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WO2019034096A1 - Fused bicyclic compounds and uses thereof in medicine - Google Patents

Fused bicyclic compounds and uses thereof in medicine Download PDF

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Publication number
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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French (fr)
Inventor
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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Sunshine Lake Pharma Co Ltd
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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.The present invention relates to fused bicyclic compounds and their uses in medicine. In particular, the invention relates to fused bicyclic compounds used as active regulators of ASK1 and the use of the compounds in the manufacture of a medicament for the treatment of an ASK1-regulated disease. The invention further relates to a pharmaceutical composition and a method of treating an ASK1-regulated disease comprising administering the compounds or pharmaceutical composition thereof.

Description

FUSED BICYCLIC COMPOUNDS AND USES THEREOF IN MEDICINE
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to Chinese Patent Application Serial No 201710707733.2, filed with the State Intellectual Property Office of china respectively on August 17, 2017, which is hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
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.
BACKGROUND OF THE INVENTION
Apoptosis signal-regulating kinase 1 (ASK1) 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-α, endoplasmic reticulum stress and intracellular concentration of calcium ions, and so on.
Research has shown that 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.
Data shows that liver disease has currently become one of the leading causes of human death. According to the duration of the 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.
At present, humans have conducted some studies to find therapeutic agents that can effectively inhibit the expression or activity of ASK1. A number of small molecule compounds have been disclosed in WO2009027283, WO2009123986, WO2010008843, WO2011008709, WO2011041293, WO2011097079, WO2012003387, WO2013112741, WO2014100541, WO2015095059, which are useful as 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.
SUMMARY OF THE INVENTION
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.
Specifically:
In one aspect, provided herein is 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,
Figure PCTCN2018100736-appb-000001
wherein
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;
each of R 1, R 2, R 3 and R 4 is independently H, deuterium, halogen, hydroxy, mercapto, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein the hydroxy, mercapto, amino, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl each are independently and optionally substituted with one, two, three, four or five substituents selected from deuterium, halogen, hydroxy, oxo (=O) , amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy;
E is 5-6 membered heteroaryl;
each R x is independently deuterium, halogen, hydroxy, mercapto, amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl or 3-10 membered heterocyclyl, wherein the hydroxy, mercapto, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl and 3-10 membered heterocyclyl each are independently and optionally substituted with one, two or three substituents selected from deuterium, halogen, hydroxy, oxo (=O) , amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy;
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;
each R z is independently H, deuterium, halogen, oxo (=O) , -OR a, -N (R b)  2, -N (R b) C (=O) R c, -C (=O) N (R b)  2, -OC (=O) R c, -C (=O) OR d, -S (O)  2OR d, -S (O)  2R c,  -N (R b) S (O)  2R c, -S (O)  2N (R b)  2, mercapto, nitro, cyano, C 1-6 alkyl, C 1-6 halohalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl or 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl and 5-10 membered heteroaryl each are independently and optionally substituted with one, two or three substituents selected from deuterium, halogen, hydroxy, oxo (=O) , amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy;
each R a, R b, R c and R d is independently H, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl or 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl and 5-10 membered heteroaryl each are independently and optionally substituted with one, two or three substituents selected from deuterium, halogen, hydroxy, oxo (=O) , amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy;
m is 1, 2 or 3;
n is 1, 2 or 3; and
k is 1, 2, 3, 4 or 5;
provided that the compound is not
Figure PCTCN2018100736-appb-000002
Figure PCTCN2018100736-appb-000003
Figure PCTCN2018100736-appb-000004
In some embodiments, 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, isopropyl, difluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, methylthio, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, epoxypropyl, tetrahydrofuryl, tetrahydropyranyl and morpholinyl each are independently and optionally substituted with one, two, three, four or five substituents selected from deuterium, F, Cl, Br, I, hydroxy, oxo (=O) , amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropoxy.
In some embodiments, E is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl or thiadiazolyl.
In some embodiments, each R x is independently deuterium, halogen, hydroxy, mercapto, amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl or 3-6 membered heterocyclyl; wherein the hydroxy, mercapto, amino, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl each are independently and optionally substituted with one, two or three substituents selected from deuterium, halogen, hydroxy, oxo (=O) , amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy.
In other embodiments, 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, methylthio, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, epoxypropyl, tetrahydrofuryl, tetrahydropyranyl and morpholinyl each are independently and optionally substituted with one, two or three substituents selected from deuterium, F, Cl, Br, I, hydroxy, oxo(=O) , amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropoxy.
In some embodiments, 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.
In some embodiments, G is an 8-12 membered fused bicyclic ring.
In other embodiments, G is
Figure PCTCN2018100736-appb-000005
Figure PCTCN2018100736-appb-000006
wherein
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 6, W 7 and W 8 is independently -O-, -S (O)  t-, -C (=O) -, -CH 2-or -NH-;
each W is independently - (CH 2)  p-, - (CH 2)  pO-, - (CH 2)  pNH-or - (CH 2)  pS (O)  t-; wherein each p is independently 0, 1, 2 or 3, each t is independently 0, 1 or 2.
In still other embodiments, G is
Figure PCTCN2018100736-appb-000007
Figure PCTCN2018100736-appb-000008
Figure PCTCN2018100736-appb-000009
In some embodiments, each R z is independently H, deuterium, halogen, oxo (=O) , -OR a, -N (R b)  2, -N (R b) C (=O) R c, -C (=O) N (R b)  2, -OC (=O) R c, -C (=O) OR d, -S (O)  2OR d, -S (O)  2R c, -N (R b) S (O)  2R c, -S (O)  2N (R b)  2, mercapto, nitro, cyano, C 1-4 alkyl, C 1-4 halohalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-12 aryl or 5-10 membered heteroaryl, wherein the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-12 aryl and 5-10 membered heteroaryl each are independently and optionally substituted with one, two or three substituents selected from deuterium, halogen, hydroxy, oxo(=O) , amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl and C 1-4 alkoxy;
each R a, R b, R c and R d is independently H, deuterium, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-12 aryl or 5-10 membered heteroaryl, wherein the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-12 aryl and 5-10 membered heteroaryl each are independently and optionally substituted with one, two or three substituents selected from deuterium, halogen, hydroxy, oxo (=O) , amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl and C 1-4 alkoxy.
In still some embodiments, each R z is independently H, deuterium, halogen, oxo (=O) , -OR a, -N (R b)  2, -N (R b) C (=O) R c, -C (=O) N (R b)  2, -OC (=O) R c, -C (=O) OR d, -S (O)  2OR d, -S (O)  2R c, -N (R b) S (O)  2R c, -S (O)  2N (R b)  2, mercapto, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, hydroxymethyl, hydroxyethyl, 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 thiadiazolyl, wherein the mercapto, methyl,  ethyl, n-propyl, isopropyl, difluoromethyl, hydroxymethyl, hydroxyethyl, 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 and thiadiazolyl each are independently and optionally substituted with one, two or three substituents selected from deuterium, F, Cl, Br, I, hydroxy, oxo (=O) , amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropoxy;
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, thienyl, thiazolyl or thiadiazolyl, wherein the 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 and thiadiazolyl each are independently and optionally substituted with one, two or three substituents selected from deuterium, halogen, hydroxy, oxo (=O) , amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropoxy.
In some embodiments, 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,
Figure PCTCN2018100736-appb-000010
Figure PCTCN2018100736-appb-000011
In other aspect, provided herein is 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.
In one aspect, 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.
In one aspect, 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.
In one aspect, provided herein is the above mentioned compound or pharmaceutical composition for use in preventing, treating or lessening a disease modulated by ASK1
In some embodiments, 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.
In some embodiments, the angiocardiopathy includes diabetes, diabetic nephropathy and other diabetic complications.
In some embodiments, the fibrosis includes pulmonary fibrosis and renal fibrosis; the respiratory disease includes chronic obstructive pulmonary, idiopathic pulmonary fibrosis and acute lung injury.
In some embodiments, 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.
In other aspect, provided herein is a method of preparing, separating or purifying the above compound.
The foregoing merely summarizes certain aspects disclosed herein and is not intended to be limiting in nature. These aspects and other aspects and embodiments are described more fully below.
DETAILED DESCRIPTION OF THE INVENTION
DEFINITIONS AND GENERAL TERMINOLOGY
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. The invention is intended  to cover all alternatives, modifications, and equivalents that may be included within the scope disclosed herein as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls.
As used herein, the following definitions shall be applied unless otherwise indicated. For purposes disclosed herein, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, and the Handbook of Chemistry and Physics, 75 th Ed. 1994. Additionally, general principles of organic chemistry are described in Sorrell et al., “Organic Chemistry” , University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry” , by Michael B. Smith and Jerry March, John Wiley &Sons, New York: 2007, all of which are incorporated herein by reference in their entireties.
The term “comprise” is an open expression, it means comprising the contents disclosed herein, but don’t exclude other contents.
As described herein, 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. It will be appreciated that the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted” . In general, whenever the term “optionally” is or is not before the term “substituted” , the term “substituted” refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure can be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position. Wherein the substituents may be, but not limited to, H, F, Cl, Br, I, nitro, cyano, oxo (=O) , hydroxy, alkyl, hydroxyalkyl, alkylamino, aminoalkyl, haloalkoxy, cycloalkyl, amino, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl, cycloalkyloxy, alkoxy, alkoxyalkyl, haloalkyl, -COOH, -alkylene-C (=O) O-alkyl, -alkylene-S (=O)  2-alkyl, -alkylene-S (=O)  2-amino, -S (=O)  2-alkyl, -S (=O)  2-amino, -S (=O)  2OH, -O-alkylene-C (=O) O-alkyl, -O-alkylene-S (=O)  2-alkyl, -O-alkylene-S (=O)  2-amino,  -O-alkylene-S (=O)  2OH, -C (=O) NH 2, -C (=O) NH-alkyl, -C (=O) N (alkyl) -alkyl, -C (=O) NHS (=O)  2-alkyl, -C (=O) NHS (=O)  2-amino, -C (=O) NHS (=O)  2OH, -N (haloalkyl) -alkyl, -N (alkyl) -S (=O)  2-alkyl, -NHS (=O)  2-alkyl, -NHS (=O)  2-haloalkyl, -N (alkyl) S (=O)  2-haloalkyl, -N (alkyl) S (=O)  2-alkylamino, -NHC (=O) -alkyl, -NHC (=O) -haloalkyl, -N (alkyl) C (=O) -haloalkyl, -N (alkyl) C (=O) -alkylamino, -N (alkyl) C (=O) O-alkyl, -NHC (=O) O-alkyl, -NHC (=O) O-haloalkyl, -N (alkyl) C (=O) O-haloalkyl, -N (alkyl) C (=O) O-aminoalkyl, -NHC (=O) -NH 2, -NHC (=O) NH- (alkyl) , -NHC (=O) NH (haloalkyl) , -NHC (=O) N (alkyl) -alkyl, -OC (=O) -alkyl, -OC (=O) -amino, -OC (=O) -alkylamino, -OC (=O) -aminoalkyl, -OC (=O) -alkoxy, -C (=O) N (alkyl) S (=O)  2-alkyl, -C (=O) N (alkyl) S (=O)  2-amino, -C (=O) NH-S (=O)  2OH, -C (=NH) NH 2, -C (=NH) NH-alkyl, -C (=NH) N (alkyl) -alkyl, -C (=N-alkyl) -NH 2, -C (=O) NH-alkylene-S (=O)  2OH, -C (=O) NHC (=O) OH, -C (=O) NHC (=O) O-alkyl, -C (=O) N (alkyl) C (=O) O-alkyl, -C (=O) NH-alkylene-C (=O) OH and -C (=O) NH-alkylene-C (=O) O-alkyl, and so on.
The term “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. Some non-limiting examples of the alkyl group further include, methyl (Me, -CH 3) , ethyl (Et, -CH 2CH 3) , n-propyl (n-Pr, -CH 2CH 2CH 3) , isopropyl (i-Pr, -CH (CH 3)  2) , n-butyl (n-Bu, -CH 2CH 2CH 2CH 3) , isobutyl (i-Bu, -CH 2CH (CH 3)  2) , sec-butyl (s-Bu, -CH (CH 3) CH 2CH 3) , tert-butyl (t-Bu, -C (CH 3)  3) , n-pentyl (-CH 2CH 2CH 2CH 2CH 3) , 2-pentyl (-CH (CH 3) CH 2CH 2CH 3) , 3-pentyl (-CH (CH 2CH 3)  2) , 2-methyl-2-butyl (-C (CH 3)  2CH 2CH 3) , 3-methyl-2-butyl (-CH (CH 3) CH (CH 3)  2) , 3-methyl-l-butyl (-CH 2CH 2CH (CH 3)  2) , 2-methyl-l-butyl (-CH 2CH (CH 3) CH 2CH 3) , n-hexyl (-CH 2CH 2CH 2CH 2CH 2CH 3) , 2-hexyl (-CH (CH 3) CH 2CH 2CH 2CH 3) , 3-hexyl (-CH (CH 2CH 3) (CH 2CH 2CH 3) ) , 2-methyl-2-pentyl (-C (CH 3)  2CH 2CH 2CH 3) , 3-methyl-2-pentyl (-CH (CH 3) CH (CH 3) CH 2CH 3) , 4-methyl-2-pentyl (-CH (CH 3) CH 2CH (CH 3)  2) , 3-methyl-3-pentyl (-C (CH 3) (CH 2CH 3)  2) , 2-methyl-3-pentyl (-CH (CH 2CH 3) CH (CH 3)  2) , 2, 3-dimethyl-2-butyl (-C (CH 3)  2CH (CH 3)  2) , 3, 3-dimethyl-2-butyl (-CH (CH 3) C (CH 3)  3, n-heptyl and n-octyl, etc. The term “alkyl” or the prefix “alk-” is inclusive of both straight chain and branched saturated carbon chain. The term “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.
The term “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. Examples of the alkenyl group include, but are not limited to, vinyl (-CH=CH 2) , allyl (-CH 2CH=CH 2) , butenyl (-CH 2CH 2CH=CH 2) , and the like.
The term “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 2C≡CH) .
The term “heteroatom” refers to one or more of oxygen (O) , sulfur (S) , nitrogen (N) , phosphorus (P) and silicon (Si) , including any oxidized form of carbon (C) , nitrogen (N) , sulfur (S) , or phosphorus (P) ; primary, secondary or tertiary amines or quaternary ammonium salts; or a substitutable nitrogen of a heterocyclic ring, for example, N (as in 3, 4-dihydro-2H-pyrrolyl) , NH (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl) ; or -C (=O) -of heterocycle oxidated from -CH 2-.
The term “halogen” refers to F (fluorine, fluoro) , Cl (chlorine, chloro) , Br (bromine, bromo) , or I (iodine, iodo) .
The term “unsaturated” refers to a moiety having one or more units of unsaturation.
The term “alkoxy” or “alkyl-oxy” refers to an alkyl group, as defined herein, attached to the other moiety of the compound molecular through an oxygen atom. In some embodiments, 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.
The term “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. In some embodiments, the alkylthio group is C 1-6 alkylthio. In other embodiments, 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.
The term “alkoxyalkyl” refers to an alkyl group substituted with one or more alkoxy groups, wherein the alkoxy and alkyl groups are as defined herein. In some embodiments, the alkoxyalkyl is C 1-6 alkoxy-C 1-6-alkyl. In other embodiments, 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.
The terms “haloalkyl” , “haloalkenyl” or “haloalkoxy” refer to alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms. In some embodiments, haloalkyl is halo C 1-6 alkyl. In other embodiments, haloalkyl is halo C 1-3 alkyl. In some embodiments, haloalkyl-oxy or haloalkoxy is halo C 1-6 alkyl-oxy or halo C 1-6 alkoxy. In other embodiments, haloalkyl-oxy or haloalkoxy is halo C 1-3 alkyl-oxy or halo C 1-3 alkoxy. Some non-limiting examples of such groups include trifluoromethyl, difluoromethyl, 2-chloro-vinyl, 2, 2-difluoroethyl, difluoromethoxy, trifluoromethoxy, and the like. And wherein each of the haloalkyl, haloalkenyl or haloalkoxy may be optionally and independently substituted with one or more substituents described herein.
The term “alkylamino” includes “N-alkylamino” and “N, N-dialkylamino” , wherein the amino groups are independently substituted with one alkyl radical or two alkyl radicals, respectively. In some embodiments, the alkylamino is a C 1-6 alkylamino group. In other embodiments, 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.
The term “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. In some embodiments, the cycloalkyl group contains 3 to 10 carbon atoms. In other embodiments, the cycloalkyl group contains 3 to 8 carbon atoms. In still other embodiments, 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.
The term “cycloalkyloxy” refers to a cycloalkyl group attached to the rest of the molecule through an oxygen atom, wherein the cycloalkyl is as defined herein.
The term “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.
The term “carbocyclyl” , “carbocycle” or “carbocyclic ring” 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. Further examples of the carbocyclyl group 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.
The term “heterocycle” , “heterocyclyl” , or “heterocyclic ring” as used interchangeably herein 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. In some embodiments, “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. Some non-limiting examples of the heterocyclyl group 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, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl and 2-oxa-5-azabicyclo [2.2.1] hept-5-yl. Some non-limiting examples of heterocyclyl wherein -CH 2-group is replaced by -C (=O) -moiety include 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl and pyrimidinedionyl, and the like. Some non-limiting examples of 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.
The term “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.
The term “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. The term “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.
The term “arylalkyl” or “aralkyl” refers to an alkyl group substituted with one or more aryl groups, wherein the alkyl group and aryl group are as defined herein. Some non-limiting examples of the arylalkyl group include phenylmethyl and phenylethyl, and the like.
The term “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. The term “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. In one embodiment, 5-10 membered heteroaryl comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, wherein N may be oxidated.
Some non-limiting examples of 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, isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 3-thiadiazolyl, 1, 3, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, pyrazinyl, 1, 3, 5-triazinyl, and the following bicycles: benzimidazolyl, benzofuryl, benzothienyl, indolyl (such as 2-indolyl) , purinyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, 4-quinolinyl) , 1, 2, 3, 4-tetrahydroisoquinolinyl, 1, 3-benzodioxolyl, indolinyl, isoquinolinyl (such as 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl) , imidazo [1, 2-a] pyridyl, pyrazolo [1, 5-a] pyridyl, pyrazolo [1, 5-a] pyrimidyl, imidazo [1, 2-b] pyridazinyl, [1, 2, 4] triazolo [4, 3-b] pyridazinyl, [1, 2, 4] triazolo [1, 5-a] pyrimidinyl, or [1, 2, 4] triazolo [1, 5-a] pyridyl, and the like.
The term “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. -CH 2-on the ring may be oxidized to form -C (=O) -; N, S, P and Si on the ring may be further oxidized. In some embodiments, “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. Some non-limiting examples of 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, 5, 6, 7, 8-tetrahydroimidazolo [1, 2-a] pyrazine, 6, 8-dihydro-5H-imidazolo [2, 1-c] [1, 4] thiazine-7, 7-dioxide, and so on. The “fused bicyclic ring”  or “fused bicyclyl” group may be optionally substituted with a substituent disclosed herein.
As described herein, 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. For example, 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.
Figure PCTCN2018100736-appb-000012
Furthermore, unless otherwise stated, the phrase “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.
Unless otherwise stated, 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.
Unless otherwise stated, 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.
“Metabolite” 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. Accordingly, 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.
Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds” , John Wiley&Sons, Inc., New York, 1994. The compounds disclosed herein may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds disclosed herein, including, but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center (s) . The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they have different stereostructures. 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.
The term “tautomer” or “tautomeric form” refers to structural isomers of different  energies which are interconvertible via a low energy barrier. Some non-limiting examples of proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. 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. Other pharmaceutically acceptable 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-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. 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.
The term “hydrate” refers to an association or complex of water and the compound disclosed herein.
The term “solvate” refers to an association or complex of one or more solvent molecules  and a compound disclosed herein. Some non-limiting examples of the solvent that form solvates include water, isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO) , ethyl acetate, acetic acid and ethanolamine.
An “ester” 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. Some non-limiting examples of 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.
An “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.
The term “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. Other prodrug forms include 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.
The term “protecting group” or “Pg” refers to a substituent that is commonly employed to block or protect a particular functionality while reacting with other functional groups on the compound. For example, 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) . Similarly, 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 2CH 2SO 2Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxy-methyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenylsulfonyl) ethyl, 2- (diphenylphosphino) -ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley &Sons, New York, 1991; and P. J. Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
The term “therapeutically 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.
The term “cardiorenal disease” as used herein 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.
The term “respiratory disease” as used herein refers to a disease comprising chronic pulmonary thromboembolic disease and idiopathic pulmonary fibrosis.
The term “nonalcoholic fatty liver (NAFLD) ” used herein refers to a metabolic disease associated with insulin resistance, comprises simple fatty liver (SFL) , nonalcoholic steatohepatitis (NASH) , fatty hepatic fibrosis and cirrhotic.
The term “liver fibrosis” as used herein 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.
The term “ASK1 modulator” used herein refers to substances which can bind to ASK1 and mudulate its activity.
The terms “a” , “an, ” “the” and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context.
DESCRIPTION OF COMPOUNDS OF THE INVENTION
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.
In one aspect, provided herein is 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,
Figure PCTCN2018100736-appb-000013
wherein E, G, X 1, X 2, X 3, X 4, R x, R y, R z, m, n and k are as defined herein;
provided that the compound is not
Figure PCTCN2018100736-appb-000014
Figure PCTCN2018100736-appb-000015
Figure PCTCN2018100736-appb-000016
In some embodiments, X 1 is C (R 1) or N; wherein R 1 is as defined herein.
In some embodiments, X 2 is C (R 2) or N; wherein R 2 is as defined herein.
In some embodiments, X 3 is C (R 3) or N; wherein R 3 is as defined herein.
In some embodiments, X 4 is C (R 4) or N; wherein R 4 is as defined herein.
In some embodiments, R 1 is H, deuterium, halogen, hydroxy, mercapto, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein the hydroxy, mercapto, amino, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 3-6 cycloalkyl and 5-6 membered heterocyclyl each are independently and optionally substituted with one, two, three, four or five substituents selected from deuterium, halogen, hydroxy, oxo (=O) , amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy.
In other embodiments, 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, methoxy, ethoxy, isopropoxy, difluoromethoxy, methylthio, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl,  epoxypropyl, tetrahydrofuryl, tetrahydropyranyl and morpholinyl each are independently and optionally substituted with one, two, three, four or five substituents selected from deuterium, F, Cl, Br, I, hydroxy, oxo (=O) , amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropoxy.
In some embodiments, R 2 is H, deuterium, halogen, hydroxy, mercapto, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein the hydroxy, mercapto, amino, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl each are independently and optionally substituted with one, two, three, four or five substituents selected from deuterium, halogen, hydroxy, oxo (=O) , amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy.
In other embodiments, 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, methoxy, ethoxy, isopropoxy, difluoromethoxy, methylthio, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, epoxypropyl, tetrahydrofuryl, tetrahydropyranyl and morpholinyl each are independently and optionally substituted with one, two, three, four or five substituents selected from deuterium, F, Cl, Br, I, hydroxy, oxo (=O) , amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropoxy.
In some embodiments, R 3 is H, deuterium, halogen, hydroxy, mercapto, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein the hydroxy, mercapto, amino, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl each are independently and optionally substituted with one, two, three, four or five substituents selected from deuterium, halogen, hydroxy, oxo (=O) , amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy.
In other embodiments, 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, methoxy, ethoxy, isopropoxy, difluoromethoxy, methylthio, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, epoxypropyl, tetrahydrofuryl, tetrahydropyranyl and morpholinyl each are independently and optionally substituted with one, two, three, four or five substituents selected from deuterium, F, Cl, Br, I, hydroxy, oxo (=O) , amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropoxy.
In some embodiments, R 4 is H, deuterium, halogen, hydroxy, mercapto, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein the hydroxy, mercapto, amino, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 3-6 cycloalkyl and 5-6 membered heterocyclyl each are independently and optionally substituted with one, two, three, four or five substituents selected from deuterium, halogen, hydroxy, oxo (=O) , amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy.
In other embodiments, 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, methoxy, ethoxy, isopropoxy, difluoromethoxy, methylthio, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, epoxypropyl, tetrahydrofuryl, tetrahydropyranyl and morpholinyl each are independently and optionally substituted with one, two, three, four or five substituents selected from deuterium, F, Cl, Br, I, hydroxy, oxo (=O) , amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropoxy.
In some embodiments, E is 5-6 membered heteroaryl.
In other embodiments, E is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl or thiadiazolyl.
In some embodiments, each R x is independently deuterium, halogen, hydroxy, mercapto, amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl or 3-10 membered heterocyclyl, wherein the hydroxy, mercapto, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl or 3-10 membered heterocyclyl each are independently and optionally substituted with one, two or three substituents selected from deuterium, halogen, hydroxy, oxo (=O) , amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy.
In other embodiments, each R x is independently deuterium, halogen, hydroxy, mercapto, amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein the hydroxy, mercapto, amino, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl each are independently and optionally substituted with one, two or three substituents selected from deuterium, halogen, hydroxy, oxo (=O) , amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy.
In other embodiments, 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, methylthio, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, epoxypropyl, tetrahydrofuryl, tetrahydropyranyl and morpholinyl each are independently and optionally substituted with one, two or three substituents selected from deuterium, F, Cl, Br, I, hydroxy, oxo(=O) , amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropoxy.
In some embodiments, 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.
In other embodiments, 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.
In some embodiments, G is a fused bicyclic ring.
In other embodiments, G is an 8-12 membered fused bicyclic ring.
In still other embodiments, G is
Figure PCTCN2018100736-appb-000017
Figure PCTCN2018100736-appb-000018
wherein W 1, W 2, W 3, W 4, W 5, W 6, W 7, W 8, R z and k are as defined herein.
In still other embodiments, G is
Figure PCTCN2018100736-appb-000019
Figure PCTCN2018100736-appb-000020
Figure PCTCN2018100736-appb-000021
wherein R z and k are as defined herein.
In some embodiments, each W 1 is independently -O-, -S-or -NH-.
In some embodiments, each W 2 is independently CH or N.
In some embodiments, each W 3 is independently CH or N.
In some embodiments, each W 4 is independently CH or N.
In some embodiments, each W 5 is independently CH or N.
In some embodiments, each W 6 is independently -O-, -S (O)  t-, -C (=O) -, -CH 2-or -NH-; wherein t is as defined herein.
In some embodiments, each W 7 is independently -O-, -S (O)  t-, -C (=O) -, -CH 2-or -NH-; wherein t is as defined herein.
In some embodiments, each W 8 is independently -O-, -S (O)  t-, -C (=O) -, -CH 2-or -NH-; wherein t is as defined herein.
In some embodiments, each W is independently - (CH 2)  p-, - (CH 2)  pO-, - (CH 2)  pNH-or - (CH 2)  pS (O)  t-; wherein p and t are as defined herein.
In some embodiments, p is 0, 1, 2 or 3.
In some embodiments, each t is independently 0, 1 or 2.
In some embodiments, each R z is independently H, deuterium, halogen, oxo (=O) , -OR a, -N (R b)  2, -N (R b) C (=O) R c, -C (=O) N (R b)  2, -OC (=O) R c, -C (=O) OR d, -S (O)  2OR d, -S (O)  2R c, -N (R b) S (O)  2R c, -S (O)  2N (R b)  2, mercapto, nitro, cyano, C 1-6 alkyl, C 1-6 halohalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl or 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl and 5-10 membered heteroaryl each are independently and optionally substituted with one, two or three substituents selected from deuterium, halogen, hydroxy, oxo(=O) , amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy; wherein R a, R b, R c and R d are as defined herein.
In other embodiments, each R z is independently H, deuterium, halogen, oxo (=O) , -OR a, -N (R b)  2, -N (R b) C (=O) R c, -C (=O) N (R b)  2, -OC (=O) R c, -C (=O) OR d, -S (O)  2OR d, -S (O)  2R c, -N (R b) S (O)  2R c, -S (O)  2N (R b)  2, mercapto, nitro, cyano, C 1-4 alkyl, C 1-4 halohalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-12 aryl or 5-10 membered heteroaryl, wherein the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkylamino, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-12 aryl and 5-10 membered heteroaryl each are independently and optionally substituted with one, two or three substituents selected from deuterium, halogen, hydroxy, oxo(=O) , amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl and C 1-4 alkoxy; wherein R a, R b, R c and  R d are as defined herein.
In still other embodiments, each R z is independently H, deuterium, halogen, oxo (=O) , -OR a, -N (R b)  2, -N (R b) C (=O) R c, -C (=O) N (R b)  2, -OC (=O) R c, -C (=O) OR d, -S (O)  2OR d, -S (O)  2R c, -N (R b) S (O)  2R c, -S (O)  2N (R b)  2, mercapto, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, hydroxymethyl, hydroxyethyl, 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 thiadiazolyl, wherein the mercapto, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, hydroxymethyl, hydroxyethyl, 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 and thiadiazolyl each are independently and optionally substituted with one, two or three substituents selected from deuterium, F, Cl, Br, I, hydroxy, oxo (=O) , amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropoxy; wherein R a, R b, R c and R d are as defined herein.
In some embodiments, each R a is independently H, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl or 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl and 5-10 membered heteroaryl each are independently and optionally substituted with one, two or three substituents selected from deuterium, halogen, hydroxy, oxo (=O) , amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy.
In other embodiments, each R a is independently H, deuterium, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-12 aryl or 5-10 membered heteroaryl, wherein the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-12 aryl and 5-10 membered heteroaryl each are independently and optionally substituted with one, two or three substituents selected from deuterium, halogen, hydroxy, oxo (=O) , amino, nitro, cyano, C 1-4 alkyl,  C 1-4 haloalkyl and C 1-4 alkoxy.
In still other embodiments, 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 thiadiazolyl, wherein the 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 and thiadiazolyl each are independently and optionally substituted with one, two or three substituents selected from deuterium, halogen, hydroxy, oxo (=O) , amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropoxy.
In some embodiments, each R b is independently H, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl or 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl and 5-10 membered heteroaryl each are independently and optionally substituted with one, two or three substituents selected from deuterium, halogen, hydroxy, oxo (=O) , amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy.
In other embodiments, each R b is independently H, deuterium, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-12 aryl or 5-10 membered heteroaryl, wherein the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-12 aryl and 5-10 membered heteroaryl each are independently and optionally substituted with one, two or three substituents selected from deuterium, halogen, hydroxy, oxo (=O) , amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl and C 1-4 alkoxy.
In still other embodiments, 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 thiadiazolyl, wherein the 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 and thiadiazolyl each are independently and optionally substituted with one, two or three substituents selected from deuterium, halogen, hydroxy, oxo (=O) , amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropoxy.
In some embodiments, each R c is independently H, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl or 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl and 5-10 membered heteroaryl each are independently and optionally substituted with one, two or three substituents selected from deuterium, halogen, hydroxy, oxo (=O) , amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy.
In other embodiments, each R c is independently H, deuterium, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-12 aryl or 5-10 membered heteroaryl, wherein the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-12 aryl and 5-10 membered heteroaryl each are independently and optionally substituted with one, two or three substituents selected from deuterium, halogen, hydroxy, oxo (=O) , amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl and C 1-4 alkoxy.
In still other embodiments, 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 thiadiazolyl, wherein the 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 and thiadiazolyl each are independently and optionally substituted with one, two or three substituents selected from deuterium, halogen, hydroxy, oxo (=O) , amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropoxy.
In some embodiments, each R d is independently H, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl or 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl and 5-10 membered heteroaryl each are independently and optionally substituted with one, two or three substituents selected from deuterium, halogen, hydroxy, oxo (=O) , amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy.
In other embodiments, each R d is independently H, deuterium, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-12 aryl or 5-10 membered heteroaryl, wherein the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-12 aryl and 5-10 membered heteroaryl each are independently and optionally substituted with one, two or three substituents selected from deuterium, halogen, hydroxy, oxo (=O) , amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl and C 1-4 alkoxy.
In still other embodiments, 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 thiadiazolyl, wherein the 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 and thiadiazolyl each are independently and optionally substituted with one, two or three substituents selected from deuterium, halogen, hydroxy, oxo (=O) , amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropoxy.
In some embodiments, m is 1, 2 or 3.
In some embodiments, n is 1, 2 or 3.
In some embodiments, k is 1, 2, 3, 4 or 5.
In some embodiments, 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,
Figure PCTCN2018100736-appb-000022
Figure PCTCN2018100736-appb-000023
wherein 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.
In other aspect, provided herein is a compound having one of the following structures, or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a solvate, a hydrate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof, but not limited to these compounds:
Figure PCTCN2018100736-appb-000024
Figure PCTCN2018100736-appb-000025
Figure PCTCN2018100736-appb-000026
In one aspect, provided herein is 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.
In other aspect, also provided herein is use of the above compound or the pharmaceutical composition thereof disclosed herein in the manufacture of a medicament for preventing, treating or lessening a disease modulated by ASK1.
In some embodiments, the disease modulated by ASK1 is autoimmune disease, inflammation, angiocardiopathy, cardiorenal disease, fibrosis, respiratory disease, liver disease, or neurodegenerative disease.
In some embodiments, the angiocardiopathy includes diabetes, diabetic nephropathy and other diabetic complications.
In some embodiments, the fibrosis includes pulmonary fibrosis and renal fibrosis.
In some embodiments, the respiratory disease includes chronic obstructive pulmonary, idiopathic pulmonary fibrosis and acute lung injury.
In some embodiments, 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.
In other aspect, provided herein is a method of preparing, separating or purifying the above compound.
PHARMACEUTICAL COMPOSITION, FORMUALTION, ADMIBISTRATION AND USE OF THE COMPOUND AND PHARMACEUTICAL COMPOSITION OF THE INVENTION
In other aspect, 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.
It will also be appreciated that certain of the compounds disclosed herein can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. Some non-limiting examples of the 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.
As described above, the pharmaceutically acceptable 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. As the following described: Troy et al., Remington: The Science and Practice of Pharmacy, 21st ed., 2005, Lippincott Williams &Wilkins, Philadelphia, and Swarbrick et al., Encyclopedia of Pharmaceutical Technology, eds. 1988-1999, Marcel Dekker, New York, both of which are herein incorporated by reference in their entireties, discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium incompatible with the compounds disclosed herein, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other components of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention.
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) . In preparing the compositions for oral dosage form, 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.
Because of their ease of administration, 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. When 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.
Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, 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, eye ointments, powders, solutions and the like, 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. In all cases, 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. For example, 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. Preferably 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.
When treating or preventing ASK1 regulated conditions for which compounds of the present invention are indicated, generally satisfactory results are obtained when 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. For most large mammals, the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligram to about 50 milligrams. In the case of a 70 kg adult human, 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. In particular, 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.
GENERAL SYNTHETIC PROCEDURES
Generally, 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.
Persons skilled in the art will recognize that the chemical reactions described may be readily adapted to prepare a number of other compounds disclosed herein, and alternative methods for preparing the compounds disclosed herein are deemed to be within the scope disclosed herein. For example, the synthesis of non-exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, and/or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds disclosed herein.
In the examples described below, unless otherwise indicated all temperatures are set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, and were used without further purification unless otherwise indicated. Common solvents were purchased from commercial suppliers such as Shantou XiLong Chemical Factory, Guangdong Guanghua Reagent Chemical Factory Co. Ltd., Guangzhou Reagent Chemical Factory, Tianjin YuYu Fine Chemical Ltd., Qingdao Tenglong Reagent Chemical Ltd., and Qingdao Ocean Chemical Factory.
Anhydrous THF, dioxane, toluene, and ether were obtained by refluxing the solvent with sodium. Anhydrous CH 2Cl 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 2SO 4 prior use.
The reactions set forth below were done generally under a positive pressure of nitrogen or argon or with a drying tube (unless otherwise stated) in anhydrous solvents, and the 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.
Column chromatography was conducted using a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory.  1H NMR spectra were recorded with a Bruker 400 MHz or 600 MHz spectrometer using CDCl 3, DMSO-d 6, CD 3OD or acetone-d 6 as solutions (reported in ppm) , and using TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard. When peak multiplicities are reported, the following abbreviations are used: s (singlet) , d (doublet) , t (triplet) , m (multiplet) , br (broadened) , dd (doublet of doublets) , q (quartet) , dt (doublet of triplets) , tt (triplet of triplets) , dddd (doublet of doublet of doublet of  doublets) , qd (quartet of doublets) , ddd (doublet of doublet of doublets) , td (triplet of doublets) , dq (doublet of quartets) , ddt (doublet of doublet of triplets) , tdd (triplet of doublet of doublets) , dtd (doublet of triplet of doublets) . Coupling constants, when given, were reported in Hertz (Hz) .
Low-resolution mass spectral (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 ℃) . G1329A autosampler and G1315B DAD detector were applied in the analysis, and an ESI source was used in the LC-MS spectrometer.
Low-resolution mass spectral (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 ℃) . G1329A autosampler and G1315D DAD detector were applied in the analysis, and an ESI source was used on the LC-MS spectrometer.
Both LC-MS spectrometers were equipped with an Agilent Zorbax SB-C18, 2.1 x 30 mm, 5 μm column. Injection volume was decided by the sample concentration. The flow rate was 0.6 mL/min. The HPLC peaks were recorded by UV-Vis wavelength at 210 nm and 254 nm. The mobile phase was 0.1%formic acid in acetonitrile (phase A) and 0.1%formic acid in ultrapure water (phase B) . The gradient elution conditions were shown in Table 1:
Table 1: The gradient condition of the mobile phase in Low-resolution mass spectrum analysis
Figure PCTCN2018100736-appb-000027
Purities of compounds were assessed by Agilent 1100 Series high performance liquid chromatography (HPLC) with UV detection at 210 nm and 254 nm (Zorbax SB-C18, 2.1 × 30 mm, 4 μm, 10 min, 0.6 mL/min flow rate, 5 to 95 % (0.1 %formic acid in CH 3CN) in (0.1 %formic acid in H 2O) . Column was operated at 40 ℃.
The following abbreviations are used throughout the specification:
CDC1 3 chloroform-d
DMF N, N-dimethylformamide
DMSO dimethylsulfoxide
DMSO-d 6 dimethyl sulfoxide-d 6
CD 3OD methyl alcohol-d 4
MeOH methanol
THF tetrahydrofuran
DCM dichloromethane
EA, EtOAc ethyl acetate
PE petroleum ether
Pd/C, Pd-C palladium on activated carbon
g gram 
mg milligram
H 2O water
M moles per liter
mol mole
mmol millimole
mL milliliter
μL microlitre
Typical synthetic procedures for preparing the compounds of the present invention disclosed are shown in the following synthetic schemes. Unless otherwise stated, wherein E, G, W, X 1, X 2, X 3, X 4, R x, R y, R z, m, n and k are as defined herein.
SCHENMES
Scheme 1
Figure PCTCN2018100736-appb-000028
wherein 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.
Scheme 2
Figure PCTCN2018100736-appb-000029
Wherein 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.
Scheme 3
Figure PCTCN2018100736-appb-000030
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) .
Scheme 4
Figure PCTCN2018100736-appb-000031
Wherein 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) .
The following examples disclosed herein are presented to further describe the invention. However, these examples should not be used to limit the scope of the invention.
DESCRIPTION OF THE EMBODIMENTS
EXAMPLES
Example 1: 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
Figure PCTCN2018100736-appb-000032
Step 1: methyl 6-bromopicolinate
To a solution of 6-bromopicolinic acid (50.0 g, 248 mmol) in methanol (350 mL) was added concentrated sulfuric acid (5 mL) dropwise at rt. After the addition, the mixture was heated to reflux until the reaction was completed, the solvent was distilled off in vacuo and the residue was diluted with water (300 mL) . The system was adjusted with saturated sodium bicarbonate aqueous solution to weakly alkaline. The resulting mixture was extracted with EtOAc (200 mL × 2) , and the combined organic layers were dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated to give the title compound as a white solid (51.5 g, 96%) .
Step 2: 6-bromopicolinohydrazide
To a solution of methyl 6-bromopicolinate (3.0 g, 14 mmol) in methanol (50 mL) was added hydrazine monohydrate (4 mL, 80 %) . The mixture was heated to reflux until the reaction was completed. The mixture was concentrated in vacuo to get the title compound as a yellow solid (2.9 g, 97%) .
Step 3: 6-methoxy-2, 3, 4, 5-tetrahydropyridine
To a solution of 2-piperidinone (3.0 g, 30 mmol) in dichloromethane (50 mL) was added trimethyloxonium tetrafluoroborate (6.0 g, 41 mmol) , the mixture was stirred at room temperature for 4 hours. The mixture was adjusted with saturated sodium bicarbonate aqueous solution to neutral under ice bath. The mixture was extracted with dichloromethane (50 mL × 2) . The organic layers were combined. The combined organic layers were washed with saturated brine (50 mL × 2) , dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the title compound as a yellow transparent oil (2.3 g, 67%) .
MS (ESI, pos. ion) m/z: 114.1 [M+1]  +.
Step 4: 3- (6-bromopyridin-2-yl) -5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [4, 3-a] pyridine
A mixture of 6-bromopicolinohydrazide (3.0 g, 14 mmol) and 6-methoxy-2, 3, 4, 5-tetrahydropyridine (2.3 g, 20 mmol) in dimethyl sulfoxide (50 mL) was heated to 90 ℃ and stirred overnight. The reaction mixture was cooled to room temperature naturally and diluted with water (50 mL) , and the mixture was extracted with EtOAc (100 mL ×3) . The combined organic layers were washed with saturated brine (80 mL) , dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (DCM/MeOH (V/V) =30/1) to give the title compound as a yellow oil (1.0 g, 26%) .
MS (ESI, pos. ion) m/z: 280.1 [M+1]  +.
Step 5: t-butyl (6- (5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [4, 3-a] pyridin-3-yl) pyridin-2-yl) carbamate
A mixture of 3- (6-bromopyridin-2-yl) -5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [4, 3-a] pyridine (1.0 g, 3.6 mmol) , t-butyl carbamate (0.5 g, 4 mmol) , cesium carbonate (3.0 g, 9.2 mmol) , palladium acetate (80 mg, 0.36 mmol) and 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (45 mg, 0.38 mmol) in 1, 4-dioxane (30 mL) was heated to 110 ℃ and stirred under nitrogen overnight. The reaction mixture was cooled to room temperature naturally and quenched with saturated ammonium chloride aqueous solution (50 mL) , and the mixture was extracted with EtOAc (100 mL × 3) . The combined organic layers were washed with saturated brine (80 mL) , dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (DCM/MeOH (V/V) =30/1) to give the title compound as a yellow oil (250 mg, 22%) .
MS (ESI, pos. ion) m/z: 316.2 [M+1]  +.
Step 6: 6- (5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [4, 3-a] pyridin-3-yl) pyridine-2-amine
To a solution of t-butyl (6- (5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [4, 3-a] pyridin-3-yl) pyridin-2-yl) carbamate (250 mg, 0.8 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (1 mL) dropwise, the mixture was further stirred for 3 hours. The mixture was adjusted with saturated sodium bicarbonate aqueous solution (30 mL) to weakly alkaline, and the mixture was extracted with DCM (30 mL × 2) . The combined organic layers were washed with saturated brine (80 mL) , dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column  chromatography (DCM/MeOH (V/V) =20/1) to give the title compound as yellow oil (50 mg, 29%) .
MS (ESI, pos. ion) m/z: 216.2 [M+1]  +.
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
To a solution of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoic acid (100 mg, 0.3842 mmol) in anhydrous DCM (20 mL) were added oxalyl chloride (0.5 mL, 6 mmol) and N, N-dimethyl formamide (0.05 mL) dropwise slowly under nitrogen protection. After stirring at room temperatrue for 2 hours, the solvent was distilled off under vacuumn to get a yellow solid 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-benzoyl chloride, and then 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-benzoyl chloride was dissolved in DCM (20 mL) , and then 6- (5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [4, 3-a] pyridin-3-yl) pyridine-2-amine (50 mg, 0.23 mmol) and 4-dimethylaminopyridine (10 mg, 0.082 mmol) were added, the resulting mixture was stirred at rt overnight. The 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. The residue was purified by silica gel column chromatography (DCM/MeOH (V/V) =25/1) to give title compound as a white solid powder (15 mg, 14%) .
MS (ESI, neg. ion) m/z: 456.2 [M-H]  -.
1H NMR (400 MHz, CDCl 3) δ 9.05 (d, J = 14.7 Hz, 1H) , 8.37 (d, J = 8.2 Hz, 1H) , 8.08 (t, J = 7.6 Hz, 2H) , 7.90 (t, J = 8.0 Hz, 1H) , 7.46 (s, 1H) , 7.21 (d, J = 12.3 Hz, 1H) , 6.81 (s, 1H) , 4.51 (t, J = 5.9 Hz, 2H) , 3.10 (t, J = 6.4 Hz, 2H) , 2.30 (s, 3H) , 2.08 -2.06 (m, 1H) , 2.01 -1.96 (m, 2H) , 1.94-1.91 (m, 2H) , 0.93 -0.89 (m, 2H) , 0.86 -0.82 (m, 2H) .
Example 2: 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
Figure PCTCN2018100736-appb-000033
Step 1: 5- (methylthio) -3, 4-dihydro-2H-pyrrole
To a solution of pyrrolidine-2-thione (4.33 g, 42.8 mmol) in dichloromethane (20 mL)  was added diethyl sulfate (8.10 mL, 85.6 mmol) , the mixture was stirred at rt overnight. The resulting mixture was quenched with saturated ammonium chloride aqueous solution (10 mL) and extracted with EtOAc (30 mL× 2) . The combined organic layers were washed with saturated brine (20 mL) , dried over anhydrous Na 2SO 4. The mixture was filtered and concentrated in vacuo, the residue was purified by column chromatography on silica gel eluted with (dichloromethane /methanol (V/V) = 4/1) to give the title compound as a pale yellow solid (4.93 g, 100%) .
MS (ESI, pos. ion) m/z: 116.2 [M + H]  +.
1H NMR (400 MHz, CDCl 3) δ 4.20 (t, J = 7.4 Hz, 2H) , 3.18 (t, J = 8.0 Hz, 2H) , 2.87 (s, 3H) , 2.44-2.36 (m, 2H) .
Step 2: 3- (6-bromopyridin-2-yl) -6, 7-dihydro-5H-pyrrolo [2, 1-c] [1, 2, 4] triazole
To a microwave tube were added 5- (methylthio) -3, 4-dihydro-2H-pyrrole (500 mg, 4.3403 mmol) , 6-bromopyridine carbohydrazide (1.41 g, 6.53 mmol) , triethylamine (1.21 mL, 8.71 mmol) and isopropanol (15 mL) , the mixture was reacted in a microwave reactor at 150 ℃ for 3 hours. The mixture cooled to rt naturally and concentrated in vacuo, the residue was purified by column chromatography on silica gel eluted with (dichloromethane /methanol (V/V) = 100/1) to give the title compound as a pale yellow solid (793 mg, 69%) .
MS (ESI, pos. ion) m/z: 265.0 [M + H]  +.
1H NMR (400 MHz, CDCl 3) δ 8.26 -8.24 (m, 1H) , 7.68 (t, J = 7.8 Hz, 1H) , 7.51 -7.49 (m, 1H) , 4.50 -4.41 (m, 2H) , 3.09 -3.01 (m, 2H) , 2.87 -2.79 (m, 2H) .
Step 3: 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride
To an ice bath cooled solution of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoic acid (24.7 g, 94.9 mmol) and N, N-dimethylformamide (0.07 mg, 0.001 mmol) in dichloromethane (100 mL) was added oxalyl chloride (16 mL, 190 mmol) dropwise slowly under nitrogen, after the addition, the mixture was stirred at rt for 3 hours and concentrated in vacuo to give the title compound as a yellow solid (26.4 g, 99.8%) .
Step 4: 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide
To a solution of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride (26.4 g, 94.7 mmol) in dichloromethane (30 mL) was added ammonium hydroxide (73 mL, 1900 mmol) dropwise slowly, the mixture was stirred at rt for 2 hours. The mixture was concentrated in vacuo, the residue was purified by column chromatography on silica gel eluted with  (dichloromethane /methanol (V/V) = 20/1) to give the title compound as a gray white solid (21.0 g, 86%) .
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
Under nitrogen, a solution of 3- (6-bromopyridin-2-yl) -6, 7-dihydro-5H-pyrrolo [2, 1-c] [1, 2, 4] triazole (291 mg, 1.01 mmol) , 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide (259 mg, 1.0 mmol) , cesium carbonate (814 mg, 2.50 mmol) , palladium acetate (23 mg, 0.10 mmol) , 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (60 mg, 0.10 mmol) in 1, 4-dioxane (10 mL) was heated to 80 ℃ and stirred overnight. The resulting mixture was cooled to rt naturally and quenched with saturated ammonium chloride aqueous solution (10 mL) and then extracted with EtOAc (20 mL× 2) . The combined organic layers were washed with saturated brine (10 mL) , dried over anhydrous Na 2SO 4. The mixture was filtered and concentrated in vacuo, the residue was purified by column chromatography on silica gel eluted with (dichloromethane /methanol (V/V) = 50/1) to give the title compound as a light black solid (150 mg, 34%) .
MS (ESI, pos. ion) m/z: 444.3 [M + H]  +.
1H NMR (400 MHz, DMSO-d 6) δ 10.91 (s, 1H) , 8.16 (s, 1H) , 8.00 (s, 1H) , 7.87 (s, 1H) , 7.71 (s, 1H) , 7.64 -7.62 (m, 1H) , 7.50 -7.48 (m, 1H) , 7.18 (s, 1H) , 4.40 -4.38 (m, 2H) , 2.89 -2.87 (m, 2H) , 2.70 -2.68 (m, 2H) , 2.25 (s, 3H) , 1.89 -1.84 (m, 1H) , 0.80 -0.70 (m, 4H) .
Example 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
Figure PCTCN2018100736-appb-000034
Step 1: 5-methoxy-3, 6-dihydro-2H-1, 4-oxazine
To a solution of 3-morpholone (2.0 g, 20 mmol) in dichloromethane (40 mL) in a 100 mL single neck flask was added trimethyloxonium tetrafluoroborate (4.0 g, 27 mmol) , the mixture was stirred at room temperature overnight. The mixture was quenched with saturated aqueous sodium bicarbonate solution (50 mL) under ice bath, and then adjusted pH to neutral. The mixture was extracted with dichloromethane (50 mL × 2) . The combined organic layers  were washed with saturated brine (50 mL × 2) , dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the title compound as a transparent oil (1.0 g, 44%) .
1H NMR (400 MHz, CDCl 3) δ 4.01 (d, J = 1.2 Hz, 2H) , 3.65 (d, J = 2.3 Hz, 3H) , 3.62 (dd, J =6.5, 3.2 Hz, 2H) , 3.51 (dd, J = 6.5, 2.9 Hz, 2H) .
Step 2: 3- (6-bromopyridin-2-yl) -6, 8-dihydro-5H- [1, 2, 4] triazole [3, 4-c] [1, 4] oxazine
A solution of 6-bromopicolinic acid hydrazide (1.9 g, 8.8 mmol) and 5-methoxy-3, 6-dihydro-2H-1, 4-oxazine (1.0 g, 8.7 mmol) in dimethyl sulfoxide (50 mL) was heated to 100 ℃ and stirred overnight. The mixture was cooled to rt naturally and diluted with water (100 mL) , the solid was obtained by filtration, and the title compound was given as a flocculent white solid (1.1 g, 45%) .
MS (ESI, pos. ion) m/z: 281.0 [M+1]  +.
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.
MS (ESI, pos. ion) m/z: 460.2 [M+1]  +.
1H NMR (400 MHz, DMSO-d 6) δ 10.98 (s, 1H) , 8.20 (d, J = 8.2 Hz, 1H) , 8.03 (t, J = 8.0 Hz, 1H) , 7.92 (d, J = 7.6 Hz, 1H) , 7.70 (s, 1H) , 7.63 (d, J = 6.5 Hz, 1H) , 7.48 (d, J = 10.7 Hz, 1H) , 7.18 (s, 1H) , 4.98 (s, 2H) , 4.57 (t, J = 5.0 Hz, 2H) , 4.04 (t, J = 5.1 Hz, 2H) , 2.25 (s, 3H) , 1.88 -1.81 (m, 1H) , 0.84 -0.77 (m, 2H) , 0.74 -0.67 (m, 2H) .
Example 4: 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
Figure PCTCN2018100736-appb-000035
Step 1: methyl 4- (4-cyclopropyl-1H-imidazol-1-yl) picolinate
A solution of 2-chloro-4- (4-cyclopropyl-1H-imidazol-1-yl) pyridine (1.0 g, 4.6 mmol) , triethylamine (1.3 mL, 9.4 mmol) and 1, 1′-bis (diphenylphosphino) ferrocene-palladium (II)  dichloride dichloromethane complex (330 mg, 0.45 mmol) in anhydrous methanol (50 mL) was degassed and purged with CO three times, and the mixture was heated to 100 ℃ under CO and stirred for 48 hours. The mixture cooled to rt naturally and filtered through a Celite pad, the filter cake was washed with methanol, the filtrate was concentrated in vacuo, the residue was purified by column chromatography on silica gel eluted with (dichloromethane /EtOAc (V/V) = 1/1) to give the title compound as a yellow oil (1.0 g, 90%) .
MS (ESI, pos. ion) m/z: 244.1 [M+H]  +.
Step 2: 4- (4-cyclopropyl-1H-imidazol-1-yl) picolinic acid 
To a solution of methyl 4- (4-cyclopropyl-1H-imidazol-1-yl) pyridinecarboxylate (800 mg, 3.3 mmol) in methanol (25 mL) was added sodium hydroxide aqueous solution (10 mL, 5 mol/L) at rt, the mixture was stirred at rt overnight. The mixture was concentrated in vacuo to remove the organic solvent, the residual water mixture was adjusted with dilute hydrochloric acid to weak acidity. The mixture was filtered, the filter cake was washed with water and dried at 50 ℃ in vacuo to get the compound as a white solid (750 mg, 100%) .
MS (ESI, pos. ion) m/z: 230.1 [M+H]  +.
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.
Step 4: 4- (4-cyclopropyl-1H-imidazol-1-yl) picolinamide
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.
MS (ESI, pos. ion) m/z: 229.2 [M+H]  +.
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.
MS (ESI, pos. ion) m/z: 413.1 [M+H]  +;
1H NMR (400 MHz, CDCl 3) δ 10.40 (s, 1H) , 8.73 (d, J = 5.4 Hz, 1H) , 8.44 (d, J = 8.1 Hz, 1H) , 8.33 (d, J = 2.0 Hz, 1H) , 8.12 (d, J = 7.6 Hz, 1H) , 8.04 (d, J = 0.9 Hz, 1H) , 7.93 (t, J = 8.0 Hz, 1H) , 7.53-7.51 (m, 1H) , 7.25 (s, 1H) , 4.58 –4.52 (m, 2H) , 3.07 (t, J = 7.7 Hz, 2H) , 2.92 –2.83 (m, 2H) , 1.98 –1.91 (m, 1H) , 0.98 –0.92 (m, 2H) , 0.91 –0.84 (m, 2H) .
Example 5: 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
Figure PCTCN2018100736-appb-000036
Step 1: methyl 3-aminobenzoate
To a solution of 3-nitromethyl benzoate (26.0 g, 144 mmol) in methanol (300 mL) was added Pd/C (2 g, 18.79mmol) , the mixture was stirred under H 2 at rt overnight. The reaction mixture was filtered through a Celite pad , the filtrate was concentrated in vacuo to get the title compound as a yellow oil (21.7 g, 100%) .
Step 2: methyl 3- ( (2-cyclopropyl-2-oxoethyl) amino) benzoate
Under nitrogen, to a solution of methyl 3-aminomethyl benzoate (21.5 g, 142 mmol) in DMF (300 mL) was added potassium carbonate (23.6 g, 171 mmol) and potassium iodide (26.0 g, 157 mmol) , the mixture was stirred at rt for 5 min, and then 2-bromo-1-cyclopropylethan-1-one (35.0 g, 215 mmol) was added dropwise slowly, after the addition, the mixture was heated to 60 ℃ and stirred overnight, after that the mixture was cooled to rt naturally. The resulting mixture was filtered through Celite and the filter cake was washed with ethyl acetate (200 mL) . The filtrate was washed with saturated brine (100 mL × 2) , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE/EtOAc (V/V) = 8/1) to give the title compound as a yellow solid (18.5 g, 56%) .
MS (ESI, pos. ion) m/z: 234.4 [M+H]  +.
Step 3: methyl 3- (4-cyclopropyl-2-mercapto-1H-imidazol-1-yl) benzoate
To a solution of methyl 3- ( (2-cyclopropyl-2-oxoethyl) amino) benzoate (18.5 g, 79.3 mmol) in acetic acid (250 mL) was added potassium rhodanate (15.5 g, 159 mmol) , the mixture was heated to 120 ℃ and stirred overnight. The resulting mixture was cooled to rt naturally and extracted with EtOAc (200 mL × 3) . The combined organic layers were washed with saturated  brine (100 mL) , dried over anhydrous Na 2SO 4, and concentrated to get the title compound as a yellow solid (21.8 g, 100 %) .
MS (ESI, neg. ion) m/z: 273.1 [M-1]  -.
Step 4: methyl 3- (4-cyclopropyl-1H-imidazol-1-yl) benzoate
To a solution of methyl 3- (4-cyclopropyl-2-mercapto-1H-imidazol-1-yl) benzoate (21.8 g, 79.5 mmol) in a mixed solvent of acetic acid (200 mL) and water (80 mL) was added hydrogen peroxide (25 mL, 831 mmol) dropwise slowly, after the addition, the mixture was heated to 45 ℃ and stirred for 1 hour. The most solvent was distilled off in vacuo, the residue was adjusted with saturated sodium bicarbonate aqueous solution to weakly alkaline, the resulting mixture was extracted with DCM (200 mL × 2) . The combined organic layers was washed with saturated aqueous NaCl (100 mL × 2) and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (V/V) = 1/1) to give the title compound as a yellow oil (8.2 g, 43%) .
MS (ESI, pos. ion) m/z: 243.1 [M+H]  +.
Step 5: 3- (4-cyclopropyl-1H-imidazol-1-yl) benzoic acid 
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.
MS (ESI, pos. ion) m/z: 229.1 [M+H]  +.
Step 6: 3- (4-cyclopropyl-1H-imidazol-1-yl) benzoyl chloride
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.
MS (ESI, pos. ion) m/z: 228.1 [M+H]  +.
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.
MS (ESI, pos. ion) m/z: 412.1 [M+H]  +.
1H NMR (400 MHz, CDCl 3) δ 8.62 (s, 1H) , 8.37 (d, J = 8.1 Hz, 1H) , 8.06 (d, J = 7.5 Hz, 1H) , 8.02 (s, 1H) , 7.95 –7.90 (m, 1H) , 7.90 –7.84 (m, 2H) , 7.65 (t, J = 7.6 Hz, 1H) , 7.60 (d, J = 7.7 Hz, 1H) , 7.14 (s, 1H) , 4.48 –4.33 (m, 2H) , 3.08 –2.95 (m, 2H) , 2.87 –2.74 (m, 2H) , 2.07 –1.96 (m, 1H) , 0.96 –0.90 (m, 2H) , 0.87 –0.81 (m, 2H) .
Example 6: 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
Figure PCTCN2018100736-appb-000037
Step 1: methyl 2-fluoro-5-nitro benzoate
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 2: methyl 5-amino-2-fluorobenzoate
To a mixture of iron powder (11.2 g, 200 mmol) and water (20 mL) was added concentrated hydrochloric acid (4.60 mL, 55.2 mmol) at rt, the mixture was adjusted to pH 1, and heated to 60 ℃ and stirred for 15 min, and then a solution of methyl 2-fluoro-5-nitro benzoate (10.0 g, 50.2 mmol) in methanol (60 mL) was added dropwise slowly. After the addition, the mixture was adjusted with concentrated hydrochloric acid (4.60 mL, 55.2 mmol) to pH 3, the mixture was refluxed and stirred for half hour. The mixture was cooled to rt naturally and adjusted with sodium hydroxide aqueous solution to pH 8. The resulting mixture was heated to 50 ℃ and filtered, the filter cake was washed with EtOAc. The filtrate was concentrated in vacuo to remove solvent, the residue was extracted with EtOAc (200 mL × 2) . The combined organic layers were washed with saturated brine (100 mL) , dried over anhydrous Na 2SO 4. The mixture was filtered and concentrated in vacuo. The residue was purified by silica-gel column chromatography (PE/EtOAc (V/V) = 10/1) to give a yellow solid (4.50 g, 53%) .
1H NMR (400 MHz, CDCl 3) δ 7.22 –7.20 (m, 1H) , 6.97 –6.92 (m, 1H) , 6.85 –6.77 (m, 1H) ,  3.93 (s, 3H) , 3.66 (s, 2H) .
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.
MS (ESI, pos. ion) m/z: 252.1 [M+H]  +.
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.
MS (ESI, pos. ion) m/z: 261.2 [M+H]  +.
Step 6: 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluorobenzoic acid 
The title compound was prepared as a light yellow solid (236 mg, 100 %) according to the method described in step 2 of example 4 by using methyl 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro benzoate (250 mg, 0.96 mmol) as a raw material. MS (ESI, pos. ion) m/z: 247.2 [M+H]  +.
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
To a solution of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluorobenzoyl chloride (252 mg, 0.95 mmol) in DCM (30 mL) were added 6- (6, 7-dihydro-5H-pyrrolo [2, 1-c] [1, 2, 4] triazol-3-yl) pyridine-2-amine (146 mg, 0.73 mmol) and 4-dimethylaminopyridine (9 mg, 0.074 mmol) , the mixture was stirred at rt overnight. The mixture was quenched with saturated sodium  bicarbonate aqueous solution (20 mL) , and the mixture was extracted with DCM (50 mL × 2) . The combined organic layers were washed with saturated brine (30 mL × 2) , dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (DCM/MeOH (V/V) =20/1) to give the title compound as a pale yellow solid (40 mg, 13%) .
MS (ESI, pos. ion) m/z: 430.1 [M+H]  +;
1H NMR (400 MHz, CDCl 3) δ 9.12 –9.09 (m, 1H) , 8.39 –8.37 (m, 1H) , 8.23 –8.21 (m, 2.8 Hz, 1H) , 8.13 (d, J = 7.6 Hz, 1H) , 7.93 (t, J = 8.0 Hz, 1H) , 7.79 (s, 1H) , 7.64 –7.54 (m, 1H) , 7.37 –7.35 (m, 1H) , 7.08 (s, 1H) , 4.47 (t, J = 7.2 Hz, 2H) , 3.07 (t, J = 7.6 Hz, 2H) , 2.93 –2.80 (m, 2H) , 1.96 –1.91 (m, 1H) , 0.96 –0.91 (m, 2H) , 0.87 –0.82 (m, 2H) .
Example 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-methylbenzamide
Figure PCTCN2018100736-appb-000038
Step 1: methyl 4-methyl-3-nitrobenzoate
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.
Step 2: 3-amino-4-methylmethyl benzoate
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.
MS (ESI, pos. ion) m/z: 257.2 [M+H]  +.
Step 6: 3- (4-cyclopropyl-1H-imidazol-1-yl) -4-methylbenzoic acid
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.  1H NMR (400 MHz, DMSO) δ 7.91–7.90 (m, 1H) , 7.73 (s, 2H) , 7.54 (d, J = 8.0 Hz, 1H) , 7.19 (s, 1H) , 2.24 (s, 3H) , 1.86–1.82 (m, 1H) , 0.85 –0.77 (m, 2H) , 0.74 –0.67 (m, 2H) .
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.
MS (ESI, pos. ion) m/z: 426.4 [M+H]  +;
1H NMR (400 MHz, DMSO-d 6) δ 10.76 (s, 1H) , 8.14 (d, J = 7.8 Hz, 1H) , 7.99–7.97 (m, 2H) , 7.92 (s, 1H) , 7.85 (d, J = 7.3 Hz, 1H) , 7.78 (s, 1H) , 7.59 (d, J = 7.6 Hz, 1H) , 7.25 (s, 1H) , 4.48–4.44 (m, 2H) , 2.31–2.87 (m, 2H) , 2.72–2.68 (m, 2H) , 2.28 (s, 3H) , 1.89–1.85 (m, 1H) , 0.82–0.80 (m, 2H) , 0.73–0.71 (m, 2H) .
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
Figure PCTCN2018100736-appb-000039
Step 1: 2-bromo-6- ( (2- (pyridin-2-yl) hydrazono) methyl) pyridine
To a solution of 2-hydrazinopyridine (1.0 g, 9.2 mmol) and 6-bromopyridine-2-carbaldehyde (1.8 g, 9.7 mmol) in anhydrous ethanol (30 mL) was added acetic acid (0.05 mL) dropwise, the mixture was heated to 80 ℃ and refluxed overnight. The mixture was filtered by suction to get the title compound as a light yellow solid (2.0 g, 79%) . MS (ESI, pos. ion) m/z: 278.1 [M+H]  +.
Step 2: 3- (6-bromopyridin-2-yl) - [1, 2, 4] triazolo [4, 3-a] pyridine
A solution of 2-bromo-6- ( (2- (pyridin-2-yl) hydrazono) methyl) pyridine (2.0 g, 7.2 mmol) and iodobenzene diacetate (6.0 g, 18 mmol) in DCM (30 mL) was stirred at rt overnight. The mixture was concentrated in vacuo. The residue was purified by silica-gel column chromatography (DCM/EtOAc (V/V) = 1/1) to give the title compound as a white solid (1.9 g, 96%) .
MS (ESI, pos. ion) m/z: 276.0 [M+H]  +.
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. MS (ESI, pos. ion) m/z: 454.1 [M+H]  +;
1H NMR (400 MHz, CDCl 3) δ 9.61 (d, J = 7.1 Hz, 1H) , 9.20 (d, J = 14.5 Hz, 1H) , 8.39 (d, J =8.2 Hz, 1H) , 8.34 (d, J = 7.6 Hz, 1H) , 8.07 (d, J = 7.3 Hz, 1H) , 7.97 (t, J = 8.0 Hz, 1H) , 7.88 (d, J = 9.2 Hz, 1H) , 7.46 (s, 1H) , 7.39 –7.35 (m, 1H) , 7.22 (d, J = 12.2 Hz, 1H) , 6.99 (t, J = 6.6 Hz, 1H) , 6.82 (s, 1H) , 2.31 (s, 3H) , 1.94 –1.88 (m, 1H) , 0.94 –0.88 (m, 2H) , 0.87 –0.80 (m, 2H) .
Example 9: 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
Figure PCTCN2018100736-appb-000040
Step 1: methyl 2-formamidoisonicotinate
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 ℃ 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. The most solvent was distilled off in vacuo, the residue was adjusted with saturated sodium bicarbonate aqueous solution (50 mL) to weakly alkaline, the resulting mixture was extracted with ethyl acetate (50 mL × 2) , the combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated in vacuo to get the title compound as a white solid (2.0 g, 84 %) .
MS (ESI, pos. ion) m/z: 181.1 [M+H]  +.
Step 2: methyl 2- (N- (2-cyclopropyl-2-oxoethyl) formamido) isonicotinate
2-Bromo-1-cycloproplyethan-1-one (2.7 mL, 28 mmol) was added into a solution of methyl 2-formamidoisonicotinate (2.0 g, 11 mmol) , potassium iodide (180 mg, 1.1 mmol) and potassium phosphate (8.2 g, 39 mmol) in N, N-dimethylformamiade (40 mL) dropwise slowly at rt.The mixture was stirred at rt overnight. The reaction mixture was diluted with water (50 mL) , and extracted with EtOAc (50 mL × 2) . The combined organic layers were washed with saturated brine (30 mL × 2) , dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (V/V) = 3/1) to give the title compound as a yellow oil (2.8 g, 96%) .
MS (ESI, pos. ion) m/z: 263.1 [M+H]  +.
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 ℃ 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 combined organic layers were washed with saturated brine (50 mL) , dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (V/V) = 1/1) to give the title compound as a light yellow solid (880 mg, 38%) .
MS (ESI, pos. ion) m/z: 244.2 [M+H]  +.
Step 4: 2- (4-cyclopropyl-1H-imidazol-1-yl) isonicotinic acid
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.
Step 5: 2- (4-cyclopropyl-1H-imidazol-1-yl) isonicotinoyl chloride
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.
MS (ESI, pos. ion) m/z: 413.1 [M+H]  +;
1H NMR (400 MHz, DMSO-d 6) δ 11.03 (s, 1H) , 8.67 (d, J = 5.0 Hz, 1H) , 8.49 (s, 1H) , 8.18 (d, J = 5.6 Hz, 2H) , 8.05 (t, J = 7.9 Hz, 1H) , 7.91 (d, J = 7.6 Hz, 1H) , 7.81 (s, 1H) , 7.75 (d, J = 5.0 Hz, 1H) , 4.45 (t, J = 7.1 Hz, 2H) , 2.91 (t, J = 7.5 Hz, 2H) , 2.75 –2.67 (m, 2H) , 1.93 –1.85 (m, 1H) , 0.86 –0.81 (m, 2H) , 0.76 –0.70 (m, 2H) .
Example 10: 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
Figure PCTCN2018100736-appb-000041
Step 1: methyl 3-amino-4-fluorobenzoate
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.
Step 2: methyl 4-fluoro-3-formamidobenzoate
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.
MS (ESI, pos. ion) m/z: 280.3 [M+H]  +.
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.
MS (ESI, pos. ion) m/z: 260.5 [M+H]  +.
Step 5: 3- (4-cyclopropyl-1H-imidazol-1-yl) -4- (methylthio) benzoic acid
To a solution of methyl 3- (4-cyclopropyl-1H-imidazol-1-yl) -4-fluorobenzoate (2.1 g, 8.1 mmol) in N, N-dimethylformamiade (30 mL) was added sodium methyl mercaptide (0.9 g, 10 mmol) in an ice bath, the mixture was stirred further 3 hours. The mixture was diluted with water (50 mL) and adjusted with dilute hydrochloric acid to weak acidic, and then concentrated in vacuo. The residue was purified by silica-gel column chromatography (DCM/MeOH (V/V) =10/1, ) to give the title compound as a yellow solid (1.4 g, 63%) .
MS (ESI, pos. ion) m/z: 275.1 [M+H]  +.
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.
MS (ESI, pos. ion) m/z: 458.4 [M+H]  +;
1H NMR (400 MHz, DMSO-d 6) δ 10.69 (s, 1H) , 8.14 (d, J = 8.2 Hz, 1H) , 8.09 –8.06 (m, 1H) , 7.99 (t, J = 8.0 Hz, 1H) , 7.95 (d, J = 1.7 Hz, 1H) , 7.86 (d, J = 7.4 Hz, 1H) , 7.70 (s, 1H) , 7.58 (d, J = 8.5 Hz, 1H) , 7.17 (s, 1H) , 4.48 –4.41 (m, 2H) , 2.93 –2.87 (m, 2H) , 2.75 –2.66 (m, 2H) , 2.52 (s, 3H) , 1.92 –1.83 (m, 1H) , 0.85 –0.79 (m, 2H) , 0.74 –0.68 (m, 2H) .
Example 11: 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- (methylsulfonyl) benzamide
Figure PCTCN2018100736-appb-000042
To a solution of 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 (example 10) (320 mg, 0.7 mmol) in methanol (15 mL) was added potassium peroxomonosulfate (850 mg, 1.4 mmol) , the mixture was stirred at rt overnight. The mixture was filtered through celite, and washed with saturated sodium bicarbonate aqueous solution (10 mL) . The mixture was concentrated in vacuo. The residue was purified by silica-gel column chromatography (DCM/MeOH (V/V) = 20/1) to give the title compound as a white solid (150 mg, 70.1%) .
MS (ESI, pos. ion) m/z: 490.4 [M+H]  +;
1H NMR (400 MHz, CDCl 3) δ 8.74 (s, 1H) , 8.40 (d, J = 8.2 Hz, 1H) , 8.35 (d, J = 8.2 Hz, 1H) , 8.16 –8.14 (m, 1H) , 8.08 (d, J = 7.6 Hz, 1H) , 7.97 (d, J = 1.4 Hz, 1H) , 7.93 (t, J = 8.0 Hz, 1H) , 7.74 (s, 1H) , 7.10 (s, 1H) , 4.42 (t, J = 7.1 Hz, 2H) , 3.03 (t, J = 7.7 Hz, 2H) , 2.87 –2.78 (m, 2H) ,  2.73 (s, 3H) , 1.97 –1.89 (m, 1H) , 0.96 –0.91 (m, 2H) , 0.89 –0.84 (m, 2H) .
Example 12: 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
Figure PCTCN2018100736-appb-000043
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.
MS (ESI, pos. ion) m/z: 455.0 [M+H]  +;
1H NMR (400 MHz, CDCl 3) δ 9.23 (s, 1H) , 8.97 –8.95 (m, 2H) , 8.59 –8.48 (m, 1H) , 8.35 –8.25 (m, 1H) , 8.01 (s, 2H) , 7.56 –7.45 (m, 1H) , 7.19 (d, J = 21.8 Hz, 2H) , 6.84 –6.79 (m, 1H) , 2.31 (s, 3H) , 2.09 –2.01 (m, 1H) , 0.96 –0.90 (m, 2H) , 0.89 –0.84 (m, 2H) .
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
Figure PCTCN2018100736-appb-000044
Step 1: 2-chloro-5-fluoro-4-iodopyridine
To a solution of 2-chloro-5-fluoropyridine (16.8 g, 128 mmol) in tetrahydrofuran (100 mL) was added lithium diisopropylamide solution (77 mL, 150 mmol) dropwise slowly at -78 ℃under nitrogen. After the addition, the mixture was further stirred for 2 hours, and then a solution of iodine (35.7 g, 141 mmol) in tetrahydrofuran (100 mL) was added dropwise slowly, after the addition, the mixture was further stirred for 1 hour. The resulting mixture was warmed to rt and quenched with saturated sodium sulfite aqueous solution (200 mL) and extracted with EtOAc (200 mL× 2) . The combined organic layers were washed with saturated brine (200 mL) , dried over anhydrous Na 2SO 4. The mixture was filtered and concentrated in vacuo. The residue was purified by silica-gel column chromatography (PE/EtOAc (V/V) = 20/1) to give a light yellow solid (23.0 g, 70%) .
1H NMR (400 MHz, CDCl 3) δ 8.15 (s, 1H) , 7.78 (d, J = 4.3 Hz, 1H) .
Step 2: 2-chloro-4- (4-cyclopropyl-1H-imidazol-1-yl) -5-fluoropyridine
To a flask were added 2-chloro-5-fluoro-4-iodopyridine (23.0 g, 89.3 mmol) , 4-cyclopropyl-1H-imidazole (29.0 g, 268 mmol) , potassium carbonate (30.8 g, 223 mmol) , cuprous iodide (340 mg, 1.79 mmol) , 8-hydroxyquinaldine (569 mg, 3.57 mmol) and dimethylsulfoxide (80 mL) under nitrogen. The mixture was heated to 90 ℃ and stirred overnight. The resulting mixture was cooled to rt naturally and quenched with water (100 mL) and then extracted with EtOAc (200 mL × 2) . The combined organic layers were washed with saturated brine (100 mL) , dried over anhydrous Na 2SO 4. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica-gel column chromatography (DCM/EtOAc (V/V) = 10/1-5/1) to give the title compound as a yellow solid (4.50 g, 21%) .  1H NMR (400 MHz, CDCl 3) δ 8.40 (d, J = 2.7 Hz, 1H) , 7.92 (s, 1H) , 7.38 (d, J = 5.4 Hz, 1H) , 7.11 (s, 1H) , 1.96–1.82 (m, 1H) , 0.96 –0.87 (m, 2H) , 0.86 –0.80 (m, 2H) .
Step 3: methyl 4- (4-cyclopropyl-1H-imidazol-1-yl) -5-methoxypicolinate
To an autoclave reactor were added 2-chloro-4- (4-cyclopropyl-1H-imidazol-1-yl) -5-fluoropyridine (8.50 g, 35.8 mmol) , [ (R) - (+) -2, 2'-bis (diphenylphosphino) -1, 1'-binaphthyl] palladium (II) chloride (114 mg, 0.14 mmol) , triethylamine (9.94 mL, 71.5 mmol) and methanol (60 mL) , carbon monoxide was fed, the mixture was heated to 90 ℃ and stirred overnight. The mixture was concentrated in vacuo. The residue was purified by silica-gel column chromatography (DCM/MeOH (V/V) = 50/1) to give the title compound as a yellow solid (2.30 g, 24%) .
Step 4: 4- (4-cyclopropyl-1H-imidazol-1-yl) -5-methoxypicolinic acid
The title compound was prepared as a yellow solid (2.20 g, 99%) according to the method described in step 2 of example 4 by using methyl 4- (4-cyclopropyl-1H-imidazol-1-yl) -5-methoxypicolinate (2.35 g, 8.60 mmol) as a raw material. Step 5: 4- (4-cyclopropyl-1H-imidazol-1-yl) -5-methoxypicolinoyl 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 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.
MS (ESI, pos. ion) m/z: 443.1 [M+H]  +;
1H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H) , 8.76 (s, 1H) , 8.30 (d, J = 8.2 Hz, 1H) , 8.23 (s, 1H) , 8.16 (s, 1H) , 8.06 (t, J = 8.0 Hz, 1H) , 7.92 (d, J = 7.2 Hz, 1H) , 7.57 (s, 1H) , 4.49 –4.44 (m, 2H) , 4.13 (s, 3H) , 2.94 –2.91 (m, 2H) , 2.77 –2.74 (m, 2H) , 1.91 –1.87 (m, 1H) , 0.85 –0.81 (m, 2H) , 0.75 –0.71 (m, 2H) .
Example 14: 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
Figure PCTCN2018100736-appb-000045
Step 1: methyl 3-formamido-2-methylbenzoate
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.
MS (ESI, pos. ion) m/z: 194.1 [M+H]  +.
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.
MS (ESI, pos. ion) m/z: 276.3 [M+H]  +.
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.
MS (ESI, pos. ion) m/z: 257.2 [M+H]  +.
Step 4: 3- (4-cyclopropyl-1H-imidazol-1-yl) -2-methylbenzoic acid 
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.
MS (ESI, pos. ion) m/z: 243.3 [M+H]  +.
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.
MS (ESI, pos. ion) m/z: 426.4 [M+H]  +;
1H NMR (600 MHz, CDCl 3) δ 8.38 (d, J = 8.1 Hz, 1H) , 8.18 (s, 1H) , 8.10 (d, J = 7.6 Hz, 1H) , 7.92 (t, J = 8.0 Hz, 1H) , 7.64 (d, J = 7.2 Hz, 1H) , 7.46 (s, 1H) , 7.43 (t, J = 7.7 Hz, 1H) , 7.39 (d, J = 7.5 Hz, 1H) , 6.82 (s, 1H) , 4.41 –4.35 (m, 2H) , 3.03 (t, J = 7.7 Hz, 2H) , 2.82 –2.74 (m, 2H) , 2.33 (s, 3H) , 1.96 –1.89 (m, 1H) , 0.95 –0.89 (m, 2H) , 0.88 –0.82 (m, 2H) .
Example 15: 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
Figure PCTCN2018100736-appb-000046
Step 1: methyl 5-amino-2-methylbenzoate
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.
Step 2: methyl 5-formamido-2-methylbenzoate
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.
MS (ESI, pos. ion) m/z: 194.1 [M+H]  +.
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.
MS (ESI, pos. ion) m/z: 276.3 [M+H]  +.
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.
MS (ESI, pos. ion) m/z: 257.3 [M+H]  +.
Step 5: 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-methylbenzoic acid
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.
Step 6: 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-methylbenzoyl chloride
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.
MS (ESI, pos. ion) m/z: 426.4 [M+H]  +;
1H NMR (400 MHz, CD 3OD) δ 8.35 (d, J = 8.2 Hz, 1H) , 8.06 (s, 1H) , 8.02 (t, J = 8.0 Hz, 1H) , 7.93 (d, J = 7.6 Hz, 1H) , 7.74 (d, J = 2.3 Hz, 1H) , 7.62 –7.60 (m, 1H) , 7.49 (d, J = 8.2 Hz, 1H) , 7.37 (s, 1H) , 4.54 –4.49 (m, 2H) , 3.23 (s, 1H) , 3.02 (t, J = 7.6 Hz, 2H) , 2.86 –2.77 (m, 2H) , 2.53 (s, 3H) , 1.95 –1.87 (m, 1H) , 0.93 –0.87 (m, 2H) , 0.79 –0.73 (m, 2H) .
Example 16: 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
Figure PCTCN2018100736-appb-000047
Step 1: methyl 3-methyl-5-nitrobenzoate
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.
Step 2: methyl 3-amino-5-methylbenzoate
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.
Step 3: methyl 3-formamido-5-methylbenzoate
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.
MS (ESI, pos. ion) m/z: 276.1 [M+H]  +;
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.
MS (ESI, pos. ion) m/z: 257.1 [M+H]  +.
Step 6: 3- (4-cyclopropyl-1H-imidazol-1-yl) -5-methylbenzoic acid 
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.
MS (ESI, pos. ion) m/z: 426.2 [M+H]  +;
1H NMR (400 MHz, CDCl 3) δ 8.44 (s, 1H) , 8.37 (d, J = 8.2 Hz, 1H) , 8.08 (d, J = 7.6 Hz, 1H) , 7.92 (t, J = 7.9 Hz, 1H) , 7.81 (s, 1H) , 7.75 (s, 1H) , 7.67 (s, 1H) , 7.41 (s, 1H) , 7.11 (s, 1H) , 4.43 (t, J = 7.1 Hz, 2H) , 3.04 (t, J = 7.6 Hz, 2H) , 2.87–2.79 (m, 2H) , 2.55 (s, 3H) , 1.97–1.90 (m, 1H) , 0.93–0.90 (m, 2H) , 0.89–0.80 (m, 2H) .
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
Figure PCTCN2018100736-appb-000048
Step 1: methyl 3-fluoro-5-formamidobenzoate
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.
MS (ESI, pos. ion) m/z: 280.2 [M+H]  +.
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.  1H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H) , 7.95 (s, 1H) , 7.89 (d, J = 9.9 Hz, 1H) , 7.64 (s, 1H) , 7.60 (d, J = 8.7 Hz, 1H) , 1.90–1.78 (m, 1H) , 0.86–0.75 (m, 2H) , 0.71 (d, J = 3.0 Hz, 2H) . Step 5: 3- (4-cyclopropyl-1H-imidazol-1-yl) -5-fluorobenzoyl chloride
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.
Step 6: 3- (4-cyclopropyl-1H-imidazol-1-yl) -5-fluorobenzamide
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.
MS (ESI, pos. ion) m/z: 246.2 [M+H]  +.
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.
MS (ESI, pos. ion) m/z: 430.4 [M+H]  +;
1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H) , 8.29 (s, 1H) , 8.15 (d, J = 8.2 Hz, 1H) , 8.09–7.98 (m, 2H) , 7.88 (d, J = 7.9 Hz, 2H) , 7.68 (d, J = 7.9 Hz, 2H) , 4.46 (t, J = 7.1 Hz, 2H) , 2.90 (t, J = 7.5 Hz, 2H) , 2.75–2.67 (m, 2H) , 1.89–1.82 (m, 1H) , 0.87–0.78 (m, 2H) , 0.72–0.70 (m,  2H) .
Example 18: 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
Figure PCTCN2018100736-appb-000049
Step 1: methyl 4-methoxy-3-nitrobenzoate
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;
1H NMR (400 MHz, CDCl 3) δ 8.53 (d, J = 2.1 Hz, 1H) , 8.25–8.23 (m, 1H) , 7.16 (d, J = 8.8 Hz, 1H) , 4.05 (s, 3H) , 3.95 (s, 3H) .
Step 2: methyl 3-amino-4-methoxybenzoate
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;
Step 3: methyl 3-formamido-4-methoxybenzoate
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.
MS (ESI, pos. ion) m/z: 210.2 [M+H]  +;
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.
MS (ESI, pos. ion) m/z: 292.2 [M+H]  +.
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.
MS (ESI, pos. ion) m/z: 273.2 [M+H]  +.
Step 6: 3- (4-cyclopropyl-1H-imidazol-1-yl) -4-methoxybenzoic acid 
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.
MS (ESI, pos. ion) m/z: 258.1 [M+H]  +.
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.
MS (ESI, pos. ion) m/z: 442.3 [M+H]  +;
1H NMR (400 MHz, CDCl 3) δ 8.46–8.30 (m, 2H) , 8.06 (d, J = 7.6 Hz, 1H) , 7.99–7.92 (m, 1H) , 7.94–7.88 (m, 1H) , 7.89–7.85 (m, 1H) , 7.73 (s, 1H) , 7.18 (d, J = 8.7 Hz, 1H) , 7.01 (s, 1H) , 4.44 (t, J = 7.1 Hz, 2H) , 3.98 (s, 3H) , 3.05 (t, J = 7.6 Hz, 2H) , 2.87–2.82 (m, 2H) , 1.98–1.90 (m, 1H) , 0.92–0.88 (m, 2H) , 0.87–0.83 (m, 2H) .
Example 19: 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
Figure PCTCN2018100736-appb-000050
Step 1: methyl 5-amino-2-methoxybenzoate
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.
MS (ESI, pos. ion) m/z: 182.2 [M+H]  +.
Step 2: methyl 5-formamido-2-methoxybenzoate
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.
MS (ESI, pos. ion) m/z: 292.2 [M+H]  +.
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.
MS (ESI, pos. ion) m/z: 273.1 [M+H]  +.
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.
MS (ESI, pos. ion) m/z: 258.2 [M+H]  +.
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.
MS (ESI, pos. ion) m/z: 442.1 [M+H]  +;
1H NMR (600 MHz, CDCl 3) δ 10.39 (s, 1H) , 8.41 (d, J = 8.2 Hz, 1H) , 8.32 (d, J = 2.7 Hz, 1H) , 8.07 (d, J = 7.6 Hz, 1H) , 7.89 (t, J = 8.0 Hz, 1H) , 7.74 (s, 1H) , 7.55–7.53 (m, 1H) , 7.18 (d, J =8.8 Hz, 1H) , 7.06 (s, 1H) , 4.48 (t, J = 7.1 Hz, 2H) , 4.15 (s, 3H) , 3.07 (t, J = 7.7 Hz, 2H) , 2.90–2.82 (m, 2H) , 1.96–1.89 (m, 1H) , 0.95–0.90 (m, 2H) , 0.86–0.81 (m, 2H) .
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
Figure PCTCN2018100736-appb-000051
Step 1: methyl 4-chloro-3-formamidobenzoate
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.
MS (ESI, pos. ion) m/z: 296.0 [M+H]  +.
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.
MS (ESI, pos. ion) m/z: 277.1 [M+H]  +.
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.
MS (ESI, pos. ion) m/z: 466.3 [M+H]  +;
1H NMR (400 MHz, CDCl 3) δ 8.80 (s, 1H) , 8.34 (d, J = 8.2 Hz, 1H) , 8.05 (d, J = 7.6 Hz, 1H) , 8.00–7.94 (m, 2H) , 7.90 (t, J = 8.0 Hz, 1H) , 7.72 (d, J = 8.6 Hz, 1H) , 7.62 (d, J = 0.9 Hz, 1H) , 6.96 (d, J = 0.8 Hz, 1H) , 4.37 (t, J = 7.1 Hz, 2H) , 3.00 (t, J = 7.7 Hz, 2H) , 2.83–2.72 (m, 2H) , 1.96–1.86 (m, 1H) , 0.94–0.87 (m, 2H) , 0.86–0.79 (m, 2H) .
Example 21: 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
Figure PCTCN2018100736-appb-000052
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;
MS (ESI, pos. ion) m/z: 279.1.1 [M+H]  +.
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.
MS (ESI, pos. ion) m/z: 277.1 [M+H]  +.
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.
MS (ESI, pos. ion) m/z: 455.3 [M+H]  +;
1H NMR (600 MHz, CDCl 3) δ 9.49 (d, J = 1.4 Hz, 1H) , 9.49–9.47 (m, 1H) , 9.18 (d, J = 15.2 Hz, 1H) , 8.47 (d, J = 8.3 Hz, 1H) , 8.40 (d, J = 7.6 Hz, 1H) , 8.11 (d, J = 7.3 Hz, 1H) , 8.09 (d, J = 4.8 Hz, 1H) , 8.04 (t, J = 8.0 Hz, 1H) , 7.48 (d, J = 0.9 Hz, 1H) , 7.27 (d, J = 12.4 Hz, 1H) , 6.83 (d, J =0.8 Hz, 1H) , 2.34 (s, 3H) , 1.97–1.91 (m, 1H) , 0.94–0.91 (m, 2H) , 0.87–0.84 (m, 2H) .
Example 22: 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
Figure PCTCN2018100736-appb-000053
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;
1H NMR (400 MHz, CDCl 3) δ 8.61 (s, 1H) , 7.95 (d, J = 7.8 Hz, 1H) , 7.81 (s, 1H) , 7.60–7.57 (m, 2H) , 7.44 (d, J = 7.8 Hz, 1H) , 7.27 (s, 1H) , 6.88 (d, J = 7.6 Hz, 1H) .
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.
MS (ESI, pos. ion) m/z: 309.1 [M+H]  +.
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.
MS (ES-API, pos. ion) m/z: 488.0 [M+H]  +;
1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H) , 8.39 (d, J = 8.5 Hz, 1H) , 8.08 (t, J = 7.9 Hz, 1H) , 7.94 (d, J = 9.1 Hz, 1H) , 7.67 (d, J = 5.9 Hz, 2H) , 7.62 (d, J = 6.6 Hz, 1H) , 7.53–7.44 (m, 1H) , 7.41 (d, J = 11.0 Hz, 1H) , 7.25 (d, J = 7.0 Hz, 1H) , 7.16 (s, 1H) , 2.22 (s, 3H) , 1.87–1.80 (m, 1H) , 0.80–0.78 (m, 2H) , 0.70–0.67 (m, 2H) .
Example 23: 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
Figure PCTCN2018100736-appb-000054
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;
MS (ESI, pos. ion) m/z: 312.1 [M+H]  +.
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.
MS (ESI, pos. ion) m/z: 309.1 [M+H]  +.
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.
MS (ESI, pos. ion) m/z: 488.3 [M+H]  +;
1H NMR (400 MHz, CDCl 3) δ 9.59 (d, J = 7.0 Hz, 1H) , 9.14 (d, J = 14.9 Hz, 1H) , 8.43 (d, J =8.3 Hz, 1H) , 8.38 (d, J = 7.7 Hz, 1H) , 8.10 (d, J = 7.3 Hz, 1H) , 8.00 (t, J = 8.0 Hz, 1H) , 7.47 (d, J = 6.3 Hz, 1H) , 7.45 (d, J = 7.1 Hz, 1H) , 7.24 (d, J = 12.3 Hz, 1H) , 6.97 (t, J = 7.1 Hz, 1H) , 6.83 (s, 1H) , 2.33 (s, 3H) , 1.98 –1.90 (m, 1H) , 0.95 –0.90 (m, 2H) , 0.88 –0.83 (m, 2H) .
Example 24: 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
Figure PCTCN2018100736-appb-000055
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.
MS (ESI, pos. ion) m/z: 291.0 [M+H]  +.
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.
MS (ESI, pos. ion) m/z: 289.1 [M+H]  +.
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.
MS (ESI, pos. ion) m/z: 468.2 [M+H]  +;
1H NMR (600 MHz, CDCl 3) δ 9.10 (d, J = 14.0 Hz, 1H) , 8.54 (d, J = 8.4 Hz, 1H) , 8.07 (d, J =7.2 Hz, 1H) , 8.00 –7.96 (m, 1H) , 7.78 (d, J = 9.7 Hz, 1H) , 7.75 (d, J = 7.4 Hz, 1H) , 7.46 (d, J =7.5 Hz, 1H) , 7.30 (s, 1H) , 7.19 (d, J = 12.1 Hz, 1H) , 6.81 (s, 1H) , 6.68 (d, J = 6.6 Hz, 1H) , 2.44 (s, 3H) , 2.30 (s, 3H) , 1.96 –1.90 (m, 1H) , 0.93 –0.90 (m, 2H) , 0.87 –0.83 (m, 2H) .
Example 25: 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
Figure PCTCN2018100736-appb-000056
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.
MS (ESI, pos. ion) m/z: 291.0 [M+H]  +.
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.
MS (ESI, pos. ion) m/z: 289.1 [M+H]  +.
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.
MS (ESI, pos. ion) m/z: 468.1 [M+H]  +;
1H NMR (600 MHz, CDCl 3) δ 9.48 (d, J = 6.9 Hz, 1H) , 9.14 (d, J = 14.7 Hz, 1H) , 8.41 (d, J =8.2 Hz, 1H) , 8.38 (d, J = 7.6 Hz, 1H) , 8.11 (d, J = 7.2 Hz, 1H) , 7.99 (t, J = 8.0 Hz, 1H) , 7.48 (s, 1H) , 7.25 (d, J = 12.2 Hz, 1H) , 7.16 (d, J = 6.5 Hz, 1H) , 6.94 (t, J = 6.8 Hz, 1H) , 6.83 (s, 1H) , 2.77 (s, 3H) , 2.33 (s, 3H) , 1.98 –1.91 (m, 1H) , 0.95 –0.91 (m, 2H) , 0.89 –0.84 (m, 2H) .
Examples of biological assay
1. Test of inhibitory activity on ASK1
(1) Test method
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. The above 10 dilutions were added into a 384 well plate with 2.5 μL 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 μL of 200 nM ASK1, after uniform oscillation, to each well was added 5 μL of substrate solution [the concentration of MBP (Myelin basic protein) was 1000 μM, the concentration of ATP was 300 μM] , after oscillation, the final concentrtions of ASK1, MBP, ATP were respectively 50 nM, 500 μM, 150 μM; 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 ℃ for 1 hour, and then tested by using ADP-Glo kinase detection kit (Promege, Cat. No. v9102/3, Lot. No. 314795) for kinase activity assay, Relative light unit (RLU) was read, inhibition rate of the compound on ASK1 activity were calculated by using the following formula, and IC 50 values was calculated by GraphPad Prism 5.  Inhibition rate (%) = (RLU buffer  well-RLU compound well) / (RLU buffer  well-RLU negative  well) × 100
(2) Results:
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 18 6.7
Example 6 9.4 Example 19 4.1
Example 7 9.1 Example 20 11
Example 8 9.7 Example 23 18
2. Pharmacokinetic test
(1) Test method
Experimental animals: 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%) . 
Administration and samples collection: the animals 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 μL 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 2EDTA anticoagulant tube, and stored at a couveuse with ice bags. All the samples in 15 min were centrifuged at 4600 r/min at 4 ℃ for 5 min, plasma samples were obtained, the concentrates of compound in the plasma samples were determined by LC/MS/MS, the pharmacokinetic parameters were calculated based on the drug concentration-time curve.
Pharmacokinetic properties of the compounds of the present invention were tested by the test above.
(2) Results
Figure PCTCN2018100736-appb-000057
Conclusions: the plasma concentration and exposure levels of the rats were high after oral administration of the compounds of the present invention, clear rate was low, and bioavailability was better. So the compounds of the present invention had good pharmacokinetic characteristics
Reference throughout this specification to “an embodiment, ” “some embodiments, ” “one embodiment” , “another example, ” “an example, ” “aspecific examples, ” or “some examples, ” means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present disclosure. In the present specification, the schematic representation of the above terms is not necessarily directed to the same embodiment. In various places throughout this specification are not necessarily referring to the same embodiment or example of the present disclosure. Furthermore, the particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments or examples. In addition, those skilled in the art can integrate and combine different embodiments or examples of the specification or the features of them as long as they are not contradictory to one another.
Finally, it should be noted that there are other ways to practice the invention. Accordingly, the present embodiments are to be considered as illustrative and not restrictive and the invention does not be limited to the details given herein. It is to be understood that the above embodiments are illustrative and are not to be construed as limiting the invention, variations, modifications, alterations and variations of the above-described embodiments may be made by those skilled in the art within the scope of the invention.

Claims (24)

  1. 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,
    Figure PCTCN2018100736-appb-100001
    wherein
    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;
    each of R 1, R 2, R 3 and R 4 is independently H, deuterium, halogen, hydroxy, mercapto, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 3-6 cycloalkyl or 3-6 membered heterocyclyl; wherein the hydroxy, mercapto, amino, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl each are independently and optionally substituted with one, two, three, four or five substituents selected from deuterium, halogen, hydroxy, oxo (=O) , amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy;
    E is 5-6 membered heteroaryl;
    each R x is independently deuterium, halogen, hydroxy, mercapto, amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl or 3-10 membered heterocyclyl; wherein the hydroxy, mercapto, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl and 3-10 membered heterocyclyl each are independently and optionally substituted with one, two or three substituents selected from deuterium, halogen, hydroxy, oxo (=O) , amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy;
    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;
    each R z is independently H, deuterium, halogen, oxo (=O) , -OR a, -N (R b)  2, -N (R b) C (=O) R c, -C (=O) N (R b)  2, -OC (=O) R c, -C (=O) OR d, -S (O)  2OR d, -S (O)  2R c, -N (R b) S (O)  2R c, -S (O)  2N (R b)  2, mercapto, nitro, cyano, C 1-6 alkyl, C 1-6 halohalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl or 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl and 5-10 membered heteroaryl each are independently and optionally substituted with one, two or three substituents selected from deuterium, halogen, hydroxy, oxo (=O) , amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy;
    each R a, R b, R c and R d is independently H, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl or 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl and 5-10 membered heteroaryl each are independently and optionally substituted with one, two or three substituents selected from deuterium, halogen, hydroxy, oxo (=O) , amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy;
    m is 1, 2 or 3;
    n is 1, 2 or 3; and
    k is 1, 2, 3, 4 or 5;
    provided that the compound is not
    Figure PCTCN2018100736-appb-100002
    Figure PCTCN2018100736-appb-100003
    Figure PCTCN2018100736-appb-100004
  2. The compound of claim 1, wherein 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, isopropyl, difluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, methylthio, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, epoxypropyl, tetrahydrofuryl, tetrahydropyranyl and morpholinyl each are independently and optionally substituted with one, two, three, four or five substituents selected from deuterium, F, Cl, Br, I, hydroxy, oxo (=O) , amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropoxy.
  3. The compound of claim 1 or 2, wherein E is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl or thiadiazolyl.
  4. The compound of any one of claims 1 to 3, wherein each R x is independently deuterium, halogen, hydroxy, mercapto, amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein the hydroxy, mercapto, amino, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl each are independently and optionally substituted with one, two or three substituents selected from deuterium, halogen,  hydroxy, oxo (=O) , amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy.
  5. The compound of any one of claims 1 to 4, wherein 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, methylthio, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, epoxypropyl, tetrahydrofuryl, tetrahydropyranyl and morpholinyl each are independently and optionally substituted with one, two or three substituents selected from deuterium, F, Cl, Br, I, hydroxy, oxo (=O) , amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropoxy.
  6. The compound of any one of claims 1 to 5, wherein 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.
  7. The compound of any one of claims 1 to 6, wherein G is an 8-12 membered fused bicyclic ring.
  8. The compound of any one of claims 1 to 7, wherein G is
    Figure PCTCN2018100736-appb-100005
    Figure PCTCN2018100736-appb-100006
    Figure PCTCN2018100736-appb-100007
    wherein
    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 6, W 7 and W 8 is independently -O-, -S (O)  t-, -C (=O) -, -CH 2-or -NH-;
    each W is independently - (CH 2)  p-, - (CH 2)  pO-, - (CH 2)  pNH-or - (CH 2)  pS (O)  t-; and
    wherein each p is independently 0, 1, 2 or 3, each t is independently 0, 1 or 2.
  9. The compound of any one of claims 1 to 8, wherein G is
    Figure PCTCN2018100736-appb-100008
    Figure PCTCN2018100736-appb-100009
    Figure PCTCN2018100736-appb-100010
  10. The compound of any one of claims 1 to 9, wherein each R z is independently H, deuterium, halogen, oxo (=O) , -OR a, -N (R b)  2, -N (R b) C (=O) R c, -C (=O) N (R b)  2, -OC (=O) R c, -C (=O) OR d, -S (O)  2OR d, -S (O)  2R c, -N (R b) S (O)  2R c, -S (O)  2N (R b)  2, mercapto, nitro, cyano, C 1-4 alkyl, C 1-4 halohalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-12 aryl or 5-10 membered heteroaryl, wherein the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-12 aryl and 5-10 membered heteroaryl each are independently and optionally substituted with one, two or three substituents selected from deuterium, halogen, hydroxy, oxo (=O) , amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl and C 1-4 alkoxy;
    each R a, R b, R c and R d is independently H, deuterium, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-12  aryl or 5-10 membered heteroaryl, wherein the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-12 aryl and 5-10 membered heteroaryl each are independently and optionally substituted with one, two or three substituents selected from deuterium, halogen, hydroxy, oxo (=O) , amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl and C 1-4 alkoxy.
  11. The compound of any one of claims 1 to 10, wherein each R z is independently H, deuterium, halogen, oxo (=O) , -OR a, -N (R b)  2, -N (R b) C (=O) R c, -C (=O) N (R b)  2, -OC (=O) R c, -C (=O) OR d, -S (O)  2OR d, -S (O)  2R c, -N (R b) S (O)  2R c, -S (O)  2N (R b)  2, mercapto, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, hydroxymethyl, hydroxyethyl, 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 thiadiazolyl, wherein the mercapto, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, hydroxymethyl, hydroxyethyl, 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 and thiadiazolyl each are independently and optionally substituted with one, two or three substituents selected from deuterium, F, Cl, Br, I, hydroxy, oxo (=O) , amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropoxy;
    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, thienyl, thiazolyl or thiadiazolyl, wherein the 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 and thiadiazolyl each are independently and optionally substituted with one, two or three substituents selected from deuterium, halogen, hydroxy, oxo (=O) , amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropoxy.
  12. The compound of any one of claims 1 to 8, 10 and 11 having 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,
    Figure PCTCN2018100736-appb-100011
    Figure PCTCN2018100736-appb-100012
  13. The compound of any one of claims 1-12 having one of the following structures:
    Figure PCTCN2018100736-appb-100013
    Figure PCTCN2018100736-appb-100014
    Figure PCTCN2018100736-appb-100015
    Figure PCTCN2018100736-appb-100016
    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.
  14. A pharmaceutical composition comprising the compound of any one of claims 1 to 13.
  15. The pharmaceutical composition according to claim 14 further comprising a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
  16. Use of the compound of any one of claims 1 to 13 or the pharmaceutical composition of any one of claims 14 to 15 in the manufacture of a medicament for preventing, treating or lessening a disease modulated by ASK1.
  17. The use of claim 16, wherein 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.
  18. The use of claim 17, wherein 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.
  19. A method of preventing, treating or lessening a disease modulated by ASK1 comprising administering a therapeutically effective amount of the compound of any one of claims 1 to 13 or the pharmaceutical composition of any one of claims 14 to 15 to the patient.
  20. The method of claim 19, wherein 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.
  21. The method of claim 20, wherein 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.
  22. The compound of any one of claims 1 to 13 or the pharmaceutical composition of any one of claims 14 to 15 for use in preventing, treating or lessening a disease modulated by ASK1.
  23. The compound or the pharmaceutical composition of claim 26, wherein 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.
  24. The compound or the pharmaceutical composition of claim 27, wherein 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.
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