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WO2018233553A1 - Composé bicyclique fusionné et son utilisation en médecine - Google Patents

Composé bicyclique fusionné et son utilisation en médecine Download PDF

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Publication number
WO2018233553A1
WO2018233553A1 PCT/CN2018/091392 CN2018091392W WO2018233553A1 WO 2018233553 A1 WO2018233553 A1 WO 2018233553A1 CN 2018091392 W CN2018091392 W CN 2018091392W WO 2018233553 A1 WO2018233553 A1 WO 2018233553A1
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Prior art keywords
group
mmol
amino
alkyl
cyano
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English (en)
Chinese (zh)
Inventor
潘圣强
马发城
张英勋
熊绍辉
杨新业
王晓军
张英俊
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Sunshine Lake Pharma Co Ltd
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Sunshine Lake Pharma Co Ltd
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Priority to CN201880040262.7A priority Critical patent/CN110770233B/zh
Publication of WO2018233553A1 publication Critical patent/WO2018233553A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a fused bicyclic compound having an enzyme inhibitory activity and a pharmaceutical composition thereof, which are useful for the preparation of a medicament for treating a disease regulated by ASK1.
  • Apoptosis signal-regulating kinase 1 is a member of the mitogen-activated protein kinase kinase (MAP3Ks) family, and MAP3Ks can activate c-Jun N. N-terminal protein kinase (JNK) and p38 MAP (mitogen-activated protein) kinase (Ichijo, H., Nishida, E., Irie, K., Dijke, PT, Saitoh, Moriguchi, T., Matsumoto , K., Miyazono, K., and Gotoh, Y. (1997) Science, 275, 90-94).
  • ASK1 also known as mitogen-activated protein kinase kinase 5 (MAPKKK5, MAP3K5), contains 1375 amino acid residues, which constitutes 11 kinase subdomains and one at the N-terminus and The serine/threonine kinase region in the middle of the side molecule of the C-terminal coiled-coil region (Wang et al. J. Biol. Chem. 1996, 271, 31607-31611, Ichijo et al. Science. 1997, 275, 90-94; Tobiume Et al. Biochem. Biophys. Res. Commun. 1997, 239, 905-910).
  • ASK1 can be activated by a variety of stimuli such as oxidative stress, reactive oxygen species, endotoxin, tumor necrosis factor- ⁇ , endoplasmic reticulum stress, and intracellular calcium concentration.
  • ASK1 not only regulates cell death, but also plays an important role in cellular activities such as cytokine response, cell differentiation, and innate immune response. Modulating the activity of ASK1 will treat or prevent a variety of diseases, including neurodegenerative diseases, cardiovascular diseases, inflammation, autoimmune diseases, and metabolic disorders. Especially in the treatment of heart and kidney diseases (including kidney disease, diabetic nephropathy and chronic kidney disease), fibrotic diseases (including pulmonary fibrosis and renal fibrosis), respiratory diseases (including chronic embolic lung damage and acute lung injury) and liver disease, ASK1 Regulators have great potential.
  • liver diseases are generally classified into acute and chronic liver diseases.
  • Liver disease can be caused by infection, injury, medication, poisoning, alcohol consumption, unclean food, abnormal accumulation of normal components of the blood, autoimmunity, genetic defects or other unknown factors.
  • Common liver diseases include chronic liver disease, metabolic liver disease, liver fibrosis, primary sclerosing cholangitis, nonalcoholic fatty liver, nonalcoholic steatohepatitis, hepatic ischemia-reperfusion injury, and primary biliary cirrhosis Wait.
  • ASK1 modulators are used as ASK1 modulators for the prevention or treatment of autoimmune diseases, inflammation, cardiovascular diseases and neurodegenerative diseases, as disclosed in WO2009027283, WO2009123986, WO2010008843, WO2011008709, WO2011041293, WO2011097079, WO2012003387, WO2013112741, WO2014100541, WO2015095059.
  • WO 2015187499 and WO2016049070 disclose the use of ASK1 modulators for the treatment of liver diseases.
  • the present invention provides a compound, or a pharmaceutical composition thereof, which is useful as a modulator of ASK1.
  • the invention further relates to the use of said compound or a pharmaceutical composition thereof for the preparation of a medicament for the treatment of a disease and/or condition by modulation of ASK1 activity by said compound.
  • the present invention further describes a method of synthesizing the compound.
  • the compounds of the invention exhibit excellent biological activity and pharmacokinetic properties.
  • the invention relates to a compound which is a compound of formula (I), or a stereoisomer, geometric isomer, tautomer, oxynitride of a compound of formula (I) a hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
  • Each W 1 is independently O, S or N(R x );
  • Each W 2 is independently CH or N;
  • Each W 3 is independently CH or N;
  • Each W 4 is independently CH or N;
  • Each W 5 is independently CH or N;
  • W 6 is C(R a ) or N;
  • W 7 is C(R b ) or N;
  • Y is -O- or -N(R y )-;
  • R a and R b are each independently hydrogen, hydrazine, fluorine, chlorine, bromine, iodine, hydroxy, decyl, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1- alkoxy or a C 1-3 haloalkoxy;
  • Each R x and R y is independently hydrogen, deuterium, C 1-3 alkyl, C 1-3 haloalkyl or C 3-6 cycloalkyl;
  • Each R 1 is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, thiol, amino, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 6 a -10 aryl or 5-10 membered heteroaryl group, wherein said hydroxy, fluorenyl, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkane , C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5 The -10 membered heteroaryl
  • Each of R 2 and R 3 is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkane Oxy or C 1-4 haloalkoxy;
  • R 4 is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1- 4 -haloalkoxy;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, 2 or 3;
  • r 0, 1, 2 or 3.
  • R a and R b are each independently hydrogen, hydrazine, fluoro, chloro, bromo, iodo, hydroxy, decyl, amino, nitro, cyano, methyl, ethyl, isopropyl, Fluoromethyl, trifluoromethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.
  • each R x and R y are independently hydrogen, deuterium, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl Or cyclohexyl.
  • each R 1 is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, thiol, amino, nitro, cyano, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 3-6 cycloalkyl, 3-8 a heterocyclic group, a C 6-10 aryl group or a 5-10 membered heteroaryl group, wherein the hydroxy group, fluorenyl group, amino group, C 1-3 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group , C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 3-6 cycloalkyl, 3-8 membered heterocyclic, C 6 The -10 aryl
  • each R 1 is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, thiol, amino, nitro, cyano, methyl, ethyl, isopropyl, allyl , propenyl, propargyl, propynyl, difluoromethyl, trifluoromethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, Methylthio, ethylthio, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, Piperazinyl, morpholinyl, phenyl, decyl, pyrrolyl, amino, nitro,
  • each R 2 and R 3 are independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl Base, trifluoromethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.
  • R 4 is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl 1,2-Difluoroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.
  • R is hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein said C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6
  • R is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, allyl, ethynyl, propargyl, cyclopropyl, cyclo Butyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, Pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl or thia An azole group, wherein the methyl,
  • 1, 2 or 3 are selected from the group consisting of hydrazine, fluorine, chlorine, bromine, iodine, hydroxy, amino, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy Substituted with a C 1-3 haloalkoxy group.
  • Q is hydrogen, hydrazine, fluoro, chloro, bromo, iodo, hydroxy, decyl, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl 1,1,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylsulfonyl, ethylsulfonyl, Acetyl, propionyl, butyryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl , tetrahydropyranyl, morpholinyl, phenyl, pyr
  • the compound of the present invention is a compound of formula (II), or a stereoisomer, geometric isomer, tautomer, oxynitride of a compound of formula (II). a hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
  • the compound of the invention is a compound of formula (III) or (IV), or a stereoisomer, geometric isomer of a compound of formula (III) or (IV), Tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), formula (II), formula (III) or (IV) of the invention, or a stereoisomer thereof, geometrically different a construct, a tautomer, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and a pharmaceutically acceptable carrier, excipient, diluent, Adjuvants, vehicles or combinations thereof.
  • the invention relates to a compound of formula (I), formula (II), formula (III) or (IV) or a pharmaceutical composition thereof for use in the manufacture of a medicament for the prevention, treatment or alleviation of a disease modulated by ASK1 in a patient use.
  • the ASK1 regulated disease of the present invention is an autoimmune disease, an inflammation, a cardiovascular disease, a heart and kidney disease, a fibrotic disease, a respiratory disease, a liver disease, or a neurodegenerative disease.
  • the invention relates to a process for the preparation, isolation and purification of a compound encompassed by formula (I), formula (II), formula (III) or (IV).
  • the present invention will list the documents corresponding to the specific content of the determination, and the examples are accompanied by the diagrams of the structural formula and the chemical formula.
  • the present invention is intended to cover all alternatives, modifications, and equivalents, which may be included in the field of the invention as defined by the appended claims.
  • Those skilled in the art will recognize many methods and materials that are similar or equivalent to those described herein, which can be used in the practice of the present invention.
  • the invention is in no way limited to the description of methods and materials. There are many documents and similar materials that differ or contradict the application of the present invention, including but not limited to the definition of terms, the use of terms, the techniques described, or the scope as controlled by the present application.
  • a compound as described herein may optionally be substituted by one or more substituents, such as a compound of the formula in the invention, or a particular example, subclass, and a class of compounds encompassed by the invention, as in the examples .
  • substituents such as a compound of the formula in the invention, or a particular example, subclass, and a class of compounds encompassed by the invention, as in the examples .
  • substituents such as a compound of the formula in the invention, or a particular example, subclass, and a class of compounds encompassed by the invention, as in the examples .
  • substituents When more than one position in the given formula can be substituted by one or more substituents selected from a particular group, the substituents can be substituted at the various positions, either identically or differently.
  • C 1-6 alkyl refers particularly to the disclosure independently methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • alkyl as used herein, includes 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, or A linear or branched monovalent hydrocarbon group of 1-2 carbon atoms, wherein the alkyl group may be independently and optionally substituted by one or more substituents described herein.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 ) CH(CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (- CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-A 2-butyl (-C(CH 3 ), 2-A
  • alkyl and its prefix “alk” are used herein to encompass both straight-chain and branched saturated carbon chains.
  • alkylene or “alkylene” is used herein to mean a saturated divalent hydrocarbon radical derived by the elimination of two hydrogen atoms from a linear or branched saturated hydrocarbon, examples of which include, but are not limited to, methylene Base, ethylene and isopropylidene, etc.
  • alkynyl means 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or a linear or branched monovalent hydrocarbon radical of 2 to 4 carbon atoms, wherein at least one carbon The carbon is a sp triple bond, wherein the alkynyl group may be independently and optionally substituted by one or more substituents described herein, specific examples including, but not limited to, ethynyl (-C ⁇ CH) and Propargyl (-CH 2 C ⁇ CH).
  • halogen means F, Cl, Br or I.
  • unsaturated as used in the present invention means that the moiety contains one or more degrees of unsaturation.
  • alkoxy or "alkyloxy” as used in the present invention relates to an alkyl group, as defined herein, attached to the other part of the compound molecule through an oxygen atom.
  • the alkoxy group is a C 1-4 alkoxy group; such examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and the like.
  • the alkoxy group may be independently unsubstituted or substituted by one or more substituents described herein.
  • alkylthio or "alkylthio” as used in the present invention relates to an alkyl group, as defined herein, attached to other moieties of the compound molecule through a sulfur atom.
  • the alkylthio group is a C 1-6 alkylthio group; in other embodiments, the alkylthio group is a C 1-3 alkylthio group, examples of which include, but are not limited to, A Alkylthio group, ethylthio group, n-propylthio group, isopropylthio group and the like.
  • the alkylthio group may be independently unsubstituted or substituted with one or more substituents described herein.
  • alkoxyalkyl as used in the present invention means that the alkyl group may be substituted by one or more alkoxy groups having the meanings as described herein.
  • the alkoxyalkyl group is a C 1-6 alkoxy C 1-6 alkyl group.
  • the alkoxyalkyl group is a C 1-3 alkoxy C 1-3 alkyl group.
  • the "alkoxyalkyl” group may be independently and optionally substituted with one or more substituents described herein.
  • haloalkyl denotes the case where an alkyl, alkenyl or alkyloxy group may be substituted by one or more halogen atoms.
  • the haloalkyl group is a halo C 1-6 alkyl group.
  • the haloalkyl group is a halo C 1-3 alkyl group.
  • the haloalkyloxy or haloalkoxy group is a halo C1-6 alkyloxy group or a halogenated C1-6 alkoxy group.
  • the haloalkyloxy or haloalkoxy group is a halo C 1-3 alkyloxy group or a halogenated C 1-3 alkoxy group.
  • Such examples include, but are not limited to, trifluoromethyl, difluoromethyl, 2-chloro-vinyl, 2,2-difluoroethyl, difluoromethoxy, trifluoromethoxy, and the like.
  • the "haloalkyl”, “haloalkenyl” and “haloalkyloxy” groups may be independently and optionally substituted by one or more substituents described herein.
  • alkylamino or “alkylamino” includes “N-alkylamino” and "N,N-dialkylamino” wherein the amino groups are each independently substituted with one or two alkyl groups.
  • the alkylamino group is a C 1-6 alkylamino group or a (C 1-6 alkyl) amino group.
  • the alkylamino group is a C 1-3 alkylamino group or a (C 1-3 alkyl)amino group.
  • Such examples include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, and N,N-diethylamino, and the like.
  • the alkylamino group can be optionally substituted with one or more substituents described herein.
  • cycloalkyl or "cycloalkane” denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic carbocyclic ring system containing from 3 to 12 carbon atoms, but never containing an aromatic ring.
  • the cycloalkyl group contains from 3 to 10 carbon atoms; in another embodiment, the cycloalkyl group contains from 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains from 3 to 6 carbon atom.
  • Such examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • the cycloalkyl group can be independently unsubstituted or substituted with one or more substituents described herein.
  • cycloalkyloxy denotes that a cycloalkyl group is attached to the other part of the compound molecule through an oxygen atom, wherein the cycloalkyl group has the meaning as described herein.
  • cycloalkylalkyl denotes the attachment of a cycloalkyl group to another moiety of the compound molecule through an alkyl group, wherein the cycloalkyl and alkyl groups have the meanings as described herein.
  • Carbocycle denotes a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated monocyclic, bicyclic or tricyclic cyclic hydrocarbon radical containing from 3 to 12 carbon atoms.
  • Carbon bicyclic groups include spirocarbon bicyclic groups and fused carbon bicyclic groups, and suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl.
  • the carbocyclic group contains 4-8 carbon atoms; in yet another embodiment, the carbocyclic group contains 4-6 carbon atoms.
  • Examples of the carbocyclic group further include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a 1-cyclopentyl-1-alkenyl group, a 1-cyclopentyl-2-alkenyl group, a 1-cyclopentyl group- 3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl Base, cyclodecyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.
  • the carbocyclyl group may be independently unsubstituted or substituted with one or more substituents described herein.
  • heterocyclyl and “heterocycle” are used interchangeably herein to refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing from 3 to 12 ring atoms, excluding aromatic rings, wherein At least one ring atom is a hetero atom.
  • heterocyclyl or “heterocycle” contains 3-10 ring atoms; in one embodiment, “heterocyclyl” or “heterocycle” contains 3-8 ring atoms; In one embodiment, “heterocyclyl” or “heterocycle” contains 5-8 ring atoms; in yet another embodiment, “heterocyclyl” or “heterocycle” contains 3-6 ring atoms; In one embodiment, “heterocyclyl” or “heterocycle” contains 5-6 ring atoms; unless otherwise stated, heterocyclyl can be carbyl or nitro, and heteroatoms have the meanings as described herein.
  • heterocyclic groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thioheterobutyl, pyrrolidinyl, 2-pyrroline, 3-pyrrolyl , pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, 1,3-dioxocyclopentyl, disulfide Pentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl , dioxoalkyl, dithiaalkyl, thiamethane, homopiperazin
  • Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, a sulfolane group and a 1,1-dioxothiomorpholinyl group.
  • the heterocyclyl group can be optionally substituted with one or more substituents described herein.
  • heterocyclylalkyl means that the heterocyclyl is attached to the other part of the compound molecule through an alkyl group, wherein the heterocyclyl and alkyl groups have the meanings as described herein.
  • aryl denotes a monocyclic, bicyclic and tricyclic carbocyclic ring system containing from 6 to 14 ring atoms, or from 6 to 12 ring atoms, or from 6 to 10 ring atoms, wherein at least one ring is aromatic Each of the rings contains a ring of 3-7 atoms and one or more attachment points are attached to the remainder of the molecule.
  • aryl can be used interchangeably with the term "aromatic ring”. Examples of the aryl group may include a phenyl group, a naphthyl group, and an anthracene. The aryl group may be independently and optionally substituted with one or more substituents described herein.
  • arylalkyl denotes an alkyl group substituted with one or more aryl groups, wherein the alkyl and aryl groups have the meanings as described herein, such examples include, but are not limited to, Benzyl and phenethyl.
  • heteroaryl denotes a monocyclic, bicyclic and tricyclic ring system having 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one of the ring systems is an aromatic ring, and At least one ring system comprises one or more heteroatoms, wherein each ring comprises a ring of 5-7 atoms and one or more attachment points are attached to the remainder of the molecule.
  • heteroaryl can be used interchangeably with the terms “heteroaryl ring” or “heteroaromatic compound”.
  • the heteroaryl group is optionally substituted with one or more substituents described herein.
  • a heteroaryl group of 5-10 atoms comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, wherein the nitrogen atom can be further oxidized.
  • heteroaryl groups include, but are not limited to, furyl, imidazolyl (eg, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl, oxazolyl (eg 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (eg N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl, pyrimidinyl (eg 2- Pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl, thiazolyl (eg 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), tetrazolyl (eg 5-tetrazolyl), Triazolyl, thienyl (such as 2-thienyl, 3-thienyl), pyrazolyl, isothiazolyl, 1,2,3-oxadia
  • a ring system formed by a substituent attached to a central ring represents that the substituent can be substituted at any substitutable position on the ring.
  • the formula (a) represents that the substituent R o may be mono- or polysubstituted at any position on the E ring which may be substituted, as shown in the formulae (b) to (h).
  • the structural formulae described herein include all isomeric forms (e.g., enantiomeric, diastereomeric, geometric or conformational): for example, R, S containing an asymmetric center Configuration, (Z), (E) isomer of double bond, and conformational isomer of (Z), (E).
  • R asymmetric center Configuration
  • Z Z
  • E isomer of double bond
  • a single stereochemical isomer of a compound of the invention, or a mixture of enantiomers, diastereomers, geometric isomers or conformational isomers thereof, is within the scope of the invention.
  • the structural formulae and compounds described herein include all isomeric forms (eg, enantiomeric, diastereomeric, geometric or conformational), nitrogen oxides, Hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs.
  • isomeric forms eg, enantiomeric, diastereomeric, geometric or conformational
  • nitrogen oxides Hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs.
  • individual stereochemical isomers, enantiomers, diastereomers, geometric isomers, conformational isomers, nitrogen oxides, hydrates, solvates, metabolites, Compounds of pharmaceutically acceptable salts and prodrugs are also within the scope of the invention.
  • the structural formulae of the compounds described herein include enriched isotopes of one or more different atoms.
  • metabolite means a product obtained by metabolism of a specific compound of the present invention or a pharmaceutically acceptable salt, analog or derivative thereof, which exhibits in vivo or in vitro with formula (I)
  • Metabolites of a compound can be identified by techniques well known in the art, and the activity can be characterized by experimental methods as described herein. Such products may be obtained by oxidative, reducing, hydrolyzing, amidating, deamidating, esterifying, defatting, or enzymatic cleavage of the administered compound.
  • the invention includes metabolites of a compound, including metabolites produced by intimate contact of a compound of the invention with a mammal for a period of time.
  • stereochemistry in the present invention is generally referred to the following documents: SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.
  • the compounds of the invention may contain asymmetric centers or chiral centers, and thus different stereoisomers are present. All stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute the present invention. portion.
  • optically active compounds Many organic compounds exist in optically active forms, that is, they have the ability to rotate planes of plane polarized light.
  • the prefix D, L or R, S is used to indicate the absolute configuration of the molecular chiral center.
  • the prefix d, l or (+), (-) is used to designate the sign of the plane-polarized light rotation of the compound, (-) or l means that the compound is left-handed, and the prefix (+) or d means that the compound is right-handed.
  • the chemical structures of these stereoisomers are the same, but their stereostructures are different.
  • a particular stereoisomer can be an enantiomer, and a mixture of isomers is often referred to as a mixture of enantiomers.
  • racemic mixture The 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may result in no stereoselectivity or stereospecificity during the chemical reaction.
  • racemic mixture and “racemate” refer to an equimolar mixture of two enantiomers that lack optical activity.
  • tautomer or "tautomeric form” means that the isomers of the structure of different energies can be converted into each other by a low energy barrier.
  • proton tautomers i.e., proton-shifted tautomers
  • the valence (valence) tautomer includes the interconversion of recombination bond electrons.
  • “Pharmaceutically acceptable salt” as used herein means an organic salt and an inorganic salt of a compound of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19, 1977.
  • Salts formed by pharmaceutically acceptable non-toxic acids include, but are not limited to, mineral acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates.
  • Organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates; or by other methods described in the literature, such as ion exchange These salts are obtained.
  • Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, besylate, benzoate, heavy sulfuric acid Salt, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, antibutene Diacid salt, glucoheptonate, glycerol phosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, milk Acid salt, laurate, lauryl sulfate
  • Salts obtained by a suitable base include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also contemplates quaternary ammonium salts formed from any of the compounds comprising a group of N. Water soluble or oil soluble or dispersed products can be obtained by quaternization.
  • the alkali metal or alkaline earth metal which can form a salt includes sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts further comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 sulfonate and aromatic sulfonate.
  • suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 sulfonate and aromatic sulfonate.
  • the "hydrate” of the present invention means that the solvent molecule is an association formed by water.
  • Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol.
  • esters of the present invention means that the compound of the formula (I), the formula (II), the formula (III) or (IV) having a hydroxyl group forms an in vivo hydrolysable ester.
  • esters are, for example, pharmaceutically acceptable esters which are hydrolyzed in a human or animal body to yield the parent alcohol.
  • the group of the in vivo hydrolysable ester of the compound of formula (I), formula (II), formula (III) or (IV) containing a hydroxyl group includes, but is not limited to, a phosphate group, an acetoxymethoxy group, 2,2- Dimethylpropionyloxymethoxy, alkanoyl, benzoyl, phenylacetyl, alkoxycarbonyl, dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylamino Formyl and the like.
  • the "nitrogen oxide” of the present invention means that when the compound contains several amine functional groups, one or more than one nitrogen atom can be oxidized to form an N-oxide.
  • N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms.
  • the corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or a peracid such as peroxycarboxylic acid to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).
  • N-oxides can be prepared by the method of LWDeady (Syn. Comm. 1977, 7, 509-514), for example in an inert solvent such as dichloromethane, to give the amine compound with m-chloroperoxybenzoic acid (MCPBA). )reaction.
  • prodrug denotes a compound which is converted in vivo to a compound of formula (I), formula (II), formula (III) or (IV). Such transformation is affected by the hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue.
  • the prodrug-like compound of the present invention may be an ester.
  • the ester may be used as a prodrug such as a phenyl ester, an aliphatic (C 1-24 ) ester, an acyloxymethyl ester, or a carbonate. , carbamates and amino acid esters.
  • a compound of the invention comprises a hydroxyl group, i.e., it can be acylated to give a compound in the form of a prodrug.
  • Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxy group on the parent.
  • protecting group refers to a substituent that is typically used to block or protect a particular functionality when reacted with other functional groups.
  • protecting group of an amino group refers to a substituent which is attached to an amino group to block or protect the functionality of an amino group in a compound.
  • Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl. (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethoxycarbonyl (Fmoc), and the like.
  • a “hydroxy protecting group” refers to a substituent of a hydroxy group used to block or protect the functionality of a hydroxy group.
  • Suitable protecting groups include methyl, methoxymethyl, acetyl and silyl groups, and the like.
  • Carboxy protecting group means a substituent of a carboxy group used to block or protect the functionality of a carboxy group.
  • Typical carboxy protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilane) Ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfonyl)ethyl, 2-(diphenyl Phosphine) ethyl, and nitroethyl, and the like.
  • a general description of protecting groups can be found in the literature: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
  • terapéuticaally effective amount refers to an amount of a compound of formula (I), formula (II), formula (III) or (IV) sufficient to achieve said effect.
  • a therapeutically effective amount of a compound of formula (I), formula (II), formula (III) or (IV) for use in the treatment of a disease modulated by ASK1 will be an amount sufficient to treat a disease modulated by ASK1.
  • kidney disease refers to a kidney function-related disease which can be caused or aggravated by cardiovascular problems such as hypertension. Hypertension is widely believed to be a major cause of kidney disease.
  • respiratory disease refers to a disease comprising chronic embolic pulmonary obstruction and idiopathic pulmonary fibrosis.
  • nonalcoholic fatty liver disease as used herein is a metabolic disease associated with insulin resistance, including simple fatty liver (SFL), nonalcoholic steatohepatitis (NASH), fatty liver fibrosis and Cirrhosis of the liver.
  • liver fibrosis includes liver fibrosis for any reason including, but not limited to, viral-induced liver fibrosis such as liver fibrosis caused by hepatitis B and hepatitis C; due to alcohol (alcoholicity) Hepatic fibrosis caused by liver disease), drug compounds, oxidative stress, cancer radiotherapy or exposure to industrial chemicals; and such as primary biliary cirrhosis, fatty liver, obesity, nonalcoholic steatohepatitis, cystic fibrosis, Liver fibrosis caused by diseases such as hemochromatosis and autoimmune hepatitis.
  • ASK1 modulator refers to a substance that binds to ASK1 and modulates its activity.
  • the present invention provides a compound or a pharmaceutical composition thereof, which is useful as a modulator of ASK1.
  • the invention further relates to the use of said compound or a pharmaceutical composition thereof for the preparation of a medicament for the treatment of a disease and/or condition by modulating ASK1 activity with said compound.
  • the invention further describes a method of synthesizing the compound.
  • the compounds of the invention exhibit improved biological activity and pharmacokinetic properties.
  • the present invention relates to a compound which is a compound represented by the formula (I), or a stereoisomer, a geometric isomer, a tautomer, an oxynitride, a hydrate of a compound represented by the formula (I). a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug,
  • Each W 1 is independently O, S or N(R x );
  • Each W 2 is independently CH or N;
  • Each W 3 is independently CH or N;
  • Each W 4 is independently CH or N;
  • Each W 5 is independently CH or N;
  • W 6 is C(R a ) or N;
  • W 7 is C(R b ) or N;
  • Y is -O- or -N(R y )-;
  • R a is hydrogen, hydrazine, fluorine, chlorine, bromine, iodine, hydroxy, decyl, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy;
  • R b is hydrogen, hydrazine, fluorine, chlorine, bromine, iodine, hydroxy, decyl, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy;
  • Each R x is independently hydrogen, deuterium, C 1-3 alkyl, C 1-3 haloalkyl or C 3-6 cycloalkyl;
  • R y is hydrogen, hydrazine, C 1-3 alkyl, C 1-3 haloalkyl or C 3-6 cycloalkyl;
  • Each R 1 is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, thiol, amino, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 6 a -10 aryl or 5-10 membered heteroaryl group, wherein said hydroxy, fluorenyl, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkane , C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5 The -10 membered heteroaryl
  • Each R 2 is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy;
  • Each R 3 is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy;
  • R 4 is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1- 4 -haloalkoxy;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, 2 or 3;
  • r 0, 1, 2 or 3.
  • R x has the meaning as described in the present invention.
  • R a is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, thiol, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoro Methyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.
  • R b is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, decyl, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoro Methyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.
  • each R x is independently hydrogen, deuterium, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. .
  • R y is hydrogen, deuterium, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • each R 1 is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, thiol, amino, nitro, cyano, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 3-6 cycloalkyl, 3-8 a heterocyclic group, a C 6-10 aryl group or a 5-10 membered heteroaryl group, wherein the hydroxy group, fluorenyl group, amino group, C 1-3 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group , C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 3-6 cycloalkyl, 3-8 membered heterocyclic, C 6 The -10 aryl
  • each R 1 is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, thiol, amino, nitro, cyano, methyl, ethyl, isopropyl, allyl , propenyl, propargyl, propynyl, difluoromethyl, trifluoromethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, Methylthio, ethylthio, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, Piperazinyl, morpholinyl, phenyl, decyl, pyrrolyl, amino, nitro,
  • each R 2 is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, tri Fluoromethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.
  • each R 3 is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, tri Fluoromethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.
  • R 4 is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl 1,2-Difluoroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.
  • R is hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein said C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6
  • R is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, allyl, ethynyl, propargyl, cyclopropyl, cyclo Butyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, Pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl or thia An azole group, wherein the methyl,
  • 1, 2 or 3 are selected from the group consisting of hydrazine, fluorine, chlorine, bromine, iodine, hydroxy, amino, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy Substituted with a C 1-3 haloalkoxy group.
  • Q is hydrogen, hydrazine, fluoro, chloro, bromo, iodo, hydroxy, decyl, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl 1,1,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylsulfonyl, ethylsulfonyl, Acetyl, propionyl, butyryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl , tetrahydropyranyl, morpholinyl, phenyl, pyr
  • the compound of the present invention is a compound of formula (II), or a stereoisomer, geometric isomer, tautomer, oxynitride of a compound of formula (II). a hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
  • the compound of the invention is a compound of formula (III) or (IV), or a stereoisomer, geometric isomer of a compound of formula (III) or (IV), Tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • the invention comprises a stereoisomer, a geometric isomer, a tautomer, an oxynitride, a solvate, a hydrate, a metabolite, or a compound of one of the following compounds or one of the following:
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a stereoisomer, geometric isomer of a compound of formula (I), formula (II), formula (III) or (IV) of the invention , tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, and pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles thereof Things, or any combination of them.
  • the invention relates to a compound of formula (I), formula (II), formula (III) or (IV) or a pharmaceutical composition thereof for use in the manufacture of a medicament for the prevention, treatment or amelioration of a disease modulated by ASK1 in a patient the use of.
  • the ASK1 regulated disease of the present invention is an autoimmune disease, an inflammation, a cardiovascular disease, a heart and kidney disease, a fibrotic disease, a respiratory disease, a liver disease, or a neurodegenerative disease.
  • the cardiovascular diseases of the present invention include diabetes, diabetic nephropathy, and other diabetic complications.
  • the fibrotic diseases of the invention include pulmonary and renal fibrosis.
  • the respiratory diseases of the present invention include chronic embolic pulmonary obstruction, idiopathic pulmonary fibrosis, and acute lung injury.
  • the liver disease of the present invention includes chronic liver disease, metabolic liver disease, liver fibrosis, primary sclerosing cholangitis, nonalcoholic fatty liver, nonalcoholic steatohepatitis, hepatic ischemia-re Perfusion injury and primary biliary cirrhosis.
  • One aspect of the invention relates to a method of preventing, treating or ameliorating a disease modulated by ASK1 in a patient comprising administering to the patient a pharmaceutically acceptable effective amount of a compound of the invention.
  • the invention relates to a process for the preparation, isolation and purification of a compound encompassed by formula (I), formula (II), formula (III) or (IV).
  • compositions for the preparation of the compounds of the invention and uses of the pharmaceutical compositions
  • the pharmaceutical composition of the present invention comprises a compound of formula (I), formula (II), formula (III) or (IV), a compound of the invention and a pharmaceutically acceptable carrier, Agent or excipient.
  • the amount of the compound in the compositions of the present invention is effective to detectably reduce or alleviate ASK1-mediated diseases in a patient.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, ester salts, or any other agent that can be administered, directly or indirectly, depending on the needs of the patient.
  • compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or excipient, as used herein, including any solvent, diluent or other liquid.
  • a pharmaceutically acceptable carrier including any solvent, diluent or other liquid.
  • Excipients, dispersing or suspending agents, surfactants, isotonic agents, thickening agents, emulsifiers, preservatives, solid binders or lubricants, and the like are suitable for the particular target dosage form.
  • a pharmaceutically acceptable carrier including any solvent, diluent or other liquid.
  • Excipients, dispersing or suspending agents, surfactants, isotonic agents, thickening agents, emulsifiers, preservatives, solid binders or lubricants, and the like are suitable for the particular target dosage form.
  • Remington The Science and Practice of Pharmacy, 21st edition, 2005, ed. DBTroy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology
  • the compound of the present invention can be uniformly incorporated in the mixture as an active ingredient together with a pharmaceutical carrier according to a conventional pharmaceutical compounding technique.
  • a pharmaceutical carrier can take a wide variety of forms.
  • any conventional pharmaceutical medium may be used, for example, water, ethylene glycol, oil, alcohol, fragrance, antiseptic when used in the preparation of oral liquid preparations such as suspensions, elixirs and solutions.
  • oral solid preparations such as powders, hard capsules, soft capsules and tablets, for example, starch, sugar, microcrystalline cellulose, diluent, granulating agent, lubricant, binder, A disintegrating agent or the like, wherein a solid oral preparation is more preferable than a liquid medicine.
  • tablets and capsules are easy to take, they represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.
  • the tablets can be coated with standard aqueous or non-aqueous techniques.
  • Such compositions and formulations should contain at least 0.1% active compound.
  • the percentage of active compound in these compositions can be varied, and the percentage can conveniently be between about 2% and about 60% by weight.
  • the active compound can be administered intranasally, for example, in the form of droplets or sprays.
  • the tablets, pills, capsules and the like may also comprise: a binder (such as gum tragacanth, acacia, corn starch or gelatin); an excipient (such as dicalcium phosphate); a disintegrating agent (such as corn starch, Potato starch, alginic acid); a lubricant (such as magnesium stearate); and a sweetener (such as sucrose, lactose or saccharin).
  • a binder such as gum tragacanth, acacia, corn starch or gelatin
  • an excipient such as dicalcium phosphate
  • a disintegrating agent such as corn starch, Potato starch, alginic acid
  • a lubricant such as magnesium stearate
  • a sweetener such as sucrose, lactose or saccharin
  • a liquid carrier such as a fatty oil.
  • a wide variety of other materials may be present as coatings or to modify the shape of the dosage unit.
  • the tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl or propylparaben as a preservative, a dye and a flavoring such as cherry or orange.
  • ophthalmic formulations ophthalmic ointments, powders, solutions, and the like.
  • the compounds of the invention may also be administered parenterally.
  • a solution or suspension of these active substances can be prepared by suitably mixing with a surfactant such as hydroxypropylcellulose in water.
  • Dispersing agents can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof, and in oils. These preparations contain a preservative to prevent the growth of microorganisms under the usual conditions of storage and use.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the preparation of sterile injectable solutions or dispersions.
  • the form of the drug must be sterile and must be in the form of an easily injectable fluid. It must be stable under the conditions of manufacture and storage and must be preserved under the conditions of contamination by microorganisms such as bacteria and fungi.
  • the carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • any suitable method of administration can be used to provide an effective amount of a compound of the invention to a mammal, especially a human.
  • oral, transrectal, topical, parenteral, transocular, transpulmonary, nasal, and the like can be used.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, emulsions, ointments, aerosols, and the like.
  • the compounds of the invention are administered orally.
  • the therapeutically effective dose of a compound, pharmaceutical composition or combination thereof of the invention will depend on the species, weight, age and individual condition of the individual, the disorder or disease to be treated or the severity thereof.
  • a physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient required to prevent, treat or inhibit the progression of the disorder or disease.
  • the total daily dose is from about 1.0 mg to about 1000 mg, preferably from about 1 mg to about 50 mg.
  • the total daily dose is generally from 7 mg to about 350 mg. This dosage method can be adjusted to provide optimal therapeutic results.
  • the compound, composition or pharmaceutically acceptable salt thereof or hydrate thereof according to the invention can be effectively used for preventing, treating, treating or alleviating a disease regulated by ASK1 in a patient, in particular, effective treatment for diabetes, diabetic nephropathy, other diabetic complications, Chronic kidney disease, lung and renal fibrosis, chronic embolic pulmonary obstruction, idiopathic pulmonary fibrosis, acute lung injury, chronic liver disease, metabolic liver disease, liver fibrosis, primary sclerosing cholangitis, nonalcoholic fatty liver Nonalcoholic steatohepatitis, hepatic ischemia-reperfusion injury, primary biliary cirrhosis, and other hepatitis.
  • the compounds of the invention can be prepared by the methods described herein, unless otherwise stated, wherein the substituents are as defined for formula (I), formula (II), formula (III) or (IV). .
  • the following reaction schemes and examples are provided to further illustrate the contents of the present invention.
  • the reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated.
  • the general reagents were purchased from Shantou Xiqiao Chemical Plant, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Plant.
  • Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether are obtained by refluxing with sodium metal.
  • Anhydrous dichloromethane and chloroform were obtained by reflux drying of calcium hydride.
  • Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were previously dried over anhydrous sodium sulfate.
  • reaction is generally carried out under a positive pressure of nitrogen or argon or on a dry solvent (unless otherwise indicated), the reaction bottle is stoppered with a suitable rubber stopper, and the substrate is driven through a syringe.
  • the glassware is dry.
  • the column is a silica gel column.
  • Silica gel 300-400 mesh
  • the nuclear magnetic resonance spectrum is tested under the conditions of room temperature, Bruker 400MHz or 600MHz nuclear magnetic instrument, using CDC1 3 , d 6 -DMSO, CD 3 OD or d 6 -acetone as solvent (reported in ppm).
  • TMS 0. ppm
  • chloroform 7.25 ppm
  • MS data was measured with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30 °C) Agilent 6320 Series LC-MS spectrometer, G1329A autosampler and G1315B DAD detector applied For analysis, the ESI source was applied to an LC-MS spectrometer.
  • MS mass spectrometry
  • Both spectrometers are equipped with an Agilent Zorbax SB-C18 column measuring 2.1 x 30 mm, 5 ⁇ m.
  • the injection volume was determined by sample concentration; the flow rate was 0.6 mL/min; the peak of HPLC was recorded by UV-Vis wavelengths at 210 nm and 254 nm.
  • the mobile phase was a 0.1% formic acid acetonitrile solution (Phase A) and a 0.1% formic acid ultrapure aqueous solution (Phase B).
  • the gradient elution conditions are shown in Table 1:
  • the compound (Ia) can be obtained by a condensation reaction of the compound (1a) and the compound (1b).
  • the reaction raw material is in a condensing agent (for example, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-(3) -dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, etc.) and a base (for example, N,N-diisopropylethylamine, N-methylmorpholine) in the presence of a solvent reaction.
  • the reaction is preferably carried out in a solvent inert to the reaction, and the solvent used includes, but is not limited to, N,N-dimethylformamide and the like.
  • L o is a halogen
  • Compound (2b) can be obtained by reacting compound (2a) with ethyl bromoacetate;
  • Compound (2c) can be obtained by coupling reaction of compound (2b) with an amino group protected by a protecting group;
  • the compound (2d) can be obtained by removing the amino group protecting group from the compound (2c), and the hydrolysis reaction can be carried out by referring to "Protective Groups in Organic Synthesis";
  • Compound (2e) can be obtained by subjecting compound (2d) to a substitution reaction with an ⁇ -haloacyl compound
  • Example 1 4-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl) Pyridin-2-yl)benzofuran-2-carboxamide
  • Step 2 4-((tert-Butoxycarbonyl)amino)benzofuran-2-carboxylic acid ethyl ester
  • the third step is 4-aminobenzofuran-2-carboxylic acid ethyl ester
  • the fourth step 4-((2-cyclopropyl-2-oxoethyl)amino)benzofuran-2-carboxylic acid ethyl ester
  • Step 5 4-(4-Cyclopropyl-2-indolyl-1H-imidazol-1-yl)benzofuran-2-carboxylic acid ethyl ester
  • Step 8 4-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)benzofuran-2-carboxamide
  • the third step is 6-aminobenzofuran-2-carboxylic acid ethyl ester
  • Trifluoroacetic acid (3 mL) was added to a solution of ethyl 6-((tert-butoxycarbonyl)amino)benzofuran-2-carboxylate (5.0 g, 16 mmol) in dichloromethane (3 mL). Stir overnight. The solvent was evaporated under reduced pressure. The mixture was evaporated. Filtration and EtOAc (EtOAc)
  • Step 5 6-(N-(2-Cyclopropyl-2-oxoethyl)carboxamido)benzofuran-2-carboxylic acid ethyl ester
  • Step 8 6-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)benzofuran-2-carboxamide
  • the third step is 5-aminobenzofuran-2-carboxylic acid ethyl ester
  • the ninth step 5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)benzofuran-2-carboxamide
  • the third step 4-(3-(methylsulfonyl)propoxy)benzofuran-2-carbonyl chloride
  • the second step is methyl 4-hydroxybenzofuran-2-carboxylate
  • the third step 4-(2-methoxyethoxy)benzofuran-2-carboxylic acid methyl ester
  • the fourth step 4-(2-methoxyethoxy)benzofuran-2-carboxylic acid
  • the second step is ethyl 4-hydroxy-3-methylbenzofuran-2-carboxylate
  • the third step is ethyl 3-methyl-4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-2-carboxylate
  • Step 4 4-((tert-Butoxycarbonyl)amino)-3-methylbenzofuran-2-carboxylic acid ethyl ester
  • Step 7 4-(N-(2-Cyclopropyl-2-oxoethyl)carboxamido)-3-methylbenzofuran-2-carboxylic acid ethyl ester
  • Step 8 4-(4-Cyclopropyl-1H-imidazol-1-yl)-3-methylbenzofuran-2-carboxylic acid ethyl ester
  • Step 10 4-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)-3-methylbenzofuran-2-carboxamide
  • 6-Bromopyridine-2-formylhydrazide 11 g, 50.92 mmol
  • 6-methoxy-2,3,4,5-tetrahydropyridine 6.0 g, 53 mmol
  • DMSO 150 mL
  • dichloromethane 200 mL ⁇ 2
  • the organic phase was combined, and the organic phase was washed with saturated brine (150 mL ⁇ 2). Drying over anhydrous sodium sulfate, EtOAc (EtOAc m. , 47%);
  • the second step (6-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-yl)carbamic acid Tert-butyl ester
  • the fourth step 4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4 ,3-a]pyridin-3-yl)pyridin-2-yl)benzofuran-2-carboxamide
  • the fourth step is 4-aminobenzo[b]thiophene-2-carboxylic acid methyl ester
  • Step 6 4-(N-(2-Cyclopropyl-2-oxoethyl)carboxamido)benzo[b]thiophene-2-carboxylic acid methyl ester
  • Step 7 4-(4-Cyclopropyl-1H-imidazol-1-yl)benzo[b]thiophene-2-carboxylic acid methyl ester
  • Step 10 4-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)benzo[b]thiophene-2-carboxamide
  • Ethyl pyruvate (11 g, 94.730) was added dropwise to a solution of 3-nitrophenylhydrazine hydrochloride (18 g, 94.9 mmol) and sodium acetate (8.6 g, 100 mmol) in ethanol/water (5:7, 360 mL) at 60 °C. A solution of ethanol/water (10:1, 30 mL) was added dropwise and stirred at room temperature overnight. Filtration, EtOAc (EtOAc)
  • Example 3 The synthesis of the first step of Example 3 was carried out using 1-(tert-butyl)2-ethyl-4-carboxamido-1H-indole-1,2-dicarboxylate (1.4 g, 4.2 mmol) as a starting material.
  • the title compound (1.0 g, 57%)
  • Step 7 4-(4-Cyclopropyl-1H-imidazol-1-yl)-1H-indole-2-carboxylic acid ethyl ester
  • Step 8 4-(4-Cyclopropyl-1H-imidazol-1-yl)-1H-indole-2-carboxylic acid
  • Step 9 4-(4-Cyclopropyl-1H-imidazol-1-yl)-1H-indole-2-carbonyl chloride
  • Step 10 4-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl) Pyridin-2-yl)-1H-indole-2-carboxamide
  • the third step 4-(4-cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carbonyl chloride
  • the fourth step 4-(4-cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carboxamide
  • Step 5 4-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2, 4]Triazol-3-yl)pyridin-2-yl)benzofuran-2-carboxamide
  • the second step is 7-nitrobenzofuran-2-carboxylic acid ethyl ester
  • the third step is 7-aminobenzofuran-2-carboxylic acid ethyl ester
  • the fourth step is 7-formamide benzofuran-2-carboxylic acid ethyl ester
  • Step 5 7-(N-(2-Cyclopropyl-2-oxoethyl)carboxamido)benzofuran-2-carboxylic acid ethyl ester
  • Step 6 7-(4-Cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carboxylic acid ethyl ester
  • Step 7 7-(4-Cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carboxylic acid
  • Step 8 7-(4-Cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carbonyl chloride
  • the ninth step 7 (4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)benzofuran-2-carboxamide
  • Second step ethyl 5-((tert-butoxycarbonyl)amino)imidazo[1,2-a]pyridine-2-carboxylate
  • Step 5 5-(N-(2-Cyclopropyl-2-oxoethyl)carboxamido)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester
  • Step 6 5-(4-Cyclopropyl-1H-imidazol-1-yl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester
  • Step 7 5-(4-Cyclopropyl-1H-imidazol-1-yl)imidazo[1,2-a]pyridine-2-carboxylic acid
  • Step 8 5-(4-Cyclopropyl-1H-imidazol-1-yl)imidazo[1,2-a]pyridine-2-carbonyl chloride
  • Step 9 5-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl) Pyridin-2-yl)imidazo[1,2-a]pyridine-2-carboxamide
  • the third step 4-(4-cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carbonyl chloride
  • Step 5 4-(4-Cyclopropyl-1H-imidazol-1-yl)-1-methyl-1H-indole-2-carboxylic acid ethyl ester
  • Step 6 4-(4-Cyclopropyl-1H-imidazol-1-yl)-1-methyl-1H-indole-2-carboxylic acid
  • Step 7 4-(4-Cyclopropyl-1H-imidazol-1-yl)-1-methyl-1H-indole-2-carbonyl chloride
  • Step 8 4-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl) Pyridin-2-yl)-1-methyl-1H-indole-2-carboxamide
  • the third step 4-(4-fluoro-1H-imidazol-1-yl)benzofuran-2-carboxylic acid
  • the fourth step 4-(4-fluoro-1H-imidazol-1-yl)benzofuran-2-carbonyl chloride
  • Step 5 4-(4-Fluoro-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine- 2-based) benzofuran-2-carboxamide
  • the fourth step 4-bromo-5-fluorobenzofuran-2-carboxylic acid ethyl ester
  • Step 8 4-(N-(2-Cyclopropyl-2-oxoethyl)carboxamido)-5-fluorobenzofuran-2-carboxylic acid ethyl ester
  • Step 9 4-(4-Cyclopropyl-1H-imidazol-1-yl)-5-fluorobenzofuran-2-carboxylic acid ethyl ester
  • the eleventh step 4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluorobenzofuran-2-carbonyl chloride
  • the second step 4-fluoro-2-hydroxy-6-methoxybenzaldehyde
  • the third step is 6-fluoro-4-methoxybenzofuran-2-carboxylic acid ethyl ester
  • the fifth step is 6-fluoro-4-hydroxybenzofuran-2-carboxylic acid ethyl ester
  • the sixth step is 6-fluoro-4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-2-carboxylic acid ethyl ester
  • Step 7 4-((tert-Butoxycarbonyl)amino)-6-fluorobenzofuran-2-carboxylic acid ethyl ester
  • Step 8 4-Amino-6-fluorobenzofuran-2-carboxylic acid ethyl ester
  • Step 10 4-(N-(2-Cyclopropyl-2-oxoethyl)carboxamido)-6-fluorobenzofuran-2-carboxylic acid ethyl ester
  • the eleventh step 4-(4-cyclopropyl-1H-imidazol-1-yl)-6-fluorobenzofuran-2-carboxylic acid ethyl ester
  • Step 12 4-(4-Cyclopropyl-1H-imidazol-1-yl)-6-fluorobenzofuran-2-carboxylic acid
  • the third step 4-(methylindenyl)-1H-imidazole
  • Step 7 N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-(4-(methylindenyl)-1H -imidazol-1-yl)benzofuran-2-carboxamide
  • the second step is ethyl 4-acetoxy-3-(dibromomethyl)benzofuran-2-carboxylate
  • the third step 4-acetoxy-3-formylbenzofuran-2-carboxylic acid ethyl ester
  • the fourth step is ethyl 4-acetoxy-3-(difluoromethyl)benzofuran-2-carboxylate
  • Step 7 4-((tert-Butoxycarbonyl)amino)-3-(difluoromethyl)benzofuran-2-carboxylic acid methyl ester
  • Step 10 4-(N-(2-Cyclopropyl-2-oxoethyl)carboxamido)-3-(difluoromethyl)benzofuran-2-carboxylic acid methyl ester
  • the eleventh step 4-(4-cyclopropyl-1H-imidazol-1-yl)-3-(difluoromethyl)benzofuran-2-carboxylic acid methyl ester
  • Step 12 4-(4-Cyclopropyl-1H-imidazol-1-yl)-3-(difluoromethyl)benzofuran-2-carboxylic acid
  • Step 13 4-(4-Cyclopropyl-1H-imidazol-1-yl)-3-(difluoromethyl)benzofuran-2-carbonyl chloride
  • Step 16 4-(4-Cyclopropyl-1H-imidazol-1-yl)-3-(difluoromethyl)-N-(6-(4-isopropyl-4H-1,2,4 -triazol-3-yl)pyridin-2-yl)benzofuran-2-carboxamide
  • Step 7 4-((tert-Butoxycarbonyl)amino)benzo[d]thiazole-2-carboxylic acid methyl ester
  • Step 10 4-(N-(2-Cyclopropyl-2-oxoethyl)carboxamido)benzo[d]thiazole-2-carboxylic acid methyl ester
  • Step 12 4-(4-Cyclopropyl-1H-imidazol-1-yl)benzo[d]thiazole-2-carboxylic acid
  • Step 2 (R)-6-(4-(1-methoxypropan-2-yl)-4H-1,2,4-triazol-3-yl)pyridinecarboxylic acid
  • Step 4 (R)-6-(4-(1-methoxypropan-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-amine
  • Step 5 4-((tert-Butoxycarbonyl)amino)-5-methylbenzofuran-2-carboxylic acid ethyl ester
  • Step 7 4-formamide-5-methylbenzofuran-2-carboxylic acid ethyl ester
  • Step 8 4-(N-(2-Cyclopropyl-2-oxoethyl)carboxamido)-5-methylbenzofuran-2-carboxylic acid ethyl ester
  • Step 9 4-(4-Cyclopropyl-1H-imidazol-1-yl)-5-methylbenzofuran-2-carboxylic acid ethyl ester
  • Step 10 4-(4-Cyclopropyl-1H-imidazol-1-yl)-5-methylbenzofuran-2-carboxylic acid
  • Step 12 4-(4-Cyclopropyl-1H-imidazol-1-yl)-5-methylbenzofuran-2-carboxamide
  • Step 13 4-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(6,7-dihydro-5H-pyrrolo[2,1-c][1, 2,4]triazol-3-yl)pyridin-2-yl)-5-methylbenzofuran-2-carboxamide
  • ASK1 apoptosis signal-regulated kinase 1 inhibitory activity test
  • the compound was diluted 3 times in a kinase buffer (20 mM HEPES, pH 7.5; 0.01% Triton X-100; 25 mM MgCl 2 ; 2 mM DTT) to obtain 10 concentration solutions from 2000 nM to 0.102 nM, and the above 10 concentration solutions were 2.5.
  • a kinase buffer (20 mM HEPES, pH 7.5; 0.01% Triton X-100; 25 mM MgCl 2 ; 2 mM DTT
  • ⁇ L/well was added to the 384-well plate so that the final concentration of the compound in the kinase assay was 500-0.025 nM; then 2.5 ⁇ L of ASK1 at a concentration of 200 nM was added to each well, and the mixture was shaken evenly and 5 ⁇ L of substrate solution was added to each well [MBP (Myelin basic) Protein, myelin basic protein concentration of 1000 ⁇ M, ATP concentration of 300 ⁇ M], shaking, the final concentration of ASK1, MBP, ATP is 50nM, 500 ⁇ M, 150 ⁇ M, respectively; at the same time set buffer hole (no compound, add the same concentration of enzyme And substrate) and negative wells (no compound and enzyme, adding the same concentration of substrate); sealing plate, 1 hour incubation at 37 ° C using ADP-Glo kinase detection kit (Promege, Cat.
  • the kinase activity was detected, and the relative light unit (RLU) was read.
  • the inhibition rate of the compound inhibiting ASK1 activity was calculated by the following formula, and the IC 50 was calculated using GraphPad Prism 5.
  • Inhibition rate (%) (RLU buffer well - RLU drug well ) / (RLU buffer well - RLU negative well ) ⁇ 100
  • mice Six healthy adult male SD rats (purchased from Hunan Slack Jingda Experimental Animal Co., Ltd.) were divided into two groups, three in each group, and intravenous intravenous injection and oral gavage were administered separately.
  • Drug configuration A certain amount of the compound of the invention was weighed, and 5% DMSO, 10% Kolliphor HS15 and 85% saline (0.9%) were added to the target concentration of the compound solution.
  • the compound of the present invention has higher blood drug concentration and exposure level after oral administration, lower clearance rate, better bioavailability, and good pharmacokinetic characteristics.

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Abstract

L'invention concerne un composé bicyclique fusionné et son utilisation dans un médicament, en particulier un nouveau composé bicyclique fusionné utilisé comme régulateur d'activité ASK1 et un stéréoisomère, un isomère géométrique, un tautomère, un oxyde d'azote, un hydrate, un solvate, un métabolite, un sel pharmaceutiquement acceptable ou un promédicament de celui-ci, et l'utilisation du composé dans la préparation d'un médicament pour le traitement d'une maladie et/ou d'une affection régulée par ASK1. L'invention concerne également une composition pharmaceutique contenant le composé et une méthode de traitement d'une maladie et/ou d'une affection à médiation par ASK1 à l'aide du composé ou de la composition pharmaceutique associée.
PCT/CN2018/091392 2017-06-19 2018-06-15 Composé bicyclique fusionné et son utilisation en médecine Ceased WO2018233553A1 (fr)

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CN113302185A (zh) * 2019-04-29 2021-08-24 上海和誉生物医药科技有限公司 苯并呋喃-6-甲酰胺衍生物、其制备方法和药学上的应用
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US11834436B2 (en) 2018-05-02 2023-12-05 Enanta Pharmaceuticals, Inc. Tetrazole containing apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
US11008304B2 (en) 2018-05-02 2021-05-18 Enanta Pharmaceuticals, Inc. Tetrazole containing apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
WO2020030107A1 (fr) * 2018-08-10 2020-02-13 江苏豪森药业集团有限公司 Composition pharmaceutique contenant des dérivés amides, son procédé de préparation et application associée
CN110818683A (zh) * 2018-08-10 2020-02-21 中国科学院上海药物研究所 2-吡啶取代脲结构小分子化合物及其合成和应用
CN110818683B (zh) * 2018-08-10 2023-04-14 中国科学院上海药物研究所 2-吡啶取代脲结构小分子化合物及其合成和应用
US10968199B2 (en) 2018-08-22 2021-04-06 Enanta Pharmaceuticals, Inc. Cycloalkyl-containing apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
US12077523B2 (en) 2018-10-18 2024-09-03 Hk Inno.N Corporation N-(isopropyl-triazolyl)pyridinyl)-heteroaryl-carboxamide derivatives and use thereof
EP3867243B1 (fr) * 2018-10-18 2024-06-05 HK inno.N Corporation Nouveaux dérivés de n-(isopropyl-triazolyl)pyridinyl)-hétéroaryl-carboxamide et leur utilisation
US11345699B2 (en) 2018-11-19 2022-05-31 Enanta Pharmaceuticals, Inc. Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
US11466033B2 (en) 2019-03-25 2022-10-11 Enanta Pharmaceuticals, Inc. Substituted pyridines as apoptosis signal-regulating kinase 1 inhibitors
CN113302185B (zh) * 2019-04-29 2024-04-09 上海和誉生物医药科技有限公司 苯并呋喃-6-甲酰胺衍生物、其制备方法和药学上的应用
CN113302185A (zh) * 2019-04-29 2021-08-24 上海和誉生物医药科技有限公司 苯并呋喃-6-甲酰胺衍生物、其制备方法和药学上的应用
CN114585616B (zh) * 2019-08-19 2024-01-16 广东东阳光药业股份有限公司 酰胺衍生物及其在药物中的应用
CN114585616A (zh) * 2019-08-19 2022-06-03 广东东阳光药业有限公司 酰胺衍生物及其在药物中的应用
WO2021031071A1 (fr) * 2019-08-19 2021-02-25 广东东阳光药业有限公司 Dérivé d'amide et son utilisation dans la médecine
CN111808079A (zh) * 2020-08-05 2020-10-23 中国药科大学 吲哚类ask1小分子抑制剂及其制备方法和应用

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