compound 20-d (955 mg, yield: 100%) was obtained.
LC-MS:tR＝1.69min,[M+H]+＝198.1。 LC-MS: t R = 1.69min , [M + H] + = 198.1.
第三步：将化合物20-d(89mg，0.45mmol)、20-e(70mg，0.30mmol)、X-phos(29mg，0.06mmol)以及Cs2CO3(195mg，0.60mmol)加入二氧六环(4mL)，抽环气，氮气保护下加入Pd2(dba)3(27mg，0.03mmol)，100℃反应过夜。反应完全，冷却至室温，加入饱和食盐水洗涤，乙酸乙酯萃取。浓缩后粗产品柱层析分 离，得化合物20-f(80mg，产率：76％)。The third step: adding compound 20-d (89 mg, 0.45 mmol), 20-e (70 mg, 0.30 mmol), X-phos (29 mg, 0.06 mmol) and Cs 2 CO 3 (195 mg, 0.60 mmol) to dioxane ring (4 mL), ring gas pump, under nitrogen was added Pd 2 (dba) 3 (27mg, 0.03mmol), 100 ℃ overnight. The reaction was completed, cooled to room temperature, washed with saturated brine and evaporated. After concentration, the crude product was separated by chromatography to afford compound 20-f (80mg, yield: 76%).
LC-MS:tR＝3.45min,[M+H]+＝350.0。 LC-MS: t R = 3.45min , [M + H] + = 350.0.
第四步：将化合物20-f(80mg，0.23mmol)溶于二氯甲烷(2mL)，冰水浴冷却，加入BBr3/CH2Cl2(0.9mL，0.91mmol，1M)，0℃反应1h。加入甲醇淬灭，二氯甲烷萃取。化合物20-g粗品直接用于下步反应。The fourth step: the compound 20-f (80 mg, 0.23 mmol) was dissolved in dichloromethane (2 mL), cooled in ice water, BBr 3 /CH 2 Cl 2 (0.9 mL, 0.91 mmol, 1 M) . It was quenched by the addition of methanol and extracted with dichloromethane. The crude compound 20-g was used directly in the next step.
LC-MS:tR＝3.05min,[M+H]+＝336.0。 LC-MS: t R = 3.05min , [M + H] + = 336.0.
第五步：将化合物20-g(40mg，0.12mmol)和I-2(36mg，0.12mmol)溶于干燥DMF(2mL)，再加入K2CO3(33mg，0.24mmol)，50℃反应过夜。反应完全后浓缩，PTLC分离，得化合物20-h(14mg，19％)。The second step: Compound 20-g (40 mg, 0.12 mmol) and 1-2 (36 mg, 0.12 mmol) were dissolved in dry DMF (2 mL), then K 2 CO 3 (33 mg, 0.24 mmol), and reacted at 50 ° C overnight. . The reaction was completed, concentrated and purified by EtOAc EtOAc (EtOAc)
LC-MS:tR＝3.74min,[M+H]+＝601.0,603.1。 LC-MS: t R = 3.74min , [M + H] + = 601.0,603.1.
第六步：将化合物20-h(14mg，0.023mmol)溶于四氢呋喃(1mL)，再加入1NNaOH(1mL)水溶液。50℃反应过夜。反应完全后加入稀盐酸中和，乙酸乙酯萃取。浓缩后粗产品经PTLC分离，得化合物20(11.4mg，产率：83％)。The sixth step: Compound 20-h (14 mg, 0.023 mmol) was dissolved in tetrahydrofuran (1 mL) and then aqueous 1N NaOH (1 mL). The reaction was carried out at 50 ° C overnight. After the reaction was completed, it was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The crude product was concentrated by PTLC to give Compound 20 (11.4 mg, yield: 83%).
LC-MS:tR＝3.42min,[M+H]+＝586.9,589.0；LC-MS: t R = 3.42 min, [M+H] + = 586.9, 589.0;
1HNMR(400MHz,CDCl3)δ7.41(d,J＝1.5Hz,1H),7.39(s,1H),7.32(dd,J＝9.1,6.9Hz,1H),7.26(d,J＝8.6Hz,1H),7.16-7.11(m,1H),7.01-6.94(m,1H),6.83(d,J＝2.6Hz,1H),6.72(dd,J＝8.6,2.6Hz,1H),6.37(dt,J＝10.4,2.2Hz,1H),4.79(s,2H),4.36(t,J＝7.6Hz,2H),4.30-4.19(m,1H),3.87(t,J＝6.7Hz,2H),2.15(tt,J＝8.4,5.1Hz,1H),1.30-1.23(m,2H),1.15(ddd,J＝11.5,7.1,4.5Hz,2H)； 1 H NMR (400 MHz, CDCl 3 ) δ 7.41 (d, J = 1.5 Hz, 1H), 7.39 (s, 1H), 7.32 (dd, J = 9.1, 6.9 Hz, 1H), 7.26 (d, J = 8.6 Hz, 1H), 7.16-7.11 (m, 1H), 7.01-6.94 (m, 1H), 6.83 (d, J = 2.6 Hz, 1H), 6.72 (dd, J = 8.6, 2.6 Hz, 1H), 6.37 (dt, J = 10.4, 2.2 Hz, 1H), 4.79 (s, 2H), 4.36 (t, J = 7.6 Hz, 2H), 4.30-4.19 (m, 1H), 3.87 (t, J = 6.7 Hz, 2H), 2.15 (tt, J = 8.4, 5.1 Hz, 1H), 1.30 - 1.23 (m, 2H), 1.15 (ddd, J = 11.5, 7.1, 4.5 Hz, 2H);
19FNMR(376MHz,CDCl3)δ-111.79。 19 F NMR (376 MHz, CDCl 3 ) δ-111.79.
实施例21 3-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噻唑-4-基)甲氧基)苯基)吖丁啶-1-基)-5-氟苯甲酸(21)Example 21 3-(3-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)phenyl)indole Butyr-1-yl)-5-fluorobenzoic acid (21)
Figure PCTCN2016111652-appb-000065
Figure PCTCN2016111652-appb-000065
第一步：化合物21-a的合成参照实施例20第一步～第五步的制备方法。First step: Synthesis of Compound 21-a Referring to the preparation method of the first to fifth steps of Example 20.
LC-MS:tR＝3.901min,[M+H]+＝617.0,619.0。 LC-MS: t R = 3.901min , [M + H] + = 617.0,619.0.
第二步：将化合物21-a(15mg，0.024mmol)溶于四氢呋喃(1mL)，再加入1NNaOH(1mL)水溶液。50℃反应过夜。反应完全后加入稀盐酸中和，乙酸乙酯萃取。浓缩后粗产品经PTLC分离，得化合物21(10.0mg，产率：68％)。The second step: Compound 21-a (15 mg, 0.024 mmol) was dissolved in THF (1 mL). The reaction was carried out at 50 ° C overnight. After the reaction was completed, it was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The crude product was concentrated by PTLC to give Compound 21 (10.0 mg, yield: 68%).
LC-MS:tR＝3.53min,[M+H]+＝603.0,605.0； LC-MS: t R = 3.53min , [M + H] + = 603.0,605.0;
1HNMR(400MHz,CDCl3)δ7.38(d,J＝1.1Hz,1H),7.36(s,1H),7.31-7.23(m,2H),7.17-7.11(m,1H),7.01-6.95(m,1H),6.84(d,J＝2.6Hz,1H),6.72(dd,J＝8.6,2.6Hz,1H),6.38(dt,J＝10.3,2.2Hz,1H),4.90(s,2H),4.36(t,J＝7.6Hz,2H),4.31-4.20(m,1H),3.88(t,J＝6.7Hz,2H) ,2.31-2.21(m,1H),1.29-1.20(m,2H),0.92(dt,J＝6.7,4.9Hz,2H)； 1 H NMR (400 MHz, CDCl 3 ) δ 7.38 (d, J = 1.1 Hz, 1H), 7.36 (s, 1H), 7.31 - 7.23 (m, 2H), 7.17-7.11 (m, 1H), 7.01-6.95 (m, 1H), 6.84 (d, J = 2.6 Hz, 1H), 6.72 (dd, J = 8.6, 2.6 Hz, 1H), 6.38 (dt, J = 10.3, 2.2 Hz, 1H), 4.90 (s, 2H), 4.36 (t, J = 7.6 Hz, 2H), 4.31-4.20 (m, 1H), 3.88 (t, J = 6.7 Hz, 2H), 2.31-2.21 (m, 1H), 1.29-1.20 (m) , 2H), 0.92 (dt, J = 6.7, 4.9 Hz, 2H);
19FNMR(376MHz,CDCl3)δ-111.78。 19 F NMR (376 MHz, CDCl 3 ) δ-111.78.
实施例22 2-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噻唑-4-基)甲氧基)苯基)-3-羟基吖丁啶-1-基)异尼古丁酸(22)Example 22 2-(3-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)phenyl)- 3-hydroxyazetidin-1-yl)iso Nicotine (22)
Figure PCTCN2016111652-appb-000066
Figure PCTCN2016111652-appb-000066
第一步：将化合物22-a(1900mg，8.8mmol)与22-b(1440mg,13.2mmol)溶于1,4-二氧六环(30mL)，依次加Cs2CO3(8600mg，26.3mmol)，BINAP(1100mg,1.76mmol)和Pd(OAc)2(400mg，1.76mmol)，氮气保护下回流16h。TLC监测反应完全，过滤，浓缩后柱层析纯化(EA/PE:20％～50％)得到化合物22-c(500mg，产率：28％)。First step: Compound 22-a (1900 mg, 8.8 mmol) and 22-b (1440 mg, 13.2 mmol) were dissolved in 1,4-dioxane (30 mL), followed by Cs 2 CO 3 (8600 mg, 26.3 mmol) BINAP (1100 mg, 1.76 mmol) and Pd(OAc) 2 (400 mg, 1.76 mmol) were refluxed under nitrogen for 16 h. The reaction was monitored by TLC, filtered, concentrated and purified by column chromatography (EA/PE: 20% to 50%) to afford compound 22-c (500 mg, yield: 28%).
第二步：将化合物22-c(500mg,2.5mmol)溶于二氯甲烷(30mL)，搅拌下加入DMP(2120mg，5mmol)。室温搅拌2h，加饱和NaHCO3水溶液淬灭反应，并用乙酸乙酯(2×30mL)萃取，有机相合并后用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析纯化，得化合物22-d(230mg，产率：29％)。The second step: Compound 22-c (500 mg, 2.5 mmol) was dissolved in dichloromethane (30mL) and DMP (2120mg, 5mmol). Was stirred at room temperature 2h, saturated aqueous NaHCO 3 was added to quench the reaction, and extracted with ethyl acetate (2 × 30mL), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give Compound 22-d (230 mg, yield: 29%).
LC-MS:tR＝1.58min,[M+H]+＝207.1。 LC-MS: t R = 1.58min , [M + H] + = 207.1.
第三步：将化合物1-a(300mg,0.93mmol))溶于干燥四氢呋喃(5mL)，氮气保护，于-70～78℃下滴加正丁基锂(1.6M的四氢呋喃溶液，0.7mL)。搅拌45min。滴加化合物22-d(175mg，0.85mmol)的四氢呋喃溶液，搅拌1h。反应液升至室温，并用饱和氯化铵溶液淬灭，乙酸乙酯萃取。有机层干燥，浓缩，柱层析纯化，得化合物22-e(30mg，产率：7％)。The third step: the compound 1-a (300 mg, 0.93 mmol) was dissolved in dry tetrahydrofuran (5 mL), and the mixture was filtered under nitrogen, and n-butyl lithium (1.6 M in tetrahydrofuran solution, 0.7 mL) was added dropwise at -70 to 78 °C. . Stir for 45 min. A solution of compound 22-d (175 mg, 0.85 mmol) in THF was evaporated. The reaction mixture was warmed to room temperature and then brined The organic layer was dried, concentrated and purified by column chromatography to afford Compound 22-e (30mg, yield: 7%).
LC-MS:tR＝3.35min,[M-OH]+＝449.2。 LC-MS: t R = 3.35min , [M-OH] + = 449.2.
第四步：将化合物22-e(30mg,0.06mmol)溶于四氢呋喃(1mL)，搅拌下滴加TBAF的四氢呋喃溶液(1M,0.18mL,0.18mmol)。室温搅拌20min后，往体系中加水，并用乙酸乙酯(2×10mL)萃取，有机相合并后用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析纯化(EA/PE:20～30％)，得化合物22-f(18mg，产率： 90％)。The fourth step: Compound 22-e (30 mg, 0.06 mmol) was dissolved in tetrahydrofuran (1 mL) and THF (THF) (1M, 0.18mL, 0.18mmol). After stirring at room temperature for 20 min, EtOAc / EtOAc (EtOAc) 20-30%), compound 22-f (18 mg, yield: 90%).
LC-MS:tR＝2.10min,[M+H]+＝335.0。 LC-MS: t R = 2.10min , [M + H] + = 335.0.
第五步：将化合物22-f(15mg,0.04mmol)与I-1(19mg,0.06mmol)溶于干燥DMF(2mL),加入K2CO3(20mg,0.16mmol)，60℃搅拌反应过夜。待反应液冷却后加乙酸乙酯(10mL)，依次用水和饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，柱层析纯化(PE/EA:10～25％)，得化合物22-g(20mg,产率：75％)。The second step: Compound 22-f (15 mg, 0.04 mmol) and I-1 (19 mg, 0.06 mmol) were dissolved in dry DMF (2 mL), K 2 CO 3 (20 mg, 0.16 mmol), and stirred at 60 ° C overnight. . After the reaction mixture was cooled, ethyl acetate (10 mL) was added, and then washed with water and brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE/EA: 10~25%) to give compound 22-g (20 mg, yield: 75%).
LC-MS:tR＝3.10min,[M+H]+＝616.0。 LC-MS: t R = 3.10min , [M + H] + = 616.0.
第六步：将化合物22-g(20mg,0.03mmol)溶于甲醇(1mL)和水(1mL)，加入NaOH(4mg,0.010mmol)。40℃搅拌2h。待反应完毕，用1N的盐酸酸化至pH为5～6，有固体析出。过滤干燥后得粗产物，粗产物经柱层析纯化，得化合物22(6mg,产率：30.7％)。The sixth step: Compound 22-g (20 mg, 0.03 mmol) was dissolved in methanol (1 mL) and water (1 mL). Stir at 40 ° C for 2 h. After the reaction was completed, it was acidified to pH 5-6 with 1N hydrochloric acid, and a solid precipitated. After filtration and drying, a crude product was obtained, which was purified by column chromatography to afford compound 22 (6 mg, yield: 30.7%).
LC-MS:tR＝2.57min,[M+H]+＝602.0；LC-MS: t R = 2.57 min, [M+H] + = 602.0;
1HNMR(400MHz,MeOD-d4)δ8.11(d,J＝5.4Hz,1H),7.50-7.43(m,2H),7.43-7.32(m,2H),7.17(d,J＝5.0Hz,1H),7.02(s,1H),6.89(d,J＝2.5Hz,1H),6.80(dd,J＝8.7,2.5Hz,1H),5.01(s,2H),4.60(d,J＝9.4Hz,2H),4.33(d,J＝9.3Hz,2H),2.47-2.32(m,1H),1.26(m,2H),0.91(m,2H)。 1 H NMR (400 MHz, MeOD-d 4 ) δ 8.11 (d, J = 5.4 Hz, 1H), 7.50-7.43 (m, 2H), 7.43-7.32 (m, 2H), 7.17 (d, J = 5.0 Hz) , 1H), 7.02 (s, 1H), 6.89 (d, J = 2.5 Hz, 1H), 6.80 (dd, J = 8.7, 2.5 Hz, 1H), 5.01 (s, 2H), 4.60 (d, J = 9.4 Hz, 2H), 4.33 (d, J = 9.3 Hz, 2H), 2.47-2.32 (m, 1H), 1.26 (m, 2H), 0.91 (m, 2H).
实施例23 5-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噻唑-4-基)甲氧基)苯基)-3-羟基吖丁啶-1-基)尼古丁酸(23)Example 23 5-(3-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)phenyl)- 3-hydroxyazetidin-1-yl)nicotonic acid (23)
Figure PCTCN2016111652-appb-000067
Figure PCTCN2016111652-appb-000067
第一步：化合物22-a的合成参照实施例21第一步～第五步的制备方法。First step: Synthesis of compound 22-a Referring to the preparation methods of the first to fifth steps of Example 21.
LC-MS:tR＝3.096min,[M+H]+＝616.0。 LC-MS: t R = 3.096min , [M + H] + = 616.0.
第二步：将化合物23-a(30mg,0.05mmol)溶于MeOH/THF(2mL,1:1)，加入NaOH水溶液(1mL,1.0M)。60℃搅拌反应1.5h。冷却后用1N的盐酸酸化至pH＝4，乙酸乙酯萃取3次，有机层干燥，过滤，浓缩，粗品经PTLC分离纯化，得化合物23(12.3mg)。The second step: Compound 23-a (30 mg, 0.05 mmol) was dissolved in MeOH / THF (2 mL, 1:1). The reaction was stirred at 60 ° C for 1.5 h. After cooling, it was acidified to pH = 4 with EtOAc (EtOAc)EtOAc.
LC-MS:tR＝2.658min,[M+H]+＝602.0；LC-MS: t R = 2.658 min, [M+H] + = 602.0;
1HNMR(400MHz,MeOD)δ8.47(s,1H),8.02(s,1H),7.77-7.22(m,5H),6.85(d,J＝34.7Hz,2H),5.01(s,2H),4.48(d,J＝8.2Hz,2H),4.29(d,J＝7.9Hz,2H),2.48-2.33(m,1H),1.31(s,2H),0.93(s,2H)。 1 H NMR (400 MHz, MeOD) δ 8.47 (s, 1H), 8.02 (s, 1H), 7.77-7.22 (m, 5H), 6.85 (d, J = 34.7 Hz, 2H), 5.01 (s, 2H) , 4.48 (d, J = 8.2 Hz, 2H), 4.29 (d, J = 7.9 Hz, 2H), 2.48-2.33 (m, 1H), 1.31 (s, 2H), 0.93 (s, 2H).
实施例24 3-(1-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噻唑-4-基)甲氧基)苯基)吖丁啶-3-基)苯甲酸(24) Example 24 3-(1-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)phenyl)indole Butyr-3-yl)benzoic acid (24)
Figure PCTCN2016111652-appb-000068
Figure PCTCN2016111652-appb-000068
第一步：将化合物24-a(1.31g，5.0mmol)溶于干燥THF(20mL)，在氮气氛下搅拌，于-70～78℃下滴加i-PrMgCl(2.0M，3mL)。搅拌1h，滴加化合物20-b(1.28g，7.5mmol)的THF(8mL)溶液。加完缓慢升至室温搅拌1h。用饱和NH4Cl水溶液(20mL)淬灭，乙酸乙酯萃取。有机层干燥，浓缩，柱层析分离，得到化合物24-b(1.5g，产率：90％)。The first step: Compound 24-a (1.31 g, 5.0 mmol) was dissolved in dry THF (20 mL), and stirred under nitrogen atmosphere, i-PrMgCl (2.0 M, 3 mL) was added dropwise at -70-78 °C. After stirring for 1 h, a solution of compound 20-b (1.28 g, 7.5 mmol) Stir slowly to room temperature and stir for 1 h. (20mL) was quenched with saturated aqueous NH 4 Cl, extracted with ethyl acetate. The organic layer was dried, concentrated and purified by column chromatography to afford Compound 24-b (l.
LC-MS:tR＝2.592min,[M-Boc]+＝208.1；LC-MS: t R = 2.592 min, [M-Boc] + = 208.1;
1HNMR(400MHz,CDCl3)δ8.18(t,J＝1.7Hz,1H),8.05-7.93(m,1H),7.77-7.67(m,1H),7.48(t,J＝7.8Hz,1H),4.23(dd,J＝26.2,9.5Hz,4H),3.93(s,3H),1.46(s,9H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.18 (t, J = 1.7 Hz, 1H), 8.05 - 7.93 (m, 1H), 7.77-7.67 (m, 1H), 7.48 (t, J = 7.8 Hz, 1H) ), 4.23 (dd, J = 26.2, 9.5 Hz, 4H), 3.93 (s, 3H), 1.46 (s, 9H).
第二步：将化合物24-b(153mg,0.50mmol)溶于干燥二氯甲烷(4mL)中，加入DIPEA(0.17mL,1.00mmol)，搅拌下滴加MsCl(0.05mL，0.65mmol)。混合物室温搅拌过夜。加入水(5mL)，二氯甲烷萃取2次。混合有机相，干燥，浓缩，快速柱层析得粗产品化合物24-c(180mg,纯度约45％)。The second step: Compound 24-b (153 mg, 0.50 mmol) was dissolved in dry methylene chloride (4 mL), DIPEA (0.17mL, 1.00 mmol) was added, and MsCl (0.05 mL, 0.65 mmol) was added dropwise with stirring. The mixture was stirred at room temperature overnight. Water (5 mL) was added and the mixture was extracted twice with dichloromethane. The organic phase was combined, dried, concentrated and flash purified eluting elut eluting
LC-MS:tR＝2.764min。 LC-MS: t R = 2.764min .
第三步：将化合物24-c(180mg,0.46mmol)溶于甲醇(5mL)中，加入Pd/C(10mg)。氢气氛下室温搅拌过夜。反应液过滤，滤液浓缩，柱层析分离纯化，得到化合物24-d(60mg)。The third step: Compound 24-c (180 mg, 0.46 mmol) was dissolved in methanol (5 mL) and Pd/C (10 mg). Stir at room temperature overnight under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated and purified by column chromatography to yield Compound 24-d (60 mg).
LC-MS:tR＝2.927min,[M-Boc]+＝192.1；LC-MS: t R = 2.927 min, [M-Boc] + = 192.1;
1HNMR(400MHz,CDCl3)δ7.98(t,J＝1.7Hz,1H),7.93(dt,J＝7.6,1.4Hz,1H),7.54-7.48(m,1H),7.43(t,J＝7.7Hz,1H),4.35(t,J＝8.7Hz,2H),3.99(dd,J＝8.7,6.0Hz,2H),3.93(s,3H),1.47(s,9H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.98 (t, J = 1.7 Hz, 1H), 7.93 (dt, J = 7.6, 1.4 Hz, 1H), 7.54 - 7.48 (m, 1H), 7.43 (t, J) = 7.7 Hz, 1H), 4.35 (t, J = 8.7 Hz, 2H), 3.99 (dd, J = 8.7, 6.0 Hz, 2H), 3.93 (s, 3H), 1.47 (s, 9H).
第四步：将化合物24-d(60mg,0.20mmol)溶于1,4-二氧六环(3mL)。加入盐酸二氧六环溶液(3mL,6.0M)。室温搅拌2h。浓缩得到47mg化合物24-e的盐酸盐，粗产品直接用于下步反应。Fourth step: Compound 24-d (60 mg, 0.20 mmol) was dissolved in 1,4-dioxane (3 mL). A solution of dioxane hydrochloride (3 mL, 6.0 M) was added. Stir at room temperature for 2 h. Concentration gave 47 mg of the hydrochloride salt of Compound 24-e, which was used directly in the next step.
第五步：将化合物24-e(47mg，0.20mmol)溶于干燥1,4-二氧六环(5mL)，之后依次加入化合物24-f(127mg,0.27mmol),Cs2CO3(205mg,0.63mmol),X-phos(30mg,0.06mmol)和Pd2(dba)3(29mg,0.03mmol)。氮气保护，105℃搅拌反应过夜。待反应冷却后硅藻土过滤，并用乙酸乙酯洗涤3次。滤液经萃取后取有机层用硫酸钠干燥，浓缩，柱层析分离，得到化合物24-g(30mg，产率：25％)。The fifth step: Compound 24-e (47 mg, 0.20 mmol) was dissolved in dry 1,4-dioxane (5 mL), followed by compound 24-f (127 mg, 0.27 mmol), Cs 2 CO 3 (205 mg) , 0.63 mmol), X-phos (30 mg, 0.06 mmol) and Pd 2 (dba) 3 (29 mg, 0.03 mmol). The reaction was stirred with nitrogen and stirred at 105 ° C overnight. After cooling the reaction, the celite was filtered and washed three times with ethyl acetate. After the filtrate was extracted, the organic layer was dried (MgSO4)
LC-MS:tR＝3.634min,[M+H]+＝583.0； LC-MS: t R = 3.346 min, [M+H] + = 583.0;
1HNMR(400MHz,CDCl3)δ7.99(s,1H),7.94(d,J＝7.8Hz,1H),7.57(d,J＝7.6Hz,1H),7.46-7.39(m,4H),7.36-7.30(m,1H),6.80(d,J＝2.6Hz,1H),6.70-6.65(m,1H),4.76(s,2H),4.62-4.52(m,2H),4.15-4.04(m,3H),3.92(s,3H),2.14(tt,J＝8.4,5.1Hz,1H),1.27(tt,J＝7.1,5.1Hz,2H),1.15(ddd,J＝11.5,7.1,4.4Hz,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.99 (s, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.46-7.39 (m, 4H), 7.36-7.30 (m, 1H), 6.80 (d, J = 2.6 Hz, 1H), 6.70-6.65 (m, 1H), 4.76 (s, 2H), 4.62-4.52 (m, 2H), 4.15-4.04 ( m, 3H), 3.92 (s, 3H), 2.14 (tt, J = 8.4, 5.1 Hz, 1H), 1.27 (tt, J = 7.1, 5.1 Hz, 2H), 1.15 (ddd, J = 11.5, 7.1, 4.4 Hz, 2H).
第六步：将化合物24-g(20mg,0.034mmol)溶于MeOH/THF(2mL，v/v＝1:1)。加入NaOH水溶液(1.0M，1mL)。50℃搅拌反应3h。冷却后用1N的盐酸酸化至pH＝5，乙酸乙酯萃取3次，有机层干燥，过滤，浓缩，柱层析分离，纯化得化合物24(9.6mg)。Sixth step: Compound 24-g (20 mg, 0.034 mmol) was dissolved in MeOH / THF (2 mL, v/v = 1:1). Aqueous NaOH (1.0 M, 1 mL) was added. The reaction was stirred at 50 ° C for 3 h. After cooling, it was acidified with 1N hydrochloric acid to pH = 5, and ethyl acetate was extracted three times. The organic layer was dried, filtered, concentrated, and purified by column chromatography to afford compound 24 (9.6 mg).
LC-MS:tR＝3.312min,[M+H]+＝569.0；LC-MS: t R = 3.312 min, [M+H] + = 569.0;
1HNMR(400MHz,MeOD)δ7.95(s,1H),7.81(d,J＝7.7Hz,1H),7.54(d,J＝7.1Hz,1H),7.43-7.33(m,4H),6.61(t,J＝2.3Hz,1H),6.58(dd,J＝8.8,2.8Hz,1H),6.50(d,J＝8.8Hz,1H),4.72(s,2H),4.34-4.22(m,2H),3.85-3.74(m,3H),2.23-2.14(m,1H),1.26-1.17(m,J＝18.3Hz,2H),1.10-1.04(m,2H)。 1 H NMR (400 MHz, MeOD) δ 7.95 (s, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.54 (d, J = 7.1 Hz, 1H), 7.43 - 7.33 (m, 4H), 6.61 (t, J = 2.3 Hz, 1H), 6.58 (dd, J = 8.8, 2.8 Hz, 1H), 6.50 (d, J = 8.8 Hz, 1H), 4.72 (s, 2H), 4.34 - 4.22 (m, 2H), 3.85-3.74 (m, 3H), 2.23 - 2.14 (m, 1H), 1.26-1.17 (m, J = 18.3 Hz, 2H), 1.10 - 10.04 (m, 2H).
实施例25 3-(1-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噻唑-4-基)甲氧基)苯基)-3-羟基吖丁啶-3-基)苯甲酸(25)Example 25 3-(1-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)phenyl)- 3-hydroxyazetidin-3-yl)benzoic acid (25)
Figure PCTCN2016111652-appb-000069
Figure PCTCN2016111652-appb-000069
第一步：将化合物22-b(1.64g，15.0mmol)溶于干燥1,4-二氧六环(100mL)，加入1-a(3.21g,10.0mmol)，Cs2CO3(11.4g,35.0mmol)，X-phos(953mg,2.0mmol)，Pd2(dba)3(916mg,1.0mmol)。氮气保护，100℃搅拌反应过夜。待反应冷却后硅藻土过滤，并用乙酸乙酯洗涤。滤液经萃取后取有机层用硫酸钠干燥，浓缩，柱层析分离，得化合物25-a(160mg，产率：5％)。First step: Compound 22-b (1.64 g, 15.0 mmol) was dissolved in dry 1,4-dioxane (100 mL), then 1-a (3.21 g, 10.0 mmol), Cs 2 CO 3 (11.4 g) , 35.0 mmol), X-phos (953 mg, 2.0 mmol), Pd 2 (dba) 3 (916 mg, 1.0 mmol). Protected with nitrogen and stirred at 100 ° C overnight. After the reaction was cooled, the Celite was filtered and washed with ethyl acetate. After the filtrate was extracted, the organic layer was dried (MgSO4)
LC-MS:tR＝3.372min.[M+H]+＝314.0；LC-MS: t R = 3.372 min. [M+H] + = 314.0;
1HNMR(400MHz,CDCl3)δ6.79(d,J＝2.7Hz,1H),6.65(dd,J＝8.7,2.7Hz,1H),6.46(d,J＝8.7Hz,1H),4.71-4.62(m,1H),4.31-4.24(m,2H),3.70-3.65(m,2H),0.96(s,9H),0.16(s,6 H)。 1 H NMR (400 MHz, CDCl 3 ) δ 6.79 (d, J = 2.7 Hz, 1H), 6.65 (dd, J = 8.7, 2.7 Hz, 1H), 6.46 (d, J = 8.7 Hz, 1H), 4.71 4.62 (m, 1H), 4.31-4.24 (m, 2H), 3.70-3.65 (m, 2H), 0.96 (s, 9H), 0.16 (s, 6 H).
第二步：化合物25-a(160mg,0.50mmol)溶于乙酸乙酯(10mL)，加入IBX(217mg,0.78mmol)。混合物回流搅拌2h。反应液冷却至室温后用乙酸乙酯稀释过滤，滤液依次水洗和食盐水洗后干燥浓缩，纯化后得化合物25-b(60mg，产率：37％)。The second step: Compound 25-a (160 mg, 0.50 mmol) was dissolved in ethyl acetate (10 mL). The mixture was stirred at reflux for 2 h. The reaction mixture was cooled to room temperature and then filtered with ethyl acetate. The filtrate was washed with water and brine, and then dried and concentrated to afford compound 25-b (60 mg, yield: 37%).
LC-MS:tR＝3.612min； LC-MS: t R = 3.612min ;
1HNMR(400MHz,CDCl3)δ6.88(d,J＝2.7Hz,1H),6.71(dd,J＝8.7,2.7Hz,1H),6.60(d,J＝8.8Hz,1H),4.74(s,4H),0.97(s,9H),0.18(s,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 6.88 (d, J = 2.7 Hz, 1H), 6.71 (dd, J = 8.7, 2.7 Hz, 1H), 6.60 (d, J = 8.8 Hz, 1H), 4.74 ( s, 4H), 0.97 (s, 9H), 0.18 (s, 6H).
第三步：将化合物24-a(60mg，0.23mmol)溶于干燥THF(3mL)，于-70～78℃下滴加i-PrMgCl(2.0M，0.13mL)。加完后在此温度下搅拌1h。-70℃滴加溶有化合物25-b(60mg，0.20mmol)的干燥THF溶液(1mL)。加完后于此温度搅拌1h。反应液升至室温搅拌1h。用饱和NH4Cl(5mL)淬灭，乙酸乙酯萃取。有机层干燥浓缩后柱层析分离，得化合物25-c(35mg，产率：40％)。The third step: Compound 24-a (60 mg, 0.23 mmol) was dissolved in dry THF (3 mL), and then, i-PrMgCl (2.0M, 0.13mL) was added dropwise at -70 to 78 °C. After the addition was completed, the mixture was stirred at this temperature for 1 h. A dry THF solution (1 mL) in which compound 25-b (60 mg, 0.20 mmol) was dissolved was dissolved at -70 °C. After the addition was completed, the mixture was stirred at this temperature for 1 h. The reaction solution was allowed to warm to room temperature and stirred for 1 h. 4 Cl (5mL) was quenched with saturated NH, extracted with ethyl acetate. The organic layer was dried and concentrated, and then purified by column chromatography to afford Compound 25-c (35 mg, yield: 40%).
LC-MS:tR＝3.728min,[M+H]+＝448.1。LC-MS: t R = 3.372 min, [M+H] + = 448.1.
第四步：将化合物25-c(35mg,0.08mmol)溶于THF(1mL)，加入TBAF(0.16mL,0.16mmol,1.0MinTHF)。室温搅拌30min。加入饱和碳酸氢钠水溶液(2mL)和乙酸乙酯(2mL)，分层后水相用乙酸乙酯(2mL)萃取2次，有机相合并用食盐水洗涤，硫酸钠干燥过滤。浓缩后PTLC分离，得化合物25-d(19mg，产率：73％,)。The fourth step: Compound 25-c (35 mg, 0.08 mmol) was dissolved in THF (1 mL) and TBAF (0.16mL, 0.16mmol, 1.0MinTHF). Stir at room temperature for 30 min. A saturated aqueous solution of sodium hydrogencarbonate (2 mL) and ethyl acetate (2 mL) was evaporated. After concentration, PTLC was separated to give compound 25-d (19 mg, yield: 73%).
LC-MS:tR＝2.467min,[M+H]+＝334.0。 LC-MS: t R = 2.467min , [M + H] + = 334.0.
第五步：将化合物25-d(19mg,0.057mmol)溶于干燥DMF(2mL)。加入I-2(21mg,0.068mmol)和K2CO3(16mg,0.110mmol)，65℃搅拌反应过夜。待反应液冷却后用水(15mL)稀释，乙酸乙酯萃取3次，合并有机相。有机相用饱和食盐水洗一次，硫酸钠干燥，过滤，浓缩，柱层析分离(PE/EA,EA:10～25％)，得化合物25-e(32mg，产率：94％)。Fifth step: Compound 25-d (19 mg, 0.057 mmol) was dissolved in dry DMF (2 mL). I-2 (21 mg, 0.068 mmol) and K 2 CO 3 (16 mg, 0.110 mmol) were added, and the mixture was stirred at 65 ° C overnight. After the reaction solution was cooled, it was diluted with water (15 mL), and extracted with ethyl acetate three times. The organic phase was washed once with a saturated aqueous solution of sodium sulfate, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography (PE/EA, EA: 10 to 25%) to give compound 25-e (32 mg, yield: 94%).
LC-MS:tR＝3.356min,[M+H]+＝599.0；LC-MS: t R = 3.356 min, [M+H] + = 599.0;
1HNMR(400MHz,CDCl3)δ8.27(t,J＝1.7Hz,1H),8.04-7.95(m,1H),7.88-7.81(m,1H),7.48(t,J＝7.8Hz,1H),7.43-7.37(m,2H),7.32(dd,J＝9.1,6.9Hz,1H),6.76(d,J＝2.7Hz,1H),6.69-6.63(m,1H),6.53(d,J＝8.9Hz,1H),4.74(s,2H),4.35(d,J＝8.6Hz,2H),4.19(d,J＝8.6Hz,2H),3.92(s,3H),2.14(ddd,J＝10.1,6.8,4.2Hz,1H),1.29-1.25(m,2H),1.14(ddd,J＝11.5,7.1,4.4Hz,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.27 (t, J = 1.7 Hz, 1H), 8.04 - 7.95 (m, 1H), 7.88-7.81 (m, 1H), 7.48 (t, J = 7.8 Hz, 1H) ), 7.43 - 7.37 (m, 2H), 7.32 (dd, J = 9.1, 6.9 Hz, 1H), 6.76 (d, J = 2.7 Hz, 1H), 6.69 - 6.63 (m, 1H), 6.53 (d, J = 8.9 Hz, 1H), 4.74 (s, 2H), 4.35 (d, J = 8.6 Hz, 2H), 4.19 (d, J = 8.6 Hz, 2H), 3.92 (s, 3H), 2.14 (ddd, J = 10.1, 6.8, 4.2 Hz, 1H), 1.29-1.25 (m, 2H), 1.14 (ddd, J = 11.5, 7.1, 4.4 Hz, 2H).
第六步：将化合物25-e(15mg,0.025mmol)溶于MeOH/THF(2mL，v/v＝1:1)。加入NaOH水溶液(1.0M，1mL)。50℃搅拌反应2h。冷却后用1N的盐酸酸化至pH＝5，乙酸乙酯萃取3次，有机层干燥过滤浓缩，柱层析分离纯化，得化合物25(9.5mg)。The sixth step: Compound 25-e (15 mg, 0.025 mmol) was dissolved in MeOH / THF (2mL, v/v = 1:1). Aqueous NaOH (1.0 M, 1 mL) was added. The reaction was stirred at 50 ° C for 2 h. After cooling, it was acidified with 1N hydrochloric acid to pH = 5, and ethyl acetate was extracted three times. The organic layer was dried, filtered and concentrated, and purified by column chromatography to give compound 25 (9.5 mg).
LC-MS:tR＝3.050min,[M+H]+＝585.0；LC-MS: t R = 3.050 min, [M+H] + = 585.0;
1HNMR(400MHz,CDCl3)δ8.34(d,J＝1.6Hz,1H),8.06(d,J＝7.8Hz,1H),7.91(d,J＝8.3 Hz,1H),7.52(dd,J＝10.2,5.5Hz,1H),7.43-7.36(m,2H),7.32(dd,J＝9.1,6.9Hz,1H),6.77(d,J＝2.7Hz,1H),6.66(dd,J＝8.8,2.8Hz,1H),6.54(d,J＝8.9Hz,1H),4.75(s,2H),4.35(d,J＝8.5Hz,2H),4.21(d,J＝8.4Hz,2H),2.14(tt,J＝8.4,5.1Hz,1H),1.29-1.23(m,2H),1.14(ddd,J＝11.5,7.1,4.5Hz,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.34 (d, J = 1.6 Hz, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.52 (dd, J = 10.2, 5.5 Hz, 1H), 7.43 - 7.36 (m, 2H), 7.32 (dd, J = 9.1, 6.9 Hz, 1H), 6.77 (d, J = 2.7 Hz, 1H), 6.66 (dd, J =8.8, 2.8 Hz, 1H), 6.54 (d, J = 8.9 Hz, 1H), 4.75 (s, 2H), 4.35 (d, J = 8.5 Hz, 2H), 4.21 (d, J = 8.4 Hz, 2H) ), 2.14 (tt, J = 8.4, 5.1 Hz, 1H), 1.29-1.23 (m, 2H), 1.14 (ddd, J = 11.5, 7.1, 4.5 Hz, 2H).
实施例26 5-(3-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噻唑-4-基)甲氧基)苯基)-3-羟基环丁基)苯基)-1,3,4-噁二唑-2(3H)-酮(26)Example 26 5-(3-(3-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)benzene) 3-hydroxycyclobutyl)phenyl)-1,3,4-oxadiazole-2(3H)-one (26)
Figure PCTCN2016111652-appb-000070
Figure PCTCN2016111652-appb-000070
第一步：化合物26-a的合成参照实施例1第一步～第三步的制备方法。First step: Synthesis of compound 26-a Referring to the preparation methods of the first to third steps of Example 1.
LC-MS:tR＝3.428；[M-OH]+＝580.0；LC-MS: t R = 3.448; [M-OH] + = 580.0;
1HNMR(400MHz,CDCl3)δ7.95(s,1H),7.88(dt,J＝7.7,1.3Hz,1H),7.50-7.33(m,6H),6.90(d,J＝2.6Hz,1H),6.75(dd,J＝8.6,2.6Hz,1H),4.83(s,2H),3.92(s,3H),3.24-3.10(m,2H),3.05-2.94(m,1H),2.58(td,J＝9.7,2.7Hz,2H),2.17(ddd,J＝8.4,6.8,4.2Hz,1H),1.29-1.25(m,2H),1.20-1.14(m,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.95 (s, 1H), 7.88 (dt, J = 7.7, 1.3 Hz, 1H), 7.50-7.33 (m, 6H), 6.90 (d, J = 2.6 Hz, 1H) ), 6.75 (dd, J = 8.6, 2.6 Hz, 1H), 4.83 (s, 2H), 3.92 (s, 3H), 3.24-3.10 (m, 2H), 3.05-2.94 (m, 1H), 2.58 ( Td, J = 9.7, 2.7 Hz, 2H), 2.17 (ddd, J = 8.4, 6.8, 4.2 Hz, 1H), 1.29-1.25 (m, 2H), 1.20-1.14 (m, 2H).
第二步：化合物26-a(60mg,0.10mmol)溶于乙醇(2.5mL)，加入水合肼(0.75mL,85％)。反应液回流1.5h。反应液浓缩后得到化合物26-b(60mg，产率：100％)。The second step: Compound 26-a (60 mg, 0.10 mmol) was dissolved in ethanol (2.5 mL) and hydrated hydrate (0.75mL, 85%). The reaction solution was refluxed for 1.5 h. The reaction mixture was concentrated to give Compound 26-b (60 mg, yield: 100%).
LC-MS:tR＝2.847min,[M-OH]+＝580.0。 LC-MS: t R = 2.847min , [M-OH] + = 580.0.
第三步：化合物26-b(60mg,0.10mmol)溶于四氢呋喃(3mL)。加入CDI(24mg)。75℃搅拌45min。反应液浓缩，柱层析分离，得到化合物26(12mg，产率：19％)。The third step: Compound 26-b (60 mg, 0.10 mmol) was dissolved in THF (3 mL). Add CDI (24 mg). Stir at 75 ° C for 45 min. The reaction mixture was concentrated and purified by column chromatography to afford compound 26 (12mg, yield: 19%).
LC-MS:tR＝3.151min,[M-OH]+＝606.0； LC-MS: t R = 3.151min , [M-OH] + = 606.0;
1HNMR(400MHz,CDCl3)δ8.76(s,1H),7.77(s,1H),7.69(dt,J＝6.8,1.8Hz,1H),7.48-7.39(m,5H),7.34(dd,J＝9.1,6.9Hz,1H),6.91(d,J＝2.6Hz,1H),6.75(dd,J＝8.6,2.6Hz,1H),4.83(s,2H),3.25-3.15(m,2H),3.09-2.92(m,2H),2.59(td,J＝9.6,2.6Hz,2H),2.17(tt,J＝8.4,5.1Hz,1H),1.31(dt,J＝6.6,4.6Hz,2H),1.17(ddd,J＝11.6,7.1,4.5Hz,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.76 (s, 1H), 7.77 (s, 1H), 7.69 (dt, J = 6.8, 1.8 Hz, 1H), 7.48-7.39 (m, 5H), 7.34 (dd , J=9.1, 6.9 Hz, 1H), 6.91 (d, J=2.6 Hz, 1H), 6.75 (dd, J=8.6, 2.6 Hz, 1H), 4.83 (s, 2H), 3.25-3.15 (m, 2H), 3.09-2.92 (m, 2H), 2.59 (td, J = 9.6, 2.6 Hz, 2H), 2.17 (tt, J = 8.4, 5.1 Hz, 1H), 1.31 (dt, J = 6.6, 4.6 Hz) , 2H), 1.17 (ddd, J = 11.6, 7.1, 4.5 Hz, 2H).
实施例27 4-(2-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噻唑-4-基)甲氧基)苯基)环丙基)苯甲酸(27) Example 27 4-(2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)phenyl)) Propyl)benzoic acid (27)
Figure PCTCN2016111652-appb-000071
Figure PCTCN2016111652-appb-000071
第一步：将化合物27-a(10g,43.6mmol)和三乙氧基膦混合加热到175℃搅拌4h。冷却至室温，减压浓缩，除去三乙氧基膦，得粗产品化合物27-b(13g)。First step: Compound 27-a (10 g, 43.6 mmol) and triethoxyphosphine were mixed and heated to 175 ° C for 4 h. After cooling to room temperature and concentration under reduced pressure, triethoxyphosphine was removed to give crude compound 27-b (13 g).
第二步：将化合物27-b(2.2g,16.9mmol)溶于四氢呋喃中，加入NaH(630mg，15.8mmol)，室温搅拌半小时，然后加入化合物27-c(1.8g，10.4mmol)，室温搅拌过夜。加入水和乙酸乙酯萃取，有机相旋干，得化合物27-d(1.5g)。The second step: Compound 27-b (2.2 g, 16.9 mmol) was dissolved in tetrahydrofuran, NaH (630 mg, 15.8 mmol) was added and stirred at room temperature for half an hour, then compound 27-c (1.8 g, 10.4 mmol) was added at room temperature. Stir overnight. Water and ethyl acetate were added for extraction and the organic phase was dried to give compound 27-d (l.
第三步：将Et2Zn(64mL,2M)加入二氯甲烷中，再加入三氟乙酸(5mL)，冷却到-78℃，搅拌30min，温度升到-30℃，加入CH2I2(8mL)，继续搅拌30min，加入化合物27-d(2g,6.6mmol)，室温反应过夜。加入饱和氯化铵水溶液淬灭，乙酸乙酯萃取。有机相干燥、过滤、浓缩，柱层析分离，得化合物28-e(1.0g)。The third step: Et 2 Zn (64 mL, 2 M) was added to dichloromethane, then trifluoroacetic acid (5 mL) was added, cooled to -78 ° C, stirred for 30 min, the temperature was raised to -30 ° C, and CH 2 I 2 was added ( 8 mL), stirring was continued for 30 min, and compound 27-d (2 g, 6.6 mmol) was added and allowed to react overnight at room temperature. It was quenched by the addition of aq. The organic phase was dried, filtered, concentrated and purified elut elut
第四步：将化合物27-e(1.0g，3.3mmol)溶于二氯甲烷，加入三溴化硼溶液(1mL)，室温搅拌1h。加入甲醇淬灭，有机相浓缩，柱层析分离，得化合物28-f(300mg)。The fourth step: Compound 27-e (1.0 g, 3.3 mmol) was dissolved in dichloromethane, and a boron tribromide solution (1 mL) was added and stirred at room temperature for 1 h. The mixture was quenched with EtOAc (EtOAc)EtOAc.
第五步：将化合物I-1(40mg，0.126mmol)和27-f(38mg，0.126mmol)溶于干燥DMF(2mL)，加入碳酸钾(17mg，0.126mmol)，60℃搅拌24h。加水，乙酸乙酯萃取。粗产品柱层析分离，得化合物27-g(13mg)。The fifth step: Compound I-1 (40 mg, 0.126 mmol) and 27-f (38 mg, 0.126 mmol) were dissolved in dry DMF (2 mL). Add water and extract with ethyl acetate. The crude product was separated by column chromatography to give compound 27- g (13 mg).
第六步：将化合物27-g(13mg，0.022mmol)溶于甲醇(1mL)，加入3N氢氧化钠溶液(1mL)、回流反应过夜。冷却，乙酸乙酯萃取。粗产品柱层析分离，得化合物27(6.5mg)。The sixth step: Compound 27-g (13 mg, 0.022 mmol) was dissolved in methanol (1 mL), 3N sodium hydroxide solution (1 mL), and refluxed overnight. Cooled and extracted with ethyl acetate. The crude product was purified by column chromatography to afford Compound 27 ( 6.5mg).
LC-MS:tR＝3.446min,[M+H]+＝570.1；LC-MS: t R = 3. 46 min, [M+H] + = 570.1;
1HNMR(400MHz,CDCl3)δ7.94(d,J＝8.4Hz,2H),7.34-7.27(m,2H),7.24-7.21(m,1H),7.17(d,J＝8.4Hz,2H),6.88(d,J＝8.6Hz,1H),6.77(d,J＝2.6Hz,1H),6.60(dd,J＝8.6,2.6Hz,1H),4.81(s,2H),2.38-2.27(m,1H),2.25-2.10(m,1H),2.02-1.88(m,1H),1.64-1.51(m,2H),1.43-1.33(m,2H),0.90-0.77(m,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.94 (d, J = 8.4 Hz, 2H), 7.34 - 7.27 (m, 2H), 7.24 - 7.21 (m, 1H), 7.17 (d, J = 8.4 Hz, 2H) ), 6.88 (d, J = 8.6 Hz, 1H), 6.77 (d, J = 2.6 Hz, 1H), 6.60 (dd, J = 8.6, 2.6 Hz, 1H), 4.81 (s, 2H), 2.38-2.27 (m, 1H), 2.25-2.10 (m, 1H), 2.02-1.88 (m, 1H), 1.64-1.51 (m, 2H), 1.43-1.33 (m, 2H), 0.90-0.77 (m, 2H) .
实施例28 3-(1-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异恶唑-4-基)甲氧基)苯基)吖丁啶-3-基)-5-氟苯甲酸(28)Example 28 3-(1-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Azetidin-3-yl)-5-fluorobenzoic acid (28)
Figure PCTCN2016111652-appb-000072
Figure PCTCN2016111652-appb-000072
第一步：化合物28-a的合成参照实施例24第一步～第五步的制备方法。First step: Synthesis of compound 28-a Referring to the preparation method of the first to fifth steps of Example 24.
1H NMR(400MHz,CDCl3)δ7.79(s,1H),7.61(dd,J＝8.9,1.4Hz,1H),7.44–7.39(m,2H),7.36–7.29(m,2H),6.78(d,J＝2.5Hz,1H),6.67(dd,J＝13.0,5.5Hz,2H),4.75(s,2H),4.49(s,2H),4.01(s,3H),3.93(s,3H),2.17–2.10(m,1H),1.31–1.26(m,2H),1.17–1.09(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ7.79 (s, 1H), 7.61 (dd, J = 8.9,1.4Hz, 1H), 7.44-7.39 (m, 2H), 7.36-7.29 (m, 2H), 6.78 (d, J = 2.5 Hz, 1H), 6.67 (dd, J = 13.0, 5.5 Hz, 2H), 4.75 (s, 2H), 4.49 (s, 2H), 4.01 (s, 3H), 3.93 (s) , 3H), 2.17–2.10 (m, 1H), 1.31–1.26 (m, 2H), 1.17–1.09 (m, 2H).
第二步：化合物28-a(90mg,0.034mmol)溶于4mL MeOH/THF(v/v＝1:1)。往溶液中加入NaOH水溶液(1.0M,2mL)，60℃搅拌反应3小时。冷却后用1N的盐酸酸化至Ph＝5，乙酸乙酯萃取3次，有机层干燥过滤浓缩，经柱层析分离，纯化后得到化合物28(33mg)。Second step: Compound 28-a (90 mg, 0.034 mmol) was dissolved in 4 mL MeOH / THF (v/v = 1:1). Aqueous NaOH solution (1.0 M, 2 mL) was added to the solution, and the mixture was stirred at 60 ° C for 3 hours. After cooling, it was acidified to pH = 5 with 1N hydrochloric acid, and extracted three times with ethyl acetate. The organic layer was dried and filtered and concentrated, and purified by column chromatography to afford compound 28 (33 mg).
LC-MS:tR＝3.344min,[M+H]+＝587.0；LC-MS: t R = 3.344 min, [M+H] + = 587.0;
1H NMR(400MHz,MeOD)δ7.88(s,1H),7.58(d,J＝9.0Hz,1H),7.53–7.39(m,4H),6.72(d,J＝2.7Hz,1H),6.68(dd,J＝8.8,2.8Hz,1H),6.60(d,J＝8.8Hz,1H),4.82(s,2H),4.37(s,2H),3.90(d,J＝3.0Hz,3H),2.30(dt,J＝16.1,6.9Hz,1H),1.29(s,2H),1.19(d,J＝3.2Hz,2H)； 1 H NMR (400MHz, MeOD) δ7.88 (s, 1H), 7.58 (d, J = 9.0Hz, 1H), 7.53-7.39 (m, 4H), 6.72 (d, J = 2.7Hz, 1H), 6.68 (dd, J = 8.8, 2.8 Hz, 1H), 6.60 (d, J = 8.8 Hz, 1H), 4.82 (s, 2H), 4.37 (s, 2H), 3.90 (d, J = 3.0 Hz, 3H) ), 2.30 (dt, J = 16.1, 6.9 Hz, 1H), 1.29 (s, 2H), 1.19 (d, J = 3.2 Hz, 2H);
19F NMR(376MHz,MeOD)δ-114.82(s)。 19 F NMR (376 MHz, MeOD) δ -11.82 (s).
实施例29 5-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异恶唑-4-基)甲氧基)苯基)吖丁啶-1-基)苯并[d]异噻唑-3(2H)-酮1,1-二氧(29)Example 29 5-(3-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Azetidin-1-yl)benzo[d]isothiazole-3(2H)-one 1,1-dioxo (29)
Figure PCTCN2016111652-appb-000073
Figure PCTCN2016111652-appb-000073
第一步：将化合物20-d(59mg，0.30mmol)、29-a(88mg，0.30mmol)、X-phos(57mg，0.12mmol)以及Cs2CO3(195mg，0.60mmol)加入二氧六环(5mL)，抽环气，氮气保护下加入Pd2(dba)3(55mg，0.06mmol)，90℃反应过夜。反应完全，冷却至室温，加入饱和食盐水洗涤，乙酸乙酯萃取。浓缩后粗产品柱层析分 离，得化合物29-b(10mg)。First step: Compound 20-d (59 mg, 0.30 mmol), 29-a (88 mg, 0.30 mmol), X-phos (57 mg, 0.12 mmol) and Cs 2 CO 3 (195 mg, 0.60 mmol) were added to dioxane. The ring (5 mL) was taken up in vacuo, and then Pd 2 (dba) 3 (55 mg, 0.06 mmol) was added under nitrogen atmosphere and reacted at 90 ° C overnight. The reaction was completed, cooled to room temperature, washed with saturated brine and evaporated. After concentration, the crude product was separated by column chromatography to yield Compound 29-b (10 mg).
LC-MS:tR＝2.696min,[M-H]-＝377.0。 LC-MS: t R = 2.696min , [MH] - = 377.0.
第二步：将化合物29-b(10mg，0.026mmol)溶于二氯甲烷(2mL)，冰水浴冷却，加入BBr3/CH2Cl2(13μL，0.053mmol，4M)，0℃反应1h。加入甲醇淬灭，二氯甲烷萃取。粗品经PTLC分离，得化合物29-c(5mg)。Step Two: Compound 29-b (10mg, 0.026mmol) was dissolved in dichloromethane (2 mL), ice-water bath, was added BBr 3 / CH 2 Cl 2 ( 13μL, 0.053mmol, 4M), 0 ℃ reaction 1h. It was quenched by the addition of methanol and extracted with dichloromethane. The crude product was isolated by PTLC to afford compound 29-c (5mg).
LC-MS:tR＝2.285min,[M-H]-＝363.1。 LC-MS: t R = 2.285min , [MH] - = 363.1.
第三步：将化合物29-c(5mg，0.0137mmol)溶于1mL干燥DMF，加入NaH(2.4mg，0.06mmol)，室温搅拌20分钟，再加入四丁基碘化铵(1mg)和I-2(5mg，0.0151mmol)，50℃反应2小时。反应完全后浓缩，加入饱和NH4Cl水溶液，EtOAc萃取3次。干燥，过滤，浓缩，粗产品PTLC分离，纯化得化合物29(2.4mg)。The third step: Compound 29-c (5 mg, 0.0137 mmol) was dissolved in 1 mL dry DMF, NaH (2.4 mg, 0.06 mmol) was added and stirred at room temperature for 20 min, then tetrabutylammonium iodide (1 mg) and I- 2 (5 mg, 0.0151 mmol), and reacted at 50 ° C for 2 hours. After concentrating the reaction was completed, saturated aqueous NH 4 Cl, EtOAc and extracted 3 times. Drying, filtration, concentration, crude product EtOAc EtOAc (EtOAc)
LC-MS:tR＝3.172min,[M-H]-＝628.0,630.0。 LC-MS: t R = 3.172min , [MH] - = 628.0,630.0.
1H NMR(400MHz,MeOD)δ7.45(d,J＝8.3Hz,1H),7.43–7.37(m,2H),7.34(dd,J＝9.4,6.5Hz,1H),7.27(d,J＝8.6Hz,1H),6.74(d,J＝2.6Hz,1H),6.72–6.66(m,2H),6.60(dd,J＝8.3,2.1Hz,1H),4.80(s,2H),4.31(t,J＝7.9Hz,2H),4.22–4.08(m,1H),3.90–3.80(m,2H),2.23(tt,J＝7.4,6.0Hz,1H),1.64–1.48(m,2H),1.15–1.05(m,2H)。 1 H NMR (400MHz, MeOD) δ7.45 (d, J = 8.3Hz, 1H), 7.43-7.37 (m, 2H), 7.34 (dd, J = 9.4,6.5Hz, 1H), 7.27 (d, J = 8.6 Hz, 1H), 6.74 (d, J = 2.6 Hz, 1H), 6.72 - 6.66 (m, 2H), 6.60 (dd, J = 8.3, 2.1 Hz, 1H), 4.80 (s, 2H), 4.31 (t, J = 7.9 Hz, 2H), 4.22 - 4.08 (m, 1H), 3.90 - 3.80 (m, 2H), 2.23 (tt, J = 7.4, 6.0 Hz, 1H), 1.64 - 1.48 (m, 2H) ), 1.15–1.05 (m, 2H).
实施例30 2-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噻唑-4-基)甲氧基)苯基)吖丁啶-1-基)苯并[d]噻唑-6-羧酸(30)Example 30 2-(3-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)phenyl)indole Butyr-1-yl)benzo[d]thiazole-6-carboxylic acid (30)
Figure PCTCN2016111652-appb-000074
Figure PCTCN2016111652-appb-000074
第一步：化合物I-13(44mg，0.08mmol)溶于干燥CH2Cl2(2mL)，冰水浴冷却下加入TFA(0.5mL)，0℃反应30分钟。反应完全，浓缩，抽干。粗品30-a直接用于下步反应。The first step: Compound I-13 (44mg, 0.08mmol) was dissolved was added TFA (0.5mL) and dried CH 2 Cl 2 (2mL), ice-water bath and the reaction 0 ℃ 30 minutes. The reaction was complete, concentrated and drained. The crude product 30-a was used directly in the next step.
LC-MS：tR＝2.509min；[M+H]+＝449.0,451.0。 LC-MS: t R = 2.509min ; [M + H] + = 449.0,451.0.
第二步：化合物30-a和I-9(22mg，0.08mmol)溶于干燥N,N-二甲基乙酰胺(2mL)，再加入Cs2CO3(65mg，0.20mmol)，加热50℃反应1小时。LC-MS监测，反应完全。加入EtOAc稀释，饱和NaCl水溶液洗涤，无水Na2SO4干燥。过滤，浓缩，粗产品经柱层析分离(PE/EA＝3:1)，得化合物30-b(47.6mg，93％)。 The second step: Compound 30-a and I-9 (22 mg, 0.08 mmol) were dissolved in dry N,N-dimethylacetamide (2 mL), then Cs 2 CO 3 (65 mg, 0.20 mmol) Reaction for 1 hour. The reaction was completed by LC-MS. EtOAc was added and washed with saturated aqueous NaCl, dried over anhydrous Na 2 SO 4. Filtration, concentration, and crude product were purified by column chromatography (EtOAc/EtOAc (EtOAc)
LC-MS：tR＝3.609min；[M+H]+＝640.0,642.0。 LC-MS: t R = 3.609min ; [M + H] + = 640.0,642.0.
第三步：化合物30-b(45mg，0.07mmol)溶于THF/MeOH(4/2mL)，加入KOH水溶液(3N,1mL)，加热70℃反应1小时。反应完全，冷却至室温，滴加稀盐酸中和。EtOAc萃取，饱和NaCl水溶液洗涤，无水Na2SO4干燥。过滤，浓缩，粗产品经PTLC分离(PE/EA＝1:1)，得产物30(28mg，64％)。The third step: Compound 30-b (45 mg, 0.07 mmol) was dissolved in THF / MeOH (4 / 2 mL). The reaction was completed, cooled to room temperature, and neutralized by dropwise addition of dilute hydrochloric acid. Extracted with EtOAc, washed with saturated aqueous NaCl, dried over anhydrous Na 2 SO 4. Filtration, concentration and EtOAc (EtOAc/EtOAc)
LC-MS：tR＝3.248min；[M+H]+＝625.9,628.0；LC-MS: t R = 3.248 min; [M+H] + = 625.9, 628.0;
1H NMR(400MHz,DMSO)δ8.40(d,J＝1.7Hz,1H),7.87(dd,J＝8.5,1.8Hz,1H),7.66–7.61(m,2H),7.58–7.45(m,3H),6.96(d,J＝2.6Hz,1H),6.82(dd,J＝8.6,2.6Hz,1H),4.92(s,2H),4.56(t,J＝8.3Hz,2H),4.43–4.28(m,1H),4.28–4.15(m,2H),2.49–2.40(m,1H),1.22–1.06(m,4H)。 1 H NMR (400 MHz, DMSO) δ 8.40 (d, J = 1.7 Hz, 1H), 7.78 (dd, J = 8.5, 1.8 Hz, 1H), 7.66 - 7.61 (m, 2H), 7.58 - 7.45 (m) , 3H), 6.96 (d, J = 2.6 Hz, 1H), 6.82 (dd, J = 8.6, 2.6 Hz, 1H), 4.92 (s, 2H), 4.56 (t, J = 8.3 Hz, 2H), 4.43 – 4.28 (m, 1H), 4.28–4.15 (m, 2H), 2.49–2.40 (m, 1H), 1.22–1.06 (m, 4H).
实施例31 2-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噻唑-4-基)甲氧基)苯基)吖丁啶-1-基)-4-氟苯并[d]噻唑-6-羧酸(31)Example 31 2-(3-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)phenyl)indole Butyr-1-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (31)
Figure PCTCN2016111652-appb-000075
Figure PCTCN2016111652-appb-000075
化合物31-a合成参照实施例30第一步到第二步。Compound 31-a was synthesized in the first to second steps of Reference Example 30.
化合物31-a：LC-MS:tR＝3.653min；[M+H]+＝658.0,660.0。Compound 31-a: LC-MS: t R = 3.653min; [M + H] + = 658.0,660.0.
化合物31-a(50mg，0.076mmol)溶于THF/MeOH(4/2mL)，加入KOH水溶液(3N，1mL)，加热70℃反应1小时。反应完全，冷却至室温，滴加稀盐酸中和。EtOAc萃取，饱和NaCl水溶液洗涤，无水Na2SO4干燥。过滤，浓缩，粗产品经PTLC分离(PE/EA＝1:1)，得产物31(34mg，69％)。Compound 31-a (50 mg, 0.076 mmol) was dissolved in THF / MeOH (4 / 2 mL). The reaction was completed, cooled to room temperature, and neutralized by dropwise addition of dilute hydrochloric acid. Extracted with EtOAc, washed with saturated aqueous NaCl, dried over anhydrous Na 2 SO 4. Filtration, concentration and EtOAc (EtOAc/EtOAc)
LC-MS:tR＝3.309min；[M+H]+＝644.0,645.8；LC-MS: t R = 3.309 min; [M+H] + = 644.0, 645.8;
1H NMR(400MHz,DMSO)δ13.02(s,1H),8.27(s,1H),7.70–7.40(m,4H),6.96(s,1H),6.82(d,J＝7.8Hz,1H),4.93(s,2H),4.59(t,J＝7.4Hz,2H),4.34(m,1H),4.31–4.17(m,2H),1.35–1.05(m,4H)； 1 H NMR (400 MHz, DMSO) δ 13.02 (s, 1H), 8.27 (s, 1H), 7.70 - 7.40 (m, 4H), 6.96 (s, 1H), 6.82 (d, J = 7.8 Hz, 1H) ), 4.93 (s, 2H), 4.59 (t, J = 7.4 Hz, 2H), 4.34 (m, 1H), 4.31 - 4.17 (m, 2H), 1.35 - 1.05 (m, 4H);
19F NMR(376MHz,DMSO)δ-126.26。 19 F NMR (376 MHz, DMSO) δ-126.26.
实施例32 2-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噻唑-4-基)甲氧基)苯基)吖丁啶-1-基)-4-甲氧基苯并[d]噻唑-6-羧酸(32)Example 32 2-(3-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)phenyl)indole Butyr-1-yl)-4-methoxybenzo[d]thiazole-6-carboxylic acid (32)
Figure PCTCN2016111652-appb-000076
Figure PCTCN2016111652-appb-000076
化合物32-a合成参照实施例30第一步到第二步。Compound 32-a was synthesized in the first to second steps of Reference Example 30.
LC-MS:tR＝3.589min,[M+H]+＝670.0。 LC-MS: t R = 3.589min , [M + H] + = 670.0.
化合物32-a(25mg，0.037mmol)溶于MeOH/THF(2/4ml)溶液中加入3M KOH水溶液(1ml)，加热75℃搅拌1h。冷却反应液，用2N HCl酸化至pH＝6，然后用乙酸乙酯萃取，有机层干燥，浓缩，硅胶柱层析分离，得化合物32(15mg，收率：60％)。Compound 32-a (25 mg, 0.037 mmol) was dissolved in MeOH / EtOAc (EtOAc (EtOAc) The reaction mixture was cooled with EtOAc EtOAc (EtOAc)
LC-MS:tR＝3.243min,[M+H]+＝655.9；LC-MS: t R = 3.243 min, [M+H] + = 655.9;
1H NMR(400MHz,CDCl3)δ8.06(d,J＝1.1Hz,1H),7.56(s,1H),7.44–7.35(m,2H),7.32(dd,J＝9.0,7.0Hz,1H),7.24(s,1H),6.84(d,J＝2.5Hz,1H),6.73(dd,J＝8.6,2.4Hz,1H),4.80(s,2H),4.66(t,J＝8.1Hz,2H),4.34(ddd,J＝24.8,14.4,6.9Hz,3H),4.05(s,3H),2.15(ddd,J＝13.5,8.4,5.1Hz,1H),1.29(dt,J＝6.5,4.6Hz,2H),1.15(td,J＝7.0,4.4Hz,2H)。 1 H NMR (400MHz, CDCl 3 ) δ8.06 (d, J = 1.1Hz, 1H), 7.56 (s, 1H), 7.44-7.35 (m, 2H), 7.32 (dd, J = 9.0,7.0Hz, 1H), 7.24 (s, 1H), 6.84 (d, J = 2.5 Hz, 1H), 6.73 (dd, J = 8.6, 2.4 Hz, 1H), 4.80 (s, 2H), 4.66 (t, J = 8.1 Hz, 2H), 4.34 (ddd, J = 24.8, 14.4, 6.9 Hz, 3H), 4.05 (s, 3H), 2.15 (ddd, J = 13.5, 8.4, 5.1 Hz, 1H), 1.29 (dt, J = 6.5, 4.6 Hz, 2H), 1.15 (td, J = 7.0, 4.4 Hz, 2H).
实施例33 2-(3-(2-氯-4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噻唑-4-基)甲氧基)苯基)吖丁啶-1-基)苯并[d]噻唑-6-羧酸(33)Example 33 2-(3-(2-Chloro-4-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isothiazol-4-yl)methoxy)benzene Azetidin-1-yl)benzo[d]thiazole-6-carboxylic acid (33)
Figure PCTCN2016111652-appb-000077
Figure PCTCN2016111652-appb-000077
化合物33-a合成参照实施例30第一步到第二步。Compound 33-a was synthesized in the first to second steps of Reference Example 30.
LC-MS:tR＝3.617min,[M+H]+＝656.0； LC-MS: t R = 3.617min , [M + H] + = 656.0;
1H NMR(400MHz,CDCl3)δ8.32(d,J＝1.6Hz,1H),8.03(d,J＝8.5Hz,1H),7.64(d,J＝8.5Hz,1H),7.57–7.48(m,2H),7.38(t,J＝7.6Hz,2H),7.28(d,J＝12.2Hz,1H),6.85(d,J＝2.5Hz,1H),6.75(dd,J＝8.5,2.3Hz,1H),4.86(s,2H),4.69(s,2H),4.48–4.25(m,3H),3.92(s,3H),2.18–2.09(m,1H),1.25(tt,J＝6.5,3.2Hz,4H),1.13(dt,J＝7.6,4.5Hz,2H)； 1 H NMR (400 MHz, CDCl 3 ) δ 8.32 (d, J = 1.6 Hz, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.57 - 7.48 (m, 2H), 7.38 (t, J = 7.6 Hz, 2H), 7.28 (d, J = 12.2 Hz, 1H), 6.85 (d, J = 2.5 Hz, 1H), 6.75 (dd, J = 8.5, 2.3 Hz, 1H), 4.86 (s, 2H), 4.69 (s, 2H), 4.48 - 4.25 (m, 3H), 3.92 (s, 3H), 2.18 - 2.09 (m, 1H), 1.25 (tt, J = 6.5, 3.2 Hz, 4H), 1.13 (dt, J = 7.6, 4.5 Hz, 2H);
19F NMR(376MHz,CDCl3)δ-57.36。 19 F NMR (376 MHz, CDCl 3 ) δ - 57.36.
化合物33-a(53mg，0.081mmol)溶于THF/MeOH(4/2mL)，加入KOH水溶液(3N，1mL)，加热70℃反应1小时。反应完全，冷却至室温，滴加稀盐酸中和。EtOAc萃取，饱和NaCl水溶液洗涤，无水Na2SO4干燥。过滤，浓缩，粗产品经PTLC分离(PE/EA＝1:2)，得产物33(15mg，29％)。Compound 33-a (53 mg, 0.081 mmol) was dissolved in THF / MeOH (4 / 2 mL). The reaction was completed, cooled to room temperature, and neutralized by dropwise addition of dilute hydrochloric acid. Extracted with EtOAc, washed with saturated aqueous NaCl, dried over anhydrous Na 2 SO 4. Filtration, concentration and crude product were purified by EtOAc (EtOAc/EtOAc:EtOAc:
LC-MS:tR＝3.275min；[M+H]+＝642.0；LC-MS: t R = 3.375 min; [M+H] + = 642.0;
1H NMR(400MHz,DMSO)δ12.69(s,1H),8.40(s,1H),7.87(d,J＝8.0Hz,1H),7.71–7.45(m,6H),7.02(s,1H),6.87(d,J＝8.1Hz,1H),4.96(s,2H),4.57(t,J＝8.1Hz,2H),4.41–4.28(m,1H),4.22(t,J＝7.1Hz,2H),2.42(m,1H),1.19–1.01(m,4H)； 1 H NMR (400 MHz, DMSO) δ 12.69 (s, 1H), 8.40 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.71 - 7.45 (m, 6H), 7.02 (s, 1H) ), 6.87 (d, J = 8.1 Hz, 1H), 4.96 (s, 2H), 4.57 (t, J = 8.1 Hz, 2H), 4.41 - 4.28 (m, 1H), 4.22 (t, J = 7.1 Hz) , 2H), 2.42 (m, 1H), 1.19–1.01 (m, 4H);
19F NMR(376MHz,DMSO)δ-56.37。 19 F NMR (376 MHz, DMSO) δ - 56.37.
实施例34 2-(3-(2-氯-4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噻唑-4-基)甲氧基)苯基)吖丁啶-1-基)-4-氟苯并[d]噻唑-6-羧酸(34) Example 34 2-(3-(2-Chloro-4-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isothiazol-4-yl)methoxy)benzene Azetidin-1-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (34)
Figure PCTCN2016111652-appb-000078
Figure PCTCN2016111652-appb-000078
化合物34-a合成参照实施例30第一步到第二步。Compound 34-a was synthesized in the first to second steps of Reference Example 30.
LC-MS:tR＝3.659min,[M+H]+＝674.0。 LC-MS: t R = 3.659min , [M + H] + = 674.0.
化合物34-a(46mg，0.068mmol)溶于THF/MeOH(4/2mL)，加入KOH水溶液(3N，1mL)，加热70℃反应1小时。反应完全，冷却至室温，滴加稀盐酸中和。EtOAc萃取，饱和NaCl水溶液洗涤，无水Na2SO4干燥。过滤，浓缩，粗产品经PTLC分离(PE/EA＝1:2)，得产物34(28mg，62％)。Compound 34-a (46 mg, 0.068 mmol) was dissolved in THF / MeOH (4 / 2 mL). The reaction was completed, cooled to room temperature, and neutralized by dropwise addition of dilute hydrochloric acid. Extracted with EtOAc, washed with saturated aqueous NaCl, dried over anhydrous Na 2 SO 4. Filtration, concentration and crude product were purified by EtOAc (EtOAc/EtOAc)
LC-MS:tR＝3.335min；[M+H]+＝660.0；LC-MS: t R = 3.335 min; [M+H] + = 660.0;
1H NMR(400MHz,DMSO)δ12.98(s,1H),8.27(d,J＝1.4Hz,1H),7.74–7.58(m,3H),7.58–7.47(m,3H),7.02(d,J＝2.5Hz,1H),6.87(dd,J＝8.7,2.5Hz,1H),4.96(s,2H),4.60(t,J＝8.3Hz,2H),4.35(dt,J＝14.8,7.4Hz,1H),4.30–4.22(m,2H),2.45–2.37(m,1H),1.19–1.07(m,4H)； 1 H NMR (400 MHz, DMSO) δ 12.98 (s, 1H), 8.27 (d, J = 1.4 Hz, 1H), 7.74 - 7.58 (m, 3H), 7.58 - 7.47 (m, 3H), 7.02 (d) , J = 2.5 Hz, 1H), 6.87 (dd, J = 8.7, 2.5 Hz, 1H), 4.96 (s, 2H), 4.60 (t, J = 8.3 Hz, 2H), 4.35 (dt, J = 14.8, 7.4 Hz, 1H), 4.30–4.22 (m, 2H), 2.45–2.37 (m, 1H), 1.19–1.07 (m, 4H);
19F NMR(376MHz,DMSO)δ-56.36,-126.29。 19 F NMR (376 MHz, DMSO) δ - 56.36, -126.29.
实施例35 2-(3-(2-氯-4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噻唑-4-基)甲氧基)苯基)吖丁啶-1-基)-4-甲氧基苯并[d]噻唑-6-羧酸(35)Example 35 2-(3-(2-Chloro-4-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isothiazol-4-yl)methoxy)benzene Azetidin-1-yl)-4-methoxybenzo[d]thiazole-6-carboxylic acid (35)
Figure PCTCN2016111652-appb-000079
Figure PCTCN2016111652-appb-000079
化合物35-a合成参照实施例30第一步到第二步。Compound 35-a was synthesized in the first to second steps of Reference Example 30.
LC-MS:tR＝3.598min,[M+H]+＝686.0。 LC-MS: t R = 3.598min , [M + H] + = 686.0.
1H NMR(400MHz,CDCl3)δ7.91(d,J＝1.3Hz,1H),7.51–7.41(m,3H),7.31(t,J＝7.6Hz,2H),7.21(s,1H),6.77(d,J＝2.5Hz,1H),6.66(dd,J＝8.6,2.5Hz,1H),4.78(s,2H),4.59(t,J＝8.0Hz,2H),4.34–4.18(m,3H),3.97(s,3H),3.85(s,3H),2.06(ddd,J＝13.5,8.4,5.1Hz,1H),1.22–1.16(m,2H),1.06(dt,J＝7.6,4.5Hz,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.91 (d, J = 1.3 Hz, 1H), 7.51 - 7.41 (m, 3H), 7.31 (t, J = 7.6 Hz, 2H), 7.21 (s, 1H) , 6.77 (d, J = 2.5 Hz, 1H), 6.66 (dd, J = 8.6, 2.5 Hz, 1H), 4.78 (s, 2H), 4.59 (t, J = 8.0 Hz, 2H), 4.34 - 4.18 ( m, 3H), 3.97 (s, 3H), 3.85 (s, 3H), 2.06 (ddd, J = 13.5, 8.4, 5.1 Hz, 1H), 1.22 - 1.16 (m, 2H), 1.06 (dt, J = 7.6, 4.5 Hz, 2H).
化合物35-a(45mg，0.066mmol)溶于MeOH/THF(2/4ml)溶液中加入3M KOH水溶液(1ml)，加热75℃搅拌1h。冷却反应液，用2N HCl酸化至pH＝6，然后用乙酸乙酯萃取，有机层干燥，浓缩，硅胶柱层析分离，得化合物35(14mg，收率：31％)。Compound 35-a (45 mg, 0.066 mmol) was dissolved in MeOH / EtOAc (EtOAc) The reaction mixture was cooled with EtOAc EtOAc (EtOAc)
LC-MS:tR＝3.267min,[M+H]+＝672.0；LC-MS: t R = 3.277 min, [M+H] + = 672.0;
1H NMR(400MHz,CDCl3)δ8.06(s,1H),7.61–7.46(m,3H),7.38(t,J＝7.7Hz,2H),7.29(s,1H),6.84(s,1H),6.74(d,J＝7.5Hz,1H),4.86(s,2H),4.68(m, 2H),4.44–4.25(m,3H),4.05(s,3H),2.13(m,1H),1.25(m,2H),1.13(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ8.06 (s, 1H), 7.61-7.46 (m, 3H), 7.38 (t, J = 7.7Hz, 2H), 7.29 (s, 1H), 6.84 (s, 1H), 6.74 (d, J = 7.5 Hz, 1H), 4.86 (s, 2H), 4.68 (m, 2H), 4.44 - 4.25 (m, 3H), 4.05 (s, 3H), 2.13 (m, 1H) ), 1.25 (m, 2H), 1.13 (m, 2H).
实施例36 2-(3-(2-氯-4-((5-环丙基-3-(2-(二氟甲氧基)苯基)异噻唑-4-基)甲氧基)苯基)吖丁啶-1-基)-4-氟苯并[d]噻唑-6-羧酸(36)Example 36 2-(3-(2-Chloro-4-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isothiazol-4-yl)methoxy)benzene Azetidin-1-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (36)
Figure PCTCN2016111652-appb-000080
Figure PCTCN2016111652-appb-000080
化合物36-a合成参照实施例30第一步到第二步。Compound 36-a was synthesized in the first to second steps of Reference Example 30.
LC-MS:tR＝3.53min，[M+H]+＝656.0。LC-MS: tR = 3.53 min.
化合物36-a(70mg,0.11mmol)溶于四氢呋喃(2mL)，再加入1毫升1N NaOH水溶液，50℃搅拌2h。反应完全后加入稀盐酸中和，乙酸乙酯萃取。浓缩后粗产品经PTLC分离，得化合物36(7mg,产率：10％)。Compound 36-a (70 mg, 0.11 mmol) was dissolved in THF (2 mL). After the reaction was completed, it was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The crude product was concentrated by PTLC to afford compound 36 (yield: 10%).
LC-MS:tR＝3.18min,[M+H]+＝642.0； LC-MS: t R = 3.18min , [M + H] + = 642.0;
1H NMR(400MHz,CDCl3)δ8.18(s,1H),7.79(d,J＝10.8Hz,1H),7.49(dd,J＝14.5,7.5Hz,2H),7.37–7.27(m,3H),6.86(s,1H),6.76(d,J＝8.6Hz,1H),6.44(t,J＝73.9Hz,1H),4.88(s,2H),4.67(t,J＝7.9Hz,2H),4.46–4.18(m,3H),2.13(d,J＝4.8Hz,1H),1.28(m,2H),1.13(m,2H)； 1 H NMR (400MHz, CDCl 3 ) δ8.18 (s, 1H), 7.79 (d, J = 10.8Hz, 1H), 7.49 (dd, J = 14.5,7.5Hz, 2H), 7.37-7.27 (m, 3H), 6.86 (s, 1H), 6.76 (d, J = 8.6 Hz, 1H), 6.44 (t, J = 73.9 Hz, 1H), 4.88 (s, 2H), 4.67 (t, J = 7.9 Hz, 2H), 4.46 - 4.18 (m, 3H), 2.13 (d, J = 4.8 Hz, 1H), 1.28 (m, 2H), 1.13 (m, 2H);
19F NMR(376MHz,CDCl3)δ-81.14，-125.23。 19 F NMR (376 MHz, CDCl 3 ) δ-81.14, -125.23.
实施例37 6-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噻唑-4-基)甲氧基)苯基)吖丁啶-1-基)-1-甲基-1H-吲哚-3-羧酸(37)Example 37 6-(3-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)phenyl)indole Butyr-1-yl)-1-methyl-1H-indole-3-carboxylic acid (37)
Figure PCTCN2016111652-appb-000081
Figure PCTCN2016111652-appb-000081
第一步：称取化合物I-12(300mg，1.12mmol)于100mL单口瓶中，加入1,4-二氧六环溶液(15mL)，之后依次加入化合物20-d(197mg,1.0mmol)、碳酸铯(980mg,3mmol)、Pd2(dba)3(137mg,0.15mmol)和X-phos(143mg,0.3mmol)，置换氮气三次。加热回流反应过夜。待反应冷却后通过硅藻土过滤，并用EA洗涤3次。滤液经萃取后取有机层用硫酸钠干燥，浓缩，柱层析分离得化合物37-a(160mg，产率41.6％)。 First step: Weighed compound I-12 (300 mg, 1.12 mmol) in a 100 mL single-mouth bottle, and added 1,4-dioxane solution (15 mL), followed by the addition of compound 20-d (197 mg, 1.0 mmol), Cesium carbonate (980 mg, 3 mmol), Pd 2 (dba) 3 (137 mg, 0.15 mmol) and X-phos (143 mg, 0.3 mmol) were replaced with nitrogen three times. The reaction was heated to reflux overnight. After cooling the reaction, it was filtered through celite and washed three times with EA. The filtrate was extracted and the organic layer was dried with sodium sulfate.
LC-MS:tR＝3.25min，[M+H]+＝385.0。 LC-MS: t R = 3.25min , [M + H] + = 385.0.
第二步：化合物37-a(160mg,0.41mmol)溶于二氯甲烷(5mL)，-78℃下缓慢滴加三溴化硼(4N)溶液，滴完后升至室温搅拌20min。冰水浴下加甲醇淬灭并搅拌30min，乙酸乙酯萃取，有机相合并用饱和食盐水洗一次，硫酸钠干燥。过滤，浓缩得化合物37-b(110mg，产率：71％)。The second step: Compound 37-a (160 mg, 0.41 mmol) was dissolved in dichloromethane (5 mL), and a boron tribromide (4N) solution was slowly added dropwise at -78 ° C. After the dropwise addition, the mixture was stirred at room temperature for 20 min. The mixture was stirred and stirred for 30 min. Filtration and concentration gave Compound 37-b (110 mg, yield: 71%).
LC-MS:tR＝2.79min，[M+H]+＝371.0。 LC-MS: t R = 2.79min , [M + H] + = 371.0.
第三步：化合物37-b(110mg，0.3mmol)和I-2(100mg，0.33mmol)溶于干燥DMF(3mL)，再加入K2CO3(83mg，0.6mmol)，50℃搅拌反应过夜。反应完全后浓缩，PTLC分离，得化合物37-c(100mg，53％)。The third step: Compound 37-b (110 mg, 0.3 mmol) and I-2 (100 mg, 0.33 mmol) were dissolved in dry DMF (3 mL), then K 2 CO 3 (83 mg, 0.6 mmol), and stirred at 50 ° C overnight. . After the reaction was completed, the mixture was concentrated and purified by EtOAc EtOAc (EtOAc)
LC-MS：tR＝3.60min，[M+H]+＝636.0。 LC-MS: t R = 3.60min , [M + H] + = 636.0.
第四步：化合物37-c(100mg，0.16mmol)溶于1,4-二氧六环(2mL)，再加入1N NaOH(1mL)水溶液，回流反应过夜。反应完全后加入稀盐酸中和，乙酸乙酯萃取。浓缩后粗产品经PTLC分离，得化合物37(44mg,产率：45％)。The fourth step: Compound 37-c (100 mg, 0.16 mmol) was dissolved in 1,4-dioxane (2 mL). After the reaction was completed, it was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The crude product was concentrated by PTLC to afford compound 37 (44 mg, yield: 45%).
LC-MS:tR＝3.29min,[M+H]+＝622.0； LC-MS: t R = 3.29min , [M + H] + = 622.0;
1H NMR(400MHz,DMSO)δ11.79(s,1H),7.80(m,2H),7.66–7.57(m,2H),7.53(dd,J＝9.1,7.0Hz,1H),7.39(d,J＝8.6Hz,1H),6.94(d,J＝2.5Hz,1H),6.79(dd,J＝8.7,2.5Hz,1H),6.57–6.38(m,2H),4.91(s,2H),4.29(t,J＝7.5Hz,2H),4.21–4.07(m,1H),3.83–3.66(m,5H),2.45(td,J＝8.3,4.2Hz,1H),1.22–1.06(m,4H)。 1 H NMR (400MHz, DMSO) δ11.79 (s, 1H), 7.80 (m, 2H), 7.66-7.57 (m, 2H), 7.53 (dd, J = 9.1,7.0Hz, 1H), 7.39 (d , J=8.6 Hz, 1H), 6.94 (d, J=2.5 Hz, 1H), 6.79 (dd, J=8.7, 2.5 Hz, 1H), 6.57–6.38 (m, 2H), 4.91 (s, 2H) , 4.29 (t, J = 7.5 Hz, 2H), 4.21 - 4.07 (m, 1H), 3.83 - 3.66 (m, 5H), 2.45 (td, J = 8.3, 4.2 Hz, 1H), 1.22 - 1.06 (m) , 4H).
实施例38 6-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噻唑-4-基)甲氧基)苯基)吖丁啶-1-基)-1-环丙基-1H-吲哚-3-羧酸(38)Example 38 6-(3-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)phenyl)indole Butyr-1-yl)-1-cyclopropyl-1H-indole-3-carboxylic acid (38)
Figure PCTCN2016111652-appb-000082
Figure PCTCN2016111652-appb-000082
第一步：二氯乙烷(30mL)置于250mL三口烧瓶中，加入化合物I-12-c(760mg,3.0mmol)，环丙基硼酸(516mg,6.0mmol)以及碳酸钠(640mg,6.0mmol)。将醋酸铜(600mg,3.0mmol)与2,2-联吡啶(470mg,3.0mmol)置于二氯乙烷(15mL)溶液，加热至呈悬浮液，将此悬浮液滴加到上述反应液中，70℃敞口搅拌5h。反应完全，冷却，加适量稀盐酸，二氯甲烷萃取，干燥，浓缩，柱层析分离，得化合物38-a(450mg,产率：51.2％)。 The first step: dichloroethane (30 mL) was placed in a 250 mL three-necked flask, and compound I-12-c (760 mg, 3.0 mmol), cyclopropylboronic acid (516 mg, 6.0 mmol) and sodium carbonate (640 mg, 6.0 mmol) were added. ). Copper acetate (600 mg, 3.0 mmol) and 2,2-bipyridine (470 mg, 3.0 mmol) were placed in a solution of dichloroethane (15 mL), heated to a suspension, and the suspension was added dropwise to the above reaction solution. Stir at 70 ° C for 5 h. The reaction was completed, cooled, added with aq. EtOAc, EtOAc (EtOAc)EtOAc.
LC-MS:tR＝3.11min。 LC-MS: t R = 3.11min .
第二步：称取化合物38-a(450mg,1.5mmol)于100mL单口瓶中，加入1,4-二氧六环溶液(15mL),之后依次加入20-d(300mg,1.5mmol)、碳酸铯(1476mg,4.5mmol)、Pd2(dba)3(140mg,0.15mmol)和X-phos(143mg,0.3mmol)，置换氮气三次，加热回流反应过夜。待反应冷却后通过硅藻土过滤，并用EA洗涤3次。滤液萃取，硫酸钠干燥，过滤，浓缩，柱层析分离得化合物38-b(276mg，产率44.5％)。The second step: weighed compound 38-a (450 mg, 1.5 mmol) in a 100 mL single-mouth bottle, added 1,4-dioxane solution (15 mL), followed by 20-d (300 mg, 1.5 mmol), carbonic acid铯 (1476 mg, 4.5 mmol), Pd 2 (dba) 3 (140 mg, 0.15 mmol) and X-phos (143 mg, 0.3 mmol) were replaced with nitrogen three times and heated to reflux overnight. After cooling the reaction, it was filtered through celite and washed three times with EA. The filtrate was extracted, dried over sodium sulfate, filtered, concentrated, and then evaporated
LC-MS:tR＝3.44min，[M+H]+＝411.1。LC-MS: t R = 3.44 min, [M+H] + = 411.1.
第三步：化合物38-b(100mg,0.24mmol)溶于二氯甲烷(5mL)，-78℃下缓慢滴加三溴化硼溶液(4N,0.24mL)，滴完升至室温搅拌20min。冰水浴下加甲醇淬灭，搅拌30min，乙酸乙酯萃取，有机相合并用饱和食盐水洗一次，硫酸钠干燥。过滤，浓缩得化合物38-c(50mg，产率：52％)。The third step: Compound 38-b (100 mg, 0.24 mmol) was dissolved in dichloromethane (5 mL), and boron tribromide solution (4N, 0.24 mL) was slowly added dropwise at -78 ° C, and the mixture was stirred at room temperature for 20 min. The mixture was quenched with EtOAc (EtOAc)EtOAc. Filtration and concentration gave Compound 38-c (50 mg, yield: 52%).
LC-MS:tR＝2.99min，[M+H]+＝397.1。 LC-MS: t R = 2.99min , [M + H] + = 397.1.
第四步：化合物38-c(50mg，0.12mmol)和I-2(40mg，0.13mmol)溶于干燥DMF(3mL)，再加入K2CO3(50mg，0.36mmol)，50℃搅拌反应过夜。反应完全后浓缩，PTLC分离，得化合物38-d(50mg，60％)。The fourth step: Compound 38-c (50 mg, 0.12 mmol) and I-2 (40 mg, 0.13 mmol) were dissolved in dry DMF (3 mL), then K 2 CO 3 (50 mg, 0.36 mmol), and stirred at 50 ° C overnight. . The reaction was completed, concentrated, and purified by PTLC to yield compound 38-d (50mg, 60%).
LC-MS:tR＝3.72min，[M+H]+＝662.0。 LC-MS: t R = 3.72min , [M + H] + = 662.0.
第五步：化合物38-d(50mg，0.075mmol)溶于1,4-二氧六环(2mL)，再加入1N NaOH(1mL)水溶液，回流48h。反应完全后加入稀盐酸中和，乙酸乙酯萃取。浓缩后粗产品经PTLC分离，得化合物38(10mg,产率：20％)。The fifth step: Compound 38-d (50 mg, 0.075 mmol) was dissolved in 1,4-dioxane (2 mL). After the reaction was completed, it was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The crude product was concentrated by PTLC to give compound 38 (10 mg, yield: 20%).
LC-MS:tR＝3.42min,[M+H]+＝648.0；LC-MS: t R = 3.42 min, [M+H] + = 648.0;
1H NMR(400MHz,MeOD)δ8.48(s,1H),7.96(d,J＝8.6Hz,1H),7.39(ddd,J＝15.9,10.7,8.2Hz,3H),7.28(d,J＝8.6Hz,1H),6.75(d,J＝2.5Hz,1H),6.69(dd,J＝8.6,2.6Hz,1H),6.59(d,J＝1.8Hz,1H),6.46(dd,J＝8.5,2.0Hz,1H),4.82(s,2H),4.28(t,J＝7.3Hz,2H),4.14(t,J＝7.3Hz,1H),3.74(t,J＝6.9Hz,2H),2.29–2.20(m,1H),1.76–1.70(m,1H),1.25–1.21(m,2H),1.13–1.11(m,2H),1.01–0.99(m,2H),0.89–0.87(m,2H)。 1 H NMR (400MHz, MeOD) δ8.48 (s, 1H), 7.96 (d, J = 8.6Hz, 1H), 7.39 (ddd, J = 15.9,10.7,8.2Hz, 3H), 7.28 (d, J = 8.6 Hz, 1H), 6.75 (d, J = 2.5 Hz, 1H), 6.69 (dd, J = 8.6, 2.6 Hz, 1H), 6.59 (d, J = 1.8 Hz, 1H), 6.46 (dd, J = 8.5, 2.0 Hz, 1H), 4.82 (s, 2H), 4.28 (t, J = 7.3 Hz, 2H), 4.14 (t, J = 7.3 Hz, 1H), 3.74 (t, J = 6.9 Hz, 2H) ), 2.29–2.20 (m, 1H), 1.76–1.70 (m, 1H), 1.25–1.21 (m, 2H), 1.13–1.11 (m, 2H), 1.01–0.99 (m, 2H), 0.89–0.87 (m, 2H).
实施例39 5-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噻唑-4-基)甲氧基)苯基)吖丁啶-1-基)-1-甲基-1H-吲哚-3-羧酸(39) Example 39 5-(3-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)phenyl)indole Butyr-1-yl)-1-methyl-1H-indole-3-carboxylic acid (39)
Figure PCTCN2016111652-appb-000083
Figure PCTCN2016111652-appb-000083
第一步：化合物39-a(0.46g，1.8mmol)溶于乙腈(20mL)，加入碳酸钾(0.75g，5.4mmol)和MeI(0.4mL,6.3mmol)，于50℃下搅拌3h。待反应液冷却后用水(20mL)稀释，乙酸乙酯萃取后合并有机相。合并后的有机相用饱和食盐水洗一次，硫酸钠干燥。过滤，浓缩，柱层析分离(PE/EA:5～15％)，得化合物39-b(0.4g，产率：83％)。The first step: Compound 39-a (0.46 g, <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; After the reaction solution was cooled, it was diluted with water (20 mL), and the organic layer was combined and evaporated. The combined organic phases were washed once with saturated brine and dried over sodium sulfate. Filtration, concentration and column chromatography (PE/EA: 5 to 15%) gave Compound 39-b (0.4 g, yield: 83%).
LC-MS:tR＝2.83min。 LC-MS: t R = 2.83min .
第二步：称取化合物39-b(200mg，0.75mmol)于100mL单口瓶中，加入1,4-二氧六环溶液(15mL),之后依次加入20-d(150mg,0.75mmol)、碳酸铯(740mg,2.25mmol)、Pd2(dba)3(70mg,0.075mmol)和X-phos(70mg,0.15mmol)，置换氮气三次。加热回流，反应过夜。待反应冷却后通过硅藻土过滤，并用EA洗涤3次。滤液经萃取后取有机层用硫酸钠干燥，浓缩，柱层析分离得化合物39-c(55mg，产率20％)。The second step: Weighing compound 39-b (200 mg, 0.75 mmol) in a 100 mL single-mouth bottle, adding 1,4-dioxane solution (15 mL), followed by 20-d (150 mg, 0.75 mmol), carbonic acid铯 (740 mg, 2.25 mmol), Pd 2 (dba) 3 (70 mg, 0.075 mmol) and X-phos (70 mg, 0.15 mmol) were replaced with nitrogen three times. Heat to reflux and react overnight. After cooling the reaction, it was filtered through celite and washed three times with EA. The filtrate was extracted and the organic layer was dried (MgSO4)
LC-MS:tR＝3.24min，[M+H]+＝385.0。 LC-MS: t R = 3.24min , [M + H] + = 385.0.
第三步：化合物39-c(55mg,0.14mmol)溶于二氯甲烷(5mL)，-78℃下缓慢滴加三溴化硼(4N)溶液，滴完后升至室温搅拌20min。冰水浴下加甲醇淬灭，搅拌30min，乙酸乙酯萃取，有机相合并用饱和食盐水洗一次，硫酸钠干燥。过滤，浓缩得化合物39-d(45mg，产率：85％)。The third step: Compound 39-c (55 mg, 0.14 mmol) was dissolved in dichloromethane (5 mL), and a solution of boron tribromide (4N) was slowly added dropwise at -78 ° C. After the dropwise addition, the mixture was stirred at room temperature for 20 min. The mixture was quenched with EtOAc (EtOAc)EtOAc. Filtration and concentration gave Compound 39-d (45 mg, yield: 85%).
LC-MS:tR＝2.65min，[M+H]+＝371.0。 LC-MS: t R = 2.65min , [M + H] + = 371.0.
第四步：化合物39-d(45mg，0.12mmol)和I-2(40mg，0.13mmol)溶于干燥DMF(3mL)，再加入K2CO3(50mg，0.36mmol)，50℃搅拌反应过夜。反应完全后浓缩，PTLC分离，得化合物39-e(60mg，78％)。The fourth step: Compound 39-d (45 mg, 0.12 mmol) and I-2 (40 mg, 0.13 mmol) were dissolved in dry DMF (3 mL), then K 2 CO 3 (50 mg, 0.36 mmol), and stirred at 50 ° C overnight. . The reaction was completed, concentrated, and purified by EtOAc EtOAc (EtOAc)
LC-MS:tR＝3.55min，[M+H]+＝636.0。 LC-MS: t R = 3.55min , [M + H] + = 636.0.
第五步：化合物39-e(60mg，0.094mmol)溶于1,4-二氧六环(2mL)，再加入1N NaOH(1mL)水溶液，回流反应过夜。反应完全后加入稀盐酸中和，乙酸乙酯萃取。浓缩后粗产品经PTLC分离，得化合物39(12mg,产率：20％)。The fifth step: Compound 39-e (60 mg, 0.094 mmol) was dissolved in 1,4-dioxane (2 mL). After the reaction was completed, it was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The crude product was concentrated by PTLC to give Compound 39 (yield: 20%).
LC-MS:tR＝3.29min,[M+H]+＝622.0； LC-MS: t R = 3.29min , [M + H] + = 622.0;
1H NMR(400MHz,CDCl3)δ7.78(s,1H),7.46–7.12(m,6H),6.82(s,1H),6.65(m,2H),4.78(s,2H),4.40(m,2H),4.25(m,1H),3.83(m,5H),2.14(m,1H),1.27(m,2H),1.14(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ7.78 (s, 1H), 7.46-7.12 (m, 6H), 6.82 (s, 1H), 6.65 (m, 2H), 4.78 (s, 2H), 4.40 ( m, 2H), 4.25 (m, 1H), 3.83 (m, 5H), 2.14 (m, 1H), 1.27 (m, 2H), 1.14 (m, 2H).
实施例40 7-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噻唑-4-基)甲氧基)苯基)吖丁啶-1-基)喹啉-3-羧酸(40)Example 40 7-(3-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)phenyl)indole Butyr-1-yl)quinoline-3-carboxylic acid (40)
Figure PCTCN2016111652-appb-000084
Figure PCTCN2016111652-appb-000084
第一步：化合物I-13(70mg，0.13mmol)溶于DCM(3ml)，冰水浴冷却下滴加TFA(1mL)，维持低温反应1h。溶液浓缩除去溶剂得化合物30-a，直接用于下步反应。The first step: Compound I-13 (70 mg, 0.13 mmol) was dissolved in DCM (3 mL). The solution was concentrated to remove the solvent to give compound 30-a, which was used directly for the next step.
第二步：往上述粗产品中加入化合物I-14(45mg，0.17mmol)、Pd2(dba)3(17mg，0.02mmol)和X-Phos(18mg,0.04mmol),溶于甲苯(6mL)。抽换气，氮气保护。加热至100℃反应6h。冷却反应液，并用乙酸乙酯/水萃取，有机层干燥浓缩后硅胶色谱纯化得到化合物40-a(59mg，收率：71％)。Step 2: To the above crude product, compound I-14 (45 mg, 0.17 mmol), Pd 2 (dba) 3 (17 mg, 0.02 mmol) and X-Phos (18 mg, 0.04 mmol) were dissolved in toluene (6 mL) . Pumping gas, nitrogen protection. Heat to 100 ° C for 6 h. The reaction mixture was cooled and extracted with EtOAc EtOAc EtOAc.
LC-MS:tR＝3.337min,[M+H]+＝648.1。LC-MS: t R = 3.337 min, [M+H] + = 648.1.
第三步：化合物40-a(59mg，0.09mmol)溶于MeOH/THF(2/4mL)，加入3M KOH水溶液(1mL)，加热75℃搅拌1h。冷却反应液，用2N HCl酸化至pH＝6，然后用乙酸乙酯/水萃取,有机层干燥，浓缩，硅胶柱层析分离，得化合物40(20mg，收率：33％)。The third step: Compound 40-a (59 mg, 0.09 mmol) was dissolved in MeOH / THF (2 / 4 mL). The reaction mixture was cooled with EtOAc EtOAc EtOAc (EtOAc)
LC-MS:tR＝2.837min,[M+H]+＝620.0；LC-MS: t R = 2.837 min, [M+H] + = 620.0;
1H NMR(400MHz,CDCl3)δ9.41(s,1H),8.80(s,1H),7.74(d,J＝8.0Hz,1H),7.44–7.27(m,4H),7.01(d,J＝14.1Hz,1H),6.95–6.66(m,3H),4.79(s,2H),4.52(s,2H),4.31(s,1H),4.08(s,2H),2.19–2.11(m,1H),1.26(d,J＝4.6Hz,2H),1.14(d,J＝5.7Hz,2H)。 1 H NMR (400MHz, CDCl 3 ) δ9.41 (s, 1H), 8.80 (s, 1H), 7.74 (d, J = 8.0Hz, 1H), 7.44-7.27 (m, 4H), 7.01 (d, J=14.1 Hz, 1H), 6.95–6.66 (m, 3H), 4.79 (s, 2H), 4.52 (s, 2H), 4.31 (s, 1H), 4.08 (s, 2H), 2.19–2.11 (m) , 1H), 1.26 (d, J = 4.6 Hz, 2H), 1.14 (d, J = 5.7 Hz, 2H).
实施例41 7-(3-(2-氯-4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噻唑-4-基)甲氧基)苯基)吖丁啶-1-基)喹啉-3-羧酸(41)Example 41 7-(3-(2-Chloro-4-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isothiazol-4-yl)methoxy)benzene Azetidin-1-yl)quinoline-3-carboxylic acid (41)
Figure PCTCN2016111652-appb-000085
Figure PCTCN2016111652-appb-000085
化合物41-a制备参照实施例40第一步到第二步。 Compound 41-a was prepared in the first to second steps of Reference Example 40.
LC-MS:tR＝3.372min,[M+H]+＝664.0。 LC-MS: t R = 3.372min , [M + H] + = 664.0.
化合物41-a(40mg，0.06mmol)溶于MeOH/THF(2/4mL)，再加入3M KOH水溶液(1mL)，加热75℃搅拌1h。冷却反应液，用2N HCl酸化至pH＝6，然后用乙酸乙酯/水萃取,有机层干燥，过滤，浓缩，硅胶柱层析分离，得化合物41(30mg，收率：75％)。Compound 41-a (40 mg, 0.06 mmol) was dissolved in MeOH / THF (2 / 4 mL). The reaction mixture was cooled with EtOAc EtOAc EtOAc (EtOAc)
LC-MS:tR＝2.859min,[M+H]+＝636.1；LC-MS: t R = 2.559 min, [M+H] + = 636.1;
1H NMR(400MHz,CDCl3)δ9.42(s,1H),8.79(s,1H),7.69(s,1H),7.49(dd,J＝19.9,7.6Hz,2H),7.33(dd,J＝17.6,9.9Hz,3H),6.98(s,1H),6.85–6.65(m,3H),4.82(s,2H),4.46(s,2H),4.27(s,1H),4.04(s,2H),2.15–2.07(m,1H),1.26-1.21(m,2H),1.12-1.07(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ9.42 (s, 1H), 8.79 (s, 1H), 7.69 (s, 1H), 7.49 (dd, J = 19.9,7.6Hz, 2H), 7.33 (dd, J = 17.6, 9.9 Hz, 3H), 6.98 (s, 1H), 6.85 - 6.65 (m, 3H), 4.82 (s, 2H), 4.46 (s, 2H), 4.27 (s, 1H), 4.04 (s , 2H), 2.15 - 2.07 (m, 1H), 1.26-1.21 (m, 2H), 1.12-1.07 (m, 2H).
实施例42 5-(3-(2-氯-4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噻唑-4-基)甲氧基)苯基)吖丁啶-1-基)-1-甲基-1H-吲哚-3-羧酸(42)Example 42 5-(3-(2-Chloro-4-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isothiazol-4-yl)methoxy)benzene Azetidin-1-yl)-1-methyl-1H-indole-3-carboxylic acid (42)
Figure PCTCN2016111652-appb-000086
Figure PCTCN2016111652-appb-000086
化合物42-a制备参照实施例40第一步到第二步。Compound 42-a was prepared in the first to second steps of Reference Example 40.
LC-MS:tR＝3.56min，[M+H]+＝652.2。 LC-MS: t R = 3.56min , [M + H] + = 652.2.
化合物42-a(40mg，0.06mmol)溶于1,4-二氧六环(2mL)，再加入1N NaOH(1mL)水溶液，100℃搅拌48h。反应完全后加入稀盐酸中和，乙酸乙酯萃取。浓缩后粗产品经PTLC分离，得化合物42(10mg,产率：25％)。Compound 42-a (40 mg, 0.06 mmol) was dissolved in 1,4-dioxane (2 mL). After the reaction was completed, it was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The crude product was concentrated by PTLC to give compound 42 (10 mg, yield: 25%).
LC-MS:tR＝3.29min,[M+H]+＝638.0；LC-MS: t R = 3.29 min, [M+H] + = 638.0;
1H NMR(400MHz,CDCl3)δ7.79(s,1H),7.51(dd,J＝17.4,7.7Hz,2H),7.40–7.26(m,4H),7.28–7.14(m,1H),6.82(d,J＝2.3Hz,1H),6.79–6.49(m,2H),4.84(s,2H),4.42(t,J＝7.3Hz,2H),4.32–4.18(m,1H),3.89(t,J＝6.6Hz,2H),2.12(td,J＝8.3,4.2Hz,1H),1.24(m,2H),1.13–1.02(m,2H)； 1 H NMR (400MHz, CDCl 3 ) δ7.79 (s, 1H), 7.51 (dd, J = 17.4,7.7Hz, 2H), 7.40-7.26 (m, 4H), 7.28-7.14 (m, 1H), 6.82 (d, J = 2.3 Hz, 1H), 6.79 - 6.49 (m, 2H), 4.84 (s, 2H), 4.42 (t, J = 7.3 Hz, 2H), 4.32 - 4.18 (m, 1H), 3.89 (t, J = 6.6 Hz, 2H), 2.12 (td, J = 8.3, 4.2 Hz, 1H), 1.24 (m, 2H), 1.13 - 1.02 (m, 2H);
19F NMR(376MHz,CDCl3)δ-57.34。 19 F NMR (376 MHz, CDCl 3 ) δ - 57.34.
实施例43 3-(3-(2-氯-4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噻唑-4-基)甲氧基)苯基)吖丁啶-1-基)-5-氟苯甲酸(43)Example 43 3-(3-(2-Chloro-4-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isothiazol-4-yl)methoxy)benzene Azetidin-1-yl)-5-fluorobenzoic acid (43)
Figure PCTCN2016111652-appb-000087
Figure PCTCN2016111652-appb-000087
化合物43-a制备参照实施例40第一步到第二步。Compound 43-a was prepared in the first to second steps of Reference Example 40.
LC-MS:tR＝3.73min，[M+H]+＝617.0。 LC-MS: t R = 3.73min , [M + H] + = 617.0.
化合物43-a(40mg，0.06mmol)溶于四氢呋喃(2mL)，再加入1N NaOH(1mL)水溶液，50℃搅拌2h。反应完全后加入稀盐酸中和，乙酸乙酯萃取。浓缩后粗产品经PTLC分离，得化合物43(18mg,产率：46％)。Compound 43-a (40 mg, 0.06 mmol) was dissolved in THF (2 mL). After the reaction was completed, it was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The crude product was concentrated by PTLC to give Compound 43 (18 mg, yield: 46%).
LC-MS:tR＝3.42min,[M+H]+＝603.0；LC-MS: t R = 3.42 min, [M+H] + = 603.0;
1H NMR(400MHz,CDCl3)δ7.58–7.46(m,2H),7.38(t,J＝7.5Hz,2H),7.29(s,1H),7.14(d,J＝8.8Hz,1H),6.98(s,1H),6.83(d,J＝2.5Hz,1H),6.72(dd,J＝8.6,2.5Hz,1H),6.39(d,J＝10.3Hz,1H),4.85(s,2H),4.37(t,J＝7.5Hz,2H),4.28(d,J＝7.7Hz,1H),3.89(t,J＝6.6Hz,2H),2.13(dd,J＝9.2,4.1Hz,1H),1.29–1.23(m,2H),1.13(m,2H)； 1 H NMR (400 MHz, CDCl 3 ) δ 7.58 - 7.46 (m, 2H), 7.38 (t, J = 7.5 Hz, 2H), 7.29 (s, 1H), 7.14 (d, J = 8.8 Hz, 1H) , 6.98 (s, 1H), 6.83 (d, J = 2.5 Hz, 1H), 6.72 (dd, J = 8.6, 2.5 Hz, 1H), 6.39 (d, J = 10.3 Hz, 1H), 4.85 (s, 2H), 4.37 (t, J = 7.5 Hz, 2H), 4.28 (d, J = 7.7 Hz, 1H), 3.89 (t, J = 6.6 Hz, 2H), 2.13 (dd, J = 9.2, 4.1 Hz, 1H), 1.29–1.23 (m, 2H), 1.13 (m, 2H);
19F NMR(376MHz,CDCl3)δ-57.35,-111.75。 19 F NMR (376 MHz, CDCl 3 ) δ - 57.35, -111.75.
实施例44 3-(3-(2-氯-4-((5-环丙基-3-(2-(二氟甲氧基)苯基)异噻唑-4-基)甲氧基)苯基)吖丁啶-1-基)-5-氟苯甲酸(44)Example 44 3-(3-(2-Chloro-4-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isothiazol-4-yl)methoxy)benzene Azetidin-1-yl)-5-fluorobenzoic acid (44)
Figure PCTCN2016111652-appb-000088
Figure PCTCN2016111652-appb-000088
化合物44-a制备参照实施例40第一步到第二步。Compound 44-a was prepared in the first to second steps of Reference Example 40.
LC-MS:tR＝3.60min，[M+H]+＝599.0； LC-MS: t R = 3.60min , [M + H] + = 599.0;
1H NMR(400MHz,CDCl3)δ7.42(dd,J＝14.5,7.6Hz,2H),7.28–7.09(m,4H),7.05(s,1H),6.76(s,1H),6.66(s,1H),6.51(d,J＝8.5Hz,1H),6.31(t,J＝73.6Hz,1H),4.40(m,2H),4.27(m,1H),3.92(m,2H),3.83(s,3H),2.11–1.98(m,1H),1.20–1.12(m,2H),1.07–0.99(m,2H)； 1 H NMR (400MHz, CDCl 3 ) δ7.42 (dd, J = 14.5,7.6Hz, 2H), 7.28-7.09 (m, 4H), 7.05 (s, 1H), 6.76 (s, 1H), 6.66 ( s, 1H), 6.51 (d, J = 8.5 Hz, 1H), 6.31 (t, J = 73.6 Hz, 1H), 4.40 (m, 2H), 4.27 (m, 1H), 3.92 (m, 2H), 3.83 (s, 3H), 2.11–1.98 (m, 1H), 1.20–1.12 (m, 2H), 1.07–0.99 (m, 2H);
19F NMR(376MHz,CDCl3)δ-81.15,-110.83。 19 F NMR (376 MHz, CDCl 3 ) δ-81.15, -110.83.
化合物44-a(56mg,0.09mmol)溶于四氢呋喃(2mL)，再加入1N NaOH(1mL)水溶液，50℃搅拌2h。反应完全后加入稀盐酸中和，乙酸乙酯萃取。浓缩后粗产品经PTLC分离，得化合物44(14mg,产率：26％)。Compound 44-a (56 mg, 0.09 mmol) was dissolved in THF (2 mL). After the reaction was completed, it was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The crude product was concentrated by PTLC to give compound 44 (14 mg, yield: 26%).
LC-MS:tR＝3.29min,[M+H]+＝585.0； LC-MS: t R = 3.29min , [M + H] + = 585.0;
1H NMR(400MHz,CDCl3)δ7.49(td,J＝9.4,1.7Hz,2H),7.35–7.23(m,3H),7.14(d,J＝8.4Hz,1H),6.98(s,1H),6.84(d,J＝2.5Hz,1H),6.73(dd,J＝8.6,2.6Hz,1H),6.43(t,J＝74Hz,1H),6.40(dd,J＝10.4,2.2Hz,1H),4.87(s,2H),4.37(t,J＝7.6Hz,2H),4.32–4.18(m,1H),3.89(t,J＝6.7Hz,2H),1.27–1.21(m,2H),1.12(dt,J＝7.6,4.4Hz,2H)； 1 H NMR (400 MHz, CDCl 3 ) δ 7.49 (td, J = 9.4, 1.7 Hz, 2H), 7.35 - 7.23 (m, 3H), 7.14 (d, J = 8.4 Hz, 1H), 6.98 (s, 1H), 6.84 (d, J = 2.5 Hz, 1H), 6.73 (dd, J = 8.6, 2.6 Hz, 1H), 6.43 (t, J = 74 Hz, 1H), 6.40 (dd, J = 10.4, 2.2 Hz) , 1H), 4.87 (s, 2H), 4.37 (t, J = 7.6 Hz, 2H), 4.32 - 4.18 (m, 1H), 3.89 (t, J = 6.7 Hz, 2H), 1.27 - 1.21 (m, 2H), 1.12 (dt, J = 7.6, 4.4 Hz, 2H);
19F NMR(376MHz,CDCl3)δ-81.15,-111.72。 19 F NMR (376 MHz, CDCl 3 ) δ - 81.15, -111.7.
实施例45 5-(3-(2-氯-4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噻唑-4-基)甲氧基)苯基)吖丁啶-1-基)苯并[d]异噻唑-3-羧酸(45) Example 45 5-(3-(2-Chloro-4-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isothiazol-4-yl)methoxy)benzene Azetidin-1-yl)benzo[d]isothiazole-3-carboxylic acid (45)
Figure PCTCN2016111652-appb-000089
Figure PCTCN2016111652-appb-000089
第一步：将化合物45-a(50mg,0.088mmol)溶于二氯甲烷(2mL)中，冰浴下加入三氟乙酸(1mL)，反应在冰浴下搅拌1小时，LCMS显示反应完全，反应液浓缩，得到化合物45-b(40mg)直接用于后续反应。The first step: Compound 45-a (50 mg, 0.088 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) The reaction mixture was concentrated to give Compound 45-b (40 mg).
第二步：将化合物45-c(5.0g,26.4mmol)溶于无水二氯甲烷(30mL)中，室温下加入草酰氯(11.0g,79.34mmol)。反应在室温下搅拌16小时。反应液旋干，得到化合物45-d。将该固体溶于二硫化碳(10mL)中，室温下缓慢分批加入无水三氯化铝(10.0g,79.34mmol)。随着三氯化铝加入，反应液呈深红色，反应在室温下搅拌16小时。之后，将反应液淬灭至冰水(约50g)中，有机相用饱和碳酸氢钠(3X 20mL)洗涤，干燥，过滤，浓缩。得到粗品化合物45-e(3.0g)。产物直接用于下一步，无需进一步纯化。The second step: Compound 45-c (5.0 g, 26.4 mmol) was dissolved in anhydrous dichloromethane (30 mL) and EtOAc (11.0 g, 79. The reaction was stirred at room temperature for 16 hours. The reaction solution was dried to give Compound 45-d. The solid was dissolved in carbon disulfide (10 mL) and anhydrous aluminum trichloride (10.0 g, 79.34 mmol) was slowly portionwise added at room temperature. The reaction mixture was dark red with the addition of aluminum trichloride, and the reaction was stirred at room temperature for 16 hours. After the reaction was quenched into EtOAc (EtOAc)EtOAc. The crude compound 45-e (3.0 g) was obtained. The product was used directly in the next step without further purification.
第三步：将45-e(3.0g)溶于甲醇(20mL)中，加入氨水(25～28％,10mL)。反应液变淡黄色，反应在室温下搅拌16小时，之后，加入H2O2(30％,3mL)，反应液立即变白色悬浊液，反应在室温下继续搅拌2小时。过滤，滤饼用水洗得到粗品白色固体45-f(2.0g)。产物直接用于下一步，无需进一步纯化。The third step: 45-e (3.0 g) was dissolved in methanol (20 mL), and aqueous ammonia (25-28%, 10 mL) was added. The reaction mixture became pale yellow, and the mixture was stirred at room temperature for 16 hr. then H 2 O 2 (30%, 3 mL) was added, and the reaction mixture was immediately whited, and the mixture was stirred at room temperature for 2 hours. Filtration and washing of the filter cake with water to give a crude white solid, 45-f (2.0 g). The product was used directly in the next step without further purification.
第四步：将粗品45-f(2.0g,7.78mmol)溶于甲醇(20mL)和H2O(20mL)中，加入氢氧化钠(1.5g,39.0mmol)。反应加热至回流，保持3小时。LCMS显示反应完全，用6N盐酸将反应液调节pH＝5～6。过滤，滤饼用水洗后，溶于甲醇(20mL)中，滴加浓硫酸(0.5mL)。反应加热至回流，保持3小时。LCMS显示反应完全，用饱和碳酸钠溶液将反应液调节pH＝6～7。将反应液浓缩。剩余物通过快速硅胶柱纯化得到产品45-g(150mg,10％)。 Step 4: The crude 45-f (2.0g, 7.78mmol) was dissolved in methanol (20mL) and H 2 O (20mL), was added sodium hydroxide (1.5g, 39.0mmol). The reaction was heated to reflux for 3 hours. LCMS showed the reaction was completed, and the mixture was adjusted to pH = 5-6 with 6N hydrochloric acid. After filtration, the filter cake was washed with water, dissolved in methanol (20 mL), and concentrated sulfuric acid (0.5 mL). The reaction was heated to reflux for 3 hours. LCMS showed the reaction was complete and the reaction was adjusted to pH = 6-7 with saturated sodium carbonate. The reaction solution was concentrated. The residue was purified on a flash silica gel column to afford product 45- g (150 mg, 10%).
第五步：将化合物45-b(40mg,0.088mmol)、45-g(48mg,0.18mmol)、Pd2(dba)3(10mg)、X-phos(20mg)和碳酸铯(150mg,0.44mmol)溶于二氧六环(10mL)中，反应在氮气保护下加热至110℃并保持5小时，LCMS显示反应完全并有部分水解产物，将反应液直接旋干，加入甲醇(10mL)、H2O(10mL)和氢氧化钠(40mg,1.0mmol)。反应在室温下搅拌3小时，LCMS显示反应完全，用6N盐酸将反应液调节pH＝5～6。反应液过滤，滤液用二氯甲烷(3X 5mL)萃取，合并有机相，干燥，过滤，浓缩。剩余物用厚制备分离得到化合物45(20.2mg,35％)。Step 5: Compound 45-b (40 mg, 0.088 mmol), 45-g (48 mg, 0.18 mmol), Pd 2 (dba) 3 (10 mg), X-phos (20 mg) and cesium carbonate (150 mg, 0.44 mmol) Dissolved in dioxane (10 mL), the reaction was heated to 110 ° C under nitrogen atmosphere for 5 hours, LCMS showed the reaction was complete and partially hydrolyzed, the reaction solution was directly dried, and methanol (10 mL), H was added. 2 O (10 mL) and sodium hydroxide (40 mg, 1.0 mmol). The reaction was stirred at room temperature for 3 hours. LCMS showed the reaction was completed, and the mixture was adjusted to pH = 5-6 with 6N hydrochloric acid. The reaction mixture was filtered and the~~~~~~~~~~~~~ The residue was isolated by thick preparative to afford compound 45 (20.2 mg, 35%).
1H NMR(400MHz,DMSO)δ8.00(s,1H),7.84(s,1H),7.72–7.62(m,1H),7.59(d,J＝7.5Hz,1H),7.56–7.50(m,2H),7.50–7.43(m,1H),6.99(s,2H),6.84(d,J＝8.2Hz,1H),4.94(s,2H),4.35(s,2H),4.18(s,1H),3.86(s,2H),2.06–1.95(m,1H),1.19–1.05(m,4H)； 1 H NMR (400 MHz, DMSO) δ 8.00 (s, 1H), 7.84 (s, 1H), 7.72 - 7.62 (m, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.56 - 7.50 (m) , 2H), 7.50–7.43 (m, 1H), 6.99 (s, 2H), 6.84 (d, J = 8.2 Hz, 1H), 4.94 (s, 2H), 4.35 (s, 2H), 4.18 (s, 1H), 3.86 (s, 2H), 2.06–1.95 (m, 1H), 1.19–1.05 (m, 4H);
LC-MS:m/z 642.1。LC-MS: m/z 642.1.
实施例46 5-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噻唑-4-基)甲氧基)苯基)吖丁啶-1-基)苯并[d]异噻唑-3-羧酸(46)Example 46 5-(3-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)phenyl)indole Butyr-1-yl)benzo[d]isothiazole-3-carboxylic acid (46)
Figure PCTCN2016111652-appb-000090
Figure PCTCN2016111652-appb-000090
将化合物30-a(40mg,0.09mmol)、45-g(48mg,0.18mmol)、Pd2(dba)3(10mg)、X-phos(20mg)和碳酸铯(150mg,0.44mmol)溶于二氧六环(10mL)中，反应在氮气保护下加热至110℃并保持5小时，LCMS显示反应完全并有部分水解产物，将反应液直接旋干，加入甲醇(10mL)、H2O(10mL)和氢氧化钠(40mg,1.0mmol)。反应在室温下搅拌3小时，LCMS显示反应完全，用6N盐酸将反应液调节pH＝5～6。反应液过滤，滤液用二氯甲烷(3X 5mL)萃取，合并有机相，干燥，过滤，浓缩。剩余物用厚制备分离得到化合物46(30.0mg,52％)。Compound 30-a (40 mg, 0.09 mmol), 45-g (48 mg, 0.18 mmol), Pd 2 (dba) 3 (10 mg), X-phos (20 mg) and cesium carbonate (150 mg, 0.44 mmol) were dissolved in two In a hexacyclohexane (10 mL), the reaction was heated to 110 ° C under nitrogen atmosphere for 5 hours. LCMS showed that the reaction was complete and partially hydrolyzed. The reaction mixture was directly dried, and methanol (10 mL) and H 2 O (10 mL) were added. And sodium hydroxide (40 mg, 1.0 mmol). The reaction was stirred at room temperature for 3 hours. LCMS showed the reaction was completed, and the mixture was adjusted to pH = 5-6 with 6N hydrochloric acid. The reaction mixture was filtered and the~~~~~~~~~~~~~ The residue was isolated by thick workup to afford compound 46 (30.0mg, 52%).
1H NMR(400MHz,DMSO)δ7.99(s,1H),7.83(s,1H),7.61(d,J＝7.7Hz,2H),7.55–7.48(m,1H),7.43(d,J＝8.1Hz,1H),6.94(s,2H),6.79(d,J＝7.7Hz,1H),4.91(s,2H),4.34(s,2H),4.16(s,1H),3.84(s,2H),2.04–1.92(m,1H),1.15(dd,J＝21.1,5.4Hz,4H)； 1 H NMR (400 MHz, DMSO) δ 7.99 (s, 1H), 7.83 (s, 1H), 7.61 (d, J = 7.7 Hz, 2H), 7.55 - 7.48 (m, 1H), 7.43 (d, J) = 8.1 Hz, 1H), 6.94 (s, 2H), 6.79 (d, J = 7.7 Hz, 1H), 4.91 (s, 2H), 4.34 (s, 2H), 4.16 (s, 1H), 3.84 (s) , 2H), 2.04–1.92 (m, 1H), 1.15 (dd, J=21.1, 5.4 Hz, 4H);
LC-MS:m/z 625.9。LC-MS: m/z 625.9.
实施例47 3-(3-(2-氯-4-((5-环丙基-3-(2-(三氟甲基)苯基)异噻唑-4-基)甲氧基)苯基)吖丁啶-1-基)-5-氟苯甲酸(47) Example 47 3-(3-(2-Chloro-4-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isothiazol-4-yl)methoxy)phenyl) ) azetidin-1-yl)-5-fluorobenzoic acid (47)
Figure PCTCN2016111652-appb-000091
Figure PCTCN2016111652-appb-000091
第一步：氢氧化钠(273mg,6.825mmol)溶于水(5ml)中，冷至0℃，加入盐酸羟胺(459mg,6.605mmol)的水(5ml)溶液，搅拌10min。滴加化合物47-a(1.0g,5.743mmol)的乙醇(5ml)溶液，搅拌1h。加水(20ml)，乙酸乙酯提取，干燥，浓缩至干得化合物47-b(1.022g，收率94.1％)。The first step: sodium hydroxide (273 mg, 6.825 mmol) was dissolved in water (5 ml), cooled to 0 ° C, and a solution of hydroxylamine hydrochloride (459 mg, 6.650 mmol) in water (5 ml) was added and stirred for 10 min. A solution of compound 47-a (1.0 g, 5.743 mmol) in EtOAc (5 mL) Water (20 ml) was added, and ethyl acetate was evaporated.
第二步：将化合物47-b(1.022g,5.403mmol)溶于DMF(15ml)，分批加NCS(808mg,6.051mmol)，搅拌1h。加水，乙酸乙酯提取，干燥，浓缩至干得化合物47-c(1.907g)。The second step: Compound 47-b (1.022 g, 5.403 mmol) was dissolved in DMF (15 mL). Water was added, extracted with ethyl acetate, dried and concentrated to dryness to afford compound 47-c (1.907g).
第三步：碳酸钾(815mg,5.897mmol)和THF(10ml)冷至-10℃，加入3-环丙基-3-氧代丙酸乙酯(895mg,5.731mmol)/THF(5ml)，搅拌30min。滴加47-c(1.907g)/THF(5ml)溶液，室温搅拌1h。加入三乙胺(5ml)，搅拌过夜。加水，乙酸乙酯提取，盐水洗，干燥，浓缩至干得化合物47-d(1.722g，二步收率98.0％)。The third step: potassium carbonate (815 mg, 5.897 mmol) and THF (10 ml) were cooled to -10 ° C, and ethyl 3-cyclopropyl-3-oxopropanoate (895 mg, 5.731 mmol) / THF (5 ml). Stir for 30 min. A 47-c (1.907 g) / THF (5 ml) solution was added dropwise and stirred at room temperature for 1 h. Triethylamine (5 ml) was added and stirred overnight. Water was added, ethyl acetate was extracted, brine was evaporated, dried and concentrated to dryness to afford compound 47-d (1.722 g, yield: 98.0%).
第四步：四氢铝锂(600mg)加入到干燥的THF(10ml)中，氮气保护下冷至-10℃，滴加47-d(1.722g)/THF(10ml)溶液，滴毕搅拌30min。加入乙酸乙酯(3ml)和水(0.6ml)，滴加15％氢氧化钠(1.8ml)溶液。搅拌10min，过滤，乙酸乙酯洗。滤液用盐水洗，干燥，浓缩得化合物47-e(1.218g，收率81.2％)。The fourth step: lithium tetrahydrogen aluminum (600 mg) was added to dry THF (10 ml), cooled to -10 ° C under nitrogen atmosphere, and a solution of 47-d (1.722 g) / THF (10 ml) was added dropwise, and the mixture was stirred for 30 min. . Ethyl acetate (3 ml) and water (0.6 ml) were added, and a 15% sodium hydroxide (1.8 ml) solution was added dropwise. Stir for 10 min, filter and wash with ethyl acetate. The filtrate was washed with brine, dried and evaporated and evaporated
第五步：将47-e(1.218g，4.300mmol)溶于二氯甲烷(10ml)，滴加氯化亚砜(2ml)，滴毕搅拌1h，浓缩至干，柱层析纯化得化合物47-f(600mg，收率46.3％)。The fifth step: 47-e (1.218 g, 4.300 mmol) was dissolved in dichloromethane (10 ml), thionyl chloride (2 ml) was added dropwise, and the mixture was stirred for 1 h, concentrated to dryness and purified by column chromatography to yield compound 47 -f (600 mg, yield 46.3%).
第六步：将47-f(200mg，0.6629mmol)、47-g(170mg,0.5991mmol)、碳酸 钾(166mg,1.201mmol)和DMF(5ml)氮气保护下50℃搅拌1h，加水，乙酸乙酯提取，干燥，柱层析纯化得化合物47-h(600mg)。Step 6: 47-f (200 mg, 0.6629 mmol), 47-g (170 mg, 0.5991 mmol), carbonic acid Potassium (166 mg, 1.201 mmol) and DMF (5 ml) were stirred at 50 ° C for 1 h under nitrogen.
第七步：将上一步得到的47-h，4M HCl/甲醇(8ml)于室温下搅拌1h，浓缩至干得到化合物47-i(260mg，二步收率89.4％)。The seventh step: 47-h, 4M HCl/methanol (8 ml) obtained in the previous step was stirred at room temperature for 1 h and concentrated to dryness to afford compound 47-i (260 mg, yield:
第八步：将47-i(180mg,0.3709mmol)、47-j(130mg,0.5578mmol)、Pd2(dba)3(35mg,0.0382mmol)、X-Phos(36mg,0.0756mmol)、碳酸铯(485mg,1.4886mmol)和甲苯(20ml)混合，100℃于氮气保护下搅拌6h，冷却至室温，过滤，甲苯洗，滤液柱层析纯化得化合物47-k。Step 8: 47-i (180 mg, 0.3709 mmol), 47-j (130 mg, 0.5578 mmol), Pd 2 (dba) 3 (35 mg, 0.0382 mmol), X-Phos (36 mg, 0.0756 mmol), cesium carbonate (485 mg, 1.4886 mmol) and toluene (20 ml) were mixed, stirred at 100 ° C for 6 h under nitrogen atmosphere, cooled to room temperature, filtered, washed with toluene, and purified by column chromatography to give compound 47-k.
第九步：将上步得到的47-k、5N氢氧化钠(2ml)溶液、THF(3ml)和甲醇(3ml)混合，于60℃搅拌3h，冷却，加水和二氯甲烷，2N盐酸调节pH 5～6，分液，二氯甲烷提取，干燥，纯化得到化合物47(137mg，二步收率62.9％)。The ninth step: mixing the 47-k, 5N sodium hydroxide (2ml) solution obtained in the previous step, THF (3ml) and methanol (3ml), stirring at 60 ° C for 3h, cooling, adding water and dichloromethane, 2N hydrochloric acid adjustment The pH was 5-6, partitioned, extracted with dichloromethane, dried and purified to give compound 47 (137 mg, yield: 62.9%).
1H NMR(400MHz,CDCl3)δ7.77(d,J＝7.4Hz,1H),7.57(p,J＝7.1Hz,2H),7.43(d,J＝6.6Hz,1H),7.30–7.16(m,1H),7.10(d,J＝8.0Hz,1H),6.95(s,1H),6.82(s,1H),6.71(d,J＝7.2Hz,1H),6.32(d,J＝9.5Hz,1H),4.72(s,2H),4.29(d,J＝6.2Hz,2H),4.21(d,J＝6.6Hz,1H),3.82(s,2H),2.11(ddd,J＝13.3,8.4,5.1Hz,1H),1.25(d,J＝2.0Hz,2H),1.13(dt,J＝7.1,4.4Hz,2H)； 1 H NMR (400MHz, CDCl 3 ) δ7.77 (d, J = 7.4Hz, 1H), 7.57 (p, J = 7.1Hz, 2H), 7.43 (d, J = 6.6Hz, 1H), 7.30-7.16 (m, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.95 (s, 1H), 6.82 (s, 1H), 6.71 (d, J = 7.2 Hz, 1H), 6.32 (d, J = 9.5 Hz, 1H), 4.72 (s, 2H), 4.29 (d, J = 6.2 Hz, 2H), 4.21 (d, J = 6.6 Hz, 1H), 3.82 (s, 2H), 2.11 (ddd, J = 13.3, 8.4, 5.1 Hz, 1H), 1.25 (d, J = 2.0 Hz, 2H), 1.13 (dt, J = 7.1, 4.4 Hz, 2H);
LC-MS:tR＝3.393min；587.0；588.1。 LC-MS: t R = 3.393min ; 587.0; 588.1.
实施例48 2-(3-(2-氯-4-((5-环丙基-3-(2-(三氟甲基)苯基)异噻唑-4-基)甲氧基)苯基)吖丁啶-1-基)-4-氟苯并[d]噻唑-6-羧酸(48)Example 48 2-(3-(2-Chloro-4-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isothiazol-4-yl)methoxy)phenyl) ) azetidin-1-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (48)
Figure PCTCN2016111652-appb-000092
Figure PCTCN2016111652-appb-000092
第一步：将47-i(80mg,0.165mmol)、I-9(53mg,0.183mmol)、碳酸铯(160mg,0.491mmol)和DMA(5ml)混合，于氮气保护下60℃搅拌6h，加水，二氯甲烷提取，干燥，纯化得化合物48-a(70mg，收率64.5％)。 The first step: mixing 47-i (80 mg, 0.165 mmol), I-9 (53 mg, 0.183 mmol), cesium carbonate (160 mg, 0.491 mmol) and DMA (5 ml), and stirring under nitrogen for 60 h at 6 ° C, adding water Dichloromethane extraction, drying and purification gave compound 48-a (70 mg, yield: 64.5%).
第二步：将48-a(70mg,0.1064mmol)、5N氢氧化钠(2ml)溶液、THF(3ml)和甲醇(3ml)混合，于60℃搅拌2h，加水和二氯甲烷，2N盐酸调节pH 5～6，分液，二氯甲烷提取，干燥，纯化得化合物48(46mg，收率67.1％)。The second step: mixing 48-a (70 mg, 0.1064 mmol), 5N sodium hydroxide (2 ml), THF (3 ml) and methanol (3 ml), stirring at 60 ° C for 2 h, adding water and dichloromethane, 2N hydrochloric acid The pH was 5-6, separated, extracted with dichloromethane, dried and purified to give Compound 48 (46 mg, yield: 67.1%).
1H NMR(400MHz,CDCl3)δ8.17(s,1H),7.80(s,2H),7.60(s,2H),7.45(s,1H),7.28(s,1H),6.81(d,J＝35.2Hz,2H),4.70(d,J＝27.1Hz,4H),4.35(d,J＝34.2Hz,3H),2.12(s,1H),1.02(d,J＝109.5Hz,4H)； 1 H NMR (400MHz, CDCl 3 ) δ8.17 (s, 1H), 7.80 (s, 2H), 7.60 (s, 2H), 7.45 (s, 1H), 7.28 (s, 1H), 6.81 (d, J = 35.2 Hz, 2H), 4.70 (d, J = 27.1 Hz, 4H), 4.35 (d, J = 34.2 Hz, 3H), 2.12 (s, 1H), 1.02 (d, J = 109.5 Hz, 4H) ;
LC-MS:tR＝3.278min；644.0；645.0。 LC-MS: t R = 3.278min ; 644.0; 645.0.
实施例49 6-(3-(2-氯-4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噻唑-4-基)甲氧基)苯基)吖丁啶-1-基)苯并[d]异噻唑-3-羧酸(49)Example 49 6-(3-(2-Chloro-4-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isothiazol-4-yl)methoxy)benzene Azetidin-1-yl)benzo[d]isothiazole-3-carboxylic acid (49)
Figure PCTCN2016111652-appb-000093
Figure PCTCN2016111652-appb-000093
第一步：将化合物49-a(5.0g,26.4mmol)溶于无水二氯甲烷(30mL)中，室温下加入草酰氯(11.0g,79.34mmol)。反应在室温下搅拌16小时。反应液旋干，得到化合物49-b。将该固体溶于二硫化碳(10mL)中，室温下缓慢分批加入无水三氯化铝(10.0g,79.34mmol)。随着三氯化铝加入，反应液呈深红色，反应在室温下搅拌16小时。之后，将反应液淬灭至冰水(约50g)中，有机相用饱和碳酸氢钠(3X20mL)洗涤，干燥，过滤，浓缩。得到粗品化合物49-c(3.0g)。产物直接用于下一步，无需进一步纯化。First step: Compound 49-a (5.0 g, 26.4 mmol) was dissolved in dry dichloromethane (30 mL). EtOAc (11.0 g, 79. The reaction was stirred at room temperature for 16 hours. The reaction solution was dried to give Compound 49-b. The solid was dissolved in carbon disulfide (10 mL) and anhydrous aluminum trichloride (10.0 g, 79.34 mmol) was slowly portionwise added at room temperature. The reaction mixture was dark red with the addition of aluminum trichloride, and the reaction was stirred at room temperature for 16 hours. After the reaction was quenched into EtOAc (EtOAc)EtOAc. The crude compound 49-c (3.0 g) was obtained. The product was used directly in the next step without further purification.
第二步：将化合物49-c(3.0g)溶于甲醇(20mL)中，加入氨水(25～28％,10mL)。反应液变淡黄色，反应在室温下搅拌16小时之后，加入H2O2(30％,3mL)，反应液立即变白色悬浊液，反应在室温下继续搅拌2小时。过滤，滤饼用水洗得到粗品49-d(2.0g)。产物直接用于下一步，无需进一步纯化。The second step: Compound 49-c (3.0 g) was dissolved in methanol (20 mL) and aqueous ammonia (25 to 28%, 10 mL) was added. The reaction mixture became light yellow. After the mixture was stirred at room temperature for 16 hrs, H 2 O 2 (30%, 3 mL) was added, and the reaction mixture was immediately whited, and the mixture was stirred at room temperature for 2 hours. Filtration and washing of the filter cake with water afforded crude product 49-d (2.0 g). The product was used directly in the next step without further purification.
第三步：将粗品49-d(2.0g,7.78mmol)溶于甲醇(20mL)和H2O(20mL)中，加入氢氧化钠(1.5g,39.0mmol)。反应加热至回流，保持3小时。LCMS显示反应完全，用6N盐酸将反应液调节pH＝5～6。过滤，滤饼用水洗后，溶于甲 醇(20mL)中，滴加浓硫酸(0.5mL)。反应加热至回流，保持3小时。LCMS显示反应完全，用饱和碳酸钠溶液将反应液调节pH＝6～7。将反应液浓缩。剩余物通过快速硅胶柱纯化得到产品49-e(150mg,10％)。Third step: The crude 49-d (2.0g, 7.78mmol) was dissolved in methanol (20mL) and H 2 O (20mL), was added sodium hydroxide (1.5g, 39.0mmol). The reaction was heated to reflux for 3 hours. LCMS showed the reaction was completed, and the mixture was adjusted to pH = 5-6 with 6N hydrochloric acid. After filtration, the filter cake was washed with water, dissolved in methanol (20 mL), and concentrated sulfuric acid (0.5 mL). The reaction was heated to reflux for 3 hours. LCMS showed the reaction was complete and the reaction was adjusted to pH = 6-7 with saturated sodium carbonate. The reaction solution was concentrated. The residue was purified by flash column eluting to afford product 49-e (150 mg, 10%).
第四步：将45-b(40mg,0.088mmol)、49-e(48mg,0.18mmol)、Pd2(dba)3(10mg)、X-phos(20mg)和碳酸铯(150mg,0.44mmol)溶于二氧六环(10mL)中，反应在氮气保护下加热至110℃并保持5小时，LCMS显示反应完全并有部分水解产物，将反应液直接旋干，加入甲醇(10mL)、H2O(10mL)和氢氧化钠(40mg,1.0mmol)。反应在室温下搅拌3小时，LCMS显示反应完全，用6N盐酸将反应液调节pH＝5～6。反应液过滤，滤液用二氯甲烷(3X 5mL)萃取，合并有机相，干燥，过滤，浓缩。剩余物用厚制备分离得到49(18.0mg,25％)。Step 4: 45-b (40 mg, 0.088 mmol), 49-e (48 mg, 0.18 mmol), Pd 2 (dba) 3 (10 mg), X-phos (20 mg) and cesium carbonate (150 mg, 0.44 mmol) Dissolved in dioxane (10 mL), the reaction was heated to 110 ° C under nitrogen atmosphere for 5 hours. LCMS showed that the reaction was complete and partially hydrolyzed, the reaction mixture was directly dried, and methanol (10 mL) and H 2 were added. O (10 mL) and sodium hydroxide (40 mg, 1.0 mmol). The reaction was stirred at room temperature for 3 hours. LCMS showed the reaction was completed, and the mixture was adjusted to pH = 5-6 with 6N hydrochloric acid. The reaction mixture was filtered and the~~~~~~~~~~~~~ The residue was isolated by thick preparative to afford 49 (18.0 mg, 25%).
1H NMR(400MHz,DMSO)δ8.61(s,2H),7.65(s,1H),7.59(d,J＝7.2Hz,1H),7.50(t,J＝18.8Hz,2H),7.00(s,2H),6.86(s,1H),6.76(s,1H),4.95(s,2H),4.38(s,2H),4.20(s,1H),3.94(s,2H),2.00(d,J＝8.4Hz,1H),1.12(d,J＝17.8Hz,4H)； 1 H NMR (400MHz, DMSO) δ8.61 (s, 2H), 7.65 (s, 1H), 7.59 (d, J = 7.2Hz, 1H), 7.50 (t, J = 18.8Hz, 2H), 7.00 ( s, 2H), 6.86 (s, 1H), 6.76 (s, 1H), 4.95 (s, 2H), 4.38 (s, 2H), 4.20 (s, 1H), 3.94 (s, 2H), 2.00 (d) , J = 8.4 Hz, 1H), 1.12 (d, J = 17.8 Hz, 4H);
LC-MS:m/z 642.0。LC-MS: m/z 642.0.
实施例50 6-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噻唑-4-基)甲氧基)苯基)吖丁啶-1-基)苯并[d]异噻唑-3-羧酸(50)Example 50 6-(3-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)phenyl)indole Butyr-1-yl)benzo[d]isothiazole-3-carboxylic acid (50)
Figure PCTCN2016111652-appb-000094
Figure PCTCN2016111652-appb-000094
将30-a(40mg,0.088mmol)、49-e(48mg,0.18mmol)、Pd2(dba)3(10mg)，X-phos(20mg)和碳酸铯(150mg,0.44mmol)溶于二氧六环(10mL)中，反应在氮气保护下加热至110℃并保持5小时，LCMS显示反应完全并有部分水解产物，将反应液直接旋干，加入甲醇(10mL)、H2O(10mL)和氢氧化钠(40mg,1.0mmol)。反应在室温下搅拌3小时，LCMS显示反应完全，用6N盐酸将反应液调节pH＝5～6。反应液过滤，滤液用二氯甲烷(3X 5mL)萃取，合并有机相，干燥，过滤，浓缩。剩余物用厚制备分离得到化合物50(8.0mg,12％)。30-a (40 mg, 0.088 mmol), 49-e (48 mg, 0.18 mmol), Pd 2 (dba) 3 (10 mg), X-phos (20 mg) and cesium carbonate (150 mg, 0.44 mmol) were dissolved in dioxane In a six-ring (10 mL), the reaction was heated to 110 ° C under nitrogen atmosphere for 5 hours. LCMS showed that the reaction was complete and partially hydrolyzed. The reaction mixture was directly dried, and methanol (10 mL) and H 2 O (10 mL) were added. And sodium hydroxide (40 mg, 1.0 mmol). The reaction was stirred at room temperature for 3 hours. LCMS showed the reaction was completed, and the mixture was adjusted to pH = 5-6 with 6N hydrochloric acid. The reaction mixture was filtered and the~~~~~~~~~~~~~ The residue was isolated by thick preparative to afford compound 50 (8.0 mg, 12%).
1H NMR(400MHz,DMSO)δ8.54(s,1H),7.61(d,J＝7.8Hz,2H),7.55(s,1H),7.43(s,1H),7.02(s,1H),6.95(s,1H),6.81(s,2H),4.91(s,2H),4.38(s,2H),4.18(s,1H),3.92(s,2H),2.00(d,J＝6.8Hz,1H),1.15(d,J＝23.6Hz,4H)； 1 H NMR (400MHz, DMSO) δ8.54 (s, 1H), 7.61 (d, J = 7.8Hz, 2H), 7.55 (s, 1H), 7.43 (s, 1H), 7.02 (s, 1H), 6.95 (s, 1H), 6.81 (s, 2H), 4.91 (s, 2H), 4.38 (s, 2H), 4.18 (s, 1H), 3.92 (s, 2H), 2.00 (d, J = 6.8 Hz) , 1H), 1.15 (d, J = 23.6 Hz, 4H);
LC-MS:m/z 625.9。LC-MS: m/z 625.9.
实施例51 6-(1-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噻唑-4-基)甲氧基)苯基)吖丁啶-3-基)-1-甲基-1H-吲哚-3-羧酸(51) Example 51 6-(1-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)phenyl)indole Butyr-3-yl)-1-methyl-1H-indole-3-carboxylic acid (51)
Figure PCTCN2016111652-appb-000095
Figure PCTCN2016111652-appb-000095
第一步：化合物I-12(1.1g,4.1mmol)、NaI(1.85g,12.3mmol)、CuI(78mg,0.4mmol)和DMEDA(72mg,0.8mmol)混合于1,4-二氧六环(10mL)中。混合物氮气氛围下于150℃微波反应6小时。反应液冷却后乙酸乙酯稀释。稀释液过滤，滤液浓缩后柱层析纯化得到化合物51-a(1.15g)。First step: compound I-12 (1.1 g, 4.1 mmol), NaI (1.85 g, 12.3 mmol), CuI (78 mg, 0.4 mmol) and DMEDA (72 mg, 0.8 mmol) in 1,4-dioxane (10mL). The mixture was subjected to microwave reaction at 150 ° C for 6 hours under a nitrogen atmosphere. The reaction solution was cooled and diluted with ethyl acetate. The diluted solution was filtered, and the filtrate was concentrated and purified by column chromatography to yield compound 51-a (1.15 g).
LC-MS:tR＝2.955min。 LC-MS: t R = 2.955min .
第二步：化合物51-a(1.0g,3.17mmol)溶于干燥THF(20mL)，并在氮气氛围下搅拌，于0℃下滴加i-PrMgCl.LiCl(1.3M,3.1mL)。加完后在此温度下继续搅拌1h。0℃滴加溶有化合物叔丁基-3-羰基吖丁啶-1-羧酸酯(815mg，4.76mmol)的干燥THF(3mL)溶液。加完后反应液0℃搅拌30分钟，升至常温搅拌过夜。用饱和NH4Cl(20mL)淬灭，之后乙酸乙酯萃取。有机层干燥浓缩后拌样过柱得到产物化合物51-b(570mg,产率：50％)。The second step: Compound 51-a (1.0 g, 3.17 mmol) was dissolved in dry THF (20 mL), and stirred under nitrogen atmosphere, i-PrMgCl. LiCl (1.3 M, 3.1 mL) was added dropwise at 0 °C. After the addition was completed, stirring was continued at this temperature for 1 h. A solution of the compound tert-butyl-3-carbonylazetidine-1-carboxylate (815 mg, 4.76 mmol) in dry THF (3 mL) was evaporated. After the addition was completed, the reaction solution was stirred at 0 ° C for 30 minutes, and the mixture was stirred at room temperature overnight. 4 Cl (20mL) and quenched with saturated NH, then extracted with ethyl acetate. The organic layer was dried and concentrated, and then the mixture was subjected to a mixture to obtain a product compound 51-b (570 mg, yield: 50%).
LC-MS:tR＝2.575min,[M-Boc]+＝261.1；LC-MS: t R = 2.575 min, [M-Boc] + = 261.1;
1H NMR(400MHz,CDCl3)δ8.17(d,J＝8.4Hz,1H),7.79(s,1H),7.48(d,J＝1.1Hz,1H),7.39(dd,J＝8.4,1.6Hz,1H),4.36(d,J＝9.8Hz,2H),4.24(d,J＝9.3Hz,2H),3.91(s,3H),3.85(s,3H),1.48(s,9H)。 1 H NMR (400MHz, CDCl3) δ8.17 (d, J = 8.4Hz, 1H), 7.79 (s, 1H), 7.48 (d, J = 1.1Hz, 1H), 7.39 (dd, J = 8.4,1.6 Hz, 1H), 4.36 (d, J = 9.8 Hz, 2H), 4.24 (d, J = 9.3 Hz, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 1.48 (s, 9H).
第三步:0℃下，三氟化硼***(4.4mL)滴加至10mL含有化合物51-b(500mg,1.39mmol)和三乙基硅氢(2.2mL)的二氯甲烷溶液中，加完后溶液常温搅拌过夜。溶液用水萃取一次，有机相经氨水碱化后浓缩，浓缩物反相纯化得到粗产物，粗产物再经正相柱层析纯化得到化合物51-c(260mg)。The third step: at 0 ° C, boron trifluoride etherate (4.4 mL) was added dropwise to 10 mL of a solution containing compound 51-b (500 mg, 1.39 mmol) and triethylsilylhydrogen (2.2 mL) in dichloromethane After the completion of the solution, the solution was stirred at room temperature overnight. The solution is extracted once with water, and the organic phase is basified with aqueous ammonia and then concentrated. The crude product is purified by reverse phase purification to afford crude product, which is purified by normal phase column chromatography to afford compound 51-c (260 mg).
LC-MS:tR＝1.704min,[M+H]+＝245.1LC-MS: t R = 1.704 min, [M+H] + =245.1
1H NMR(400MHz,MeOD)1.1Hz,1H),7.39(dd,J＝8.4,1.6Hz,1H),4.36(d,J＝9.8Hz,2H),4.,6H)J＝8.4,1.6Hz,1H),4.36(d,J＝9.8Hz,2H),4.24)。 1 H NMR (400MHz, MeOD) 1.1Hz, 1H), 7.39 (dd, J = 8.4,1.6Hz, 1H), 4.36 (d, J = 9.8Hz, 2H), 4., 6H) J = 8.4,1.6 Hz, 1H), 4.36 (d, J = 9.8 Hz, 2H), 4.24).
第四步:化合物51-c(24mg，0.10mmol)置于10mL微波管中，加入干燥1,4-二氧六环(2mL)，之后依次加入化合物24-f(62mg,0.13mmol)、碳酸铯(66 mg,0.20mmol)、X-phos(14mg,0.03mmol)和Pd2(dba)3(14mg,0.015mmol)。氮气氛下换气1分钟，然后100℃微波2小时。待反应冷却后硅藻土过滤，并用EA洗涤3次。滤液经萃取后取有机层用硫酸钠干燥，浓缩后TLC纯化得到化合物51-d(20mg，产率：31％)。The fourth step: Compound 51-c (24 mg, 0.10 mmol) was placed in a 10 mL microwave tube, and dry 1,4-dioxane (2 mL) was added, followed by the addition of compound 24-f (62 mg, 0.13 mmol), carbonic acid.铯 (66 mg, 0.20 mmol), X-phos (14 mg, 0.03 mmol) and Pd 2 (dba) 3 (14 mg, 0.015 mmol). The air was ventilated for 1 minute under a nitrogen atmosphere, and then microwaved at 100 ° C for 2 hours. After cooling the reaction, the celite was filtered and washed three times with EA. The filtrate was extracted and dried (MgSO4)
LC-MS:tR＝3.599min,[M+H]+＝636.1。 LC-MS: t R = 3.599min , [M + H] + = 636.1.
第五步：化合物51-d(20mg,0.03mmol)溶于二氧六环(2mL)中。往溶液中加入NaOH水溶液(5.0M,1mL)和甲醇(1mL)。反应液于回流搅拌72小时。冷却后用3N的盐酸酸化至Ph＝5，乙酸乙酯萃取3次，有机层干燥过滤浓缩，经TLC纯化后化合物51(7.0mg)。The fifth step: Compound 51-d (20 mg, 0.03 mmol) was dissolved in dioxane (2 mL). Aqueous NaOH (5.0 M, 1 mL) and methanol (1 mL) were added to the solution. The reaction solution was stirred at reflux for 72 hours. After cooling, it was acidified with EtOAc (3 mL).
LC-MS:tR＝3.296min,[M+H]+＝622.0； LC-MS: t R = 3.296min , [M + H] + = 622.0;
1H NMR(400MHz,MeOD)M+H]+＝622.0,7.39(dd,J＝8.4,1.6Hz,1H),4.36(d,J＝9.8Hz,2H),4.,6H),J＝9.3Hz,2H),3.91(s,3H),3.85(s,3H),1.48(s,9H)4(s,2H),2.126(d,J＝4.6Hz,2H),1.14(d,J1.22 2),2.34–2.25(m,1H),1.22–1.14(m,4H)。 1 H NMR (400 MHz, MeOD) M + H] + = 622.0, 7.39 (dd, J = 8.4, 1.6 Hz, 1H), 4.36 (d, J = 9.8 Hz, 2H), 4., 6H), J = 9.3 Hz, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 1.48 (s, 9H) 4 (s, 2H), 2.126 (d, J = 4.6 Hz, 2H), 1.14 (d, J1) .22 2), 2.34–2.25 (m, 1H), 1.22–1.14 (m, 4H).
生物学评价Biological evaluation
实验例1：FXR受体结合活性测试(时间分辨荧光检测方法TR-FRET法)Experimental Example 1: FXR receptor binding activity test (time-resolved fluorescence detection method TR-FRET method)
为了测试化合物对FXR受体结合的影响，发明人选用商业化的FXR受体结合活性测试试剂盒来测试化合物对FXR与其结合蛋白片段的影响(LBD结构域与SRC1片段结合)(试剂盒供应商lifetechnologyInvitrogenCatalog：PV4835；cisbioCatalog：610SAXLA和61GSTKLA)。具体方法见试剂盒说明书。操作如下：To test the effect of compounds on FXR receptor binding, the inventors used a commercial FXR receptor binding activity assay kit to test the effect of compounds on FXR and its binding protein fragments (LBD domain binds to SRC1 fragment) (kit supplier) Lifetechnology Invitrogen Catalog: PV4835; cisbioCatalog: 610 SAXLA and 61 GSTKLA). See the kit instructions for specific methods. The operation is as follows:
1、准备2xGST标签的FXR-LBD/抗GST的Eu混合液至所需体积，GST-FXR-LBD的浓度为6nM，Eu为50nl/孔；1. Prepare 2xGST-labeled FXR-LBD/GST-containing Eu mixture to the required volume, GST-FXR-LBD concentration is 6nM, and Eu is 50nl/well;
2、准备2x生物素标记的SRC1/链霉素-别藻蓝素(SA-APC)混合液至所需体积，SRC1浓度为1000nM，链霉素-别藻蓝素为50nl/孔；2. Prepare 2x biotinylated SRC1/streptomycin-allophycocyanin (SA-APC) mixture to the required volume, SRC1 concentration is 1000nM, streptomycin-allophycocyanin is 50nl/well;
3、将2xGST-FXR/Eu和SRC1/SA-APC两种混合液1：1混合；3. Mix 1:1 mixture of 2xGST-FXR/Eu and SRC1/SA-APC;
4、将20μlGST-FXR/Eu和SRC1/SA-APC混合液加到含有待测化合物的384孔板；4. Add 20 μl of GST-FXR/Eu and SRC1/SA-APC mixture to a 384-well plate containing the test compound;
5、1000rpm离心1min；室温孵育180min；5. Centrifuge at 1000 rpm for 1 min; incubate for 180 min at room temperature;
6、时间分辨荧光检测：EnVision读板器读板。6. Time-resolved fluorescence detection: EnVision plate reader reads the plate.
7、结果分析：7. Analysis of the results:
(1)665nm处数值除以615nm处数值；(1) The value at 665 nm is divided by the value at 615 nm;
(2)计算激动率(2) Calculate the activation rate
激动率＝(X-Min)/(Max-Min)*100％Excitation rate = (X-Min) / (Max-Min) * 100%
■X代表每个浓度的665/615值；■ X represents the value of 665/615 for each concentration;
■Min代表未加化合物的665/615值；■Min represents the 665/615 value of the unadded compound;
■Max代表参照化合物的665/615值。 ■Max represents the 665/615 value of the reference compound.
本发明化合物的生化学活性通过以上的试验进行测定，测得EC50值见下表。The biochemical activity of the compounds of the present invention was determined by the above test, and the EC 50 values were measured as shown in the following table.
Figure PCTCN2016111652-appb-000096
Figure PCTCN2016111652-appb-000096
结论：本发明实施例化合物对FXR活性均有明显地激动作用。Conclusion: The compounds of the examples of the present invention have significant agonistic effects on FXR activity.
实验例2：(FXR报告基因表达测试)Experimental Example 2: (FXR Report Gene Expression Test)
为了分析测试化合物对FXR调控的基因表达的影响，发明人利用Promega 公司的双荧光素酶检测***(Promega#E1980)在瞬时转染了FXRGal4报告基因片段的HepG2肝癌细胞株(ATCC#HB-8065)中检测化合物对FXR报告基因的影响。具体实验方法如下：In order to analyze the effect of test compounds on FXR-regulated gene expression, the inventors used Promega The company's dual luciferase assay system (Promega #E1980) detects the effect of compounds on the FXR reporter gene in a HepG2 liver cancer cell line (ATCC#HB-8065) transiently transfected with the FXRGal4 reporter gene fragment. The specific experimental methods are as follows:
1、HepG2细胞培养和维护；1. HepG2 cell culture and maintenance;
2、消化细胞并以10mL完全培养基种植合适密度的细胞，然后37℃5％CO2潮湿条件下培养24h；2. Digest the cells and grow cells of appropriate density in 10 mL complete medium, and then culture at 37 ° C under 5% CO 2 for 24 h;
3、细胞种植和转染，转染试剂为FugeneHD(Promega#E231A)3. Cell planting and transfection, the transfection reagent is FugeneHD (Promega#E231A)
(1)根据下表准备转染混合物(1) Prepare the transfection mixture according to the table below
pBIND-FXR(ng/孔)pBIND-FXR(ng/hole) 2525
pG5Luc(ng/孔)pG5Luc (ng/hole) 2525
FuGENEHD(μl/孔)FuGENEHD (μl / hole) 0.150.15
无血清培养基(μl/孔)Serum-free medium (μl/well) 1.851.85
总混合物(μl/孔)Total mixture (μl/well) 2.52.5
(2)剧烈地混匀管内的混合物，室温孵育15min；(2) vigorously mix the mixture in the tube, incubate for 15 min at room temperature;
(3)消化培养皿内的细胞并计数；(3) digesting the cells in the culture dish and counting;
(4)稀释细胞混悬液至密度为60万/mL的所需体积(96孔板100μl/孔)；(4) Dilute the cell suspension to the required volume of 600,000 / mL (100 μl / well in 96-well plate);
(5)将所需体积的转染混合物加到细胞混悬液中，然后100μl/孔铺板；(5) adding the required volume of the transfection mixture to the cell suspension, and then plating at 100 μl/well;
(6)37℃、5％CO2潮湿条件下孵育24h。(6) Incubate for 24 h at 37 ° C, 5% CO 2 in humid conditions.
4、处理化合物4, treatment of compounds
(1)准备10mM的化合物母液，然后用DMSO3倍连续稀释；(1) Preparing a 10 mM compound mother liquor, and then serially diluting with DMSO 3 times;
(2)加10μL的化合物至90μL完全培养基(10x)；(2) add 10 μL of the compound to 90 μL of complete medium (10x);
(3)每孔加5μl的化合物溶液(21x)；(3) adding 5 μl of compound solution (21x) per well;
(4)37℃、5％CO2潮湿条件下孵育18h。(4) Incubate for 18 h at 37 ° C, 5% CO 2 in humid conditions.
5、双荧光素酶检测5, dual luciferase assay
由Promega公司的双荧光素酶检测***检测萤火虫荧光素酶和海肾荧光素酶信号(Promega#E1980)。Firefly luciferase and Renilla luciferase signals were detected by Promega's dual luciferase assay system (Promega #E1980).
6、结果分析6, the result analysis
检测得到的数值由萤火虫荧光素酶信号(F)除以海肾荧光素酶信号(R)，即F/R。这种数据处理排除了细胞数量和转染效率带来的差异。The value obtained was determined by dividing the firefly luciferase signal (F) by the Renilla luciferase signal (R), ie F/R. This data processing eliminates the difference in cell number and transfection efficiency.
7、计算激动率，根据GraphPrism5.0计算EC50：7. Calculate the activation rate and calculate the EC 50 according to GraphPrism 5.0 :
激动率＝(X-Min)/(Max-Min)*100％Excitation rate = (X-Min) / (Max-Min) * 100%
■X代表每个浓度的F/R值；■ X represents the F/R value for each concentration;
■Min代表未加化合物的F/R值；■Min represents the F/R value of the unadded compound;
■Max代表参照化合物的F/R值。■Max represents the F/R value of the reference compound.
本发明化合物的生化学活性通过以上的试验进行测定，测得的EC50值见下表。 The biochemical activity of the compounds of the present invention was determined by the above test, and the measured EC 50 values are shown in the following table.
Figure PCTCN2016111652-appb-000097
Figure PCTCN2016111652-appb-000097
结论：本发明实施例化合物对FXR活性均有明显地激动作用。 Conclusion: The compounds of the examples of the present invention have significant agonistic effects on FXR activity.

Claims (12)

  1. 式(I)化合物、其立体异构体或其药学上可接受盐：a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2016111652-appb-100001
    Figure PCTCN2016111652-appb-100001
    其中，among them,
    X选自S或O；X is selected from S or O;
    Y选自CR6或N；Y is selected from CR 6 or N;
    Z选自CR6、N或NO；Z is selected from CR 6 , N or NO;
    Ar选自C5-10芳基或5-10元杂芳基，任选进一步被一个或多个选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR7、-C0-8-O-R8、-C0-8-C(O)OR8、-C0-8-C(O)R8、-C0-8-O-C(O)R9、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R9或-N(R10)-C(O)OR8的取代基所取代，Ar is selected from C 5-10 aryl or 5-10 membered heteroaryl, optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, azide, C 1-8 alkyl, C 2 - 8 -alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylsulfide Base, -C 0-8 -S(O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -C(O)R 8 , -C 0-8 -OC(O)R 9 , -C 0-8 -NR 10 R 11 , -C 0-8 -C(O)NR 10 R 11 , -N(R 10 )-C(O Substituting a substituent of R 9 or -N(R 10 )-C(O)OR 8 ,
    再任选进一步被一个或多个选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR7、-C0-8-O-R8、-C0-8-C(O)OR8、-C0-8-C(O)R8、-C0-8-O-C(O)R9、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R9或-N(R10)-C(O)OR8的取代基所取代；Then optionally further substituted with one or more groups selected from halo, cyano, nitro, azido, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, a halogen substituted C 1 to -8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5 -10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 - S(O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -C(O)R 8 , -C 0-8 -OC (O)R 9 , -C 0-8 -NR 10 R 11 , -C 0-8 -C(O)NR 10 R 11 , -N(R 10 )-C(O)R 9 or -N(R Substituted by a substituent of 10 )-C(O)OR 8 ;
    R选自C3-8环烷基或3-8元杂环基，任选进一步被一个或多个选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR7、-C0-8-O-R8、-C0-8-C(O)OR8、-C0-8-C(O)R8、-C0-8-O-C(O)R9、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R9或-N(R10)-C(O)OR8的取代基所取代；R is selected from C 3-8 cycloalkyl or 3-8 membered heterocyclyl, optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, azide, C 1-8 alkyl, C 2 8 -alkenyl, C 2-8 alkynyl, halogen-substituted C 1-8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3 -8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy Base, 5-10 membered heteroarylthio group, -C 0-8 -S(O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -C(O)R 8 , -C 0-8 -OC(O)R 9 , -C 0-8 -NR 10 R 11 , -C 0-8 -C(O)NR 10 R 11 , Substituted with a substituent of -N(R 10 )-C(O)R 9 or -N(R 10 )-C(O)OR 8 ;
    R1、R2、R3、R4、R5、R6各自独立的选自氢、氘、卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR7、-C0-8-O-R8、 -C0-8-C(O)OR8、-C0-8-C(O)R8、-C0-8-O-C(O)R9、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R9或-N(R10)-C(O)OR8，R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen, hydrazine, halogen, cyano, nitro, azide, C 1-8 alkyl, C 2-8 chain. Alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5 10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -C(O)R 8 ,- C 0-8 -OC(O)R 9 , -C 0-8 -NR 10 R 11 , -C 0-8 -C(O)NR 10 R 11 , -N(R 10 )-C(O)R 9 or -N(R 10 )-C(O)OR 8 ,
    任选进一步被一个或多个选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR7、-C0-8-O-R8、-C0-8-C(O)OR8、-C0-8-C(O)R8、-C0-8-O-C(O)R9、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R9或-N(R10)-C(O)OR8的取代基所取代；Optionally further substituted with one or more groups selected from halo, cyano, nitro, azido, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, a halogen substituted C 1- 8- alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5 - 10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S (O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -C(O)R 8 , -C 0-8 -OC( O) R 9 , -C 0-8 -NR 10 R 11 , -C 0-8 -C(O)NR 10 R 11 , -N(R 10 )-C(O)R 9 or -N(R 10 Substituted by a substituent of -C(O)OR 8 ;
    R7选自氢、氘、C1-8烷基、C2-8链烯基、C3-8环烷基、卤取代C1-8烷基、苯基、对甲基苯基、氨基、单C1-8烷基氨基、二C1-8烷基氨基或C1-8烷酰氨基；R 7 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 2-8 alkenyl, C 3-8 cycloalkyl, halogen substituted C 1-8 alkyl, phenyl, p-methylphenyl, amino , a mono C 1-8 alkylamino group, a di C 1-8 alkylamino group or a C 1-8 alkanoylamino group;
    R8选自氢、氘、C1-8烷基、C3-8环烷基、卤取代C1-8烷基或羟取代C1-8烷基；R 8 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 3-8 cycloalkyl, halogen substituted C 1-8 alkyl or hydroxy substituted C 1-8 alkyl;
    R9选自氢、氘、C1-8烷基、C1-8烷氧基、C3-8环烷基、C3-8环烷氧基、卤取代C1-8烷基、卤取代C1-8烷氧基、羟取代C1-8烷基或羟取代C1-8烷氧基；R 9 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, halogen substituted C 1-8 alkyl, halogen Substituting a C 1-8 alkoxy group, a hydroxy-substituted C 1-8 alkyl group or a hydroxy-substituted C 1-8 alkoxy group;
    R10、R11各自独立的选自氢、氘、羟基、氨基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、C5-10芳基、5-10元杂芳基或C1-8烷酰基，R 10 and R 11 are each independently selected from the group consisting of hydrogen, hydrazine, hydroxy, amino, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3 -8 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group or C 1-8 alkanoyl group,
    任选进一步被一个或多个选自卤素、羟基、巯基、氰基、硝基、乙酰氨基、叠氮基、磺酰基、甲磺酰基、C1-8烷基、三氟甲基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、C1-8烷氧基、C1-8烷氧羰基、C1-8烷基羰基、C1-8烷基羰基氧基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、氨基、单C1-8烷基氨基或二C1-8烷基氨基的取代基所取代；Optionally further substituted with one or more substituents selected from halo, hydroxy, mercapto, cyano, nitro, acetamido, azido, a sulfonyl group, mesyl group, C 1-8 alkyl, trifluoromethyl, C 2 8 -alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 1-8 alkoxy, C 1-8 alkoxycarbonyl, C 1-8 Alkylcarbonyl, C 1-8 alkylcarbonyloxy, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, amino, mono C 1-8 alkylamino or di C Substituted by a substituent of a 1-8 alkylamino group;
    m为0、1或2；m is 0, 1 or 2;
    r为0、1或2。r is 0, 1, or 2.
  2. 根据权利要求1所述式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，Y选自CR6；A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein Y is selected from CR 6 ;
    Ar选自选自C6-10芳基或6-10元杂芳基，任选进一步被一个或多个选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR7、-C0-8-O-R8、-C0-8-C(O)OR8、-C0-8-C(O)R8、-C0-8-O-C(O)R9、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R9或-N(R10)-C(O)OR8的取代基所取代，Ar is selected from a C 6-10 aryl group or a 6-10 membered heteroaryl group, optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl group, C 2-8 alkynyl group, C 3-8 cycloalkyl group, 3-8 membered heterocyclic group, 3-8 membered heterocyclic oxy group, 3-8 membered heterocyclic thio group , C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroaryl Thiothio group, -C 0-8 -S(O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -C(O) R 8, -C 0-8 -OC (O ) R 9, -C 0-8 -NR 10 R 11, -C 0-8 -C (O) NR 10 R 11, -N (R 10) -C Substituted by a substituent of (O)R 9 or -N(R 10 )-C(O)OR 8 ,
    再任选进一步被一个或多个选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR7、-C0-8-O-R8、 -C0-8-C(O)OR8、-C0-8-C(O)R8、-C0-8-O-C(O)R9、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R9或-N(R10)-C(O)OR8的取代基所取代；Then optionally further substituted with one or more groups selected from halo, cyano, nitro, azido, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, a halogen substituted C 1 to -8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5 -10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 - S(O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -C(O)R 8 , -C 0-8 -OC (O)R 9 , -C 0-8 -NR 10 R 11 , -C 0-8 -C(O)NR 10 R 11 , -N(R 10 )-C(O)R 9 or -N(R Substituted by a substituent of 10 )-C(O)OR 8 ;
    R选自C3-6环烷基或3-6元杂环基，任选进一步被一个或多个选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR7、-C0-8-O-R8、-C0-8-C(O)OR8、-C0-8-C(O)R8、-C0-8-O-C(O)R9、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R9或-N(R10)-C(O)OR8的取代基所取代；R is selected from C 3-6 cycloalkyl or 3-6 membered heterocyclyl, optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, azide, C 1-8 alkyl, C 2 8 -alkenyl, C 2-8 alkynyl, halogen-substituted C 1-8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3 -8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy Base, 5-10 membered heteroarylthio group, -C 0-8 -S(O) r R 7 , -C 0-8 -OR 8 , -C 0-8 -C(O)OR 8 , -C 0-8 -C(O)R 8 , -C 0-8 -OC(O)R 9 , -C 0-8 -NR 10 R 11 , -C 0-8 -C(O)NR 10 R 11 , Substituted with a substituent of -N(R 10 )-C(O)R 9 or -N(R 10 )-C(O)OR 8 ;
    R1、R2、R4、R5、R6各自独立的选自氢、氘、卤素、氰基、硝基、叠氮基、C1-8烷基、卤取代C1-8烷基、卤取代C1-8烷氧基、C2-8链烯基、C2-8链炔基、C3-8环烷基、卤取代C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR7、-C0-8-O-R8、-C0-8-C(O)OR8、-C0-8-C(O)R8、-C0-8-O-C(O)R9、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R9或-N(R10)-C(O)OR8；R 1 , R 2 , R 4 , R 5 , R 6 are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-8 alkyl, halo-substituted C 1-8 alkyl Halogen substituted C 1-8 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, halogen substituted C 3-8 cycloalkyl, 3-8 membered Cyclo, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5- 10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 7 , -C 0-8 -OR 8 ,- C 0-8 -C(O)OR 8 , -C 0-8 -C(O)R 8 , -C 0-8 -OC(O)R 9 , -C 0-8 -NR 10 R 11 ,- C 0-8 -C(O)NR 10 R 11 , -N(R 10 )-C(O)R 9 or -N(R 10 )-C(O)OR 8 ;
    m为0。m is 0.
  3. 根据权利要求1所述式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，Y选自CR6；A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein Y is selected from CR 6 ;
    Ar选自如下结构：Ar is selected from the following structures:
    Figure PCTCN2016111652-appb-100002
    Figure PCTCN2016111652-appb-100002
    任选进一步被一个或多个选自卤素、C5-10芳基、5-10元杂芳基、-C0-8-O-R8、-C0-4-S(O)rR7、-C0-4-C(O)OR8、-C0-4-C(O)R8、-C0-4-O-C(O)R9或-C0-4-C(O)NR10R11的取代基所取代，再任选进一步被一个或多个选自卤素、C5-10芳基、5-10元杂芳基、-C0-4-S(O)rR7、-C0-4-C(O)OR8、-C0-4-C(O)R8、-C0-4-O-C(O)R9或-C0-4-C(O)NR10R11的取代基所取代；Optionally further selected from one or more selected from the group consisting of halogen, C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -OR 8 , -C 0-4 -S(O) r R 7 , -C 0-4 -C(O)OR 8 , -C 0-4 -C(O)R 8 , -C 0-4 -OC(O)R 9 or -C 0-4 -C(O)NR Substituted by a substituent of 10 R 11 , optionally further selected from one or more selected from the group consisting of halogen, C 5-10 aryl, 5-10 membered heteroaryl, -C 0-4 -S(O) r R 7 , -C 0-4 -C(O)OR 8 , -C 0-4 -C(O)R 8 , -C 0-4 -OC(O)R 9 or -C 0-4 -C(O) Substituted by a substituent of NR 10 R 11 ;
    R选自如下结构：
    Figure PCTCN2016111652-appb-100003
    R is selected from the following structures:
    Figure PCTCN2016111652-appb-100003
    任选进一步被一个或多个选自卤素、巯基、-C0-4-O-R8或-C0-4-NR10R11的取代基所取代；Optionally further substituted with one or more substituents selected from halogen, fluorenyl, -C 0-4 -OR 8 or -C 0-4 -NR 10 R 11 ;
    R1、R2、R4、R5、R6各自独立的选自氢、氘、卤素、C1-4烷基、卤取代C1-4 烷基、卤取代C1-4烷氧基、C2-4链烯基、C2-4链炔基、C3-6环烷基、卤取代C3-6环烷基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、-C0-4-S(O)rR7、-C0-4-O-R8、-C0-4-C(O)OR8、-C0-4-C(O)R8、-C0-4-O-C(O)R9、-C0-4-NR10R11、-C0-4-C(O)NR10R11、-N(R10)-C(O)R9或-N(R10)-C(O)OR8；R 1 , R 2 , R 4 , R 5 and R 6 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-4 alkyl, halo-substituted C 1-4 alkyl, halo-substituted C 1-4 alkoxy. , C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halogen substituted C 3-6 cycloalkyl, 3-6 membered heterocyclic, 3-6 membered heterocyclic Oxy, 3-6 membered heterocyclylthio, -C 0-4 -S(O) r R 7 , -C 0-4 -OR 8 , -C 0-4 -C(O)OR 8 ,- C 0-4 -C(O)R 8 , -C 0-4 -OC(O)R 9 , -C 0-4 -NR 10 R 11 , -C 0-4 -C(O)NR 10 R 11 , -N(R 10 )-C(O)R 9 or -N(R 10 )-C(O)OR 8 ;
    m为0。m is 0.
  4. 根据权利要求1所述式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，选自式(Ⅱ)化合物：A compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 1, which is selected from the group consisting of the compound of the formula (II):
    Figure PCTCN2016111652-appb-100004
    Figure PCTCN2016111652-appb-100004
    其中，Ar选自如下结构：Wherein Ar is selected from the following structures:
    Figure PCTCN2016111652-appb-100005
    Figure PCTCN2016111652-appb-100005
    任选进一步被一个或多个选自氟、氯、羧基、磺酰基、甲磺酰基、异丙磺酰基、甲氧羰基、乙氧羰基、异丙氧羰基、乙酰基或选自如下结构的取代基所取代：Optionally further substituted by one or more selected from the group consisting of fluorine, chlorine, carboxyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, acetyl or a structure selected from Substituted by:
    Figure PCTCN2016111652-appb-100006
    Figure PCTCN2016111652-appb-100006
    R选自如下结构：
    Figure PCTCN2016111652-appb-100007
    R is selected from the following structures:
    Figure PCTCN2016111652-appb-100007
    任选进一步被一个或多个选自羟基、巯基、甲氧基、乙氧基或氨基的取代基所取代；Optionally further substituted with one or more substituents selected from hydroxy, thiol, methoxy, ethoxy or amino;
    R1选自氢、氘、甲基、乙基、异丙基、三氟甲基、烯丙基、乙炔基、环丙基、甲氧基、乙氧基、异丙氧基或氨基；R 1 is selected from the group consisting of hydrogen, hydrazine, methyl, ethyl, isopropyl, trifluoromethyl, allyl, ethynyl, cyclopropyl, methoxy, ethoxy, isopropoxy or amino;
    R2选自氢、氘、氟、氯、羟基、巯基、甲基、乙基、异丙基、三氟甲基、烯丙基、乙炔基、环丙基、环丁基、甲氧基、乙氧基、异丙氧基或氨基。R 2 is selected from the group consisting of hydrogen, hydrazine, fluorine, chlorine, hydroxy, decyl, methyl, ethyl, isopropyl, trifluoromethyl, allyl, ethynyl, cyclopropyl, cyclobutyl, methoxy, Ethoxy, isopropoxy or amino.
    R4、R5各自独立的选自氢、氟、氯、甲基、乙基、异丙基、三氟甲基、环丙基、甲氧基或乙氧基。R 4 and R 5 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, methoxy or ethoxy.
  5. 根据权利要求1-4任一所述式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，选自如下化合物： A compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, which is selected from the group consisting of the following compounds:
    Figure PCTCN2016111652-appb-100008
    Figure PCTCN2016111652-appb-100008
    Figure PCTCN2016111652-appb-100009
    Figure PCTCN2016111652-appb-100009
  6. 根据权利要求1所述式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，选自式(Ⅲ)化合物：A compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 1, which is selected from the group consisting of the compound of the formula (III):
    Figure PCTCN2016111652-appb-100010
    Figure PCTCN2016111652-appb-100010
    其中，among them,
    Ar选自如下结构：Ar is selected from the following structures:
    Figure PCTCN2016111652-appb-100011
    Figure PCTCN2016111652-appb-100011
    任选进一步被一个或多个选自卤素、苯基、-C0-8-O-R8、-C0-4-S(O)rR7、-C0-4-C(O)OR8、-C0-4-C(O)R8、-C0-4-O-C(O)R9、-C0-4-C(O)NR10R11或选自如下结构的取代基所取代； Optionally further selected from one or more selected from the group consisting of halogen, phenyl, -C 0-8 -OR 8 , -C 0-4 -S(O) r R 7 , -C 0-4 -C(O)OR 8 , -C 0-4 -C(O)R 8 , -C 0-4 -OC(O)R 9 , -C 0-4 -C(O)NR 10 R 11 or a substituent selected from the following structures Replace
    Figure PCTCN2016111652-appb-100012
    Figure PCTCN2016111652-appb-100012
    R选自如下结构：
    Figure PCTCN2016111652-appb-100013
    R is selected from the following structures:
    Figure PCTCN2016111652-appb-100013
    任选进一步被一个或多个选自卤素、巯基、-C0-4-O-R8或-C0-4-NR10R11的取代基所取代；Optionally further substituted with one or more substituents selected from halogen, fluorenyl, -C 0-4 -OR 8 or -C 0-4 -NR 10 R 11 ;
    R4、R5各自独立的选自氢、氘、卤素、C1-4烷基、卤取代C1-4烷基、卤取代C1-4烷氧基、C2-4链烯基、C2-4链炔基、C3-6环烷基、卤取代C3-6环烷基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、-C0-4-S(O)rR7、-C0-4-O-R8、-C0-4-C(O)OR8、-C0-4-C(O)R8、-C0-4-O-C(O)R9、-C0-4-NR10R11、-C0-4-C(O)NR10R11、-N(R10)-C(O)R9或-N(R10)-C(O)OR8。R 4 and R 5 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-4 alkyl, halo-substituted C 1-4 alkyl, halo-substituted C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halogen substituted C 3-6 cycloalkyl, 3-6 membered heterocyclic, 3-6 membered heterocyclyloxy, 3-6 membered heterocyclic ring Thiothio group, -C 0-4 -S(O) r R 7 , -C 0-4 -OR 8 , -C 0-4 -C(O)OR 8 , -C 0-4 -C(O) R 8 , -C 0-4 -OC(O)R 9 , -C 0-4 -NR 10 R 11 , -C 0-4 -C(O)NR 10 R 11 , -N(R 10 )-C (O) R 9 or -N(R 10 )-C(O)OR 8 .
  7. 根据权利要求6所述式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，选自式(Ⅲa)、(Ⅲb)、(Ⅲc)或(Ⅲd)化合物：A compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 6, which is selected from the group consisting of compounds of the formula (IIIa), (IIIb), (IIIc) or (IIId):
    Figure PCTCN2016111652-appb-100014
    Figure PCTCN2016111652-appb-100014
    其中，Ar选自如下结构：Wherein Ar is selected from the following structures:
    Figure PCTCN2016111652-appb-100015
    Figure PCTCN2016111652-appb-100015
    任选进一步被一个或多个选自氟、氯、甲氧基、乙氧基、羧基、磺酰基、甲磺酰基、异丙磺酰基、甲氧羰基、乙氧羰基、异丙氧羰基、乙酰基或选自如下结构的取代基所取代：Optionally further one or more selected from the group consisting of fluorine, chlorine, methoxy, ethoxy, carboxy, sulfonyl, methylsulfonyl, isopropylsulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, acetyl Substituted or substituted with a substituent selected from the following structures:
    Figure PCTCN2016111652-appb-100016
    Figure PCTCN2016111652-appb-100016
    R4、R5各自独立的选自氢、氟、氯、甲基、乙基、异丙基、三氟甲基、三氟甲氧基、二氟甲氧基、环丙基、甲氧基或乙氧基。R 4 and R 5 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl, methoxy. Or ethoxylated.
  8. 根据权利要求1、6或7所述式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，选自如下化合物： A compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 1, 6 or 7, which is selected from the group consisting of the following compounds:
    Figure PCTCN2016111652-appb-100017
    Figure PCTCN2016111652-appb-100017
    Figure PCTCN2016111652-appb-100018
    Figure PCTCN2016111652-appb-100018
    Figure PCTCN2016111652-appb-100019
    Figure PCTCN2016111652-appb-100019
  9. 药物组合物，其包括治疗有效剂量的权利要求1-8任一所述的式(I)化合物、其立体异构体或其药学上可接受盐及可药用的载体。A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to any of claims 1-8, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  10. 权利要求1-8任一所述的式(I)化合物、其立体异构体或其药学上可接受盐，或权利要求9所述的药物组合物在制备用于预防或治疗FXR介导的疾病或状况的药物中的应用；所述FXR介导的疾病或状况优选自心血管疾病、动脉粥样硬化、动脉硬化、高胆甾醇血、高血脂慢性肝炎疾病、慢性肝病、胃肠疾病、肾病、心血管疾病、代谢疾病、癌症(例如结直肠癌)或神经迹象如中风。A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to any one of claims 1-8, or a pharmaceutical composition according to claim 9 for use in the prophylaxis or treatment of FXR-mediated Use in a drug for a disease or condition; the FXR-mediated disease or condition is preferably selected from cardiovascular disease, atherosclerosis, arteriosclerosis, hypercholesterolemia, hyperlipidemia, chronic hepatitis disease, chronic liver disease, gastrointestinal disease, Kidney disease, cardiovascular disease, metabolic disease, cancer (such as colorectal cancer) or nerve signs such as stroke.
  11. 根据权利要求10所述的应用，其特征在于，所述慢性肝病选自乙肝、 原发性硬化(PBC)、脑脏性黄瘤症(CTX)、原发性硬化性胆囊炎(PSC)、药物导致的胆汁郁积、妊娠肝内胆汁淤积症、肠外吸收相关胆汁郁积(PNAC)、细菌过度生长或脓血症胆汁郁积、自身免疫肝炎、慢性病毒性肝炎、酒精性肝病、非酒精性脂肪肝疾病(NAFLD)、非酒精性脂肪性肝炎(NASH)、肝移植相关移植物抗宿主病、活供体肝移植再生、先天性肝纤维化、胆总管结石、肉芽性肝病、肝内或外恶性肿瘤、Sjogren综合征、结节病、Wilson's疾病、Gaucher's疾病、血色病或α1一抗膜蛋白酶缺乏症；所述胃肠疾病优选自炎症性肠病(IBD)(包括Crohn's疾病和溃病性肠炎)、肠易激综合征(IBS)、细菌过度生长、营养吸收不良、反射后结肠炎或微小性结肠炎；所述肾病优选自糖尿病肾病、局灶节段性肾小球硬化症(FSGS)、高血压肾病、慢性肾小球炎、慢性移植性肾小球病、慢性间质性肾炎或多囊肾病；所述心血管疾病优选自动脉硬化症、动脉硬化、血脂障碍、高胆固醇血症或高甘油三酯血症；所述代谢疾病优选自胰岛素抗性、I型糖尿病、II型糖尿病或肥胖。The use according to claim 10, wherein said chronic liver disease is selected from the group consisting of hepatitis B, Primary sclerosis (PBC), cerebral xanthoma (CTX), primary sclerosing cholecystitis (PSC), drug-induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral absorption-related cholestasis (PNAC) ), bacterial overgrowth or sepsis cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver transplantation-related graft resistance Host disease, live donor liver transplant regeneration, congenital liver fibrosis, common bile duct stones, granulomatous liver disease, intrahepatic or extraneous malignancy, Sjogren syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis or alpha 1 Anti-membrane protease deficiency; the gastrointestinal disease is preferably selected from inflammatory bowel disease (IBD) (including Crohn's disease and ulcerative enteritis), irritable bowel syndrome (IBS), bacterial overgrowth, malabsorption, and after reflex Colitis or microcolitis; the kidney disease is preferably from diabetic nephropathy, focal segmental glomerulosclerosis (FSGS), hypertensive nephropathy, chronic glomerulitis, chronic allograft glomerulopathy, chronic Qualitative nephritis Polycystic kidney disease; the cardiovascular disease is preferably from arteriosclerosis, arteriosclerosis, dyslipidemia, hypercholesterolemia or hypertriglyceridemia; the metabolic disease is preferably selected from insulin resistance, type I diabetes, type II diabetes Or obesity.
  12. 一种预防或治疗FXR介导的疾病或状况的方法，包括施用治疗有效量的权利要求1-8任一所述的式(I)化合物、其立体异构体或其药学上可接受盐，或权利要求9所述的药物组合物。 A method of preventing or treating a FXR-mediated disease or condition comprising administering a therapeutically effective amount of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-8, Or the pharmaceutical composition of claim 9.
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