WO2019034096A1 - Composés bicycliques fusionnés et leurs utilisations en médecine - Google Patents

Composés bicycliques fusionnés et leurs utilisations en médecine Download PDF

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WO2019034096A1
WO2019034096A1 PCT/CN2018/100736 CN2018100736W WO2019034096A1 WO 2019034096 A1 WO2019034096 A1 WO 2019034096A1 CN 2018100736 W CN2018100736 W CN 2018100736W WO 2019034096 A1 WO2019034096 A1 WO 2019034096A1
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independently
alkyl
cyclopropyl
methyl
amino
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PCT/CN2018/100736
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Xinye YANG
Shengqiang PAN
Facheng MA
Yingxun ZHANG
Xiaojun Wang
Yingjun Zhang
Chuanfei JIN
Ji Zhang
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Sunshine Lake Pharma Co., Ltd.
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Publication of WO2019034096A1 publication Critical patent/WO2019034096A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to fused bicyclic compounds having enzyme inhibitory activity and pharmaceutical compositions thereof, the compounds and compositions can be used in the manufacture of a medicament for treating a disease modulated by ASK1.
  • Apoptosis signal-regulating kinase 1 is a member of the mitogen-activated protein kinase kinase kinase (MAP3Ks) family, MAP3Ks can activate c-Jun N-terminal protein kinase (JNK) and p38 mitogen-activated protein (MAP) kinase (Ichijo, H., Nishida, E., Irie, K., Dijke, P.T., Saitoh, Moriguchi, T., Matsumoto, K., Miyazono, K., and Gotoh, Y. (1997) Science, 275, 90-94) .
  • ASK1 also known as mitogen-activated protein kinase kinase kinase 5 (MAPKKK5, MAP3K5) , includes 1375 amino acid residues composing 11 kinase subdomains and one serine/threonine kinase area located in the middle part of the side molecule of the N terminal and C terminal coiled coil (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 may be activated by various stimuluses, for example, oxidative stress, active oxygen, endotoxin, tumor necrosis factor- ⁇ , endoplasmic reticulum stress and intracellular concentration of calcium ions, and so on.
  • 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.
  • Various diseases can be treated and prevented by regulating the activity of ASK1, including neurodegenerative diseases, cardiovascular diseases, inflammation, autoimmune diseases and metabolic disorders.
  • ASK1 modulators particularly have an enormous potential in the treatment of cardiorenal diseases (including kidney disease, diabetic nephropathy, and chronic kidney disease) , fibrosis (including pulmonary fibrosis and renal fibrosis) , respiratory diseases (including chronic pulmonary thromboembolic disease and acute lung injury) and liver disease.
  • liver diseases are generally classified into acute and chronic liver diseases.
  • Liver disease may 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.
  • the common liver diseases include chronic liver disease, metabolic liver disease, liver fibrosis, primary sclerosing cholangitis, nonalcoholic fatty liver, nonalcoholic steatohepatitis, liver ischemia-reperfusion injury and primary biliary cirrhosis, and so on.
  • ASK1 modulators for the prevention or treatment of autoimmune diseases, inflammation, cardiovascular diseases and neurodegenerative diseases.
  • the use of ASK1 modulators to treat liver disease is disclosed in WO2015187499 and WO2016049070. However, there is still a need for more and better ASK1 modulators in the clinic.
  • the present invention provides a compound and a pharmaceutical composition thereof, which may be used as an ASK1 modulator.
  • the present invention further relates to use of the compound and the composition thereof in the manufacture of a medicament for modulating ASK1 activity to treat a disorder or disease.
  • the present invention further describes the synthetic method of the compound.
  • the compounds of the invention show good bioactivity and pharmacokinetic properties.
  • a compound having Formula (I) or a stereoisomer a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
  • X 1 is C (R 1 ) or N;
  • X 2 is C (R 2 ) or N;
  • X 3 is C (R 3 ) or N;
  • X 4 is C (R 4 ) or N;
  • E is 5-6 membered heteroaryl
  • each R y is independently H, deuterium, halogen, hydroxy, amino, nitro, cyano, acetyl, acetamido, -COOH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy;
  • G is a fused bicyclic ring
  • n 1, 2 or 3;
  • n 1, 2 or 3;
  • k is 1, 2, 3, 4 or 5;
  • each of R 1 , R 2 , R 3 and R 4 is independently H, deuterium, F, Cl, Br, I, hydroxy, mercapto, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, methylthio, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, epoxypropyl, tetrahydrofuryl, tetrahydropyranyl or morpholinyl, wherein the hydroxy, mercapto, amino, methyl, ethyl, n-propyl, isoprop
  • E is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl or thiadiazolyl.
  • each R x is independently deuterium, F, Cl, Br, I, hydroxy, mercapto, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, methylthio, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, epoxypropyl, tetrahydrofuryl, tetrahydropyranyl or morpholinyl, wherein the hydroxy, mercapto, amino, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy, isopropoxy,
  • each R y is independently H, F, Cl, Br, I, hydroxy, amino, nitro, cyano, acetyl, acetamido, -COOH, methyl, ethyl, isopropyl, t-butyl, trifluoromethyl, difluoromethyl, methoxy, isopropoxy, trifluoromethoxy or difluoromethoxy.
  • G is an 8-12 membered fused bicyclic ring.
  • G is
  • each W 1 is independently -O-, -S-or -NH-;
  • each W 2 , W 3 , W 4 and W 5 is independently CH or N;
  • each W is independently - (CH 2 ) p -, - (CH 2 ) p O-, - (CH 2 ) p NH-or - (CH 2 ) p S (O) t -; wherein each p is independently 0, 1, 2 or 3, each t is independently 0, 1 or 2.
  • G is
  • each R a , R b , R c and R d is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, isopropoxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, epoxypropyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thieny
  • the compound disclosed herein has Formula (IIa) , (IIb) , (IIc) , (IId) or (IIe) , or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
  • a pharmaceutical composition comprising the above compound or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, or a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
  • provided herein is use of the above mentioned compound or pharmaceutical composition thereof disclosed herein in the manufacture of a medicament for preventing, treating or lessening a disease modulated by ASK1.
  • provided herein is a method of preventing, treating or lessening a disease modulated by ASK1 comprising administering a therapeutically effective amount of the above mentioned compound or pharmaceutical composition to the patient.
  • provided herein is the above mentioned compound or pharmaceutical composition for use in preventing, treating or lessening a disease modulated by ASK1
  • the disease modulated by ASK1 is an autoimmune disease, inflammation, angiocardiopathy, a cardiorenal disease, fibrosis, a respiratory disease, a liver disease, or a neurodegenerative disease.
  • the angiocardiopathy includes diabetes, diabetic nephropathy and other diabetic complications.
  • the fibrosis includes pulmonary fibrosis and renal fibrosis; the respiratory disease includes chronic obstructive pulmonary, idiopathic pulmonary fibrosis and acute lung injury.
  • the liver disease includes chronic liver diseases, metabolic liver diseases, liver fibrosis, primary sclerosing cholangitis, nonalcoholic fatty liver, nonalcoholic steatohepatitis, liver ischemia-reperfusion injury and primary biliary cirrhosis.
  • provided herein is a method of preparing, separating or purifying the above compound.
  • compounds disclosed herein may optionally be substituted with one or more substituents, such as are illustrated generally below, or as exemplified by particular classes, subclasses, and species of the invention.
  • substituents such as are illustrated generally below, or as exemplified by particular classes, subclasses, and species of the invention.
  • the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted” .
  • substituted refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent.
  • an optionally substituted group may have a substituent at each substitutable position of the group.
  • alkyl or “alkyl group” refers to a saturated linear or branched-chain monovalent hydrocarbon radical of 1 to 20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, or 1-2 carbon atoms, wherein the alkyl radical may be optionally and independently substituted with one or more substituents described herein.
  • alkyl group further include, 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 )
  • alkyl or the prefix “alk-” is inclusive of both straight chain and branched saturated carbon chain.
  • alkylidene or “alkylene” used herein refers to a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms. Examples of alkylene groups include, but are not limited to, methylene, ethylene, isopropylene, and the like.
  • alkenyl refers to a linear or branched chain monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, with at least one site of unsaturation, i.e., a carbon-carbon, sp 2 double bond, wherein the alkenyl radical may be independently and optionally substituted with one or more substituents described herein, and includes radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations.
  • alkynyl refers to a linear or branched chain monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, with at least one carbon-carbon, sp triple bond, wherein the alkynyl radical may be optionally and independently substituted with one or more substituents described herein.
  • Specific examples of the alkynyl group include, but are not limited to, ethynyl (-C ⁇ CH) , propargyl (-CH 2 C ⁇ CH) .
  • halogen refers to F (fluorine, fluoro) , Cl (chlorine, chloro) , Br (bromine, bromo) , or I (iodine, iodo) .
  • unsaturated refers to a moiety having one or more units of unsaturation.
  • alkoxy refers to an alkyl group, as defined herein, attached to the other moiety of the compound molecular through an oxygen atom.
  • the alkoxy group is C 1-4 alkoxy.
  • Some non-limiting examples of the alkoxy group include methoxy, ethoxy, propoxy and butoxy, and the like.
  • the alkoxy group may be optionally and independently substituted with one or more substituents disclosed herein.
  • alkylthio or “alkyl-thio” refers to an alkyl group, as defined herein, attached to the other moiety of the compound molecular through a sulphur atom.
  • the alkylthio group is C 1-6 alkylthio.
  • the alkylthio group is C 1-3 alkylthio.
  • Some non-limiting examples of the alkylthio group include methylthio, ethylthio, n-propylthio and isopropylthio, and the like.
  • the alkylthio group may be optionally and independently substituted with one or more substituents disclosed herein.
  • alkoxyalkyl refers to an alkyl group substituted with one or more alkoxy groups, wherein the alkoxy and alkyl groups are as defined herein.
  • the alkoxyalkyl is C 1-6 alkoxy-C 1-6 -alkyl.
  • the alkoxyalkyl is C 1-3 alkoxy-C 1-3 -alkyl.
  • the “alkoxyalkyl” group may be independently and optionally substituted with one or more substituents disclosed herein.
  • haloalkyl refers to alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms.
  • haloalkyl is halo C 1-6 alkyl.
  • haloalkyl is halo C 1-3 alkyl.
  • haloalkyl-oxy or haloalkoxy is halo C 1-6 alkyl-oxy or halo C 1-6 alkoxy.
  • haloalkyl-oxy or haloalkoxy is halo C 1-3 alkyl-oxy or halo C 1-3 alkoxy.
  • haloalkyl, haloalkenyl or haloalkoxy may be optionally and independently substituted with one or more substituents described herein.
  • alkylamino includes “N-alkylamino” and “N, N-dialkylamino” , wherein the amino groups are independently substituted with one alkyl radical or two alkyl radicals, respectively.
  • the alkylamino is a C 1-6 alkylamino group.
  • the alkylamino is a C 1-3 alkylamino group.
  • Some non-limiting examples of such group include N-methylamino, N-ethylamino, N, N-dimethylamino, N, N-diethylamino, and the like. And wherein the alkylamino group is optionally substituted with one or more substituents described herein.
  • cycloalkyl or “cycloalkane” refers to a monovalent or multivalent saturated ring having 3 to 12 carbon atoms as a monocyclic, bicyclic, or tricyclic ring system, but not containing an aromatic ring.
  • the cycloalkyl group contains 3 to 10 carbon atoms.
  • the cycloalkyl group contains 3 to 8 carbon atoms.
  • the cycloalkyl group contains 3 to 6 carbon atoms.
  • Some non-limiting examples of such group include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, etc.
  • the cycloalkyl group may be independently unsubstituted or substituted with one or more substituents disclosed herein.
  • cycloalkyloxy refers to a cycloalkyl group attached to the rest of the molecule through an oxygen atom, wherein the cycloalkyl is as defined herein.
  • cycloalkylalkyl refers to a cycloalkyl group attached to the rest of the molecule through an alkyl group, wherein the cycloalkyl and alkyl are as defined herein.
  • carbobicyclyl refers to a monovalent or multivalent, nonaromatic, saturated or partially unsaturated ring having 3 to 12 carbon atoms as a monocyclic, bicyclic or tricyclic hydrocarbon.
  • a carbobicyclyl group includes a spiro carbobicyclyl group or a fused carbobicyclyl group. Suitable carbocyclyl groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl. In one embodiment, the cycloalkyl group contains 4 to 8 carbon atoms. In other embodiment, the cycloalkyl group contains 4 to 6 carbon atoms.
  • carbocyclyl group examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l-enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-l-enyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like
  • the cycloalkyl group may be independently unsubstituted or substituted with one or more substituents disclosed herein.
  • heterocycle refers to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing 3-12 ring atoms of which at least one ring atom is heteroatom, but not containing an aromatic ring.
  • heterocyclyl or “heterocycle” contains 3-10 ring atoms; in some embodiments, “heterocyclyl” or “heterocycle” contains 3-8 ring atoms; in other embodiments, “heterocyclyl” or “heterocycle” contains 5-8 ring atoms; in yet other embodiments, “heterocyclyl” or “heterocycle” contains 3-6 ring atoms; in still yet other embodiments, “heterocyclyl” or “heterocycle” contains 5-6 ring atoms; unless otherwise indicated, heterocyclyl may be a carbon radical or heteroatom radical, the heteroatom is as defined herein.
  • heterocyclyl group examples include oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, ox
  • heterocyclyl wherein the ring sulfur atom is oxidized is sulfolanyl and 1, 1-dioxo-thiomorpholinyl.
  • the heterocyclyl group may be optionally substituted with one or more substituents disclosed herein.
  • heterocyclylalkyl refers to a heterocyclyl group attached to the rest of the molecule through an alkyl group, wherein the heterocyclyl and alkyl are as defined herein.
  • aryl refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems having a total of 6 to 14 ring members, or 6 to 12 ring members, or 6 to 10 ring members, wherein at least one ring in the system is aromatic, wherein each ring in the system contains 3 to 7 ring members and that has a single point or multipoint of attachment to the rest of the molecule.
  • aryl may be used interchangeably with the term “aryl ring” or “aromatic” . Examples of aryl ring may include phenyl, naphthyl and anthracene.
  • the aryl group may be optionally and independently substituted with one or more substituents disclosed herein.
  • arylalkyl refers to an alkyl group substituted with one or more aryl groups, wherein the alkyl group and aryl group are as defined herein.
  • arylalkyl group include phenylmethyl and phenylethyl, and the like.
  • heteroaryl refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems having a total of five to twelve ring members, or five to ten ring members, or five to six ring members, wherein at least one ring in the system is aromatic ring, and in which at least one ring member is selected from heteroatom, and wherein each ring in the system contains 5 to 7 ring members and that has a single point or multipoint of attachment to the rest of the molecule.
  • heteroaryl and “heteroaromatic ring” or “heteroaromatic compound” can be used interchangeably herein.
  • the heteroaryl group is optionally substituted with one or more substituents disclosed herein.
  • 5-10 membered heteroaryl comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, wherein N may be oxidated.
  • heteroaryl rings include furanyl, imidazolyl (such as N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl) , isoxazolyl, oxazolyl (such as 2-oxazolyl, 4-oxazolyl, 5-oxazolyl) , pyrrolyl (such as N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl) , pyridyl, pyrimidinyl (such as 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl) , pyridazinyl, thiazolyl (such as 2-thiazolyl, 4-thiazolyl, 5-thiazolyl) , tetrazolyl (such as 5-tetrazolyl) , triazolyl, thienyl (such as 2-thienyl, 3-thienyl) , pyrazolyl, isothiazo
  • fused bicyclic ring or “fused bicyclyl” refers to a monovalent or multiple valent and saturated, partially unsaturated, or aromatic bicyclic and fused ring system containing 0, 1, 2, 3, 4, 5, 6 heteroatoms independently selected from N, O, S, P and Si.
  • “fused bicyclic ring” or “fused bicyclyl” contains 4-16 ring atoms; In other embodiments, “fused bicyclic ring” or “fused bicyclyl” contains 6-16 ring atoms; In still other embodiments, ” fused bicyclic ring” or “fused bicyclyl” contains 8-14 ring atoms; In yet other embodiments, ” fused bicyclic ring” or “fused bicyclyl” contains 8-12 ring atoms; In yet other embodiments, ” fused bicyclic ring” or “fused bicyclyl” contains 8-10 ring atoms. Unless specified otherwise, “fused bicyclyl” may be carbon radical or nitrogen radical.
  • “Fused bicyclic ring” system may be [4, 5] , [4, 6] , [4, 7] , [4, 8] , [5, 5] , [5, 6] , [5, 7] , [5, 8] , [6, 6] , [6, 7] or [6, 8] system.
  • fused bicyclic rings include 5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [4, 3-a] pyridine, 6, 8-dihydro-5H- [1, 2, 4] triazolo [3, 4-c] [1, 4] oxazine, 5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [4, 3-a] pyrazine, 6, 8-dihydro-5H- [1, 2, 4] triazolo [3, 4-c] [1, 4] thiazine-7, 7-dioxide, 6, 7-dihydro-5H-pyrrolo [2, 1-c] [1, 2, 4] triazole, 6, 7-dihydro-5H-pyrrolo [1, 2-a] imidazole, 5, 6, 7, 8-tetrahydroimidazolo [1, 2-a] pyridine, 6, 8-dihydro-5H-imidazolo [2, 1-c] [1, 4] oxazine,
  • a bond drawn from a substituent to the one ring within a ring system represents substitution of the substituent at any substitutable or reasonable position on the ring.
  • Formula (a) represents mono-or poly-substitutions of a substituent R o at any substitutable or reasonable position on the ring A and ring B, as shown in Formula (b) to Formula (h) , wherein each R o may be selected from same or different substituents.
  • each...is independently is used interchangeably with the phrase “each (of) ...and...is independently” . It should be understood broadly that the specific options expressed by the same symbol are independently of each other in different radicals; or the specific options expressed by the same symbol are independently of each other in same radicals.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, geometric or conformational) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, geometric or conformational mixtures of the present compounds are within the scope disclosed herein.
  • structures and the compound depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, geometric or conformational) forms of the structure, N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof. Therefore, single stereochemical isomers, enantiomeric isomers, diastereomeric isomerrs, geometric isomerrs, conformational isomers, N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt and a prodrug thereof of the present compounds are within the scope disclosed herein. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • Metal depicted herein which shows the similar active with the above compound in vivo or in vitro is a product produced through metabolism in the body of a specified compound or pharmaceutically acceptable salt, analogue or ramification thereof.
  • the metabolites of a compound may be identified using routine techniques known in the art and their activities may be determined using tests such as those described herein. Such products may result for example from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzyme cleavage, and the like, of the administered compound.
  • the invention includes metabolites of compounds disclosed herein, including metabolites produced by contacting a compound disclosed herein with a mammal for a sufficient time period.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50: 50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • the term “racemic mixture” or “racemate” refers to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • tautomer or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • a “pharmaceutically acceptable salts” refers to organic or inorganic salts of a compound disclosed herein.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmacol Sci, 1977, 66: 1-19, which is incorporated herein by reference.
  • Some non-limiting examples of pharmaceutically acceptable and nontoxic salts include salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid and malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phen
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil soluble or dispersable products may be obtained by such quaternization.
  • Representative alkali or alkaline earth metal used for forming salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C 1-8 sulfonate or aryl sulfonate.
  • hydrate refers to an association or complex of water and the compound disclosed herein.
  • solvate refers to an association or complex of one or more solvent molecules and a compound disclosed herein.
  • solvent molecules include water, isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO) , ethyl acetate, acetic acid and ethanolamine.
  • DMSO dimethylsulfoxide
  • esters refers to an in vivo hydrolysable ester of the above compound containing hydroxy group, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent alcohol.
  • in vivo hydrolysable ester forming groups for hydroxy include phosphate, acetoxymethoxy, 2, 2-dimethylpropionyloxymethoxy, alkanoyl, benzoyl, phenylacetyl, alkoxycarbonyl, dialkylcarbamoyl, N- (dialkylaminoethyl) -N-alkylcarbamoyl, and the like.
  • N-oxide refers to one or more than one nitrogen atoms oxidised to form an N-oxide, where a compound contains several amine functions.
  • Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
  • N-oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid) (See, Advanced Organic Chemistiy, by Jerry March, 4th Edition, Wiley Interscience, pages) . More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA) , for example, in an inert solvent such as dichloromethane.
  • MCPBA m-chloro
  • prodrug refers to a compound that is transformed in vivo into the above compound. Such a transformation can be affected, for example, by hydrolysis of the prodrug form in blood or enzymatic transformation to the parent form in blood or tissue.
  • Prodrugs of the compounds disclosed herein may be, for example, esters. Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound disclosed herein that contains a hydroxy group may be acylated at this position in its prodrug form.
  • prodrug forms include phosphates, such as, those phosphate compounds derived from the phosphonation of a hydroxy group on the parent compound.
  • phosphates such as, those phosphate compounds derived from the phosphonation of a hydroxy group on the parent compound.
  • a thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and S. J. Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345, all of which are incorporated herein by reference in their entireties.
  • protecting group refers to a substituent that is commonly employed to block or protect a particular functionality while reacting with other functional groups on the compound.
  • an “amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxy-carbonyl (BOC, Boc) , benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethylenoxy-carbonyl (Fmoc) .
  • a “hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.
  • Suitable protecting groups include methyl, methoxymethyl, acetyl and silyl, and so on.
  • a “carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxy-methyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenylsulfonyl) ethyl, 2- (diphenylphosphino) -ethyl, nitroethyl and the like.
  • terapéuticaally effective amount refers to an amount of the above compound which is sufficient to achieve the stated effect. Accordingly, a therapeutical effective amount of the above compound used in for the treatment of a condition modulated by ASK1 will be an amount sufficient for the treatment of the condition modulated by ASK1.
  • cardiovascular disease refers to a disease related to kidney function, which may be triggered 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 pulmonary thromboembolic disease and idiopathic pulmonary fibrosis.
  • nonalcoholic fatty liver used herein refers to a metabolic disease associated with insulin resistance, comprises simple fatty liver (SFL) , nonalcoholic steatohepatitis (NASH) , fatty hepatic fibrosis and cirrhotic.
  • 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; liver fibrosis due to contaction with alcohol (alcoholic liver disease) , pharmaceutical compounds, oxidative stress, cancer radiotherapy or industrial chemicals; and liver fibrosis caused by diseases such as primary biliary cirrhosis, fatty liver, obesity, nonalcoholic steatohepatitis, cystic fibrosis, hemochromatosis and autoimmune hepatitis, and so on.
  • diseases such as primary biliary cirrhosis, fatty liver, obesity, nonalcoholic steatohepatitis, cystic fibrosis, hemochromatosis and autoimmune hepatitis, and so on.
  • ASK1 modulator used herein refers to substances which can bind to ASK1 and mudulate its activity.
  • the present invention provides a compound or a pharmaceutical composition thereof, which may be an ASK1 modulator.
  • the present invention further relates to use of the compound or the composition thereof in the manufacture of a medicament for modulating ASK1 activity to treat a disorder or disease.
  • the present invention further describes the synthetic method of the compound.
  • the compounds of the invention show improved bioactivity and pharmacokinetic properties.
  • a compound having Formula (I) or a stereoisomer a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
  • E, G, X 1 , X 2 , X 3 , X 4 , R x , R y , R z , m, n and k are as defined herein;
  • X 1 is C (R 1 ) or N; wherein R 1 is as defined herein.
  • X 2 is C (R 2 ) or N; wherein R 2 is as defined herein.
  • X 3 is C (R 3 ) or N; wherein R 3 is as defined herein.
  • X 4 is C (R 4 ) or N; wherein R 4 is as defined herein.
  • R 1 is H, deuterium, F, Cl, Br, I, hydroxy, mercapto, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, methylthio, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, epoxypropyl, tetrahydrofuryl, tetrahydropyranyl or morpholinyl, wherein the hydroxy, mercapto, amino, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, me
  • R 2 is H, deuterium, F, Cl, Br, I, hydroxy, mercapto, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, methylthio, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, epoxypropyl, tetrahydrofuryl, tetrahydropyranyl or morpholinyl, wherein the hydroxy, mercapto, amino, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, me
  • R 3 is H, deuterium, F, Cl, Br, I, hydroxy, mercapto, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, methylthio, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, epoxypropyl, tetrahydrofuryl, tetrahydropyranyl or morpholinyl, wherein the hydroxy, mercapto, amino, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, me
  • R 4 is H, deuterium, F, Cl, Br, I, hydroxy, mercapto, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, methylthio, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, epoxypropyl, tetrahydrofuryl, tetrahydropyranyl or morpholinyl, wherein the hydroxy, mercapto, amino, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, me
  • E is 5-6 membered heteroaryl.
  • E is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl or thiadiazolyl.
  • each R x is independently deuterium, F, Cl, Br, I, hydroxy, mercapto, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, methylthio, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, epoxypropyl, tetrahydrofuryl, tetrahydropyranyl or morpholinyl, wherein the hydroxy, mercapto, amino, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy, isopropoxy,
  • each R y is independently H, deuterium, halogen, hydroxy, amino, nitro, cyano, acetyl, acetamido, -COOH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy.
  • each R y is independently H, F, Cl, Br, I, hydroxy, amino, nitro, cyano, acetyl, acetamido, -COOH, methyl, ethyl, isopropyl, t-butyl, trifluoromethyl, difluoromethyl, methoxy, isopropoxy, trifluoromethoxy or difluoromethoxy.
  • G is a fused bicyclic ring.
  • G is an 8-12 membered fused bicyclic ring.
  • G is
  • W 1 , W 2 , W 3 , W 4 , W 5 , W 6 , W 7 , W 8 , R z and k are as defined herein.
  • G is
  • R z and k are as defined herein.
  • each W 1 is independently -O-, -S-or -NH-.
  • 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.
  • each W is independently - (CH 2 ) p -, - (CH 2 ) p O-, - (CH 2 ) p NH-or - (CH 2 ) p S (O) t -; wherein p and t are as defined herein.
  • p is 0, 1, 2 or 3.
  • each t is independently 0, 1 or 2.
  • each R a is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, isopropoxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, epoxypropyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl or
  • each R b is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, isopropoxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, epoxypropyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl or
  • each R c is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, isopropoxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, epoxypropyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl or
  • each R d is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, isopropoxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, epoxypropyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl or
  • m is 1, 2 or 3.
  • n 1, 2 or 3.
  • k is 1, 2, 3, 4 or 5.
  • the compound disclosed herein has Formula (IIa) , (IIb) , (IIc) , (IId) or (IIe) , or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
  • X 1 , X 2 , X 3 , X 4 , W, W 1 , W 2 , W 3 , W 4 , W 5 , W 6 , W 7 , W 8 , R x , R y , R z , n and k are as defined herein.
  • a pharmaceutical composition comprising the above compound or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, or a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
  • the disease modulated by ASK1 is autoimmune disease, inflammation, angiocardiopathy, cardiorenal disease, fibrosis, respiratory disease, liver disease, or neurodegenerative disease.
  • the angiocardiopathy includes diabetes, diabetic nephropathy and other diabetic complications.
  • the fibrosis includes pulmonary fibrosis and renal fibrosis.
  • the respiratory disease includes chronic obstructive pulmonary, idiopathic pulmonary fibrosis and acute lung injury.
  • the liver diseases includes chronic liver disease, metabolic liver disease, liver fibrosis, primary sclerosing cholangitis, nonalcoholic fatty liver, nonalcoholic steatohepatitis, liver ischemia-reperfusion injury and primary biliary cirrhosis, and so on.
  • the present invention relates to a method of preventing, treating or lessening a disease modulated by ASK1 in a patient, comprising administering a therapeutically effective amount of a pharmaceutically acceptable effective amount of the compound to the patient.
  • provided herein is a method of preparing, separating or purifying the above compound.
  • the characteristic of the pharmaceutical composition disclosed herein is, the pharmaceutical composition comprises the above compound, the compound listed in the invention and a pharmaceutically acceptable carrier, excipient, or adjuvant.
  • the amount of the compound in the composition of the invention can effectively and detectably treat or lessen the severity of a disease modulated by ASK1.
  • certain of the compounds disclosed herein can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof.
  • pharmaceutically acceptable derivative include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adducts or derivatives which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
  • compositions disclosed herein further comprise a pharmaceutically acceptable carrier, an adjuvant, or a vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable carrier includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • the compounds of the present invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous) .
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • oral liquid preparations such as, for example, suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparation
  • tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or non-aqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit.
  • the active compounds can also be administered intranasally as, for example, liquid drops or spray.
  • the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • 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 and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • Ophthalmic formulations are also contemplated as being within the scope of this invention.
  • the compounds of the present invention may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol) , suitable mixtures thereof, and vegetable oils.
  • Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention.
  • oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • compounds of the present invention are administered orally.
  • the therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated.
  • a physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.
  • the compounds of the present invention are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form.
  • the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligram to about 50 milligrams.
  • the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • the compound, composition or pharmaceutically acceptable salt thereof or hydrate thereof according to the present invention can be effectively used for preventing, managing, treating or lessening a disease modulated by ASK1 in a patient.
  • it can effectively treat 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 fiber, primary sclerosing cholangitis, nonalcoholic fatty liver, nonalcoholic steatohepatitis, hepatic ischemia-reperfusion injury, primary biliary cirrhosis, and other hepatitis.
  • the compounds disclosed herein may be prepared by methods described herein, wherein the substituents are as defined above, except where further noted.
  • the following non-limiting schemes and examples are presented to further exemplify the invention.
  • Anhydrous THF, dioxane, toluene, and ether were obtained by refluxing the solvent with sodium.
  • Anhydrous CH 2 Cl 2 and CHCl 3 were obtained by refluxing the solvent with CaH 2 .
  • EtOAc, PE, n-hexane, DMAC and DMF were treated with anhydrous Na 2 SO 4 prior use.
  • reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried.
  • MS data were determined by an Agilent 6320 Series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column was operated at 30 °C) .
  • G1329A autosampler and G1315B DAD detector were applied in the analysis, and an ESI source was used in the LC-MS spectrometer.
  • MS data were determined by an Agilent 6120 Series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column was operated at 30 °C) .
  • G1329A autosampler and G1315D DAD detector were applied in the analysis, and an ESI source was used on the LC-MS spectrometer.
  • Table 1 The gradient condition of the mobile phase in Low-resolution mass spectrum analysis
  • L 1 is halogen
  • Compound (I) can be obtained by reaction of compound (Ia) with compound (Ib) .
  • the reaction material can be reacted in a solvent in the presence of a base (e.g., N, N-diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, etc. ) .
  • the reaction is preferably carried out in an inert solvent, including but not limited to dichloromethane, N, N-dimethylformamide and the like.
  • L 2 is a leaving group including, but not limited to, halogen, methanesulfonyloxy, p-methylbenzenesulfonyloxy and the like.
  • Compound (I) can be obtained by a coupling reaction of compound (Ic) with compound (Id) under the action of a palladium catalyst.
  • the reaction material can be reacted in a solvent in the presence of a base (e.g., sodium carbonate, cesium carbonate, etc. ) .
  • the reaction is preferably carried out in an inert solvent, including but not limited to dioxane, tetrahydrofuran and the like.
  • Carboxylic acid compound (Ie) can react with a chlorinating reagent to obtain an acyl chloride compound (If) , and the acyl chloride compound (If) can further react with aqueous ammonia to obtain amide compound (Ic) .
  • L 2 is a leaving group including, but not limited to, halogen, methanesulfonyloxy, p-methylbenzenesulfonyloxy and the like.
  • Hydrazide compound (Ih) and compound (Ii) are heated in an inert solvent to perform a ring-closing reaction to form compound (Ij) .
  • Step 4 3- (6-bromopyridin-2-yl) -5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [4, 3-a] pyridine
  • Step 5 t-butyl (6- (5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [4, 3-a] pyridin-3-yl) pyridin-2-yl) carbamate
  • Step 6 6- (5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [4, 3-a] pyridin-3-yl) pyridine-2-amine
  • Step 7 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [4, 3-a] pyridin-3-yl) pyridin-2-yl) benzamide
  • reaction was quenched with saturated sodium bicarbonate aqueous solution (20 mL) .
  • the reaction mixture was extracted with DCM (50 mL ⁇ 2) , the combined organic layers were washed with saturated aqueous NaCl (30 mL ⁇ 2) and concentrated in vacuo to remove the solvent.
  • Step 2 3- (6-bromopyridin-2-yl) -6, 7-dihydro-5H-pyrrolo [2, 1-c] [1, 2, 4] triazole
  • Step 3 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride
  • Step 5 5- (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) -2-fluoro-4-methylbenzamide
  • Step 2 3- (6-bromopyridin-2-yl) -6, 8-dihydro-5H- [1, 2, 4] triazole [3, 4-c] [1, 4] oxazine
  • Step 3 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 8-dihydro-5H- [1, 2, 4] triazole [3, 4-c] [1, 4] oxazin-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
  • the title compound was prepared as a white solid (400 mg, 49 %) according to the method described in step 5 of example 2 by using 3- (6-bromopyridin-2-yl) -6, 8-dihydro-5H- [1, 2, 4] triazole [3, 4-c] [1, 4] oxazine (500 mg, 1.8 mmol) and 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide (500 mg, 1.9 mmol) as raw materials.
  • Step 1 methyl 4- (4-cyclopropyl-1H-imidazol-1-yl) picolinate
  • Step 3 4- (4-cyclopropyl-1H-imidazol-1-yl) pyridinecarbonyl chloride
  • the title compound was prepared as a yellow solid (750 mg, 99%) according to the method described in step 3 of example 2 by using 4- (4-cyclopropyl-1H-imidazol-1-yl) picolinic acid (700 mg, 3.05 mmol) as a raw material.
  • the title compound was prepared as a white solid (400 mg, 58%) according to the method described in step 4 of example 2 by using 4- (4-cyclopropyl-1H-imidazol-1-yl) pyridinecarbonyl chloride (750 mg, 3.0 mmol) as a raw material.
  • 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) picolinamide
  • the title compound was prepared as a white solid (50 mg, 14%) according to the method described in step 5 of example 2 by using 4- (4-cyclopropyl-1H-imidazol-1-yl) picolinamide (200 mg, 0.87 mmol) as a raw material.
  • Step 2 methyl 3- ( (2-cyclopropyl-2-oxoethyl) amino) benzoate
  • Step 3 methyl 3- (4-cyclopropyl-2-mercapto-1H-imidazol-1-yl) benzoate
  • Step 4 methyl 3- (4-cyclopropyl-1H-imidazol-1-yl) benzoate
  • the title compound was prepared as a yellow solid (1.5 g, 55%) according to the method described in step 2 of example 4 by using methyl 3- (4-cyclopropyl-1H-imidazol-1-yl) benzoate (2.90 g, 12.0 mmol) as a raw material.
  • the title compound was prepared as a yellow solid (620 mg, 96%) according to the method described in step 3 of example 2 by using 3- (4-cyclopropyl-1H-imidazol-1-yl) benzoic acid (600 mg, 2.6 mmol) as a raw material.
  • Step 7 3- (4-cyclopropyl-1H-imidazol-1-yl) benzamide
  • the title compound was prepared as a yellow solid (100 mg, 22%) according to the method described in step 4 of example 2 by using 3- (4-cyclopropyl-1H-imidazol-1-yl) benzoyl chloride (500 mg, 2.0 mmol) as a raw material.
  • Step 8 3- (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) benzamide
  • the title compound was prepared as a white solid (8 mg, 4%) according to the method described in step 5 of example 2 by using 3- (4-cyclopropyl-1H-imidazol-1-yl) benzamide (100 mg, 0.44 mmol) and 3- (6-bromopyridin-2-yl) -6, 7-dihydro-5H-pyrrolo [2, 1-c] [1, 2, 4] triazole (120 mg, 0.45 mmol) as raw materials.
  • the title compound was prepared as a yellow solid (10.0 g, 93%) according to the method described in step 1 of example 1 by using 2-fluoro-5-nitrobenzoic acid (10.0 g, 54.0 mmol) as a raw material.
  • Step 3 methyl 5- ( (2-cyclopropyl-2-oxoethyl) amino) -2-fluoro benzoate
  • the title compound was prepared as a yellow solid (3.33 g, 100%) according to the method described in step 2 of example 5 by using methyl 5-amino-2-fluorobenzoate (2.24 g, 13.2 mmol) as a raw material.
  • Step 4 methyl 5- (4-cyclopropyl-2-mercapto-1H-imidazol-1-yl) -2-fluoro benzoate
  • the title compound was prepared as a yellow solid (3.87 g, 100%) according to the method described in step 3 of example 5 by using methyl 5- ( (2-cyclopropyl-2-oxoethyl) amino) -2-fluoro benzoate (3.33 g, 13.3 mmol) as a raw material.
  • Step 5 methyl 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro benzoate
  • the title compound was prepared as a yellow solid (250 mg, 7%) according to the method described in step 4 of example 5 by using methyl 5- (4-cyclopropyl-2-mercapto-1H-imidazol-1-yl) -2-fluoro benzoate (3.87 g, 13.2 mmol) as a raw material.
  • Step 7 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluorobenzoyl chloride
  • the title compound was prepared as a yellow solid (253 mg, 100%) according to the method described in step 3 of example 2 by using 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluorobenzoic acid (236 mg, 0.96 mmol) as a raw material.
  • Step 8 5- (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) -2-fluorobenzamide
  • the title compound was prepared as a pale yellow solid (5.00 g, 99%) according to the method described in step 1 of example 1 by using 4-methyl-3-nitrobenzoic acid (4.70 g, 25.9 mmol) as a raw material.
  • the title compound was prepared as a pale yellow solid (4.23 g, 100%) according to the method described in step 1 of example 5 by using methyl 4-methyl-3-nitrobenzoate (5.00 g, 25.6 mmol) as a raw material.
  • Step 3 methyl 3- ( (2-cyclopropyl-2-oxoethyl) amino) -4-methyl benzoate
  • the title compound was prepared as a yellow solid (6.33 g, 100%) according to the method described in step 2 of example 5 by using methyl 3-amino-4-methylbenzoate (4.23 g, 25.6 mmol) as a raw material.
  • Step 4 methyl 3- (4-cyclopropyl-2-mercapto-1H-imidazol-1-yl) -4-methylbenzoate
  • the title compound was prepared as a yellow solid (7.38 g, 100%) according to the method described in step 3 of example 5 by using methyl 3- ( (2-cyclopropyl-2-oxoethyl) amino) -4-methyl benzoate (6.33 g, 25.6 mmol) as a raw material.
  • Step 5 methyl 3- (4-cyclopropyl-1H-imidazol-1-yl) -4-methylbenzoate
  • the title compound was prepared as a yellow solid (1.70 g, 26%) according to the method described in step 4 of example 5 by using methyl 3- (4-cyclopropyl-2-mercapto-1H-imidazol-1-yl) -4-methylbenzoate (7.38 g, 25.6 mmol) as a raw material.
  • the title compound was prepared as a light yellow solid (1.10 g, 68%) according to the method described in step 2 of example 4 by using methyl 3- (4-cyclopropyl-1H-imidazol-1-yl) -4-methyl benzoate (1.70 g, 6.63 mmol) as a raw material.
  • Step 7 3- (4-cyclopropyl-1H-imidazol-1-yl) -4-methylbenzoyl chloride
  • the title compound was prepared as a yellow solid (332 mg, 100%) according to the method described in step 3 of example 2 by using 3- (4-cyclopropyl-1H-imidazol-1-yl) -4-methylbenzoic acid (309 mg, 1.28 mmol) as a raw material.
  • Step 8 3- (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) -4-methylbenzamide
  • the title compound was prepared as a light yellow solid (80 mg, 18%) according to the method described in step 8 of example 6 by using 3- (4-cyclopropyl-1H-imidazol-1-yl) -4-methylbenzoyl chloride (331 mg, 1.27 mmol) and 6- (6, 7-dihydro-5H-pyrrolo [2, 1-c] [1, 2, 4] triazol-3-yl) pyridine-2-amine (213 mg, 1.06 mmol) as raw materials.
  • Example 8 N- (6- ( [1, 2, 4] triazolo [4, 3-a] pyridin-3-yl) pyridin-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide
  • Step 1 2-bromo-6- ( (2- (pyridin-2-yl) hydrazono) methyl) pyridine
  • Step 2 3- (6-bromopyridin-2-yl) - [1, 2, 4] triazolo [4, 3-a] pyridine
  • Step 3 N- (6- ( [1, 2, 4] triazolo [4, 3-a] pyridin-3-yl) pyridin-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide
  • the title compound was prepared as a white solid (240 mg, 29%) according to the method described in step 5 of example 2 by using 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide (470 mg, 1.8 mmol) and 3- (6-bromopyridin-2-yl) - [1, 2, 4] triazolo [4, 3-a] pyridine (500 mg, 1.8 mmol) as raw materials.
  • Formic acid (1.5 mL, 40 mmol) was added to acetic anhydride (4 mL, 42.6 mmol) dropwise slowly. After the addition, the mixture was heated to 65 °C and stirred for 2 h, and then cooled to rt. The above mixture was added into a solution of methyl 2-aminoisonicotinate (2.0 g, 13 mmol) in tetrahydrofuran (20 mL) dropwise slowly in an ice bath. After the addition, the mixture was warmed to rt and stirred overnight.
  • Step 2 methyl 2- (N- (2-cyclopropyl-2-oxoethyl) formamido) isonicotinate
  • Step 3 methyl 2- (4-cyclopropyl-1H-imidazol-1-yl) isonicotinate
  • Methyl 2- (N- (2-cyclopropyl-2-oxoethyl) formamido) isonicotinate (2.5 g, 9.5 mmol) was dissolved in glacial acetic acid (40 mL) , and ammonium acetate (2.2 g, 29 mmol) was added, the mixture was heated to 120 °C and refluxed overnight. The mixture was cooled to rt naturally and concentrated in vacuo to remove the most solvent. The reaction mixture was diluted with water (20 mL) , and adjusted with saturated sodium bicarbonate aqueous solution to weakly alkaline. The resulting mixture was extracted with EtOAc (50 mL ⁇ 2) .
  • the title compound was prepared as a light yellow solid (550 mg, 66%) according to the method described in step 2 of example 4 by using methyl 2- (4-cyclopropyl-1H-imidazol-1-yl) isonicotinate (880 mg, 3.6 mmol) as a raw material.
  • the title compound was prepared as a white solid (300 mg, 93%) according to the method described in step 3 of example 2 by using 2- (4-cyclopropyl-1H-imidazol-1-yl) isonicotinic acid (300 mg, 1.3 mmol) as a raw material.
  • Step 6 2- (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) isonicotinamide
  • the title compound was prepared as a white solid (320 mg, 64 %) according to the method described in step 8 of example 6 by using 2- (4-cyclopropyl-1H-imidazol-1-yl) isonicotinoyl chloride (300 mg, 1.2 mmol) and 6- (6, 7-dihydro-5H-pyrrolo [2, 1-c] [1, 2, 4] triazol-3-yl) pyridine-2-amine (240 mg, 1.19 mmol) as raw materials.
  • the title compound was prepared as a light yellow solid (4.00 g, 94 %) according to the method described in step 1 of example 5 by using methyl 4-fluoro-3-nitrobenzoate (5 g, 25 mmol) as a raw material.
  • the title compound was prepared as a white solid (4.3 g, 97%) according to the method described in step 1 of example 9 by using methyl 3-amino-4-fluorobenzoate (4.0 g, 22 mmol) as a raw material.
  • Step 3 methyl 3- (N- (2-cyclopropyl-2-oxoethyl) formamido) -4-fluorobenzoate
  • the title compound was prepared as a yellow oil (5.8 g, 97%) according to the method described in step 2 of example 9 by using methyl 4-fluoro-3-formamidobenzoate (4.0 g, 22 mmol) as a raw material.
  • Step 4 methyl 3- (4-cyclopropyl-1H-imidazol-1-yl) -4-fluorobenzoate
  • the title compound was prepared as a yellow oil (4.0 g, 72%) according to the method described in step 3 of example 9 by using methyl 3- (N- (2-cyclopropyl-2-oxoethyl) formamido) -4-fluorobenzoate (6.0 g, 21 mmol) as a raw material.
  • Step 5 3- (4-cyclopropyl-1H-imidazol-1-yl) -4- (methylthio) benzoic acid
  • Step 6 3- (4-cyclopropyl-1H-imidazol-1-yl) -4- (methylthio) benzoyl chloride
  • the title compound was prepared as a light yellow solid (850 mg, 100%) according to the method described in step 3 of example 2 by using 3- (4-cyclopropyl-1H-imidazol-1-yl) -4- (methylthio) benzoic acid (800 mg, 2.92 mmol) as a raw material.
  • Step 7 3- (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) -4- (methylthio) benzamide
  • the title compound was prepared as a white solid (550 mg, 41%) according to the method described in step 8 of example 6 by using 3- (4-cyclopropyl-1H-imidazol-1-yl) -4- (methylthio) benzoyl chloride (850 mg, 2.9 mmol) and 6- (6, 7-dihydro-5H-pyrrolo [2, 1-c] [1, 2, 4] triazol-3-yl) pyridine-2-amine (500 mg, 2.5 mmol) as raw materials.
  • Step 1 2- (2- ( (6-bromopyridin-2-yl) methylene) hydrazinyl) pyrimidine
  • the title compound was prepared as a light yellow solid (400 mg, 32%) according to the method described in step 1 of example 8 by using 2-hydrazinylpyrimidine (500 mg, 4.5 mmol) and 6-bromopyridine-2-carbaldehyde (850 mg, 4.5 mmol) as raw materials.
  • Step 2 3- (6-bromopyridin-2-yl) - [1, 2, 4] triazolo [4, 3-a] pyrimidine
  • the title compound was prepared as a white solid (340 mg, 86%) according to the method described in step 2 of example 8 by using 2- (2- ( (6-bromopyridin-2-yl) methylene) hydrazinyl) pyrimidine (400 mg, 1.4 mmol) as a raw material.
  • Step 3 N- (6- ( [1, 2, 4] triazolo [4, 3-a] pyrimidin-3-yl) pyridin-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide
  • the title compound was prepared as a white solid (5 mg, 1%) according to the method described in step 5 of example 2 by using 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide (290 mg, 1.12 mmol) and 3- (6-bromopyridin-2-yl) - [1, 2, 4] triazolo [4, 3-a] pyrimidine (340 mg, 1.23 mmol) as raw materials.
  • Example 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-methoxypicolinamide
  • Step 3 methyl 4- (4-cyclopropyl-1H-imidazol-1-yl) -5-methoxypicolinate
  • Step 4 4- (4-cyclopropyl-1H-imidazol-1-yl) -5-methoxypicolinic acid
  • the title compound was prepared as a yellow solid (332 mg, 100%) according to the method described in step 3 of example 2 by using 4- (4-cyclopropyl-1H-imidazol-1-yl) -5-methoxypicolinic acid (310 mg, 1.20 mmol) as a raw material.
  • Step 6 4- (4-cyclopropyl-1H-imidazol-1-yl) -5-methoxypicolinamide
  • the title compound was prepared as a light yellow solid (200 mg, 65%) according to the method described in step 4 of example 2 by using 4- (4-cyclopropyl-1H-imidazol-1-yl) -5-methoxypicolinoyl chloride (332 mg, 1.20 mmol) as a raw material.
  • Step 7 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-methoxypicolinamide
  • the title compound was prepared as a light yellow solid (130 mg, 38%) according to the method described in step 5 of example 2 by using 4- (4-cyclopropyl-1H-imidazol-1-yl) -5-methoxypicolinamide (200 mg, 0.77 mmol) and 3- (6-bromopyridin-2-yl) -6, 7-dihydro-5H-pyrrolo [2, 1-c] [1, 2, 4] triazole (226 mg, 0.85 mmol) as raw materials.
  • the title compound was prepared as a white solid (5.7 g, 99%) according to the method described in step 1 of example 9 by using methyl 3-amino-2-methylbenzoate (5.0 g, 30 mmol) as a raw material.
  • Step 2 methyl 3- (N- (2-cyclopropyl-2-oxoethyl) formamido) -2-methylbenzoate
  • the title compound was prepared as a light yellow solid (3.2 g, 39%) according to the method described in step 2 of example 9 by using methyl 3-formamido-2-methylbenzoate (5.7 g, 30 mmol) as a raw material.
  • Step 3 methyl 3- (4-cyclopropyl-1H-imidazol-1-yl) -2-methyl benzoate
  • the title compound was prepared as a yellow oil (2.75 g, 84%) according to the method described in step 3 of example 9 by using methyl 3- (N- (2-cyclopropyl-2-oxoethyl) formamido) -2-methylbenzoate (3.5 g, 13 mmol) as a raw material.
  • the title compound was prepared as a white solid (1.6 g, 63%) according to the method described in step 2 of example 4 by using methyl 3- (4-cyclopropyl-1H-imidazol-1-yl) -2-methyl benzoate (2.7 g, 11 mmol) as a raw material.
  • Step 5 3- (4-cyclopropyl-1H-imidazol-1-yl) -2-methylbenzoyl chloride
  • the title compound was prepared as a light yellow solid (280 mg, 96%) according to the method described in step 3 of example 2 by using 3- (4-cyclopropyl-1H-imidazol-1-yl) -2-methylbenzoic acid (270 mg, 1.1 mmol) as a raw material.
  • Step 6 3- (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) -2-methylbenzamide
  • the title compound was prepared as a white solid (150 mg, 33%) according to the method described in step 8 of example 6 by using 3- (4-cyclopropyl-1H-imidazol-1-yl) -2-methylbenzoyl chloride (280 mg, 1.1 mmol) and 6- (6, 7-dihydro-5H-pyrrolo [2, 1-c] [1, 2, 4] triazol-3-yl) pyridine-2-amine (200 mg, 1.0 mmol) as raw materials.
  • the title compound was prepared as yellow oil (5.3 g, 97%) according to the method described in step 1 of example 1 by using 5-amino-2-methylbenzoic acid (5 g, 32.4 mmol) as a raw material.
  • the title compound was prepared as a yellow solid (5.6 g, 98%) according to the method described in step 1 of example 9 by using methyl 5-amino-2-methylbenzoate (5.0 g, 30 mmol) as a raw material.
  • Step 3 methyl 5- (N- (2-cyclopropyl-2-oxoethyl) formamido) -2-methylbenzoate
  • the title compound was prepared as yellow oil (6.2 g, 78%) according to the method described in step 2 of example 9 by using methyl 5-formamido-2-methylbenzoate (5.6 g, 29 mmol) as a raw material.
  • Step 4 methyl 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-methylbenzoate
  • the title compound was prepared as yellow oil (2.0 g, 35%) according to the method described in step 3 of example 9 by using methyl 5- (N- (2-cyclopropyl-2-oxoethyl) formamido) -2-methylbenzoate (6.2 g, 23 mmol) as a raw material.
  • the title compound was prepared as a light yellow solid (1.2 g, 63%) according to the method described in step 2 of example 4 by using methyl 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-methylbenzoate (2.0 g, 7.8 mmol) as a raw material.
  • the title compound was prepared as a light yellow solid (300 mg, 93%) according to the method described in step 3 of example 2 by using 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-methylbenzoic acid (300 mg, 1.24 mmol) as a raw material.
  • Step 7 5- (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) -2-methylbenzamide
  • the title compound was prepared as a white solid (35 mg, 7%) according to the method described in step 8 of example 6 by using 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-methylbenzoyl chloride (300 mg, 1.2 mmol) and 6- (6, 7-dihydro-5H-pyrrolo [2, 1-c] [1, 2, 4] triazol-3-yl) pyridine-2-amine (230 mg, 1.2 mmol) as raw materials.
  • the title compound was prepared as a light yellow solid (5.39 g, 100%) according to the method described in step 1 of example 1 by using 3-methyl-5-nitrobenzoic acid (5.00 g, 27.6 mmol) as a raw material.
  • the title compound was prepared as a yellow solid (4.56 g, 100%) according to the method described in step 1 of example 5 by using methyl 3-methyl-5-nitrobenzoate (5.39 g, 27.6 mmol) as a raw material.
  • the title compound was prepared as a light yellow solid (5.33 g, 100%) according to the method described in step 1 of example 9 by using methyl 3-amino-5-methylbenzoate (4.56 g, 27.6 mmol) as a raw material.
  • Step 4 methyl 3- (N- (2-cyclopropyl-2-oxoethyl) formamido) -5-methylbenzoate
  • the title compound was prepared as a yellow solid (7.59 g, 100%) according to the method described in step 2 of example 9 by using methyl 3-formamido-5-methylbenzoate (5.33 g, 27.6 mmol) as a raw material.
  • Step 5 methyl 3- (4-cyclopropyl-1H-imidazol-1-yl) -5-methylbenzoate
  • the title compound was prepared as a yellow solid (4.00 g, 57%) according to the method described in step 3 of example 9 by using methyl 3- (N- (2-cyclopropyl-2-oxoethyl) formamido) -5-methylbenzoate (7.59 g, 27.6 mmol) as a raw material.
  • the title compound was prepared as a yellow solid (1.50 g, 83%) according to the method described in step 2 of example 4 by using methyl 3- (4-cyclopropyl-1H-imidazol-1-yl) -5-methylbenzoate (1.91 g, 7.45 mmol) as a raw material.
  • Step 7 3- (4-cyclopropyl-1H-imidazol-1-yl) -5-methylbenzoyl chloride
  • the title compound was prepared as a light yellow solid (442 mg, 100%) according to the method described in step 3 of example 2 by using 3- (4-cyclopropyl-1H-imidazol-1-yl) -5-methylbenzoic acid (411 mg, 1.70 mmol) as a raw material.
  • Step 8 3- (4-cyclopropyl-1H-imidazol-1-yl) -5-methylbenzamide
  • the title compound was prepared as a light yellow solid (409 mg, 100%) according to the method described in step 4 of example 2 by using 3- (4-cyclopropyl-1H-imidazol-1-yl) -5-methylbenzoyl chloride (442 mg, 1.7 mmol) as a raw material.
  • Step 9 3- (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-methylbenzamide
  • the title compound was prepared as a light yellow solid (60 mg, 39%) according to the method described in step 5 of example 2 by using 3- (4-cyclopropyl-1H-imidazol-1-yl) -5-methylbenzamide (87 mg, 0.36 mmol) and 3- (6-bromopyridin-2-yl) -6, 7-dihydro-5H-pyrrolo [2, 1-c] [1, 2, 4] triazole (108 mg, 0.41 mmol) as raw materials.
  • Example 17 3- (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-fluorobenzamide
  • the title compound was prepared as a light yellow solid (5.70 g, 98%) according to the method described in step 1 of example 9 by using methyl 3-amino-5-fluorobenzoate (5.00 g, 29.6 mmol) as a raw material.
  • Step 2 methyl 3- (N- (2-cyclopropyl-2-oxoethyl) formamido) -5-fluorobenzoate
  • the title compound was prepared as a yellow solid (8.07 g, 100%) according to the method described in step 2 of example 9 by using methyl 3-fluoro-5-formamidobenzoate (5.70 g, 28.9 mmol) as a raw material.
  • Step 3 methyl 3- (4-cyclopropyl-1H-imidazol-1-yl) -5-fluorobenzoate
  • the title compound was prepared as a yellow solid (6.00 g, 80%) according to the method described in step 3 of example 9 by using methyl 3- (N- (2-cyclopropyl-2-oxoethyl) formamido) -5-fluorobenzoate (8.07 g, 28.9 mmol) as a raw material.
  • Step 4 3- (4-cyclopropyl-1H-imidazol-1-yl) -5-fluorobenzoic acid
  • the title compound was prepared as a yellow solid (1.50 g, 70%) according to the method described in step 2 of example 4 by using methyl 3- (4-cyclopropyl-1H-imidazol-1-yl) -5-fluorobenzoate (2.26 g, 8.68 mmol) as a raw material.
  • the title compound was prepared as a light yellow solid (322 mg, 100%) according to the method described in step 3 of example 2 by using 3- (4-cyclopropyl-1H-imidazol-1-yl) -5-fluorobenzoic acid (300 mg, 1.22 mmol) as a raw material.
  • the title compound was prepared as a light yellow solid (290 mg, 97.22%) according to the method described in step 4 of example 2 by using 3- (4-cyclopropyl-1H-imidazol-1-yl) -5-fluorobenzoyl chloride (322 mg, 1.22 mmol) as a raw material.
  • Step 7 3- (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-fluorobenzamide
  • the title compound was prepared as a light yellow solid (110 mg, 72%) according to the method described in step 5 of example 2 by using 3- (4-cyclopropyl-1H-imidazol-1-yl) -5-fluorobenzamide (87 mg, 0.35 mmol) and 3- (6-bromopyridin-2-yl) -6, 7-dihydro-5H-pyrrolo [2, 1-c] [1, 2, 4] triazole (122 mg, 0.46 mmol) as raw materials.
  • the title compound was prepared as a light yellow solid (8.00 g, 100%) according to the method described in step 1 of example 1 by using 4-methoxy-3-nitrobenzoic acid (7.50 g, 38.0 mmol) as a raw material;
  • the title compound was prepared as a yellow solid (6.86 g, 100%) according to the method described in step 1 of example 5 by using methyl 4-methoxy-3-nitrobenzoate (8.00 g, 37.9 mmol) as a raw material;
  • the title compound was prepared as a light yellow solid (7.92 g, 100%) according to the method described in step 1 of example 9 by using methyl 3-amino-4-methoxybenzoate (6.86 g, 37.9 mmol) as a raw material.
  • Step 4 methyl 3- (N- (2-cyclopropyl-2-oxoethyl) formamido) -4-methoxybenzoate
  • the title compound was prepared as a yellow solid (11.0 g, 100%) according to the method described in step 2 of example 9 by using methyl 3-formamido-4-methoxybenzoate (7.92 g, 37.9 mmol) as a raw material.
  • Step 5 methyl 3- (4-cyclopropyl-1H-imidazol-1-yl) -4-methoxybenzoate
  • the title compound was prepared as a yellow solid (4.00 g, 39%) according to the method described in step 3 of example 9 by using methyl 3- (N- (2-cyclopropyl-2-oxoethyl) formamido) -4-methoxybenzoate (11.0 g, 37.8 mmol) as a raw material.
  • the title compound was prepared as a light yellow solid (1.80 g, 90%) according to the method described in step 2 of example 4 by using methyl 3- (4-cyclopropyl-1H-imidazol-1-yl) -4-methoxybenzoate (2.12 g, 7.79 mmol) as a raw material.
  • Step 7 3- (4-cyclopropyl-1H-imidazol-1-yl) -4-methoxybenzoyl chloride
  • the title compound was prepared as a light yellow solid (589 mg, 100%) according to the method described in step 3 of example 2 by using 3- (4-cyclopropyl-1H-imidazol-1-yl) -4-methoxybenzoic acid (550 mg, 2.13 mmol) as a raw material.
  • Step 8 3- (4-cyclopropyl-1H-imidazol-1-yl) -4-methoxybenzamide
  • the title compound was prepared as a light yellow solid (365 mg, 67%) according to the method described in step 4 of example 2 by using 3- (4-cyclopropyl-1H-imidazol-1-yl) -4-methoxybenzoyl chloride (322 mg, 1.22 mmol) as a raw material.
  • Step 9 3- (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) -4-methoxybenzamide
  • the title compound was prepared as a light yellow solid (60 mg, 40%) according to the method described in step 5 of example 2 by using 3- (4-cyclopropyl-1H-imidazol-1-yl) -4-methoxybenzamide (87 mg, 0.35 mmol) and 3- (6-bromopyridin-2-yl) -6, 7-dihydro-5H-pyrrolo [2, 1-c] [1, 2, 4] triazole (108 mg, 0.41 mmol) as raw materials.
  • the title compound was prepared as a brown oil (4.0 g, 94%) according to the method described in step 1 of example 5 by using methyl 2-methoxy-5-nitrobenzoate (5 g, 23.2 mmol) as a raw material.
  • the title compound was prepared as a yellow solid (3.2 g, 66%) according to the method described in step 1 of example 9 by using methyl 5-amino-2-methoxybenzoate (4.2 g, 23 mmol) as a raw material.
  • Step 3 methyl 5- (N- (2-cyclopropyl-2-oxoethyl) formamido) -2-methoxybenzoate
  • the title compound was prepared as yellow oil (4.2 g, 94%) according to the method described in step 2 of example 9 by using methyl 5-formamido-2-methoxybenzoate (3.2 g, 15 mmol) as a raw material.
  • Step 4 methyl 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-methoxybenzoate
  • the title compound was prepared as yellow oil (2.0 g, 51%) according to the method described in step 3 of example 9 by using methyl 5- (N- (2-cyclopropyl-2-oxoethyl) formamido) -2-methoxybenzoate (4.2 g, 14 mmol) as a raw material.
  • Step 5 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-methoxybenzoic acid
  • the title compound was prepared as yellow oil (550 mg, 97%) according to the method described in step 2 of example 4 by using methyl 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-methoxybenzoate (600 mg, 2.2 mmol) as a raw material.
  • Step 6 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-methoxybenzoyl chloride
  • the title compound was prepared as a light yellow solid (500 mg, 93%) according to the method described in step 3 of example 2 by using 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-methoxybenzoic acid (500 mg, 1.9 mmol) as a raw material.
  • Step 7 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-methoxybenzamide
  • the title compound was prepared as a light yellow solid (300 mg, 65%) according to the method described in step 4 of example 2 by using 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-methoxybenzoyl chloride (500 mg, 1.8 mmol) as a raw material.
  • Step 8 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2, 1-c] [1, 2, 4] triazol-3-yl) pyridin-yl) -2-methoxybenzamide
  • the title compound was prepared as a white solid (90 mg, 26%) according to the method described in step 5 of example 2 by using 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-methoxybenzamide (200 mg, 0.78 mmol) and 3- (6-bromopyridin-2-yl) -6, 7-dihydro-5H-pyrrolo [2, 1-c] [1, 2, 4] triazole (230 mg, 0.87 mmol) as raw materials.
  • Example 20 4-chloro-3- (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) benzamide
  • the title compound was prepared as a white solid (5.7 g, 99%) according to the method described in step 1 of example 9 by using methyl 3-amino-4-chlorobenzoate (5.0 g, 27 mmol) as a raw material.
  • Step 2 methyl 4-chloro-3- (N- (2-cyclopropyl-2-oxoethyl) formamido) benzoate
  • the title compound was prepared as a light yellow solid (7.5 g, 95%) according to the method described in step 2 of example 9 by using methyl 4-chloro-3-formamidobenzoate (5.7 g, 27 mmol) as a raw material.
  • Step 3 methyl 4-chloro-3- (4-cyclopropyl-1H-imidazol-1-yl) benzoate
  • the title compound was prepared as yellow oil (5.0 g, 71%) according to the method described in step 3 of example 9 by using methyl 4-chloro-3- (N- (2-cyclopropyl-2-oxoethyl) formamido) benzoate (7.5 g, 25 mmol) as a raw material.
  • Step 4 4-chloro-3- (4-cyclopropyl-1H-imidazol-1-yl) benzoic acid
  • the title compound was prepared as a yellow solid (280 mg, 84%) according to the method described in step 2 of example 4 by using methyl 4-chloro-3- (4-cyclopropyl-1H-imidazol-1-yl) benzoate (350 mg, 1.27 mmol) as a raw material.
  • Step 5 4-chloro-3- (4-cyclopropyl-1H-imidazol-1-yl) benzoyl chloride
  • the title compound was prepared as a yellow solid (290 mg, 97 %) according to the method described in step 3 of example 2 by using 4-chloro-3- (4-cyclopropyl-1H-imidazol-1-yl) benzoic acid (280 mg, 1.1 mmol) as a raw material.
  • Step 6 4-chloro-3- (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) benzamide
  • the title compound was prepared as a white solid (240 mg, 54%) according to the method described in step 8 of example 6 by using 4-chloro-3- (4-cyclopropyl-1H-imidazol-1-yl) benzoyl chloride (280 mg, 0.99 mmol) and 6- (6, 7-dihydro-5H-pyrrolo [2, 1-c] [1, 2, 4] triazol-3-yl) pyridine-2-amine (200 mg, 0.99 mmol) as raw materials.
  • Step 1 2- (2- ( (6-bromopyridin-2-yl) methylene) hydrazinyl) pyrazine
  • the title compound was prepared as a light yellow solid (1.8 g, 71%) according to the method described in step 1 of example 8 by using 2-hydrazinylpyrazine (1.0 g, 9.1 mmol) as a raw material;
  • Step 2 3- (6-bromopyridin-2-yl) - [1, 2, 4] triazolo [4, 3-a] pyrazine
  • the title compound was prepared as a white solid (480 mg, 97 %) according to the method described in step 2 of example 8 by using 2- (2- ( (6-bromopyridin-2-yl) methylene) hydrazinyl) pyrazine (500 mg, 1.8 mmol) as a raw material.
  • Step 3 N- (6- ( [1, 2, 4] triazolo [4, 3-a] pyrazin-3-yl) pyridin-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide
  • the title compound was prepared as a light yellow solid (80 mg, 24%) according to the method described in step 5 of example 2 by using 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide (190 mg, 0.73 mmol) and 3- (6-bromopyridin-2-yl) - [1, 2, 4] triazolo [4, 3-a] pyrazine (200 mg, 0.72 mmol) as raw materials.
  • Step 1 2-bromo-6- ( (2- (6-chloropyridin-2-yl) hydrazono) methyl) pyridine
  • the title compound was prepared as a light yellow solid (1.00 g, 92%) according to the method described in step 1 of example 8 by using 2-chloro-6-hydrazinylpyridine (500 mg, 3.48 mmol) as a raw material;
  • Step 2 3- (6-bromopyridin-2-yl) -5-chloro- [1, 2, 4] triazolo [4, 3-a] pyridine
  • the title compound was prepared as a light yellow solid (900 mg, 91%) according to the method described in step 2 of example 8 by using 2-bromo-6- ( (2- (6-chloropyridin-2-yl) hydrazono) methyl) pyridine (1.00 g, 3.21 mmol) as a raw material.
  • Step 3 N- (6- (5-chloro- [1, 2, 4] triazolo [4, 3-a] pyridin-3-yl) pyridin-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide
  • the title compound was prepared as a light yellow solid (30 mg, 16%) according to the method described in step 5 of example 2 by using 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide (100 mg, 0.39 mmol) and 3- (6-bromopyridin-2-yl) -5-chloro- [1, 2, 4] triazolo [4, 3-a] pyridine (143 mg, 0.46 mmol) as raw materials.
  • Step 1 2- (2- ( (6-bromopyridin-2-yl) methylene) hydrazinyl) -3-chloropyridine
  • the title compound was prepared as a light yellow solid (1.05 g, 97%) according to the method described in step 1 of example 8 by using 3-chloro-2-hydrazinylpyridine (500 mg, 3.5 mmol) as a raw material;
  • Step 2 3- (6-bromopyridin-2-yl) -8-chloro- [1, 2, 4] triazolo [4, 3-a] pyridine
  • the title compound was prepared as a white solid (0.90 g, 91%) according to the method described in step 2 of example 8 by using 2- (2- ( (6-bromopyridin-2-yl) methylene) hydrazinyl) -3-chloropyridine (1.0 g, 3.2 mmol) as a raw material.
  • Step 3 N- (6- (8-chloro- [1, 2, 4] triazolo [4, 3-a] pyridin-3-yl) pyridin-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide
  • the title compound was prepared as a light yellow solid (50 mg, 15%) according to the method described in step 5 of example 2 by using 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide (175 mg, 0.67 mmol) and 3- (6-bromopyridin-2-yl) -8-chloro- [1, 2, 4] triazolo [4, 3-a] pyridine (210 mg, 0.68 mmol) as raw materials.
  • Step 1 2-bromo-6- ( (2- (6-methylpyridin-2-yl) hydrazono) methyl) pyridine
  • the title compound was prepared as a yellow solid (650 mg, 71%) according to the method described in step 1 of example 8 by using 2-hydrazinyl-6-methylpyridine hydrochloride (500 mg, 3.1 mmol) as a raw material.
  • Step 2 3- (6-bromopyridin-2-yl) -5-methyl- [1, 2, 4] triazolo [4, 3-a] pyridine
  • the title compound was prepared as a light yellow solid (50 mg, 28%) according to the method described in step 2 of example 8 by using 2-bromo-6- ( (2- (6-methylpyridin-2-yl) hydrazono) methyl) pyridine (180 mg, 0.62 mmol) as a raw material.
  • Step 3 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-methyl- [1, 2, 4] triazolo [4, 3-a] pyridin-3-yl) pyridin-2-yl) benzamide
  • the title compound was prepared as a white solid (8 mg, 10%) according to the method described in step 5 of example 2 by using 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide (50 mg, 1.8 mmol) and 3- (6-bromopyridin-2-yl) -5-methyl- [1, 2, 4] triazolo [4, 3-a] pyridine (50 mg, 0.17 mmol) as raw materials.
  • Step 1 2- (2- ( (6-bromopyridin-2-yl) methylene) hydrazinyl) -3-methylpyridine
  • the title compound was prepared as a yellow solid (1.1 g, 93%) according to the method described in step 1 of example 8 by using 2-hydrazinyl-3-methylpyridine (500 mg, 4.1 mmol) as a raw material.
  • Step 2 3- (6-bromopyridin-2-yl) -8-methyl- [1, 2, 4] triazolo [4, 3-a] pyridine
  • the title compound was prepared as a light yellow solid (600 mg, 55%) according to the method described in step 2 of example 8 by using 2- (2- ( (6-bromopyridin-2-yl) methylene) hydrazinyl) -3-methylpyridine (1.1 g, 3.8 mmol) as a raw material.
  • Step 3 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (8-methyl- [1, 2, 4] triazolo [4, 3-a] pyridin-3-yl) pyridin-2-yl) benzamide
  • the title compound was prepared as a white solid (80 mg, 20%) according to the method described in step 5 of example 2 by using 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide (225 mg, 1.8 mmol) and 3- (6-bromopyridin-2-yl) -8-methyl- [1, 2, 4] triazolo [4, 3-a] pyridine (250 mg, 0.86 mmol) as raw materials.
  • the compound was diluted with kinase buffer (20 mM HEPES, pH 7.5; 0.01%Triton X-100; 25 mM MgCl 2 ; 2 mM DTT) in a 3-fold dilution series to obtain 10 dilutions with a final concentration range of 2000 nM to 0.102 nM.
  • kinase buffer (20 mM HEPES, pH 7.5; 0.01%Triton X-100; 25 mM MgCl 2 ; 2 mM DTT
  • the above 10 dilutions were added into a 384 well plate with 2.5 ⁇ L per well, the final concentration of the compound used in kinase test was between 500 nM and 0.025 nM; after that, to each well was added 2.5 ⁇ L of 200 nM ASK1, after uniform oscillation, to each well was added 5 ⁇ L of substrate solution [the concentration of MBP (Myelin basic protein) was 1000 ⁇ M, the concentration of ATP was 300 ⁇ M] , after oscillation, the final concentrtions of ASK1, MBP, ATP were respectively 50 nM, 500 ⁇ M, 150 ⁇ M; Also buffer well (free of compound, adding the same concentration of enzyme and substrate) and negative well (free of compound and enzyme, adding the same concentration of substrate) were set; the plate was sealed and incubated at 37 °C for 1 hour, and then tested by using ADP-Glo kinase detection kit (Promege, Cat.
  • Example 10 No. IC 50 (nM) No. IC 50 (nM) Example 1 18
  • Example 10 6.7
  • Example 2 6.1
  • Example 13 7.8
  • Example 4 4.9
  • Example 16 14
  • Example 5 10
  • Example 6 9.4
  • Example 19 4.1
  • Example 20 11
  • Example 8 9.7
  • Example 23 18
  • mice 6 healthy male adult SD rats (purchased from Hunan SJA Laboratory Animal Co.; Ltd) were randomized into 2 groups, 3 in each group, the groups were administered by intravenous injection or gavage respectively.
  • Preparation of drugs an amount of the compound was weighed, and the target concentrate of the compound was prepared by addition of 5%DMSO, 10%Kolliphor HS15 and 85%saline (0.9%) .
  • mice were fasted 12 hours before administration and feed 3 hours later after administration, SD rats were administrated by intravenous injection from hindlimb peduncular veins (iv, 1 mg/kg) and by gavage (po, 5 mg/kg) .
  • 200-400 ⁇ L of blood was collected at different time points 0, 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24 h from rats tail vein.
  • the blood collected at each time point was placed in K 2 EDTA anticoagulant tube, and stored at a couveuse with ice bags.

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Abstract

La présente invention concerne des composés bicycliques fusionnés et leurs utilisations en médecine. En particulier, l'invention concerne des composés bicycliques fusionnés utilisés en tant que régulateurs actifs d'ASK1 et l'utilisation des composés dans la fabrication d'un médicament pour le traitement d'une maladie à régulation par l'ASK1. L'invention concerne en outre une composition pharmaceutique et une méthode de traitement d'une maladie à régulation par l'ASK1 comprenant l'administration des composés ou de la composition pharmaceutique de ceux-ci.
PCT/CN2018/100736 2017-08-17 2018-08-16 Composés bicycliques fusionnés et leurs utilisations en médecine WO2019034096A1 (fr)

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CN110577540A (zh) * 2019-07-16 2019-12-17 广州安岩仁医药科技有限公司 苯甲酰氨基吡啶衍生物的盐及其在药物中的应用
WO2020015721A1 (fr) * 2018-07-20 2020-01-23 福建广生堂药业股份有限公司 Forme cristalline utilisée en tant qu'inhibiteur d'ask1, son procédé de préparation et son utilisation
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
WO2020034988A1 (fr) * 2018-08-14 2020-02-20 江苏豪森药业集团有限公司 Sel d'inhibiteur de kinase 1 de régulation du signal de l'apoptose et forme cristalline de celui-ci
US10968199B2 (en) 2018-08-22 2021-04-06 Enanta Pharmaceuticals, Inc. Cycloalkyl-containing apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
US10988458B2 (en) 2017-05-12 2021-04-27 Enanta Pharmaceuticals, Inc. Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
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

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