WO2018157857A1 - 凋亡信号调节激酶抑制剂及其制备方法和应用 - Google Patents

凋亡信号调节激酶抑制剂及其制备方法和应用 Download PDF

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WO2018157857A1
WO2018157857A1 PCT/CN2018/077873 CN2018077873W WO2018157857A1 WO 2018157857 A1 WO2018157857 A1 WO 2018157857A1 CN 2018077873 W CN2018077873 W CN 2018077873W WO 2018157857 A1 WO2018157857 A1 WO 2018157857A1
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group
alkyl
cycloalkyl
heteroaryl
alkyl group
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PCT/CN2018/077873
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English (en)
French (fr)
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高鹏
谭松良
修文华
张福军
刘磊
包如迪
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江苏豪森药业集团有限公司
上海翰森生物医药科技有限公司
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Priority to CN202211259633.5A priority Critical patent/CN115504986B/zh
Priority to CN201880015032.5A priority patent/CN111094250B/zh
Publication of WO2018157857A1 publication Critical patent/WO2018157857A1/zh

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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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    • 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
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    • 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
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    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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    • 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

Definitions

  • the invention belongs to the field of drug synthesis, and in particular relates to an amide derivative inhibitor, a preparation method and application thereof.
  • the mitogen-activated protein kinase (MAPK) signaling pathway mediates a variety of cellular functions, including cell growth, differentiation, inflammation, survival, and apoptosis, and is a key signaling pathway for cell mitosis and apoptosis.
  • MAPK is divided into three major types, namely mitogen-activated protein kinase kinase kinase (MAP3K), mitogen-activated protein kinase kinase (MAP2K) and mitogen-activated protein kinase (MAPK).
  • MAP3K is activated by environmental signal stimulation, which activates MAP2K.
  • MAP2K further activates MAPK, which mediates the corresponding cellular effects by phosphorylating its downstream substrates such as transcription factors.
  • Apoptosis signal-regulated kinase 1 also known as mitogen-activated protein kinase kinase kinase 5 (MAP3K5), is a member of the MAPK family and mediates MAPK signaling pathway activation.
  • ASK1 activates its downstream MAP2K (eg, MKK3/6 and MKK4/7) by activation of autophosphorylation under stress conditions including oxidative stress, endoplasmic reticulum stress, and calcium influx, further activating c-Jun N-terminus Kinase (JNK) and p38 mitogen-activated protein kinases cause cellular effects such as apoptosis.
  • ASK1 activation and its signaling pathway play an important role in neurological retirement, cardiovascular disease, inflammation, autoimmunity and metabolic diseases.
  • NASH nonalcoholic steatohepatitis
  • ASK1 inhibitors have great potential for the clinical treatment of NASH, and have potential application value in the treatment of other diseases including neurological retirement diseases, cardiovascular diseases, inflammation, autoimmune and metabolic diseases.
  • Inhibitors of the disclosed inhibitors of selective inhibition of ASK1 include WO2011008709, WO2016025474, WO2012003387, WO2016105453, WO2016106384 and WO2008008375, and the like.
  • ASK1 inhibitors have good application prospects in the pharmaceutical industry as a drug, and the present invention will provide a novel structure of selective ASK1 inhibitors, and it has been found that compounds having such structures exhibit excellent effects and effects.
  • An object of the present invention is to provide a compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (I) has the following structure:
  • M 1 , M 2 , M 3 and M 4 are each independently selected from N or -CR 6 ;
  • X and Y are each independently selected from a bond, -NR 7 -, -CR 7 R 8 -, -S(O) m -,
  • Ring A is selected from aryl or heteroaryl, wherein said aryl and heteroaryl are optionally further selected from the group consisting of a halogen atom, an alkyl group, a halogenated alkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, Alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, -(CH 2 ) n OR 9 , -(CH 2 ) n SR 9 , -(CH 2 ) n C(O R 9 , —(CH 2 ) n C(O)OR 9 , —(CH 2 ) n S(O) m R 9 , —(CH 2 ) n NR 10 R 11 , —(CH 2 ) n C( O) NR 10 R 11 , -(CH 2 ) n C(O)NHR 10 , -
  • R 1 is the same or different and is each independently selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen group, an amino group, a nitro group, a hydroxyl group, a cyano group, and a ring.
  • the group, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of a halogen atom, an alkyl group,
  • R 2 is the same or different and is each independently selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen group, an amino group, a nitro group, a hydroxyl group, a cyano group, and a ring.
  • R 3 is selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, said alkyl group, haloalkyl group, ring
  • the alkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from the group consisting of a halogen atom, an alkyl group, a halogenated alkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkane group.
  • Base cycloalkyl, heterocyclic, aryl, heteroaryl, -(CH 2 ) n OR 9 , -(CH 2 ) n SR 9 , -(CH 2 ) n C(O)R 9 , -( CH 2 ) n C(O)OR 9 , —(CH 2 ) n S(O) m R 9 , —(CH 2 ) n NR 10 R 11 , —(CH 2 ) n C(O)NR 10 R 11 , -(CH 2 ) n C(O)NHR 10 , -(CH 2 ) n NR 10 C(O)R 9 and -(CH 2 ) n NR 10 S(O) m R 9 ;
  • R 3 and M 3 , M 3 and M 4 are each bonded to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl or heteroaryl
  • said cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further selected from the group consisting of a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, Heterocyclyl, aryl and heteroaryl, -(CR 9 R 10 ) n -, -(CH 2 ) n OR 9 , -(CH 2 ) n SR
  • R 1 and X or Y, M 1 and X or Y link form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, respectively, wherein said cycloalkyl, heterocyclyl, aryl or
  • the heteroaryl group is optionally further selected from the group consisting of a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, and a ring.
  • R 6 , R 7 and R 8 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, Hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n OR 9 , -(CH 2 ) n SR 9 , -(CH 2 ) n C(O)R 9 , -(CH 2 ) n C(O)OR 9 , -(CH 2 ) n S(O) m R 9 , -(CH 2 ) n NR 10 R 11 , -(CH 2 ) n C(O)NR 10 R 11 , —(CH 2 ) n C(O
  • R 9 is selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, a hydroxyl group, an amino group, an alkoxy group, a halogenated alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from the group consisting of a halogen atom, an alkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxyl group, a hydroxyalkyl group, Alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CH 2 ) n OR 12 , -(CH 2 ) n
  • R 10 and R 11 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group.
  • alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are further optionally selected from the group consisting of a halogen atom, an alkyl group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, an alkoxy group, Hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, -(CH 2 ) n OR 12 , -(CH 2 ) n SR 12 , -(CH 2 ) n C(O)R 12 , -(CH 2 ) n C(O)OR 12 , -(CH 2 ) n S(O) m R 12 , -(CH 2 ) n NR 12 R 13 , -(CH 2 ) n C(O)NR 12
  • R 13 —(CH 2 ) n C(O)NHR 13 , —(CH 2 )NHR 13
  • R 12 and R 13 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, a hydroxyl group, an amino group, an ester group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are further optionally selected from the group consisting of a halogen atom, an alkyl group, a halogen group, a hydroxyl group, an amino group, a nitro group, a cyano group, and an ester group. Substituted by one or more substituents of a group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an ary
  • x is an integer of 0, 1, 2, 3 or 4;
  • y is an integer of 0, 1, or 2;
  • n is an integer of 0, 1, or 2;
  • n is an integer of 0, 1, 2, 3, 4 or 5.
  • the compound of the formula (I) is a compound represented by the formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • R 4 is selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group, and an aromatic group.
  • heteroaryl -(CH 2 ) n OR 9 , -(CH 2 ) n SR 9 , -(CH 2 ) n C(O)R 9 , -(CH 2 ) n C(O)OR 9 , -(CH 2 ) n S(O) m R 9 , -(CH 2 ) n NR 10 R 11 , -(CH 2 ) n C(O)NR 10 R 11 , -(CH 2 ) n C(O) NHR 10 , -(CH 2 ) n NR 10 C(O)R 9 and -(CH 2 ) n NR 10 S(O) m R 9 ; wherein the alkyl group, haloalkyl group, cycloalkyl group, heterocyclic ring
  • the base, aryl and heteroaryl are optionally further selected from the group consisting of a halogen atom, an alkyl group, a halogenated alkyl group,
  • heterocyclic group aryl, heteroaryl, -(CH 2 ) n OR 12 , -(CH 2 ) n SR 12 , -(CH 2 ) n C(O)R 12 , -(CH 2 ) n C (O)OR 12 , -(CH 2 ) n S(O) m R 12 , -(CH 2 ) n NR 12 R 13 , -(CH 2 ) n C(O)NR 12 R 13 , -(CH 2 ) n C (O) NHR 13 , - (CH 2) n NR 13 C (O) R 12 and - (CH 2) n NR 13 S in a 12 (O) m R or more substituents
  • R 3 and R 4 are bonded to form a heterocyclic or heteroaryl ring, wherein said heterocyclic or heteroaryl ring is optionally further selected from the group consisting of a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, a halogen, an amino group, and a nitrate.
  • R 3 and R 4 are bonded to form a heterocyclic or heteroaryl ring, and any two substituents on the heterocyclic or heteroaryl ring may form a new cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group.
  • said forming a new cycloalkyl, arylcyclo, heterocyclyl or heteroaryl ring group is further selected from the group consisting of a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, a halogen group, an amino group, and a nitro group.
  • Ring A, M 1 , M 2 , X, Y, R 1 - R 4 , x, y, m and n are as described for the general formula (I).
  • the compound of the formula (I) is a compound represented by the formula (III), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • R 5 is selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cyano group, a cycloalkyl group, and a heterocyclic group.
  • Ring A, M 1 , M 2 , X, Y, R 1 - R 5 , x, y, m and n are as described in the general formula (I).
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof characterized in that -YX- is selected from the group consisting of :
  • the compound of the formula (I) is a compound represented by the formula (IV), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • M 1 is CR 6 or N; preferably CH;
  • M 2 is CR 6 or N; preferably N;
  • R 1 is selected from a hydrogen atom, a C 1-8 alkyl group, a halogen, a C 3-8 cycloalkyl group, a halogenated C 1-8 alkyl group, a C 1-8 halogenated alkyl group or a —(CH 2 ) n S ( O) m R 9 ; preferably C 1-6 alkyl or halogen;
  • R 2 is selected from a hydrogen atom or a C 1-8 alkyl group; preferably a hydrogen atom;
  • R 3 is selected from C 1-8 alkyl, C 3-8 cycloalkyl, halo C 1-8 alkyl, C 1-8 haloalkyl or 3-6 membered heterocyclyl, wherein said C 1-8 alkyl, C 3-8 cycloalkyl, halo C 1-8 alkyl, C 1-8 haloalkyl and 3-6 membered heterocyclyl are optionally further selected from fluorene atoms, C 1 One of -8 alkyl, C 1-8 haloalkyl, halogen, hydroxy, C 1-8 alkoxy, C 1-8 hydroxyalkyl, C 3-8 cycloalkyl or 3-6 membered heterocyclic Or substituted with a plurality of substituents; preferably isopropyl;
  • R 4 is selected from a hydrogen atom, a C 1-8 alkyl group, a halogen, a C 3-8 cycloalkyl group, a halogenated C 1-8 alkyl group or a C 1-8 halogenated alkyl group; preferably a hydrogen atom;
  • R 3 and R 4 together form a 5-6 membered heterocyclic ring, wherein said 5-6 membered heterocyclic ring is optionally further selected from a hydrogen atom, a C 1-8 alkyl group or a C 1-8 alkoxy group. Substituted by one or more substituents in the substituted C 1-8 alkyl group; preferably a C 1-6 alkyl group;
  • R 5 is selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, a C 3-8 cycloalkyl group; preferably a cyclopropyl group;
  • x is an integer of 1, 2, 3, 4 or 5;
  • y is an integer of 0, 1, or 2.
  • the compound of the formula (I) is a compound represented by the formula (V), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • M 1 , M 2 , R 1 , R 2 , R 5 , x and y are as described in the general formula (IV).
  • the compound of the formula (I) is a compound represented by the formula (VI), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • R 1 is selected from a hydrogen atom, a C 1-6 alkyl group or a halogen
  • R 3 is selected from C 1-6 alkyl or C 3-6 cycloalkyl
  • R 4 is selected from a hydrogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group or a C 3-6 cycloalkyl group;
  • x is an integer of 1, 2, 3, 4 or 5.
  • the compound of the formula (I) is a compound represented by the formula (VII), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • R 1 is selected from C 1-8 alkyl, halogen, C 3-8 cycloalkyl, halogenated C 1-8 alkyl or C 1-8 haloalkyl;
  • R 4 is selected from a hydrogen atom, a C 1-8 alkyl group, a C 1-8 halogenated alkyl group, a halogenated C 1-8 alkyl group or a C 3-8 cycloalkyl group;
  • x is selected from 1, 2, 3 or 4.
  • the compound of the formula (I) is a compound represented by the formula (VIII), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • M 5 is selected from S or CH; preferably CH;
  • Ring B is a heterocyclic or heteroaryl ring
  • R 1 is selected hydrogen, halogen, C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl and 3 -10 membered heterocyclic group;
  • R 3 is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl and 3-10 membered heterocyclic ring base;
  • R 4 is selected from the group consisting of a hydrogen atom and a C 1-8 alkyl group
  • R b is selected from a hydrogen atom, C 1-8 alkyl, C 1-8 deuterated alkyl group or a C 1-8 haloalkyl;
  • x is selected from 2, 3 or 4;
  • p is an integer of 0, 1, 2, 3 or 4;
  • q is an integer of 0 or 1.
  • R 1 is selected from C 1-8 alkyl, C 3-8 Cycloalkyl, 5-10 membered heteroaryl, C 1-8 haloalkyl, -(CH 2 ) n S(O) m R 9 and halogen, preferably 5-6 membered heteroaryl, halogen, C 1 a -6 alkyl group and a C 1-6 haloalkyl group, more preferably a pyrazole, a fluorine atom, a methyl group and a deuterated methyl group, wherein the R 9 is a C 1-6 alkyl group and a C 1-6 deuterated group Alkyl; R 2 is selected from a hydrogen atom; R 3 is selected from C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 a cycloalkyl group and
  • the formula, the stereoisomer thereof or a pharmaceutically acceptable salt thereof wherein M 1 is -CR 6 , wherein said R 6 is preferably hydrogen Atom, C 1-8 alkyl or C 3-8 cycloalkyl, preferably a hydrogen atom; M 2 is N.
  • the formula, the stereoisomer thereof or a pharmaceutically acceptable salt thereof characterized in that R 4 is selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, C 1-8 halogenated alkyl, halogenated C 1-8 alkyl and C 3-8 cycloalkyl; preferably a hydrogen atom; R 5 is selected from a hydrogen atom, a C 1-8 alkyl group and a C 3-8 cycloalkyl group ; preferably a cyclopropyl group.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the general formula, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable salts Carrier, diluent or excipient.
  • the compound of the formula (VI-A) and the compound of the formula (VI-B) are condensed to give a compound of the formula (III), which is optionally further thiolated and further condensed to give a different formula (III).
  • a compound; wherein the thio reagent in the thio reaction is preferably a Lawesson reagent;
  • W 1 and W 2 are the same or different and are each independently selected from -NH 2 , -S(O) m W, Or W; wherein W is a hydroxyl group or a halogen, and halogen is preferably bromine and chlorine;
  • Ring A, M 1 , M 2 , X, Y, R 1 - R 5 , x and y are as described for the general formula (III).
  • the present invention also relates to a method of treating a disease preventing and/or treating a disease which prevents ASK1-mediated pathological conditions, comprising administering to a patient a therapeutically effective amount of a compound of the formula (I), a stereoisomer thereof or A pharmaceutically acceptable salt, or a pharmaceutical composition thereof.
  • the invention further relates to the use of a compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the ASK1 inhibitor.
  • the present invention further relates to a compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the preparation of a neurodegenerative disorder, a cardiovascular disorder, an inflammatory disorder, a metabolic disorder For use in drugs with ASK1, the inflammatory disorder is preferably nonalcoholic steatohepatitis (NASH).
  • NASH nonalcoholic steatohepatitis
  • the present invention further relates to a compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the preparation of a method for treating nonalcoholic steatohepatitis (NASH).
  • NASH nonalcoholic steatohepatitis
  • the present invention also relates to a method for the prophylactic treatment and/or treatment of a pre-prepared treatment for a neurodegenerative disorder, a cardiovascular disorder, an inflammatory disorder, a metabolic disorder, comprising administering to a patient a therapeutically effective dose of the formula (I) A compound whose stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • alkyl refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms.
  • the alkyl group is most preferably an alkyl group of 1 to 3 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -methylhexyl, 3-methylhexyl, 4-methylhexyl,
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of an alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, naphthenic An oxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group, and a methyl group, an ethyl group, an isopropyl group, a t-butyl group or a halogenated alkyl group is preferred in the invention.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. One carbon atom.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like.
  • the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from nitrogen, oxygen or S(O).
  • a hetero atom of m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. It preferably comprises from 3 to 8 ring atoms, wherein from 1 to 4 are heteroatoms; more preferably from 3 to 6 ring atoms; most preferably from 3 to 6 ring atoms.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine.
  • the base, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl and the like are preferably tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperazinyl and pyranyl.
  • the polycyclic heterocyclic group includes a spiro ring, a fused ring, and a bridged ring heterocyclic group; wherein the heterocyclic group of the spiro ring, the fused ring, and the bridged ring is optionally bonded to the other group through a single bond, or through a ring Any two or more atoms above are further and ring-bonded to other cycloalkyl, heterocyclic, aryl and heteroaryl groups.
  • the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene. Base and naphthyl. More preferred is phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle An alkylthio group, a carboxyl group or a carboxylate group.
  • heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 5 to 10 members, more preferably 5 or 6 members, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl , pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more optionally triazolyl, pyrrolyl, thienyl , thiazolyl and pyrimidinyl.
  • the heteroaryl ring may be fused to an aryl, hetero
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
  • Haloalkyl means an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.
  • Haloalkoxy means an alkoxy group substituted by one or more halogens, wherein alkoxy is as defined above.
  • Hydroalkyl means an alkyl group substituted by a hydroxy group, wherein alkyl is as defined above.
  • Alkenyl means an alkenyl group, also known as an alkenyl group, wherein the alkenyl group may be further substituted with other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkyl Amino, halogen, decyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkyl sulphide Base, carboxyl or carboxylate group.
  • Alkynyl means (CH ⁇ C-) wherein the alkynyl group may be further substituted by other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, Halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, Carboxyl or carboxylate group.
  • Hydrophilicity refers to an -OH group.
  • Halogen means fluoro, chloro, bromo or iodo.
  • Amino means -NH 2 .
  • Niro means -NO 2 .
  • Carboxy refers to -C(O)OH.
  • THF tetrahydrofuran
  • EtOAc means ethyl acetate
  • MeOH refers to methanol
  • DMF N,N-dimethylformamide
  • DIPEA diisopropylethylamine
  • TFA trifluoroacetic acid
  • MeCN means ⁇ .
  • DMA N,N-dimethylacetamide
  • Et 2 O means diethyl ether
  • DCE 1,2 dichloroethane
  • DIPEA N,N-diisopropylethylamine
  • NBS N-bromosuccinimide
  • NIS N-iodosuccinimide
  • Cbz-Cl means benzyl chloroformate
  • Pd 2 (dba) 3 refers to tris(dibenzylideneacetone) dipalladium.
  • Dppf means 1,1'-bisdiphenylphosphinoferrocene.
  • HATU means 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
  • KHMDS means potassium hexamethyldisilazide
  • LiHMDS refers to lithium bistrimethylsilylamine.
  • MeLi means methyl lithium
  • n-BuLi means n-butyllithium
  • NaBH(OAc) 3 refers to sodium triacetoxyborohydride.
  • X is selected from A, B, or C
  • X is selected from A, B, and C
  • X is A, B, or C
  • X is A, B, and C
  • the hydrogen atom of the present invention may be substituted by its isotope ruthenium, and any of the hydrogen atoms in the examples of the present invention may also be substituted by a ruthenium atom.
  • Stepoisomerization includes three types of geometric isomerism (cis-trans isomerization), optical isomerism, and conformational isomerism.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS).
  • NMR chemical shift ( ⁇ ) is given in parts per million (ppm).
  • NMR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ).
  • the internal standard was four.
  • Methyl silane (TMS) Methyl silane
  • LC-MS was determined by LC-MS using an Agilent 1200 Infinity Series mass spectrometer.
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C 18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C 18 150 x 4.6 mm column).
  • the thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification for TLC is 0.15mm ⁇ 0.20mm, and the specification for separation and purification of thin layer chromatography is 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.
  • the first step the synthesis of 6-aminomethylpyridylhydrazide
  • Methyl 6-aminomethylpyridonate (2.0 g, 13 mmol) was dissolved in ethanol (60 mL) at room temperature and hydrazine hydrate (45.1 g, 80 wt%, 66 mmol) was added. The reaction was heated to 80 ° C, stirred at this temperature for 5 hours, and then slowly cooled to room temperature. The solid which precipitated from the reaction mixture was filtered, and the filter cake was collected to give the title compound 6-aminomethylpyridylhydrazide (1.6 g, 80%) ).
  • the third step preparation of 5-amino-2-fluoro-4-methylbenzonitrile
  • the first step the synthesis of 6-aminomethylpyridylhydrazide
  • Methyl 6-aminomethylpyridonate (10 g, 66 mmol) was dissolved in methanol (100 mL) and hydrazine hydrate (10.5 g, 80 wt%, 263 mmol) was added. The reaction was heated to 80 ° C, stirred at this temperature for 4 hours, then slowly cooled to room temperature, filtered, and then filtered, and the crude title compound 6-aminomethylpyridine hydrazide was used directly to the next step.
  • the crude 6-aminomethylpyridine hydrazide was dissolved in DMF-DMA (150 mL) at room temperature, and the mixture was stirred under reflux for 4 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. Used in the next step.
  • the third step synthesis of 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine
  • Second step Preparation of 7-(4-cyclopropyl-1H-imidazol-1-yl)-6-methyl-3,4-dihydroisoquinoline-1(2H)-one
  • the third step the synthesis of 6-chloromethylpyridine hydrazide
  • Methyl 6-chloropicolinate (1.0 g, 5.8 mmol) was dissolved in methanol (30 mL) at room temperature and hydrazine hydrate (1.5 g, 80 wt%, 23 mmol). The reaction was heated to 60 ° C, stirred at this temperature for 2 hr, then cooled slowly to room temperature and concentrated to give the title compound 6-chloromethylpyridine hydrazide as a crude material.
  • Step 6 7-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine Preparation of 2-yl)-6-methyl-3,4-dihydroisoquinoline-1(2H)-one
  • Oxygen was allowed to stand for 5 minutes and then stirred in a microwave reactor at 145 ° C for two hours. After cooling, the organic solvent was concentrated under reduced pressure and dichloromethane and water layer. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate )-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-methyl-3,4-dihydroisoquinoline -1(2H)-one (39 mg, 42%).
  • the second step preparation of 2-aminopyrimidine-4-formylhydrazine hydrochloride
  • N'-(4-(2-((Dimethylamino)methylene)indole-1-carbonyl)pyrimidin-2-yl)-N,N-dimethylformamidine (239 mg, 0.91 mmol) dissolved in CH 3 CN / HOAc (8 mL / 2 mL), N 2 was replaced three times, isopropylamine (268 mg, 4.55 mmol) was added, and the mixture was stirred at 90 ° C for 2 hours. After cooling, the organic solvent was concentrated to remove saturated aqueous sodium hydrogen carbonate. The aqueous phase was extracted twice with CH 2 Cl 2 . The organic layer was combined, dried over anhydrous sodium sulfate 45mg, three steps yield 24%).
  • Step 5 5-(4-Cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(4-(4-isopropyl-4H-1,2,4-triazole-3) Synthesis of -yl)pyrimidin-2-yl)-4-methylbenzamide
  • the third step synthesis of 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)-3-nitropyridin-2-amine
  • the fifth step 2-(5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylphenyl)-5-(4-isopropyl-4H-1, Synthesis of 2,4-triazol-3-yl)-3H-imidazo[4,5-b]pyridine
  • the sixth step 2-(5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylphenyl)-5-(4-isopropyl-4H-1, Synthesis of 2,4-triazol-3-yl)-3H-imidazo[4,5-b]pyridine
  • the third step 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazole-3) Of -pyridyl-2-yl)thiophene-3-carboxamide
  • the third step 2-chloro-5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazole-3) Of -pyridyl-2-yl)thiophene-3-carboxamide
  • 6-Aminomethylpyridylhydrazide (2.35 g, 15.4 mmol) was dissolved in 2-pentanol (15 mL) and acetic acid (2 mL) at room temperature, and (R)-5-methoxy-2-methyl was added.
  • -3,4-Dihydro-2H-pyrrole (1.93 g, 17.1 mmol).
  • the reaction was heated to 125 ° C, stirred at this temperature for 12 hours, cooled to room temperature and then concentrated. Then, a saturated aqueous solution of NaHCO 3 (5 mL), EtOAc (EtOAc m. 5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine (1.62 g, two-step yield 49%).
  • the second step synthesis of 6-(fluorene carbonyl)-o-picolinic acid
  • 6-(Carboxymethyl ⁇ methoxycarbonyl>)-o-picolinic acid (1.81 g, 10.0 mmol) was dissolved in methanol (20 mL), and hydrazine hydrate (1.87 g, 30 mmol) was added. The reaction was heated to 70 ° C, stirred at this temperature for 4 hours, and then slowly cooled to room temperature. The solid precipitated from the reaction mixture was filtered, and then filtered to give the title compound 6-(indole carbonyl) o-picamic acid (1.63 g, 90 %).
  • the third step synthesis of 6-(2-((dimethylamino)methylene)fluorene-1-carbonyl)-o-picoic acid
  • 6-(indolylcarbonyl)-o-picolinic acid (1.63 g, 9.0 mmol) was dissolved in DMF-DMA (10 mL).
  • (Dimethylamino)methylene)indole-1-carbonyl)-o-picolinic acid 850 mg, 40%).
  • the fifth step N-(5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylphenyl)-6-(4-isopropyl-4H-1, Synthesis of 2,4-triazol-3-yl)methylpyridineamide
  • 6-(4-Isopropyl-4H-1,2,4-triazol-3-yl)-o-picolinic acid (46.4 mg, 2 mmol), 5-(4-cyclopropyl-1H-imidazol-1- 2-fluoro-4-methylaniline (55.7 mg, 2.4 mmol), HATU (1.14 g, 3 mmol), NMM (405 mg, 4 mmol) dissolved in DMF (3 mL).
  • 6-Amino-5-methylisoindoline-1-one (370 mg, 2.28 mmol), 2-bromo-1-cyclopropylethane-1-one (409 mg, 2.51 mmol), KI (38.0 mg) , 0.228 mmol), K 2 CO 3 (378 mg, 2.74 mmol) was mixed in DMF (5 mL) and stirred at 55 ° C for 2 hr. After cooling, water was added to the mixture, which was extracted twice with dichloromethane. After the organic phases were combined, they were washed three times with saturated brine, dried and evaporated.
  • the fourth step preparation of 6-(4-cyclopropyl-2-mercapto-1H-imidazol-1-yl)-5-methylisoindoline-1-one
  • the crude product of the third step was dissolved in AcOH (10 mL), and then KSCN (442 mg, 4.56 mmol) was added to the solution, followed by stirring at 120 ° C for 2 hours. After cooling, the reaction solution was concentrated, and the crude material was applied to the next step.
  • the crude product of the fourth step was dissolved in a mixed solvent of AcOH (10 mL) and water (2 mL), and stirred, and hydrogen peroxide (30 wt%, 10.0 g, 87.8 mmol) was slowly added dropwise to the solution at 50 °C. After the dropwise addition was completed, stirring was continued at this temperature for 1 hour.
  • the reaction solution was cooled, and a 20 wt% aqueous Na 2 SO 3 solution (30 mL) was slowly added and stirred at room temperature for 30 min.
  • the organic solvent was removed under reduced pressure and the aqueous extracted twice with dichloromethane. The organic phase was combined and washed with aq. NaHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH -yl)-5-methylisoindoline-1-one (180 mg, five-step yield: 42%).
  • Step 6 6-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine Preparation of 2-yl)-5-methylisoindoline-1-one
  • 6-(4-Cyclopropyl-1H-imidazol-1-yl)-5-methylisoindoline-1-one 50 mg, 0.197 mmol
  • 2-chloro-6-(4-isopropyl -4H-1,2,4-triazol-3-yl)pyridine 61 mg, 0.276 mmol
  • cesium carbonate (128 mg, 0.394 mm) mixed in 1,4-dioxane (4 mL), deoxygenated with nitrogen
  • Xantphos 23.0 mg, 0.0394 mmol
  • Pd(PPh 3 ) 4 23.0 mg, 0.0197 mmol
  • the second step preparation of 5-methyl-3-methyleneisoindoline-1-one
  • the third step preparation of 3,5-dimethylisoindoline-1-one
  • the fourth step preparation of 6-iodo-3,5-dimethylisoindoline-1-one
  • 6-iodo-3,5-dimethylisoindoline-1-one 130 mg, 0.453 mmol
  • 4-cyclopropyl-1H-imidazole (245 mg, 2.26 mmol)
  • CuI 60 mg, 0.317 mmol
  • 8-hydroxyquinoline 66 mg, 0.453 mmol
  • cesium carbonate 222 mg, 0.680 mmol
  • Step 6 6-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine Preparation of 2-yl)-3,5-dimethylisoindoline-1-one
  • the thieno[2,3-d]pyridazin-4(5H)-one (304mg, 2mmol) was dissolved in concentrated sulfuric acid (5mL) and trifluoromethanesulfonic acid (5mL), cooled to 0 ° C, added in portions Dibromohydantoin (572 mg, 2 mmol). The reaction was carried out at 0 ° C for 1 hour, and ice cubes were added to terminate the reaction.
  • Second step Preparation of 2-(4-cyclopropyl-1H-imidazol-1-yl)thieno[2,3-d]pyridazine-4(5H)-one
  • 2-bromothieno[2,3-d]pyridazin-4(5H)-one (231 mg, 1 mmol), 4-cyclopropyl-1H-imidazole (216 mg, 2 mmol), CuI (19 mg, 0.1 mmol), 4,7-dimethoxy-1,10-phenanthroline (48mg, 0.2mmol), Cs 2 CO 3 (977mg, 3mmol) mixed in DMSO (5mL), under nitrogen, with stirring at 140 °C 4h.
  • reaction was carried out at 145 ° C for two hours in the reactor. After cooling, the reaction mixture was concentrated with dichloromethane and water. The organic phase was separated, washed with brine, dried over anhydrous sodium sulfate (6-(4-Isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)thieno[2,3-d]pyridazin-4(5H)-one ( 89 mg, yield 40%).
  • the third step 2-(4-cyclopropyl-1H-imidazol-1-yl)-5-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine Preparation of 2-yl)-6,6-dimethyl-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one
  • reaction mixture was evaporated to crystallijjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • the third step 4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine Preparation of 2-yl)-5-methylthiophene-2-carboxamide
  • the third step 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(1-isopropyl-1H-tetrazol-5-yl)pyridine-2 Preparation of -yl)-4-methylbenzamide
  • EtOAc EtOAc m. -1H-imidazol-1-yl-2-fluoro-N-(6-(1-isopropyl-1H-tetrazol-5-yl)pyridin-2-yl)-4-methylbenzamide (280 mg , 45%).
  • TR-FRET fluorescence resonance energy transfer
  • Adding 1 to 5 uL of the substrate mixture comprises a final concentration of the substrate polypeptide of 100 to 5000 nM and a final concentration of ATP of 100 to 1000 uM.
  • a microplate reader was used to measure the fluorescence signal values of about 615 nm and 665 nm for each well.
  • Example 1 Compound number ASK1 IC 50 (nM) Example 1 6.7 Example 3 33.8 Example 9 12.2 Example 13 2.2 Example 21 9.9 Example 22 2.5 Example 23 28.0 Example 29 5.6 Example 31 49.9 Example 42 9.1 Example 43 3.9 Example 44 3.9 Example 45 4.9 Example 46 13.9 Example 50 14.1 Example 51 2.5 Example 53 32.7
  • the compounds of the above examples all significantly inhibited the enzymatic activity of ASK1 kinase, and some compounds showed potent inhibitory effects on ASK1 kinase.
  • the IC 50 of inhibition of kinase activity was less than 10 nM. These compounds are effective inhibitors of ASK1 for the treatment of NASH. Has great application potential.
  • the rat pharmacokinetic test of the preferred embodiment of the present invention was carried out using SD male rats (Shanghai Jiesijie Experimental Animal Co., Ltd.).
  • ⁇ Mode of administration single oral administration.
  • Formulation formulation 5% EtOH-75% PG-10% Kolliphor-10% Water, sonicated.
  • ⁇ Sampling points 0.5, 1, 2, 4, 6, 8, and 24 hours after administration.
  • the plasma sample was added to 160 uL of acetonitrile precipitate in 40 ⁇ L, and mixed for 500 to 2000 ⁇ g for 5 to 20 minutes.
  • mice pharmacokinetic test of the preferred embodiment of the present invention was carried out using Balb/c male mice (Shanghai Jiesijie Experimental Animal Co., Ltd.).
  • ⁇ Mode of administration single oral administration.
  • Formulation formulation 0.5% CMC-Na, sonicated.
  • ⁇ Sampling points 0.5, 1, 2, 4, 6, 8, and 24 hours after administration.
  • the plasma sample was added to 160 uL of acetonitrile precipitate in 40 ⁇ L, and mixed for 500 to 2000 ⁇ g for 5 to 20 minutes.
  • the purpose of this test is to determine whether the compounds of the present invention can down-regulate the levels of ALT and AST in the serum of non-alcoholic steatohepatitis mice.
  • ALT/GPT alanine aminotransferase test kit: Nanjing Jiancheng Technology Co., Ltd.
  • Aspartate aminotransferase (AST/GOT) test kit Nanjing Jiancheng Technology Co., Ltd.
  • mice After 5-7 days of adaptive feeding in the SPF (no specific pathogen) barrier, C57BL/6 mice were replaced with HFD feed and the feeding period was 8 weeks. On the fifth week of HFD feeding, mice after HFD induction were randomly divided according to the body weight of the animals, and CCl 4 induction was orally administered twice a week for 4 weeks. The administration of CCl 4 was started orally, and the frequency of administration was once a day for 28 days. The vehicle control group was administered with a solvent corresponding to the test sample, and the administration volume was 10 mL/kg. After the last administration of CCl 4 for 48 hours, the mice were euthanized with CO 2 , and the animals were collected from the heart for non-anticoagulated venous blood.
  • SPF no specific pathogen
  • the whole blood was allowed to stand at room temperature for at least 30 minutes, and centrifuged at 4 to 5000 rpm for 5 minutes.
  • the serum was separated, divided into two portions, and placed in a 1.5 mL EP tube, and stored at -80 ° C until use.
  • Serum ALT and AST levels were measured using the alanine aminotransferase (ALT/GPT) test kit and the aspartate aminotransferase (AST/GOT) test kit.
  • the ALT (or AST) test substrate solution was preheated in a 37 ° C incubator; 20 uL of the substrate solution was pipetted into a 96-well plate, and 5 uL of serum was taken and added to a 96-well plate as a measuring well. After mixing, the sealing film was sealed using a sealing film. Incubate in a 37 ° C incubator for 30 min.
  • ALT (or AST) standard curve add 25uL to the 96-well plate; then add 20uL of plasma to the 96-well plate as a control well; add 2,4-dinitrophenylhydrazine solution 20uL to each well, mix and use
  • the parafilm seal was placed in a 37 ° C incubator for 20 min.
  • Absolute OD value measured well OD value - control well OD value.
  • the absolute OD value is taken into the standard curve to determine the ALT (or AST) content of the sample. Samples that exceed the calibration range are diluted to the appropriate concentration and retested.
  • the compounds of the present invention showed good effects in down-regulating the levels of ALT and AST in the serum of non-alcoholic steatohepatitis mice compared to the prior art ASK1.

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Abstract

提供酰胺类衍生物抑制剂、其制备方法和应用。特别地，涉及通式(I)所示的化合物、其制备方法及含有该化合物的药物组合物，及其作为ASK1 抑制剂在治疗神经退休性疾病、心血管疾病、炎症、自身免疫和代谢性疾病的用途，其中通式(I)中的各取代基与说明书中的定义相同。

Description

凋亡信号调节激酶抑制剂及其制备方法和应用 技术领域
本发明属于药物合成领域，具体涉及一种酰胺类衍生物抑制剂及其制备方法和应用。
背景技术
有丝分裂激活蛋白激酶(MAPK)信号通路介导多种不同的细胞功能，包括细胞生长、分化、炎症、生存和凋亡，是细胞有丝分裂和凋亡的关键信号通路。MAPK分为三大类型，分别为有丝分裂激活蛋白激酶激酶激酶(MAP3K)、有丝分裂激活蛋白激酶激酶(MAP2K)和有丝分裂激活蛋白激酶(MAPK)。MAP3K在环境信号刺激下激活，从而激活MAP2K，MAP2K进一步激活MAPK，MAPK通过磷酸化其下游底物如转录因子等介导相应的细胞效应。
凋亡信号调节激酶1(ASK1)也叫有丝分裂激活蛋白激酶激酶激酶5(MAP3K5)，属于MAPK家族中的一员，介导MAPK信号通路激活。ASK1可在应激反应包括氧化应激、内质网应激和钙流入等状态下通过自身磷酸化激活，从而激活其下游MAP2K(如MKK3/6and MKK4/7)，进一步激活c-Jun N端激酶(JNK)和p38有丝分裂激活蛋白激酶，导致细胞凋亡等相关细胞效应。ASK1激活及其信号通路在神经退休性疾病、心血管疾病、炎症、自身免疫和代谢性疾病等过程中起着重要作用。
非酒精性脂肪性肝炎(NASH)发病率高，全球或国内大约有2％～5％的NASH患者，市场规模在2025年预计将达到350亿～400亿美元。目前NASH临床上没有批准上市的药物，早期在研的治疗NASH靶点包括FXR、PPAR和GLP等，但FXR和PPAR靶点存在较大的安全性问题，而GLP属于早期的糖尿病治疗靶点，疗效还没有得到确切的临床终点验证，且属于肽类药物需每天皮下注射给药。ASK1正成为是NASH治疗领域的新机制和新靶点，其信号通路通过促进肝组织炎症和纤维化，在NASH发生发展过程中起重要作用。ASK1抑制剂对NASH的临床治疗具有巨大的潜力，对其他疾病领域包括神经退休性疾病、心血管疾病、炎症、自身免疫和代谢性疾病等的治疗也具有潜在的应用价值。
公开的选择性抑制ASK1的抑制剂专利申请包括WO2011008709、WO2016025474、WO2012003387、WO2016105453、WO2016106384和WO2008008375等。
ASK1抑制剂作为药物在医药行业具有良好的应用前景，本发明将提供一种新型结构的选择性ASK1抑制剂，并发现具有此类结构的化合物表现出优异的效果和作用。
发明内容
本发明的目的在于提供一种通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其中通式(I)所示的化合物结构如下：
Figure PCTCN2018077873-appb-000001
其中：
M 1、M 2、M 3和M 4各自独立地选自N或-CR 6；
X和Y各自独立地选自键、
Figure PCTCN2018077873-appb-000002
-NR 7-、-CR 7R 8-、-S(O) m-、
Figure PCTCN2018077873-appb-000003
Figure PCTCN2018077873-appb-000004
环A选自芳基或杂芳基，其中所述的芳基和杂芳基任选进一步被选自氘原子、烷基、氘代烷基、卤素、氨基、硝基、羟基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代；
R 1相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9；其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代；
R 2相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、 -(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9；
R 3选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟基、氨基、环烷基、杂环基、芳基和杂芳基，所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9；
或者，R 3和M 3、M 3和M 4链接分别形成一个环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基或杂芳基任选进一步被选自氘原子、烷基、氘代烷基、卤代烷基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代；
又或者，R 1和X或Y、M 1和X或Y链接分别形成一个环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基或杂芳基任选进一步被选自氘原子、烷基、氘代烷基、卤代烷基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代；
R 6、R 7和R 8相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9；其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代；
R 9选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟基、氨基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤素、氨基、 硝基、氰基、羟基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代；
R 10和R 11相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟基、氨基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤素、羟基、氨基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代；
R 12和R 13相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟基、氨基、酯基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤素、羟基、氨基、硝基、氰基、酯基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
x为0、1、2、3或4的整数；
y为0、1或2的整数；
m为0、1或2的整数；且
n为0、1、2、3、4或5的整数。
在本发明的一个优选实施例方案中，所述的通式(I)所示的化合物，其为通式(II)所示的化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2018077873-appb-000005
其中：
R 4选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9；其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 12、 -(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代；
R 3和R 4链接形成一个杂环或杂芳环，其中所述的杂环或杂芳环任选进一步被选自氘原子、烷基、氘代烷基、卤代烷基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代；
或者，R 3和R 4链接形成的杂环或杂芳环，所述杂环或杂芳环上的任意两个取代基可以形成新的环烷基、杂环基、芳基和杂芳基，其中所述的形成新的环烷基、芳环基、杂环基或杂芳环基任选进一步被选自氘原子、烷基、氘代烷基、卤代烷基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代；
环A、M 1、M 2、X、Y、R 1-R 4、x、y、m和n如通式(I)所述。
在本发明的一个优选实施例方案中，所述的通式(I)所示的化合物，其为通式(III)所示的化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2018077873-appb-000006
其中：
R 5选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、羟烷基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9；其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、 -(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代；优选环丙基。
环A、M 1、M 2、X、Y、R 1-R 5、x、y、m和n如通式(I)所述。
在本发明的一个优选实施例方案中，所述的通式(I)所示的化合物，其立体异构体或其药学上可接受的盐，其特征在于，-Y-X-选自如下基团：
Figure PCTCN2018077873-appb-000007
在本发明的一个优选实施例方案中，所述的通式(I)所示的化合物，其为通式(IV)所示的化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2018077873-appb-000008
其中：
M 1为CR 6或N；优选CH；
M 2为CR 6或N；优选N；
R 1选自氢原子、C 1-8烷基、卤素、C 3-8环烷基、卤代C 1-8烷基、C 1-8氘代烷基或-(CH 2) nS(O) mR 9；优选C 1-6烷基或卤素；
R 2选自氢原子或C 1-8烷基；优选氢原子；
R 3选自C 1-8烷基、C 3-8环烷基、卤代C 1-8烷基、C 1-8氘代烷基或3-6元杂环基，其中所述的C 1-8烷基、C 3-8环烷基、卤代C 1-8烷基、C 1-8氘代烷基和3-6元杂环基任选进一步被选自氘原子、C 1-8烷基、C 1-8卤代烷基、卤素、羟基、C 1-8烷氧基、C 1-8羟烷基、C 3-8环烷基或3-6元杂环基中的一个或多个取代基所取代；优选异丙基；
R 4选自氢原子、C 1-8烷基、卤素、C 3-8环烷基、卤代C 1-8烷基或C 1-8氘代烷基；优选氢原子；
或者R 3和R 4一起形成一个5-6元杂环，其中所述的5-6元杂环任选进一步被选自氢原子、C 1-8烷基或被C 1-8烷氧基取代的C 1-8烷基中的一个或多个取代基所取代；优选C 1-6烷基；
R 5选自氢原子、C 1-8烷基、C 3-8环烷基；优选环丙基；
x为1、2、3、4或5的整数；且
y为0、1或2的整数。
在本发明的一个优选实施例方案中，所述的通式(I)所示的化合物，其为通式(V)所示的化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2018077873-appb-000009
其中：
M 1、M 2、R 1、R 2、R 5、x和y如通式(IV)所述。
在本发明的一个优选实施例方案中，所述的通式(I)所示的化合物，其为通式(VI)所示的化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2018077873-appb-000010
其中：
-Y-X-选自
Figure PCTCN2018077873-appb-000011
R 1选自氢原子、C 1-6烷基或卤素；
R 3选自C 1-6烷基或C 3-6环烷基；
R 4选自氢原子、C 1-6烷基、C 1-6卤代烷基或C 3-6环烷基；且
x为1、2、3、4或5的整数。
在本发明的一个优选实施例方案中，所述的通式(I)所示的化合物，其为通式(VII)所示的化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2018077873-appb-000012
其中：
R 1选自C 1-8烷基、卤素、C 3-8环烷基、卤代C 1-8烷基或C 1-8氘代烷基；
R 4选自氢原子、C 1-8烷基、C 1-8氘代烷基、卤代C 1-8烷基或C 3-8环烷基；且
x选自1、2、3或4。
在本发明的一个优选实施例方案中，所述的通式(I)所示的化合物，其为通式(VIII)所示的化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2018077873-appb-000013
其中：
M 5选自S或CH；优选CH；
环B为杂环或杂芳环；
R 1选自氢原子、卤素、C 1-8烷基、C 1-8氘代烷基、C 1-8烷氧基、C 1-8卤代烷氧基、C 3-8环烷基和3-10元杂环基；
R 3选自C 1-8烷基、C 1-8氘代烷基、C 1-8烷氧基、C 1-8卤代烷氧基、C 3-8环烷基和3-10元杂环基；
R 4选自氢原子、C 1-8烷基；
R b选自氢原子、C 1-8烷基、C 1-8氘代烷基或C 1-8卤代烷基；
x选自2、3或4；
p为0、1、2、3或4的整数；且
q为0或1的整数。
在本发明的一个优选实施例方案中，所示各通式、其立体异构体或其药学上可接受的盐，其特征在于，环A选自如下基团：
Figure PCTCN2018077873-appb-000014
在本发明的一个优选实施例方案中，所示各通式、其立体异构体或其药学上可接受的盐，其特征在于，R 1选自C 1-8烷基、C 3-8环烷基、5-10元杂芳基、C 1-8氘代烷基、-(CH 2) nS(O) mR 9和卤素，优选5-6元杂芳基、卤素、C 1-6烷基和C 1-6氘代烷基，更优选吡唑、氟原子、甲基和氘代甲基，其中所述的R 9为C 1-6烷基和C 1-6氘代烷基；R 2选自氢原子；R 3选自C 1-8烷基、C 1-8氘代烷基、C 1-8烷氧基、 C 1-8卤代烷氧基、C 3-8环烷基和3-10元杂环基，其中所述的C 1-8烷基任选进一步被选自氢原子、C 1-8烷氧基、C 1-8卤代烷氧基、C 3-8环烷基和3-10元杂环基中的一个或多个取代基所取代；优选C 1-6烷基；更优选异丙基。
在本发明的一个优选实施例方案中，所示各通式、其立体异构体或其药学上可接受的盐，其特征在于，M 1为-CR 6，其中所述的R 6优选氢原子、C 1-8烷基或C 3-8环烷基，优选氢原子；M 2为N。
在本发明的一个优选实施例方案中，所示各通式、其立体异构体或其药学上可接受的盐，其特征在于，R 4选自氢原子、C 1-8烷基、C 1-8氘代烷基、卤代C 1-8烷基和C 3-8环烷基；优选氢原子；R 5选自氢原子、C 1-8烷基和C 3-8环烷基；优选环丙基。
本发明的另一方面涉及一种药物组合物，其包括治疗有效剂量的各通式所述的化合物、其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
在本发明的一个优选实施例方案中，一种制备所示的通式(III-C)化合物、其立体异构体或其药学上可接受的盐的制备方法，包括如下步骤：
Figure PCTCN2018077873-appb-000015
通式(VI-A)化合物和通式(VI-B)化合物缩合后得到通式(III)化合物，该通式(III)化合物任选进一步硫代，进一步被缩合得到不同的通式(III)化合物；其中硫代反应中硫代试剂优选Lawesson试剂；
其中：
W 1和W 2相同或不同，且各自独立地选自为
Figure PCTCN2018077873-appb-000016
-NH 2、-S(O) mW、
Figure PCTCN2018077873-appb-000017
或W；其中所述的W为羟基或卤素，卤素优选溴和氯；
环A、M 1、M 2、X、Y、R 1-R 5、x和y如通式(III)所述。
本发明还涉及一种治疗预防和/或治疗预防ASK1介导的病理学特征的疾病的方法，其包括向患者施用治疗有效剂量的通式(I)所示的化合物其立体异构体或其药学上可接受的盐，或其药物组合物。
本发明进一步涉及通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，或其药物组合物在制备ASK1抑制剂药物中的应用。
本发明进一步涉及通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，或其药物组合物在制备治疗神经变性障碍、心血管障碍、炎性障碍、代谢障碍和ASK1的药物中的应用，所述的炎症障碍优选非酒精性脂肪性肝炎(NASH)。
本发明进一步涉及通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，或其药物组合物在制备治疗非酒精性脂肪性肝炎(NASH)的方法。
本发明还涉及一种治疗预防和/或治疗预制备治疗神经变性障碍、心血管障碍、炎性障碍、代谢障碍疾病的方法，其包括向患者施用治疗有效剂量的通式(I)所示的化合物其立体异构体或其药学上可接受的盐，或其药物组合物。
发明的详细说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至8个碳原子的烷基，更优选1至6个碳原子的烷基，最更优选1至3个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基，本发明优选甲基、乙基、异丙基、叔丁基、卤代烷基、氘代烷基、烷氧基取代的烷基和羟基取代的烷基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基，优选环丙基、环丁基、环己基、环戊基和环庚基。所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的 环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至8个环原子，其中1～4个是杂原子；更优选包含3至6个环原子；最优选包含3至6个环原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基等，优选四氢呋喃基、吡唑烷基、吗啉基、哌嗪基和吡喃基。多环杂环基包括螺环、稠环和桥环的杂环基；其中涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接，或者通过环上的任意两个或者两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接。杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2018077873-appb-000018
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，更优选为5元或6元，例 如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、三唑基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选为三唑基、噻吩基、咪唑基、吡唑基或嘧啶基、噻唑基；更有选三唑基、吡咯基、噻吩基、噻唑基和嘧啶基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2018077873-appb-000019
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基如上所定义。
“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。
“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。
“烯基”指链烯基，又称烯烃基，其中所述的烯基可以进一步被其他相关基团取代，例如：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
“炔基”指(CH≡C-)，其中所述的炔基可以进一步被其他相关基团取代，例如：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
“羟基”指-OH基团。
“卤素”指氟、氯、溴或碘。
“氨基”指-NH 2。
“氰基”指-CN。
“硝基”指-NO 2。
“羧基”指-C(O)OH。
“THF”指四氢呋喃。
“EtOAc”指乙酸乙酯。
“MeOH”指甲醇。
“DMF”指N、N-二甲基甲酰胺。
“DIPEA”指二异丙基乙胺。
“TFA”指三氟乙酸。
“MeCN”指乙晴。
“DMA”指N,N-二甲基乙酰胺。
“Et 2O”指乙醚。
“DCE”指1,2二氯乙烷。
“DIPEA”指N，N-二异丙基乙胺。
“NBS”指N-溴代琥珀酰亚胺。
“NIS”指N-碘代丁二酰亚胺。
“Cbz-Cl”指氯甲酸苄酯。
“Pd 2(dba) 3”指三(二亚苄基丙酮)二钯。
“Dppf”指1,1’-双二苯基膦二茂铁。
“HATU”指2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯。
“KHMDS”指六甲基二硅基胺基钾。
“LiHMDS”指双三甲基硅基胺基锂。
“MeLi”指甲基锂。
“n-BuLi”指正丁基锂。
“NaBH(OAc) 3”指三乙酰氧基硼氢化钠。
“X选自A、B、或C”、“X选自A、B和C”、“X为A、B或C”、“X为A、B和C”等不同用语均表达了相同的意义，即表示X可以是A、B、C中的任意一种或几种。
本发明所述的氢原子均可被其同位素氘所取代，本发明涉及的实施例化合物中的任一氢原子也均可被氘原子取代。
“立体异构”包含几何异构(顺反异构)、旋光异构、构象异构三类。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3 个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。
具体实施方式
以下结合实施例进一步描述本发明，但这些实施例并非限制着本发明的范围。
实施例
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代甲醇(CD 3OD)和氘代氯仿(CDCl 3)，内标为四甲基硅烷(TMS)。
液质联用色谱LC-MS的测定用Agilent 1200Infinity Series质谱仪。HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C 18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C 18 150×4.6mm色谱柱)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，TLC采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
本发明实施例中的起始原料是已知的并且可以在市场上买到，或者可以采用或按照本领域已知的方法来合成。
在无特殊说明的情况下，本发明的所有反应均在连续的磁力搅拌下，在干燥氮气或氩气氛下进行，溶剂为干燥溶剂，反应温度单位为摄氏度。
实施例1
5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(4-异丙基-5-甲基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基苯酰胺
Figure PCTCN2018077873-appb-000020
第一步：6-氨基甲基吡啶酰肼的合成
Figure PCTCN2018077873-appb-000021
室温下，将甲基6-氨基甲基吡啶酸酯(2.0g,13mmol)溶于乙醇(60mL)中，加入水合肼(45.1g,80wt％,66mmol)。反应加热至80℃，在此温度下搅拌5小时，缓慢冷却至室温后，将反应液中析出的固体过滤，收集滤饼，得到标题化合物6-氨基甲基吡啶酰肼(1.6g,80％)。
MS m/z(ESI):153.2[M+H] +.
第二步：6-(4-异丙基-5-甲基-4H-1,2,4-三唑-3-基)吡啶-2-胺的合成
Figure PCTCN2018077873-appb-000022
冰浴下，向N-异丙基乙酰胺(0.35g,3.46mmol)和2,6-二甲基吡啶(0.74g,6.92mmol)的二氯甲烷(10mL)溶液中，缓慢滴加草酰氯(0.44g,3.46mmol)。反应在此温度下搅拌1小时。然后加入6-氨基甲基吡啶酰肼(0.53g,3.46mmol)，缓慢升至室温，并搅拌5小时。减压浓缩后，加入饱和碳酸氢钠溶液(15mL)，升温至100℃，反应3小时。冷却至升温后，加入二氯甲烷(50mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩后柱层析得到标题化合物6-(4-异丙基-5-甲基-4H-1,2,4-三唑-3-基)吡啶-2-胺(210mg,28％)。
MS m/z(ESI):218.2[M+H] +.
第三步：5-氨基-2-氟-4-甲基苯甲腈的制备
Figure PCTCN2018077873-appb-000023
5-溴-4-氟-2-甲基苯胺(10.0g,49.0mmol)，氰化亚铜(8.78g,98.0mmol)混合于NMP(50mL)中，氮气保护下，在180℃下搅拌1小时，然后在100℃下搅拌过夜。冷却后，加入28wt％的氨水溶液，搅拌15分钟，用EtOAc萃取三次。合并有机相，用饱和食盐水洗涤三次，然后有机相用无水硫酸钠干燥，减压浓缩后柱层析得到标题化合物5-氨基-2-氟-4-甲基苯甲腈(5.70g,78％)。
MS m/z(ESI):151.1[M+H] +.
第四步：5-((2-环丙基-2-羰基乙基)氨基)-2-氟-4-甲基苯甲腈的制备
Figure PCTCN2018077873-appb-000024
5-氨基-2-氟-4-甲基苯甲腈(5.70g,38.0mmol)，K 2CO 3(6.30g,45.6mmol),KI(0.630g,3.80mmol)，2-溴-1-环丙基乙烷-1-酮(7.43g,45.6mmol)混合于 DMF(50mL)中，氮气保护下，80℃下搅拌90分钟。反应冷却后，补加2-溴-1-环丙基乙烷-1-酮(3.00g,18.4mmol)，K 2CO 3(2.54g,18.4mmol)，再在75℃下搅拌1小时。冷却至室温，向反应瓶中加入水，静置15分钟后，过滤，滤饼用水洗涤，干燥后得标题化合物5-((2-环丙基-2-羰基乙基)氨基)-2-氟-4-甲基苯甲腈粗品(6.80g,77％)。
MS m/z(ESI):233.1[M+H] +.
第五步：5-(4-环丙基-2-巯基-1H-咪唑-1-基)-2-氟-4-甲基苯甲腈的制备
Figure PCTCN2018077873-appb-000025
5-((2-环丙基-2-羰基乙基)氨基)-2-氟-4-甲基苯甲腈(6.80g,29.3mmol),KSCN(5.69g,58.6mmol)的醋酸溶液(100mL)在110℃下搅拌4小时，冷却后，浓缩，加入CH 2Cl 2和水，分出有机相，水相再用CH 2Cl 2萃取一次。合并有机相，用无水硫酸钠干燥，减压浓缩后得5-(4-环丙基-2-巯基-1H-咪唑-1-基)-2-氟-4-甲基苯甲腈粗品8.00g，直接用于下一步反应。
MS m/z(ESI):274.1[M+H] +.
第六步：5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲腈的制备
Figure PCTCN2018077873-appb-000026
50℃下，向上述粗品的醋酸(160mL)和水(32mL)的溶液中，缓慢滴加入双氧水(30wt％,10.0mL)，滴加完毕，再在该温度下搅拌一小时。冷却至室温，再缓慢加入Na 2SO 3水溶液(20wt％,100mL)，然后搅拌30分钟。浓缩除去有机溶剂，水相用CH 2Cl 2萃取两次。合并有机相，依次用饱和碳酸氢钠水溶液、饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后柱层析得到标题化合物5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲腈(3.3g,两步收率47％)。
MS m/z(ESI):242.1[M+H] +.
第七步：5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲酰氯的合成
Figure PCTCN2018077873-appb-000027
将5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲腈(1.8g,7.47mmol)溶于30mL浓盐酸中，加热回流下搅拌过夜，冷却后浓缩，干燥后得到5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲酸盐酸盐(2g,粗产品)直接用于下一步。
室温下，将上述5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲酸盐酸盐(100 mg,上述粗产品)，溶于二氯亚砜(5mL)中，加热回流下搅拌2小时，冷却后减压浓缩，得到浅黄色固体产品(2g,粗产品)直接用于下一步反应。
第八步5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(4-异丙基-5-甲基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基苯酰胺的合成
Figure PCTCN2018077873-appb-000028
室温下，将6-(4-异丙基-5-甲基-4H-1,2,4-三唑-3-基)吡啶-2-胺(31mg,0.14mmol)加入5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲酰氯粗品(90mg)的THF(5mL)和吡啶(5mL)溶液中，然后加入4-二甲氨基吡啶(5.9mg,0.048mmol)。将反应加热至45℃，并在该温度下搅拌2小时，然后加入水(5mL),二氯甲烷(50mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩有机溶剂后柱层析得标题化合物5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(4-异丙基-5-甲基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基苯酰胺(39mg,59％)。
1H NMR(400MHz,CDCl 3)δ9.04(d,J＝15.5Hz,1H),8.32(dd,J＝6.8,2.4Hz,1H),8.00(d,J＝7.3Hz,1H),7.83-7.82(m,2H),7.39(s,1H),7.12(d,J＝12.4Hz,1H),6.73(s,1H),5.30-5.23(m,1H),2.57(s,3H),2.21(s,3H),1.84(m,1H),1.51(d,J＝7.0Hz,6H),0.84-0.81(m,2H),0.77-0.75(m,2H)；
MS m/z(ESI):460.2[M+H] +.
实施例2
5-(4-环丙基-1H-咪唑-1-基)-N-(6-(4,5-二异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-2-氟-4-甲基苯酰胺
Figure PCTCN2018077873-appb-000029
5-(4-环丙基-1H-咪唑-1-基)-N-(6-(4,5-二异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-2-氟-4-甲基苯酰胺的制备方法参照实施例1。
MS m/z(ESI):488.2[M+H] +.
实施例3
5-(4-环丙基-1H-咪唑-1-基)-N-(6-(5-环丙基-4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-2-氟-4-甲基苯酰胺
Figure PCTCN2018077873-appb-000030
5-(4-环丙基-1H-咪唑-1-基)-N-(6-(5-环丙基-4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-2-氟-4-甲基苯酰胺的制备方法参照实施例1。
1H NMR(400MHz,CD 3OD)δ9.13(d,J＝1.2Hz,1H),8.47(d,J＝8.2Hz,1H),8.11(t,J＝8.0Hz,1H),8.01(d,J＝6.4Hz,1H),7.83(d,J＝7.4Hz,1H),7.59(s,1H),7.49(d,J＝11.0Hz,1H),5.76-5.68(m,1H),2.48-2.42(m,1H),2.34(s,3H),2.11-2.05(m,1H),1.73(d,J＝7.0Hz,6H),1.45-1.39(m,2H),1.36-1.30(m,2H),1.19-1.13(m,2H),0.96-0.90(m,2H)；
MS m/z(ESI):486.2[M+H] +.
实施例4
5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(4-异丙基-5-(三氟甲基)-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基苯酰胺
Figure PCTCN2018077873-appb-000031
5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(4-异丙基-5-(三氟甲基)-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基苯酰胺的制备方法参照实施例1。
1H NMR(400MHz,CD 3OD)δ9.13(d,J＝1.5Hz,1H),8.47(d,J＝8.4Hz,1H),8.13-8.06(m,1H),8.02(d,J＝6.5Hz,1H),7.80(d,J＝7.5Hz,1H),7.60(s,1H),7.49(d,J＝11.1Hz,1H),5.36-5.26(m,1H),2.34(s,3H),2.12-1.06(m,1H),1.60(d,J＝6.9Hz,6H),1.19-1.13(m,2H),0.96-0.90(m,2H)；
MS m/z(ESI):514.2[M+H] +.
实施例5
5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(1-异丙基-1H-苯并[d]咪唑-2-基)吡啶-2-基)-4-甲基苯酰胺
Figure PCTCN2018077873-appb-000032
5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(1-异丙基-1H-苯并[d]咪唑-2-基)吡啶-2-基)-4-甲基苯酰胺的制备方法参照实施例1。
MS m/z(ESI):495.2[M+H] +.
实施例6
5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基苯磺酰胺
Figure PCTCN2018077873-appb-000033
第一步：6-氨基甲基吡啶酰肼的合成
Figure PCTCN2018077873-appb-000034
室温下，将甲基6-氨基甲基吡啶酸酯(10g,66mmol)溶于甲醇(100mL)中，加入水合肼(10.5g,80wt％,263mmol)。反应加热至80℃，在此温度下搅拌4小时，缓慢冷却至室温后，过滤，收集滤饼，得到标题化合物6-氨基甲基吡啶酰肼粗品直接用于下一步。
MS m/z(ESI):153.1[M+H] +.
第二步：(E)-N'-(6-(2-((E)-(二甲氨基)亚甲基)肼-1-羰基)吡啶-2-基)-N,N-二甲基甲脒的合成
Figure PCTCN2018077873-appb-000035
室温下，将上一步6-氨基甲基吡啶酰肼粗品溶于DMF-DMA(150mL)中，加热回流下，搅拌4小时，反应体系冷却至室温后，减压浓缩得到粗品未经纯化，直接用于下一步。
MS m/z(ESI):263.2[M+H] +.
第三步：6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-胺的合成
Figure PCTCN2018077873-appb-000036
将上一步(E)-N'-(6-(2-((E)-(二甲氨基)亚甲基)肼-1-羰基)吡啶-2-基)-N,N-二甲基甲脒粗品溶于乙腈(200mL)中，再依次加入醋酸(50mL)和异丙胺(20.0g,0.329mol)，在加热回流下搅拌过夜。反应体系冷却后减压浓缩有机溶剂，再往反应瓶中依次加入四氢呋喃(50mL)和1M NaOH水溶液(100mL)，在室温下搅拌过夜。减压除去有机溶剂，水相用二氯甲烷萃取，有机相用无水硫酸钠干燥，减压浓缩有机溶剂后柱层析分离得到标题化合物6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-胺(8.0g，三步总收率：60％)。
1H NMR(400MHz,DMSO-d 6)δ8.77(s,1H),7.52(dd,J＝8.0,7.2Hz,1H),7.17(dd,J＝7.2,0.8Hz,1H),6.53(dd,J＝8.0,0.2Hz,1H),6.16(brs,2H),5.53(m,1H),1.43(d,J＝6.8Hz,6H)；
MS m/z(ESI):204.1[M+H] +.
第四步：5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基苯磺酰胺的合成
Figure PCTCN2018077873-appb-000037
5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基苯磺酰胺的制备方法参照实施例1第七步、第八步。
1H NMR(400MHz,CDCl 3)δ8.35(s,1H),7.95(d,J＝7.6Hz,1H),7.78(m,2H),7.35(m,2H),7.09(d,J＝10.0Hz,1H),6.61(d,J＝2.0Hz,1H),5.30(m,1H),2.20(s,3H),1.90(m,1H),1.43(d,J＝6.8Hz,6H),0.90(m,2H),0.81(m,2H)；
MS m/z(ESI):482.2[M+H] +.
实施例7
5-(4-环丙基-1H-咪唑-1-基)-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基-2-(甲硫基)苯酰胺
Figure PCTCN2018077873-appb-000038
5-(4-环丙基-1H-咪唑-1-基)-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基-2-(甲硫基)苯酰胺的制备方法参照实施例1。
MS m/z(ESI):474.2[M+H] +.
实施例8
5-(4-环丙基-1H-咪唑-1-基)-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基-2-(甲磺酰)苯酰胺
Figure PCTCN2018077873-appb-000039
5-(4-环丙基-1H-咪唑-1-基)-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基-2-(甲磺酰)苯酰胺的制备方法参照实施例1。
MS m/z(ESI):506.2[M+H] +.
实施例9
5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基苯并硫代酰胺
Figure PCTCN2018077873-appb-000040
5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基苯酰胺(50mg,0.11mmol,上海楼岚生物科技有限公司)，Lawesson试剂(65mg,0.16mmol)混合于甲苯(4mL)中，加热回流下搅拌过夜。冷却，浓缩除去有机溶剂，用二氯甲烷稀释后，依次用饱和碳酸氢钠水溶液、饱和食盐水洗涤，减压浓缩后柱层析得到标题化合物5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基苯并硫代酰胺(4.6mg,9％).
1H NMR(400MHz,CDCl 3)δ10.06(br s,1H),8.96-7.94(m,4H),7.52(s,1H),7.21-6.80(m,2H),5.50(m,1H),2.32(s,3H),1.90(m,1H),1.59(m,6H),0.89(m,4H)；
MS m/z(ESI):462.2[M+H] +.
实施例10
5-(4-环丙基-1H-咪唑-1-基)-2-氟-N'-羟基-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基苯脒
Figure PCTCN2018077873-appb-000041
5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基苯并硫代酰胺(10mg,0.022mmol)，盐酸羟胺(3.0mg,0.043mmol)，乙酸钠(7.1mg,0.087mmol)混合于3mL无水乙醇中，加热回流下搅拌过夜。冷却后浓缩，用二氯甲烷稀释。有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓 缩，制备板纯化得到标题化合物5-(4-环丙基-1H-咪唑-1-基)-2-氟-N'-羟基-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基苯脒(2.0mg,20％)。
1H NMR(400MHz,CDCl 3)δ8.26(s,1H),7.83(br s,1H),7.75(d,J＝7.6Hz,1H),7.69(s,1H),7.54(m.1H),7.41(d,J＝6.0Hz,1H),6.85(d,J＝10.4Hz,1H),6.71(s,1H),6.49(d,J＝8.4Hz,1H),5.23(m,1H),2.13(s,3H),1.86(m,1H),1.30(d,J＝6.8Hz,6H),0.85(m,4H)；
MS m/z(ESI):461.2[M+H] +.
实施例11
5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-N'-甲氧基-4-甲基苯脒
Figure PCTCN2018077873-appb-000042
5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-N'-甲氧基-4-甲基苯脒的制备方法参照实施例10。
1H NMR(400MHz,CDCl 3)δ8.38(s,1H),8.30(s,1H),7.83(d,J＝7.6Hz,1H),7.69(s,1H),7.59(m,1H),7.45(m,2H),6.75(m,1H),6.47(d,J＝8.4Hz,1H),5.33(m,1H),4.02(s,3H),2.29(s,3H),2.00(m,1H),1.30(d,J＝6.8Hz,6H),0.87(m,4H)；
MS m/z(ESI):475.2[M+H] +.
实施例12
N-(1-(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯基)-2,2,2-三氟乙基)-6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-胺
Figure PCTCN2018077873-appb-000043
N-(1-(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯基)-2,2,2-三氟乙基)-6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-胺的制备方法参照实施例1。
MS m/z(ESI):500.2[M+H] +.
实施例13
7-(4-环丙基-1H-咪唑-1-基)-2-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-6-甲基-3,4-二氢异喹啉-1(2H)-酮
Figure PCTCN2018077873-appb-000044
第一步：7-碘-6-甲基-3,4-二氢异喹啉-1(2H)-酮的制备
Figure PCTCN2018077873-appb-000045
0℃，往6-甲基-3,4-二氢异喹啉-1(2H)-酮(500mg,3.11mmol)的TfOH(10mL)溶液中分批加入NIS(768mg,3.42mmol)，然后缓慢升至室温，并在室温下搅拌过夜。减压浓缩溶剂后柱层析，得到标题化合物7-碘-6-甲基-3,4-二氢异喹啉-1(2H)-酮(900mg，收率：100％，含25％的异构副产物)。
MS m/z(ESI):288.0[M+H] +.
第二步：7-(4-环丙基-1H-咪唑-1-基)-6-甲基-3,4-二氢异喹啉-1(2H)-酮的制备
Figure PCTCN2018077873-appb-000046
7-碘-6-甲基-3,4-二氢异喹啉-1(2H)-酮(450mg,1.57mmol，约75％纯度)，4-环丙基-1H-咪唑(847mg,7.84mmol)，CuI(209mg,1.10mmol)，Cs 2CO 3(768mg,2.36mmol)混合于DMSO(15mL)中，用氮气除氧10分钟，然后加入8-羟基喹啉(227mg,1.57mmol)，再用氮气除氧5分钟，然后在氮气保护下，在150℃下搅拌过夜。反应冷却后减压浓缩，柱层析分离得到标题化合物7-(4-环丙基-1H-咪唑-1-基)-6-甲基-3,4-二氢异喹啉-1(2H)-酮(205mg,收率：65％)。
MS m/z(ESI):268.1[M+H] +.
第三步：6-氯甲基吡啶酰肼的合成
Figure PCTCN2018077873-appb-000047
室温下，将甲基6-氯甲基吡啶酸酯(1.0g,5.8mmol)溶于甲醇(30mL)中，加入水合肼(1.5g,80wt％,23mmol)。反应加热至60℃，在此温度下搅拌2小时，缓慢冷却至室温后，浓缩，得到标题化合物6-氯甲基吡啶酰肼粗品直接用于下一步。
MS m/z(ESI):172.1[M+H] +.
第四步：(E)-N'-(6-氯甲基吡啶酰)-N,N-二甲基甲腙酰胺的合成
Figure PCTCN2018077873-appb-000048
室温下，将上一步6-氯甲基吡啶酰肼粗品溶于DMF-DMA(30mL)中，升温至100℃后，搅拌5小时，反应体系冷却至室温后，减压浓缩后得到标题化合物(E)-N'-(6-氯甲基吡啶酰)-N,N-二甲基甲腙酰胺粗品直接用于下一步。
MS m/z(ESI):227.1[M+H] +.
第五步：2-氯-6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶的合成
Figure PCTCN2018077873-appb-000049
将上一步(E)-N'-(6-氯甲基吡啶酰)-N,N-二甲基甲腙酰胺粗品溶于乙腈(30mL)中，再依次加入醋酸(7.5mL)和异丙胺(1.7g,29mmol)，在加热回流下搅拌过夜。反应体系冷却至室温后，减压浓缩溶剂，残余物用二氯甲烷溶解，然后依次用饱和碳酸氢钠水溶液、饱和食盐水洗涤，用无水硫酸钠干燥后，减压浓缩有机溶剂，柱层析分离得到标题化合物2-氯-6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶(750mg，三步收率：58％)。
1H NMR(400MHz,DMSO-d 6):δ8.95(s,1H),8.10(m,2H),7.65(d,J＝8.4Hz,1H),5.30(m,1H),1.50(d,J＝6.8Hz,6H)；
MS m/z(ESI):223.1[M+H] +.
第六步：7-(4-环丙基-1H-咪唑-1-基)-2-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-6-甲基-3,4-二氢异喹啉-1(2H)-酮的制备
Figure PCTCN2018077873-appb-000050
7-(4-环丙基-1H-咪唑-1-基)-6-甲基-3,4-二氢异喹啉-1(2H)-酮(55.0mg,0.206mmol)，2-氯-6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶(68mg,0.306mmol)，碳酸铯(134mg,0.412mml)混合于1,4-二氧六环(10mL)中，氮气除氧5分钟，加入Xantphos(25.0mg,0.0437mmol),再用氮气除氧5分钟，然后加入Pd(PPh 3) 4(25.0mg,0.0218mmol)，继续用氮气除氧5分钟，然后在微波反应器中，145℃下搅拌两个小时。冷却后减压浓缩有机溶剂，用二氯甲烷和水分层。分出有机相，用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩二氯甲烷后用制备薄层析纯化，得到标题化合物7-(4-环丙基-1H-咪唑-1-基)-2-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-6-甲基-3,4-二氢异喹啉-1(2H)-酮(39mg,42％)。
1H NMR(400MHz,CDCl 3)δ8.37(s,1H),8.10(d,J＝7.6Hz,1H),8.06(s,1H),8.01(d,J＝8.0Hz,1H),7.91(m,1H),7.75(br s,1H),7.29(s,1H),6.83(s,1H),5.47(m,1H),4.29(t,J＝6.4Hz,2H),3.19(t,J＝6.4Hz,2H),2.28(s,3H),2.00(m,1H),1.56(d,J＝6.8Hz,6H),0.94(m,4H)；
MS m/z(ESI):454.2[M+H] +.
实施例14
5-(4-环丙基-1H-咪唑-1-基)-N-(3-环丙基-6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-
基)-2-氟-4-甲基苯酰胺
Figure PCTCN2018077873-appb-000051
5-(4-环丙基-1H-咪唑-1-基)-N-(3-环丙基-6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-2-氟-4-甲基苯酰胺的制备方法参照实施例1。
1H NMR(400MHz,CDCl 3)δ9.22(d,J＝14.7Hz,1H),8.36(s,1H),8.10(d,J＝6.3Hz,2H),7.62(d,J＝7.3Hz,1H),7.55(s,1H),7.22-7.19(m,1H),6.82(s,1H),6.18-6.05(m,1H),2.29(s,3H),1.98-1.83(m,2H),1.54(d,J＝5.7Hz,6H),1.33-1.23(m,2H),1.18-1.07(m,2H),0.93-0.78(m,4H)；
MS m/z(ESI):486.2[M+H] +.
实施例15
5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(4-(4-异丙基-4H-1,2,4-三唑-3-基)嘧啶-2-基)-4-甲基苯酰胺
Figure PCTCN2018077873-appb-000052
第一步：叔-丁基2-(2-氨基嘧啶-4-羰基)肼-1-羧酸酯的制备
Figure PCTCN2018077873-appb-000053
2-氨基嘧啶-4-羧酸(300mg,2.16mmol)，叔-丁基肼羧酸酯(570mg,4.32mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.65g,4.32mmol)，N,N-二异丙基乙胺(836mg,6.48mmol)，混合于DMSO/CH 2Cl 2(30mL/10mL)中，氮气保护下，室温搅拌3小时。加入100mL CH 2Cl 2，用H 2O洗涤二次。合并有机相，有机相用无水硫酸钠干燥，减压浓缩后柱层析得到标题化合物叔-丁基2-(2-氨基嘧啶-4-羰基)肼-1-羧酸酯(230mg,42％)。
MS m/z(ESI):254.1[M+H] +.
第二步：2-氨基嘧啶-4-甲酰肼盐酸盐的制备
Figure PCTCN2018077873-appb-000054
叔丁基2-(2-氨基嘧啶-4-羰基)肼-1-羧酸酯(230mg,0.91mmol)溶于CH 2Cl 2(25mL)中，加入盐酸/二氧六环(10mL)，室温搅拌1h。浓缩，得标题化合物2-氨基嘧啶-4-甲酰肼盐酸盐粗品(139mg)。
MS m/z(ESI):154.1[M+H] +.
第三步：N'-(4-(2-((二甲氨基)亚甲基)肼-1-羰基)嘧啶-2-基)-N,N-二甲基甲脒的制备
Figure PCTCN2018077873-appb-000055
2-氨基嘧啶-4-甲酰肼盐酸盐粗品(139mg)溶于DMF-DMA(5mL)中，在100℃下搅拌3小时，冷却后，减压浓缩得到标题化合物N'-(4-(2-((二甲氨基)亚甲基)肼-1-羰基)嘧啶-2-基)-N,N-二甲基甲脒粗品(239mg)，直接用于下一步反应。
MS m/z(ESI):264.1[M+H] +.
第四步：4-(4-异丙基-4H-1,2,4-三唑-3-基)嘧啶-2-胺的制备
Figure PCTCN2018077873-appb-000056
N'-(4-(2-((二甲氨基)亚甲基)肼-1-羰基)嘧啶-2-基)-N,N-二甲基甲脒(239mg,0.91mmol)溶于CH 3CN/HOAc(8mL/2mL)中，N 2置换三次，加入异丙基胺(268mg,4.55mmol)，在90℃下搅拌2小时，冷却后，浓缩除去有机溶剂，加入饱和碳酸氢钠水溶液，水相用CH 2Cl 2萃取两次。合并有机相，无水硫酸钠干燥，减压浓缩后柱层析得到标题化合物4-(4-异丙基-4H-1,2,4-三唑-3-基)嘧啶-2-胺(45mg,三步收率24％)。
MS m/z(ESI):205.1[M+H] +.
第五步：5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(4-(4-异丙基-4H-1,2,4-三唑-3-基)嘧啶-2-基)-4-甲基苯酰胺的合成
Figure PCTCN2018077873-appb-000057
5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(4-(4-异丙基-4H-1,2,4-三唑-3-基)嘧啶-2-基)-4-甲基苯酰胺的制备方法参照实施例1第七步、第八步。
MS m/z(ESI):447.2[M+H] +.
实施例16
2-(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯基)-5-(4-异丙基-4H-1,2,4-三唑-3-基)-3H-咪唑并[4,5-b]吡啶
Figure PCTCN2018077873-appb-000058
第一步：6-(4-异丙基-5-甲基-4H-1,2,4-三唑-3-基)吡啶-2-胺的合成
Figure PCTCN2018077873-appb-000059
6-(4-异丙基-5-甲基-4H-1,2,4-三唑-3-基)吡啶-2-胺的制备方法参照实施例1第一步。
MS m/z(ESI):198.1[M+H] +.
第二步：N'-(6-(2-((E)-(二甲氨基)亚甲基)肼-1-羰基)-3-硝基吡啶-2-基)-N,N-二甲基甲脒的合成
Figure PCTCN2018077873-appb-000060
N'-(6-(2-((E)-(二甲氨基)亚甲基)肼-1-羰基)-3-硝基吡啶-2-基)-N,N-二甲基甲脒的制备方法参照实施例15第三步。
MS m/z(ESI):308.1[M+H] +.
第三步：6-(4-异丙基-4H-1,2,4-三唑-3-基)-3-硝基吡啶-2-胺的合成
Figure PCTCN2018077873-appb-000061
6-(4-异丙基-4H-1,2,4-三唑-3-基)-3-硝基吡啶-2-胺的制备方法参照实施例15第四步。
MS m/z(ESI):249.1[M+H] +.
第四步：6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2,3-二胺的合成
Figure PCTCN2018077873-appb-000062
氮气氛下，向6-(4-异丙基-4H-1,2,4-三唑-3-基)-3-硝基吡啶-2-胺(200mg,0.81mmol)的甲醇(10mL)和乙酸乙酯(10mL)溶液中加入10％的湿Pd/C(20mg)，常温常压在氢气氛下反应12小时后，用硅藻土滤除催化剂。滤液浓缩，得标题化合物6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2,3-二胺，直接用于下一步反应。
MS m/z(ESI):219.1[M+H] +.
第五步：2-(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯基)-5-(4-异丙基-4H-1,2,4-三唑-3-基)-3H-咪唑并[4,5-b]吡啶的合成
Figure PCTCN2018077873-appb-000063
2-(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯基)-5-(4-异丙基-4H-1,2,4-三唑-3-基)-3H-咪唑并[4,5-b]吡啶的制备方法参照实施例1第八步。
MS m/z(ESI):461.1[M+H] +.
第六步：2-(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯基)-5-(4-异丙基-4H-1,2,4-三唑-3-基)-3H-咪唑并[4,5-b]吡啶的合成
Figure PCTCN2018077873-appb-000064
向N-(2-氨基-6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-3-基)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯酰胺和N-(3-氨基-6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯酰胺的混合物(30mg,65umol)的二甲苯溶液(5mL)中，加入乙酸(2mL)。反应缓慢加热至110℃，并在此温度下反应12小时。冷却后，减压浓缩溶剂，加入饱和NaHCO 3水溶液(5mL)，二氯甲烷(50mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩后经柱层析得到标题化合物2-(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯基)-5-(4-异丙基-4H-1,2,4-三唑-3-基)-3H-咪唑并[4,5-b]吡啶(9.6mg,33％)。
1H NMR(400MHz,CDCl 3)δ8.33(m,2H),8.24(d,J＝8.4Hz,1H),8.05(d,J＝8.5Hz,1H),7.53(s,1H),7.16(d,J＝12.1Hz,1H),6.76(s,1H),5.83-5.81(m,1H),2.22(s,3H),1.88-1.82(m,1H),1.51-1.49(d,J＝6.7Hz,6H),0.85-0.81(m,2H),0.78-0.75(m,2H)；
MS m/z(ESI):443.1[M+H] +.
实施例17
2-(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯基)-7-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶并[2,3-d]嘧啶
2-(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯基)-7-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶并[2,3-d]嘧啶的制备方法参照实施例16。
MS m/z(ESI):455.2[M+H] +.
实施例18
2-环丙基-5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-1-甲基-1H-苯并[d]咪唑-6-甲酰胺
Figure PCTCN2018077873-appb-000066
2-环丙基-5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-1-甲基-1H-苯并[d]咪唑-6-甲酰胺的制备方法参照实施例1。
1H NMR(400MHz,CD 3OD)δ8.72(s,1H),8.41(br s,1H),8.31(d,J＝8.4Hz,1H),7.94(m,2H),7.79(d,J＝8.0Hz,1H),7.25(d,J＝8.0Hz,1H),5.58(m,1H),3.87(s,3H),2.15(m,1H),1.46(d,J＝6.8Hz,6H),1.10(m,4H)；
MS m/z(ESI):420.2[M+H] +.
实施例19
2-(环丙羰基)-6-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)喹啉-7-甲酰胺
Figure PCTCN2018077873-appb-000067
2-(环丙羰基)-6-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)喹啉-7-甲酰胺的制备方法参照实施例1。
MS m/z(ESI):445.2[M+H] +.
实施例20
1-(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯基)-3-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)脲
Figure PCTCN2018077873-appb-000068
1-(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯基)-3-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)脲的制备方法参照实施例1。
1H NMR(400MHz,CDCl 3)δ10.83(s,1H),9.25(s,1H),8.39(s,1H),8.25(d,J＝7.5Hz,1H),7.85-7.76(m,1H),7.62(d,J＝7.0Hz,1H),7.47(d,J＝1.1Hz,1H),7.34(d,J＝8.3Hz,1H),6.97(d,J＝11.4Hz,1H),6.79(d,J＝1.1Hz,1H),5.14-5.06(m,1H),2.13(s,3H),1.93-1.89(m,1H),1.39(d,J＝6.7Hz,6H),0.90-0.86(m,2H),0.84-0.78(m,2H)；
MS m/z(ESI):461.2[M+H] +.
实施例21
5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)噻吩-3-甲酰胺的制备
Figure PCTCN2018077873-appb-000069
第一步：5-溴-2-氟噻吩-3-羧酸的制备
Figure PCTCN2018077873-appb-000070
2-氟噻吩-3-羧酸(730mg,5.0mmol)，NBS(1.34g,7.5mmol)混合于DMF(7mL)中，氮气保护下，室温搅拌4小时，减压浓缩后柱层析得到标题化合物5-溴-2-氟噻吩-3-羧酸(900mg,80％)。
MS m/z(ESI):222.9[M-H] -.
第二步：5-(4-环丙基-1H-咪唑-1-基)-2-氟噻吩-3-羧酸的制备
Figure PCTCN2018077873-appb-000071
5-溴-2-氟噻吩-3-羧酸(900mg,4mmol)，4-环丙基-1H-咪唑(1.08g,10mmol)，CuI(76mg,0.4mmol)，4,7-二甲氧基-1,10-菲咯啉(144mg,0.6mmol)，Cs 2CO 3(3.9g，12mmol)混合于DMSO(12mL)中，氮气保护下，140℃下搅拌4h。冷却至室温，减压浓缩后柱层析得标题化合物5-(4-环丙基-1H-咪唑-1-基)-2- 氟噻吩-3-羧酸(504mg,50％)。
MS m/z(ESI):251.2[M-H] -.
第三步：5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)噻吩-3-甲酰胺的制备
Figure PCTCN2018077873-appb-000072
5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)噻吩-3-甲酰胺的制备方法参照实施例1第七、第八步。
1H NMR(400MHz,CD 3OD)δ9.45-9.35(m,1H),9.29(s,1H),8.40-8.30(m,1H),8.09(t,J＝7.9Hz,1H),8.00-7.90(m,1H),7.72(s,1H),7.60(d,J＝3.7Hz,1H),5.90-5.80(m,1H),2.10-2.00(m,1H),1.61(d,J＝6.6Hz,6H),1.18-1.11(m,2H),0.93-0.89(m,2H)；
MS m/z(ESI):438.1[M+H] +.
实施例22
2-氯-5-(4-环丙基-1H-咪唑-1-基)-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)噻吩-3-甲酰胺
Figure PCTCN2018077873-appb-000073
第一步：5-溴-2-氯噻吩-3-羧酸的制备
Figure PCTCN2018077873-appb-000074
2-氯噻吩-3-羧酸(813mg,5.0mmol)，NBS(1.34g,7.5mmol)混合于DMF(7mL)中，氮气保护下，室温搅拌4小时，减压浓缩后柱层析得到标题化合物5-溴-2-氯噻吩-3-羧酸(966mg,80％)。
MS m/z(ESI):240.9[M-H] -.
第二步：5-(4-环丙基-1H-咪唑-1-基)-2-氯噻吩-3-羧酸的制备
Figure PCTCN2018077873-appb-000075
5-溴-2-氯噻吩-3-羧酸(966mg,4mmol)，4-环丙基-1H-咪唑(1.08g,10mmol)，CuI(76mg,0.4mmol),4,7-二甲氧基-1,10-菲咯啉(144mg,0.6mmol)，Cs 2CO 3(3.9g,12mmol)混合于DMSO(12mL)中，氮气保护下，125℃下搅拌 4h。冷却至室温，减压浓缩后柱层析得标题化合物5-(4-环丙基-1H-咪唑-1-基)-2-氯噻吩-3-羧酸(322mg,30％)。
MS m/z(ESI):266.9[M-H] -.
第三步：2-氯-5-(4-环丙基-1H-咪唑-1-基)-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)噻吩-3-甲酰胺的制备
Figure PCTCN2018077873-appb-000076
2-氯-5-(4-环丙基-1H-咪唑-1-基)-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)噻吩-3-甲酰胺的制备方法参照实施例1第七、第八步。
1H NMR(400MHz,CD 3OD)δ9.55-9.40(m,1H),9.32(s,1H),8.50-8.30(m,1H),8.10(t,J＝7.9Hz,1H),8.05-7.90(m,1H),7.74(s,2H),5.97-5.82(m,1H),2.08-2.02(m,1H),1.61(d,J＝6.7Hz,6H),1.17-1.12(m,2H),0.93-0.89(m,2H).
MS m/z(ESI):454.1[M+H] +.
实施例23
(R)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]三唑-3-基)吡啶-2-基)噻吩-3-甲酰胺
Figure PCTCN2018077873-appb-000077
第一步(R)-5-甲氧基-2-甲基-3,4-二氢-2H-吡咯的合成
Figure PCTCN2018077873-appb-000078
冰浴下，向(R)-5-甲基吡咯烷-2-酮(1.7g,17.2mmol)的二氯甲烷(40mL)溶液中，分批加入三甲基氧鎓四氟硼酸(3.55g,24.0mmol)。反应缓慢升至室温，在此温度下搅拌5小时，然后加入饱和NaHCO 3水溶液(5mL)，二氯甲烷(50mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，加入冰醋酸(5mL)，减压浓缩，得到粗品直接用于下一步反应。
MS m/z(ESI):114.1[M+H] +.
第二步(R)-6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]三唑-3-基)吡啶-2-胺的合成
Figure PCTCN2018077873-appb-000079
室温下，将6-氨基甲基吡啶酰肼(2.35g,15.4mmol)溶于2-戊醇(15mL)和乙酸(2mL)中，加入(R)-5-甲氧基-2-甲基-3,4-二氢-2H-吡咯(1.93g,17.1mmol)。反应加热至125℃，在此温度下搅拌12小时，冷却至室温后，减压浓缩。然后加入饱和NaHCO 3水溶液(5mL)，二氯甲烷(50mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩后经柱层析得到标题化合物(R)-6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]三唑-3-基)吡啶-2-胺(1.62g,两步产率49％)。
1H NMR(400MHz,CDCl 3)δ7.65(m,1H),7.61-7.42(m,1H),6.54(m,1H),5.17-4.88(m,1H),3.18-2.77(m,3H),2.43-2.31(m,1H),1.53-1.37(m,3H)；
MS m/z(ESI):216.1[M+H] +.
Figure PCTCN2018077873-appb-000080
(R)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]三唑-3-基)吡啶-2-基)噻吩-3-甲酰胺的制备方法参照实施例1第七、第八步。
1H NMR(400MHz,CDCl 3)δ8.45(d,J＝8.7Hz,1H),8.27(dd,J＝8.3,0.7Hz,1H),8.10(dd,J＝7.7,0.8Hz,1H),7.88(t,J＝8.0Hz,1H),7.58(d,J＝1.3Hz,1H),7.18(d,J＝4.0Hz,1H),6.89(d,J＝1.2Hz,1H),5.04-4.97(m,1H),3.11-2.97(m,3H),2.45-2.38(m,1H),1.92-1.83(m,1H),1.53(d,J＝6.5Hz,3H),0.93-0.88(m,2H),0.84-0.79(m,2H)；
MS m/z(ESI):450.1[M+H] +.
实施例24
(S)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]三唑-3-基)吡啶-2-基)噻吩-3-甲酰胺
Figure PCTCN2018077873-appb-000081
(S)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]三唑-3-基)吡啶-2-基)噻吩-3-甲酰胺的制备方法参照实施例23。
1H NMR(400MHz,CD 3OD)δ8.15(d,J＝8.1Hz,1H),7.90-7.78(m,3H),7.18(d,J＝3.8Hz,1H),7.09(s,1H),5.20-5.13(m,1H),3.04-2.85(m,3H),2.40-2.34(m,1H),1.80-1.75(m,1H),1.38(d,J＝6.4Hz,3H),0.80-0.77(m,2H),0.66-0.62(m,2H)；
MS m/z(ESI):450.1[M+H] +.
实施例25
(S)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(5-(甲氧基甲基)-6,7-二氢-5H-吡咯并 [2,1-c][1,2,4]三唑-3-基)吡啶-2-基)噻吩-3-甲酰胺
Figure PCTCN2018077873-appb-000082
(S)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(5-(甲氧基甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]三唑-3-基)吡啶-2-基)噻吩-3-甲酰胺的制备方法参照实施例23。
MS m/z(ESI):480.2[M+H] +.
实施例26
(R)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(5-(甲氧基甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]三唑-3-基)吡啶-2-基)噻吩-3-甲酰胺
Figure PCTCN2018077873-appb-000083
(R)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(5-(甲氧基甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]三唑-3-基)吡啶-2-基)噻吩-3-甲酰胺的制备方法参照实施例23。
MS m/z(ESI):480.2[M+H] +.
实施例27
2-(4-环丙基-1H-咪唑-1-基)-5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)噻唑-4-甲酰胺
Figure PCTCN2018077873-appb-000084
2-(4-环丙基-1H-咪唑-1-基)-5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)噻唑-4-甲酰胺的制备方法参照实施例21。
MS m/z(ESI):439.1[M+H] +.
实施例28
5-(4-环丙基-1H-咪唑-1-基)-N-(3-(4-异丙基-4H-1,2,4-三唑-3-基)苯基)异噻唑-3-甲酰胺
Figure PCTCN2018077873-appb-000085
5-(4-环丙基-1H-咪唑-1-基)-N-(3-(4-异丙基-4H-1,2,4-三唑-3-基)苯基)异噻唑-3-甲酰胺的制备方法参照实施例21。
1H NMR(400MHz,CD 3OD)δ8.81(s,1H),8.16-8.06(m,2H),7.98(s,1H),7.93(d,J＝8.2Hz,1H),7.57(t,J＝7.9Hz,1H),7.39(d,J＝7.7Hz,1H),7.36(s,1H),4.66-4.56(m,1H),1.91-1.83(m,1H),1.51(d,J＝6.7Hz,6H),0.91-0.84(m,2H),0.77-0.72(m,2H)；
MS m/z(ESI):420.2[M+H] +.
实施例29
5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)噻吩-3-甲酰胺
Figure PCTCN2018077873-appb-000086
第一步：5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯胺的合成
Figure PCTCN2018077873-appb-000087
5-溴-2-氟-4-甲基苯胺(816mg,4mmol)，4-环丙基-1H-咪唑(1.08g,10mmol)，CuI(76mg,0.4mmol),4,7-二甲氧基-1,10-菲咯啉(144mg,0.6mmol)，Cs 2CO 3(3.9g,12mmol)混合于DMSO(12mL)中，氮气保护下，140℃下搅拌4h。冷却至室温，减压浓缩后柱层析得标题化合物5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯胺(555mg,60％)。
MS m/z(ESI):232.1[M+H] +.
第二步：6-(肼羰基)邻吡啶甲酸的合成
Figure PCTCN2018077873-appb-000088
将6-(甲酯基<甲氧羰基>)邻吡啶甲酸(1.81g,10.0mmol)溶于甲醇(20mL)中，加入水合肼(1.87g,30mmol)。反应加热至70℃，在此温度下搅拌4小时，缓慢冷却至室温后，将反应液中析出的固体过滤，收集滤饼，得到标题化合物6-(肼羰基)邻吡啶甲酸(1.63g,90％)。
MS m/z(ESI):182.1[M+H] +.
第三步：6-(2-((二甲氨基)亚甲基)肼-1-羰基)邻吡啶甲酸的合成
Figure PCTCN2018077873-appb-000089
将6-(肼羰基)邻吡啶甲酸(1.63g,9.0mmol)溶于DMF-DMA(10mL)中，加热至回流反应4小时，减压浓缩后柱层析得标题化合物6-(2-((二甲氨基)亚甲基)肼-1-羰基)邻吡啶甲酸(850mg,40％)。
MS m/z(ESI):237.1[M+H] +.
第四步：6-(4-异丙基-4H-1,2,4-三唑-3-基)邻吡啶甲酸的合成
Figure PCTCN2018077873-appb-000090
将6-(2-((二甲氨基)亚甲基)肼-1-羰基)邻吡啶甲酸(850mg,3.6mmol)溶于乙腈-乙酸(10mL，4:1)中，加入丙烷-2-胺(638mg,10.8mmol)。加热至回流反应4小时，减压浓缩后柱层析得标题化合物6-(4-异丙基-4H-1,2,4-三唑-3-基)邻吡啶甲酸(464mg,56％)。
MS m/z(ESI):233.1[M+H] +.
第五步：N-(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯基)-6-(4-异丙基-4H-1,2,4-三唑-3-基)甲基吡啶酰胺的合成
Figure PCTCN2018077873-appb-000091
将6-(4-异丙基-4H-1,2,4-三唑-3-基)邻吡啶甲酸(46.4mg,2mmol)，5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯胺(55.7mg,2.4mmol)，HATU(1.14g,3mmol)，NMM(405mg,4mmol)溶于DMF(3mL)中，室温反应1小时，加入饱和NaHCO 3水溶液(30mL)，二氯甲烷(30mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后柱层析得标题化合物N-(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯基)-6-(4-异丙基-4H-1,2,4-三唑-3-基)甲基吡啶酰胺(45mg,50％)。
1H NMR(400MHz,CD 3OD)δ9.15(m,2H),8.62(d,J＝7.2Hz,1H),8.43-8.39(m,2H),8.33-8.27(m,1H),7.61(m,1H),7.46(d,J＝11.5Hz,1H),5.61(m,1H),2.26(s,3H),2.09(m,1H),1.69(d,J＝6.7Hz,6H),1.20-1.14(m,2H),0.97-0.92(m,2H)；
MS m/z(ESI):446.2[M+H] +.
实施例30
N-(3-(4-环丙基-1H-咪唑-1-基)苯基)-6-(4-异丙基-4H-1,2,4-三唑-3-基)甲基吡啶酰胺
Figure PCTCN2018077873-appb-000092
N-(3-(4-环丙基-1H-咪唑-1-基)苯基)-6-(4-异丙基-4H-1,2,4-三唑-3-基)甲基吡啶酰胺的制备方法参照实施例29。
MS m/z(ESI):414.2[M+H] +.
实施例31
N-(3-(4-环丙基-1H-咪唑-1-基)-4-甲基苯基)-6-(4-异丙基-4H-1,2,4-三唑-3-基)甲基吡啶酰胺
Figure PCTCN2018077873-appb-000093
N-(3-(4-环丙基-1H-咪唑-1-基)-4-甲基苯基)-6-(4-异丙基-4H-1,2,4-三唑-3-基)甲基吡啶酰胺的制备方法参照实施例29。
1H NMR(400MHz,CDCl 3)δ9.61(s,1H),8.47-8.36(m,3H),8.12(t,J＝7.9Hz,1H),7.80(d,J＝2.2Hz,1H),7.51-7.47(m,2H),7.34(d,J＝8.4Hz,1H),6.83(d,J＝1.2Hz,1H),5.39-5.31(m,1H),2.21(s,3H),1.95-1.88(m,1H),1.69(d,J＝6.8Hz,6H),0.93-0.87(m,2H),0.86-0.81(m,2H)；
MS m/z(ESI):428.2[M+H] +.
实施例32
N-(5-(4-环丙基-1H-咪唑-1-基)-2-氟苯基)-6-(4-异丙基-4H-1,2,4-三唑-3-基)甲基吡啶酰胺
Figure PCTCN2018077873-appb-000094
N-(5-(4-环丙基-1H-咪唑-1-基)-2-氟苯基)-6-(4-异丙基-4H-1,2,4-三唑-3-基)甲基吡啶酰胺的制备方法参照实施例29。
MS m/z(ESI):432.2[M+H] +.
实施例33
N-(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯基)-6-(4-环丙基-4H-1,2,4-三唑-3-基)甲基吡啶酰胺
N-(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯基)-6-(4-环丙基-4H-1,2,4-三唑-3-基)甲基吡啶酰胺的制备方法参照实施例29。
MS m/z(ESI):444.2[M+H] +.
实施例34
N-(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯基)-6-(4-(噁丁环-3-基)-4H-1,2,4-三唑-3-基)甲基吡啶酰胺
Figure PCTCN2018077873-appb-000096
N-(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯基)-6-(4-(噁丁环-3-基)-4H-1,2,4-三唑-3-基)甲基吡啶酰胺的制备方法参照实施例29。
MS m/z(ESI):460.2[M+H] +.
实施例35
6-(4-环丙基-4H-1,2,4-三唑-3-基)-N-(2-氟-5-(4-异丙基-1H-咪唑-1-基)-4-甲基苯基)甲基吡啶酰胺
Figure PCTCN2018077873-appb-000097
6-(4-环丙基-4H-1,2,4-三唑-3-基)-N-(2-氟-5-(4-异丙基-1H-咪唑-1-基)-4-甲基苯基)甲基吡啶酰胺的制备方法参照实施例29。
MS m/z(ESI):446.2[M+H] +.
实施例36
N-(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯基)-6-(4-(环丙基甲基)-4H-1,2,4-三唑-3-基)甲基吡啶酰胺
Figure PCTCN2018077873-appb-000098
N-(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯基)-6-(4-(环丙基甲基)-4H-1,2,4-三唑-3-基)甲基吡啶酰胺的制备方法参照实施例29。
MS m/z(ESI):458.2[M+H] +.
实施例37
N-(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯基)-6-(4-(噁丁环-3-基甲基)-4H-1,2,4-三唑-3-基)甲基吡啶酰胺
Figure PCTCN2018077873-appb-000099
N-(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯基)-6-(4-(噁丁环-3-基甲基)-4H-1,2,4-三唑-3-基)甲基吡啶酰胺的制备方法参照实施例29。
MS m/z(ESI):474.2[M+H] +.
实施例38
N-(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯基)-6-(4-(1-甲氧基丙烷-2-基)-4H-1,2,4-三唑-3-基)甲基吡啶酰胺
Figure PCTCN2018077873-appb-000100
N-(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯基)-6-(4-(1-甲氧基丙烷-2-基)-4H-1,2,4-三唑-3-基)甲基吡啶酰胺的制备方法参照实施例29。
MS m/z(ESI):476.2[M+H] +.
实施例39
N-(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯基)-6-(4-异丙基-5-甲基-4H-1,2,4-三唑-3-基)甲基吡啶酰胺
Figure PCTCN2018077873-appb-000101
N-(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯基)-6-(4-异丙基-5-甲基-4H-1,2,4-三唑-3-基)甲基吡啶酰胺的制备方法参照实施例29。
MS m/z(ESI):460.2[M+H] +.
实施例40
5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-氘代甲基苯酰胺
Figure PCTCN2018077873-appb-000102
5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-氘代甲基苯酰胺的制备方法参照实施例1。
MS m/z(ESI):449.2[M+H] +.
实施例41
5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(4-氘代异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基苯酰胺
Figure PCTCN2018077873-appb-000103
5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(4-氘代异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基苯酰胺的制备方法参照实施例1。
MS m/z(ESI):452.2[M+H] +.
实施例42
5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(4-异丙基-5-甲基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基苯酰胺
Figure PCTCN2018077873-appb-000104
5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(4-异丙基-5-甲基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基苯酰胺的制备同实施例1。
1H NMR(400MHz,CDCl 3)δ9.03(d,J＝15.6Hz,1H),8.39-8.22(m,1H),8.02(d,J＝7.3Hz,1H),7.93-7.77(m,2H),7.55(s,1H),7.14(d,J＝12.4Hz,1H),6.74(s,1H),5.33-5.19(m,1H),2.23(s,3H),1.96-1.77(m,1H),1.52(d,J＝7.0Hz,6H),0.94-0.84(m,2H),0.83-0.76(m,2H)；
MS m/z(ESI):466.2[M+H] +.
实施例43
6-(4-环丙基-1H-咪唑-1-基)-2-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-5-甲基异二氢吲哚-1-酮
Figure PCTCN2018077873-appb-000105
第一步：甲基5-氨基-2-氰基-4-甲基苯酸酯的制备
Figure PCTCN2018077873-appb-000106
甲基5-氨基-2-溴-4-甲基苯酸酯(900mg,3.69mmol)，CuCN(657mg,7.38mmol)混合于NMP(10mL)中，180℃下搅拌2小时，冷却后加入水，过滤，滤饼干燥得到标题化合物甲基5-氨基-2-氰基-4-甲基苯酸酯粗品(1.5g)，直接用于下一步。
MS m/z(ESI):191.1[M+H] +.
第二步：6-氨基-5-甲基异二氢吲哚-1-酮的制备
Figure PCTCN2018077873-appb-000107
将上述粗品溶于甲醇(20mL)中，加入Raney Ni(约100mg)，在H 2氛(2～3atm)、常温的条件下，搅拌过夜。用硅藻土过滤除去催化剂，滤液浓缩，柱层析，得到标题化合物6-氨基-5-甲基异二氢吲哚-1-酮(800mg,粗产品)。
MS m/z(ESI):163.1[M+H] +.
第三步：6-((2-环丙基-2-羰基乙基)氨基)-5-甲基异二氢吲哚-1-酮的制备
Figure PCTCN2018077873-appb-000108
6-氨基-5-甲基异二氢吲哚-1-酮(370mg,2.28mmol),2-溴-1-环丙基乙烷-1-酮(409mg,2.51mmol)，KI(38.0mg,0.228mmol)，K 2CO 3(378mg,2.74mmol)混合于DMF(5mL)中，55℃下搅拌2小时。冷却，往混合物中加入水，再用二氯甲烷萃取两次。有机相合并后，用饱和食盐水洗涤三次，干燥后减压除去有机溶剂，粗品直接用于下一步。
MS m/z(ESI):245.1[M+H] +.
第四步：6-(4-环丙基-2-巯基-1H-咪唑-1-基)-5-甲基异二氢吲哚-1-酮的制备
Figure PCTCN2018077873-appb-000109
将第三步的粗品溶于AcOH(10mL)，然后再往溶液中加入KSCN(442mg,4.56mmol)，然后在120℃下搅拌2小时。冷却后反应液浓缩，粗品直接用于下一步。
MS m/z(ESI):286.1[M+H] +.
第五步：6-(4-环丙基-1H-咪唑-1-基)-5-甲基异二氢吲哚-1-酮的制备
Figure PCTCN2018077873-appb-000110
将第四步粗品溶于AcOH(10mL)和水(2mL)的混合溶剂中，搅拌，在50℃下，往该溶液中缓慢滴加入双氧水(30wt％,10.0g,87.8mmol)。滴加完毕后，在该温度下继续搅拌1小时。冷却反应液，缓慢加入20wt％的Na 2SO 3水溶液(30mL)，在室温下搅拌30分钟。减压除去有机溶剂，水相用二氯甲烷萃取两次。有机相合并后，依次用饱和碳酸氢钠水溶液、饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后柱层析分离，得到标题化合物6-(4-环丙基-1H-咪唑-1-基)-5-甲基异二氢吲哚-1-酮(180mg,五步收率:42％)。
MS m/z(ESI):254.1[M+H] +.
第六步：6-(4-环丙基-1H-咪唑-1-基)-2-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-5-甲基异二氢吲哚-1-酮的制备
Figure PCTCN2018077873-appb-000111
6-(4-环丙基-1H-咪唑-1-基)-5-甲基异二氢吲哚-1-酮(50mg,0.197mmol),2-氯-6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶(61mg,0.276mmol)，碳酸铯(128mg,0.394mml)混合于1,4-二氧六环(4mL)中，氮气除氧5分钟，加入Xantphos(23.0mg,0.0394mmol)，氮气再除氧5分钟，再加入Pd(PPh 3) 4(23.0mg,0.0197mmol)，继续用氮气除氧5分钟，然后在微波反应器中，145℃下搅拌两个小时。冷却，浓缩，用二氯甲烷和水分层。分出有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩有机溶剂后用制备薄层析纯化，得到标题化合物7-(4-环丙基-1H-咪唑-1-基)-2-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-6-甲基-3,4-二氢异喹啉-1(2H)-酮(30mg，收率：35％)。
1H NMR(400MHz,CDCl 3)δ8.72(d,J＝8.4Hz,1H),8.41(s,1H),8.07(d,J＝7.6Hz,1H),7.93(d,J＝8.0Hz,1H),7.79(s,1H),7.56(s,1H),7.48(s,1H),6.83(s,1H),5.59(m,1H),5.08(s,2H),2.35(s,3H),1.93(m,1H),1.66(d,J＝6.8Hz,6H),0.90(m,2H),0.85(m,2H)；
MS m/z(ESI):440.2[M+H] +.
实施例44
6-(4-环丙基-1H-咪唑-1-基)-2-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-3,5-二甲基异二氢吲哚-1-酮
Figure PCTCN2018077873-appb-000112
第一步：2-乙酰基-4-甲基苯基三氟甲磺酸酯的制备
Figure PCTCN2018077873-appb-000113
0℃，往1-(2-羟基-5-甲基苯基)乙烷-1-酮(5.00g,33.3mmol)，吡啶(13.4mL,167mmol)的CH 2Cl 2溶液(100mL)中缓慢滴入Tf 2O(10.3g,36.3mmol),然后缓慢升至室温，并在室温下继续搅拌1小时。用饱和食盐水洗涤，有机相用无水硫酸钠干燥，浓缩有机溶剂后柱层析得到标题化合物2-乙酰基-4-甲基苯基三氟甲磺酸酯(9.0g,收率96％)。
MS m/z(ESI):283.0[M+H] +.
第二步：5-甲基-3-亚甲基异二氢吲哚-1-酮的制备
Figure PCTCN2018077873-appb-000114
2-乙酰基-4-甲基苯基三氟甲磺酸酯(2.82g,10.0mmol),Zn(CN) 2(2.35g,20.0mmol),Pd(PPh 3) 4(1.16g,1.00mmol)混合于DMF(40mL)中，在氮气氛围中，80℃下搅拌过夜。冷却后减压除去有机溶剂，柱层析得到标题化合物5-甲基-3-亚甲基异二氢吲哚-1-酮(300mg,收率19％)。
1H NMR(400MHz,CDCl 3)δ8.14(br s,1H),7.73(d,J＝7.6Hz,1H),7.50(s,1H),7.34(d,J＝7.6Hz,1H),5.16(d,J＝2.0Hz,1H),4.92(d,J＝2.0Hz,1H),2.49(s,3H)；
MS m/z(ESI):160.1[M+H] +.
第三步：3,5-二甲基异二氢吲哚-1-酮的制备
Figure PCTCN2018077873-appb-000115
5-甲基-3-亚甲基异二氢吲哚-1-酮(280mg,1.76mmol)，Pd/C(10wt％,50 mg)，MeOH(10mL)，AcOH(1mL)混合，常温常压，在氢气氛下搅拌过夜。硅藻土过滤除去不溶物，滤液浓缩，残余物用二氯甲烷溶解，依次用饱和碳酸氢钠水溶液、饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩有机溶剂后得标题化合物3,5-二甲基异二氢吲哚-1-酮粗品。
1H NMR(400MHz,CDCl 3)δ7.72(d,J＝7.6Hz,1H),7.26(m,2H),6.90(br s,1H),4.65(m,1H),2.45(s,3H),1.45(d,J＝6.8Hz,3H)；
MS m/z(ESI):162.1[M+H] +.
第四步：6-碘-3,5-二甲基异二氢吲哚-1-酮的制备
Figure PCTCN2018077873-appb-000116
上述3,5-二甲基异二氢吲哚-1-酮粗品溶于TfOH(10mL)中，冰盐浴下，分批加入NIS(417mg,1.85mmol)，然后缓慢升至室温，并继续搅拌2小时。
减压除去有机溶剂，残余物用二氯甲烷溶解，依次用饱和碳酸氢钠水溶液、饱和食盐水洗涤，无水硫酸钠干燥，浓缩有机溶剂后柱层析分离，得到标题化合物6-碘-3,5-二甲基异二氢吲哚-1-酮(130mg,两步收率26％)
1H NMR(400MHz,CDCl 3)δ8.26(s,1H),8.07(br s,1H),7.31(s,1H),4.63(m,1H),2.53(s,3H),1.49(d,J＝6.8Hz,3H)；
MS m/z(ESI):288.0[M+H] +.
第五步：6-(4-环丙基-1H-咪唑-1-基)-3,5-二甲基异二氢吲哚-1-酮的制备
Figure PCTCN2018077873-appb-000117
6-碘-3,5-二甲基异二氢吲哚-1-酮(130mg,0.453mmol)，4-环丙基-1H-咪唑(245mg,2.26mmol)，CuI(60mg,0.317mmol)，8-羟基喹啉(66mg,0.453mmol)，碳酸铯(222mg,0.680mmol)混合于DMSO(5mL)中，氮气保护下，在150℃下搅拌过夜。冷却，加入水，用CH 2Cl 2萃取两次。合并有机相，用饱和食盐水洗涤三次，无水硫酸钠干燥，浓缩有机溶剂后柱层析分离，得到目标化合物6-(4-环丙基-1H-咪唑-1-基)-3,5-二甲基异二氢吲哚-1-酮(45mg,37％)。
MS m/z(ESI):268.1[M+H] +.
第六步：6-(4-环丙基-1H-咪唑-1-基)-2-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-3,5-二甲基异二氢吲哚-1-酮的制备
Figure PCTCN2018077873-appb-000118
6-(4-环丙基-1H-咪唑-1-基)-3,5-二甲基异二氢吲哚-1-酮(50mg，0.19mmol)，2-氯-6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶(50mg,0.22mmol)，碳酸铯(122mg,0.37mml)混合于1,4-二氧六环(3mL)中，氮气除氧5分钟，加入Pd 2(dba) 3(17mg,0.019mmol)，氮气除氧5分钟，再加入Xantphos(22mg,0.037mmol)，继续氮气除氧5分钟，然后在130℃、氮气保护下，搅拌过夜。冷却，浓缩，用二氯甲烷和水分层。分出有机相，用饱和食盐水洗涤，无水硫酸钠干燥，减压蒸馏除去有机溶剂，柱层析纯化，得到标题化合物6-(4-环丙基-1H-咪唑-1-基)-2-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-3,5-二甲基异二氢吲哚-1-酮(61mg，72％)。 1H NMR(400MHz,CDCl 3)δ8.53(dd，J＝8.4,0.8Hz,1H),8.42(s,1H)，8.07(dd,J＝7.6,0.8Hz,1H),7.98(t,J＝8.0Hz,1H),7.79(s,1H),7.50(dd,J＝8.4,0.8Hz,2H),6.83(d,J＝1.2Hz,1H),5.58(m,2H),2.36(s,3H),1.93(m,1H),1.64(m,9H),0.86(m,4H)；
MS m/z(ESI):454.2[M+H] +.
实施例45
5-(4-环丙基-1H-咪唑-1-基)-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)噻吩-3-甲酰胺
Figure PCTCN2018077873-appb-000119
5-(4-环丙基-1H-咪唑-1-基)-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)噻吩-3-甲酰胺的制备方法参照实施例21。
1H NMR(400MHz,CD 3OD)δ9.36-9.27(m,2H),8.44(d,J＝1.5Hz,1H),8.40-8.31(m,1H),8.12-8.05(m,1H),7.99(d,J＝1.6Hz,1H),7.97-7.87(m,1H),7.78(s,1H),5.94-5.86(m,1H),2.08-2.03(m,1H),1.60(d,J＝6.7Hz,6H),1.18-1.13(m,2H),0.95-0.90(m,2H)；
MS m/z(ESI):420.1[M+H] +.
实施例46
(R)-2-氯-5-(4-环丙基-1H-咪唑-1-基)-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]三唑-3-基)吡啶-2-基)噻吩-3-甲酰胺
Figure PCTCN2018077873-appb-000120
(R)-2-氯-5-(4-环丙基-1H-咪唑-1-基)-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]三唑-3-基)吡啶-2-基)噻吩-3-甲酰胺的制备方法参照实施例23。
1H NMR(400MHz,CDCl 3)δ8.90(s,1H),8.30(dd,J＝8.3,0.7Hz,1H),8.11(dd,J＝7.7,0.8Hz,1H),7.89(t,J＝8.0Hz,1H),7.60(d,J＝1.0Hz,1H),7.38(s,1H),6.91(d,J＝1.2Hz,1H),5.05-4.93(m,1H),3.12-2.98(m,3H),2.46-2.38(m,1H),1.92-1.84(m,1H),1.54(d,J＝6.5Hz,3H),0.93-0.88(m,2H),0.84-0.80(m,2H)；
MS m/z(ESI):466.1[M+H] +.
实施例47
(S)-2-氯-5-(4-环丙基-1H-咪唑-1-基)-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]三唑-3-基)吡啶-2-基)噻吩-3-甲酰胺
Figure PCTCN2018077873-appb-000121
(S)-2-氯-5-(4-环丙基-1H-咪唑-1-基)-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]三唑-3-基)吡啶-2-基)噻吩-3-甲酰胺的制备方法参照实施例23。
1H NMR(400MHz,CD 3OD)δ8.26(d,J＝8.0Hz,1H),8.01-7.90(m,3H),7.44(s,1H),7.24(s,1H),5.31-5.23(m,1H),3.15-2.94(m,3H),2.50-2.42(m,1H),1.93-1.84(m,1H),1.47(d,J＝6.4Hz,3H),0.93-0.88(m,2H),0.78-0.73(m,2H)；
MS m/z(ESI):466.1[M+H] +.
实施例48
2-(4-环丙基-1H-咪唑-1-基)-5-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)噻吩并[2,3-d]哒嗪-4(5H)-酮的制备
Figure PCTCN2018077873-appb-000122
第一步：2-溴噻吩并[2,3-d]哒嗪-4(5H)-酮的制备
Figure PCTCN2018077873-appb-000123
将噻吩并[2,3-d]哒嗪-4(5H)-酮(304mg,2mmol)溶于浓硫酸(5mL)和三氟甲磺酸(5mL)中，冷却至0℃，分批加入二溴海因(572mg,2mmol)。0℃反应1小时，加入冰块终止反应。然后加入饱和Na 2CO 3水溶液调反应液至碱性(PH＝10)，二氯甲烷(50mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠 干燥，有机溶剂减压浓缩后柱层析分离得标题化合物2-溴噻吩并[2,3-d]哒嗪-4(5H)-酮(277mg,收率60％)。
MS m/z(ESI):231.9[M+H] +.
第二步：2-(4-环丙基-1H-咪唑-1-基)噻吩并[2,3-d]哒嗪-4(5H)-酮的制备
Figure PCTCN2018077873-appb-000124
2-溴噻吩并[2,3-d]哒嗪-4(5H)-酮(231mg,1mmol),4-环丙基-1H-咪唑(216mg,2mmol)，CuI(19mg,0.1mmol)，4,7-二甲氧基-1,10-菲咯啉(48mg,0.2mmol)，Cs 2CO 3(977mg，3mmol)混合于DMSO(5mL)中，氮气保护下，140℃下搅拌4h。冷却至室温，减压浓缩后柱层析得标题化合物2-(4-环丙基-1H-咪唑-1-基)噻吩并[2,3-d]哒嗪-4(5H)-酮(129mg,收率50％)。
MS m/z(ESI):259.1[M+H] +.
第三步：2-(4-环丙基-1H-咪唑-1-基)-5-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)噻吩并[2,3-d]哒嗪-4(5H)-酮的制备
Figure PCTCN2018077873-appb-000125
2-(4-环丙基-1H-咪唑-1-基)噻吩并[2,3-d]哒嗪-4(5H)-酮(129.2mg,0.5mmol)，2-氯-6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶(223mg,1.0mmol)，碳酸铯(489mg,1.5mmol)混合于1,4-二氧六环(10mL)中，氮气除氧5分钟，加入Xantphos(58mg,0.1mmol)，氮气再除氧5分钟，再加入Pd 2(dba) 3(46mg,0.05mmol)，继续用氮气除氧5分钟，然后在微波反应器中，145℃下反应两个小时。冷却后浓缩反应液，用二氯甲烷和水分层。分出有机相，用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩有机溶剂后柱层析分离得到标题化合物2-(4-环丙基-1H-咪唑-1-基)-5-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)噻吩并[2,3-d]哒嗪-4(5H)-酮(89mg,收率40％)。
1H NMR(400MHz,CD 3OD)δ8.87(s,1H),8.68(s,1H),8.25-8.19(m,2H),8.14(s,1H),7.99(s,1H),7.87-7.80(m,1H),7.23(s,1H),5.64-5.55(m,1H),2.08-2.02(m,1H),1.53(d,J＝6.6Hz,6H),0.91-0.86(m,2H),0.78-0.72(m,2H)；
MS m/z(ESI):445.1[M+H] +.
实施例49
2-(4-环丙基-1H-咪唑-1-基)-5-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-6,6-二甲基-5,6-二氢-4H-噻吩并[2,3-c]吡咯-4-酮
Figure PCTCN2018077873-appb-000126
第一步：2-溴-6,6-二甲基-5,6-二氢-4H-噻吩并[2,3-c]吡咯-4-酮的制备
Figure PCTCN2018077873-appb-000127
室温下，将6,6-二甲基-5,6-二氢-4H-噻吩并[2,3-c]吡咯-4-酮(335mg,2mmol)溶于乙腈(10mL)中，加入NBS(534mg,3mmol)。升温至50℃反应过夜，降至室温，反应液减压浓缩后柱层析分离得标题化合物2-溴-6,6-二甲基-5,6-二氢-4H-噻吩并[2,3-c]吡咯-4-酮(394mg,80％)。
MS m/z(ESI):246.9[M+H] +.
第二步：2-(4-环丙基-1H-咪唑-1-基)-6,6-二甲基-5,6-二氢-4H-噻吩并[2,3-c]吡咯-4-酮的制备
Figure PCTCN2018077873-appb-000128
2-溴-6,6-二甲基-5,6-二氢-4H-噻吩并[2,3-c]吡咯-4-酮(246mg,1mmol),4-环丙基-1H-咪唑(216mg,2mmol)，CuI(19mg,0.1mmol)，4,7-二甲氧基-1,10-菲咯啉(48mg,0.2mmol)，Cs 2CO 3(977mg,3mmol)混合于DMSO(5mL)中，氮气保护下，140℃下搅拌4h。冷却至室温，减压浓缩后柱层析分离得标题化合物2-(4-环丙基-1H-咪唑-1-基)-6,6-二甲基-5,6-二氢-4H-噻吩并[2,3-c]吡咯-4-酮(150mg,55％)。
MS m/z(ESI):274.1[M+H] +.
第三步：2-(4-环丙基-1H-咪唑-1-基)-5-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-6,6-二甲基-5,6-二氢-4H-噻吩并[2,3-c]吡咯-4-酮的制备
Figure PCTCN2018077873-appb-000129
2-(4-环丙基-1H-咪唑-1-基)-6,6-二甲基-5,6-二氢-4H-噻吩并[2,3-c]吡咯-4-酮(137mg,0.5mmol)，2-氯-6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶(223mg,1.0mmol)，碳酸铯(489mg,1.5mmol)混合于1,4-二氧六环(10mL)中，氮气除氧5分钟，加入Xantphos(58mg,0.1mmol)，氮气再除氧5分钟，再加入Pd 2(dba) 3(46mg,0.05mmol)，氮气再次除氧5分钟，然后在微波反应器中，145℃下反应 两个小时。冷却后浓缩反应液，用二氯甲烷和水分层。分出有机相，用饱和食盐水洗涤，无水硫酸钠干燥，有机溶剂减压浓缩后柱层析分离得到标题化合物2-(4-环丙基-1H-咪唑-1-基)-5-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-6,6-二甲基-5,6-二氢-4H-噻吩并[2,3-c]吡咯-4-酮(80mg,收率35％)。
MS m/z(ESI):460.2[M+H] +.
实施例50
4-(4-环丙基-1H-咪唑-1-基)-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-5-甲基噻吩-2-甲酰胺
Figure PCTCN2018077873-appb-000130
第一步：4-溴-5-甲基噻吩-2-甲酰胺的制备
Figure PCTCN2018077873-appb-000131
4-溴-5-甲基噻吩-2-羧酸(1.20g,5.43mmol)，NH 4Cl(871mg,16.3mmol)，HATU(2.89g,7.60mmol)，DIPEA(4.47mL,27.1mmol)混合于二氯甲烷(30mL)中，室温下搅拌90分钟。用饱和食盐水洗涤，无水硫酸钠干燥，浓缩反应液后柱层析分离得到标题化合物4-溴-5-甲基噻吩-2-甲酰胺(1.10g,收率92％)。
MS m/z(ESI):220.0[M+H] +.
第二步：4-(4-环丙基-1H-咪唑-1-基)-5-甲基噻吩-2-甲酰胺的制备
Figure PCTCN2018077873-appb-000132
4-溴-5-甲基噻吩-2-甲酰胺(300mg,1.36mmol)，4-环丙基-1H-咪唑(300mg,2.73mmol)，CuI(77mg,0.409mmol)，K 2CO 3(377mg,2.73mmol)混合于NMP(5mL)中，用氮气除氧10分钟，然后加入L-脯氨酸(94mg，0.82mmol)，再用氮气除氧5分钟，然后在氮气保护下，在145℃下搅拌过夜。冷却后浓缩反应液柱层析分离得到标题化合物4-(4-环丙基-1H-咪唑-1-基)-5-甲基噻吩-2-甲酰胺(130mg,收率39％)。
MS m/z(ESI):248.1[M+H] +.
第三步：4-(4-环丙基-1H-咪唑-1-基)-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-5-甲基噻吩-2-甲酰胺的制备
Figure PCTCN2018077873-appb-000133
4-(4-环丙基-1H-咪唑-1-基)-5-甲基噻吩-2-甲酰胺(43mg,0.174mmol)，2-氯-6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶(46mg,0.209mmol)，Pd(OAc) 2(7.8mg,0.035mmol)，Xantphos(40mg,0.07mmol)，Cs 2CO 3(113mg,0.35mmol)混合于1,4-二氧六环(5mL)中，氮气保护下，110℃反应两天。
反应冷却后浓缩反应液，用二氯甲烷溶解。有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩有机溶剂后柱层析分离得到4-(4-环丙基-1H-咪唑-1-基)-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-5-甲基噻吩-2-甲酰胺(3mg)
1H NMR(400MHz,CDCl 3)δ8.66(s,1H),8.37(s,1H),8.29(d,J＝8.0Hz,1H),7.90(m,2H),7.72(s,2H),6.88(s,1H),5.38(m,1H),2.48(s,3H),1.90(m,1H),1.50(d,J＝6.8Hz,6H),0.90(m,4H)；
MS m/z(ESI):434.2[M+H] +.
实施例51
5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(1-异丙基-1H-四唑-5-基)吡啶-2-基)-4-甲基苯酰胺
Figure PCTCN2018077873-appb-000134
第一步：2-氯-6-(1-异丙基-1H-四唑-5-基)吡啶的制备
Figure PCTCN2018077873-appb-000135
-10℃下，往6-氯-N-异丙基甲基吡啶酰胺(1.75g,8.86mmol))，NaN 3(2.29g,35.2mmol)的MeCN溶液(50mL)中，缓慢加入三氟甲磺酸酐(2.96mL,17.6mmol)，然后在室温下搅拌过夜。反应液中加入饱和碳酸氢钠水溶液，减压除去有机溶剂，加入二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤后减压浓缩有机溶剂，柱层析分离得到标题化合物2-氯-6-(1-异丙基-1H-四唑-5-基)吡啶(720mg，36％)。
MS m/z(ESI):224.1[M+H] +
第二步：5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯酰胺的制备
Figure PCTCN2018077873-appb-000136
5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲酸盐酸盐(1.00g,3.37mmol),氯化铵(361mg,6.74mmol)，HATU(1.54g,4.04mmol)，三乙胺(2.36mL，16.9mmol)混合于二氯甲烷(30mL)中，室温下搅拌1小时，然后依次用饱和碳酸氢钠水溶液、饱和食盐水洗涤，有机相用无水硫酸钠干燥，减压浓缩后柱层析分离得到标题化合物5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯酰胺(780mg,80％)。
MS m/z(ESI):260.1[M+H] +
第三步：5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(1-异丙基-1H-四唑-5-基)吡啶-2-基)-4-甲基苯酰胺的制备
Figure PCTCN2018077873-appb-000137
5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯酰胺(300mg,1.16mmol),2-氯-6-(1-异丙基-1H-四唑-5-基)吡啶(259mg,1.16mmol)，碳酸铯(570mg,1.74mmol)混合于1,4-二氧六环(10mL)中，氮气鼓泡5分钟，加入Pd 2(dba) 3(106mg,0.116mmol)，然后用氮气继续除氧5分钟，再加入Xantphos(134mg,0.232mmol)，氮气鼓泡5分钟。在微波反应器中，130℃下搅拌1.5小时。冷却后，反应液用二氯甲烷稀释，然后用饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤后有机相减压浓缩，柱层析分离得到标题化合物5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(1-异丙基-1H-四唑-5-基)吡啶-2-基)-4-甲基苯酰胺(280mg,45％)。
1H NMR(400MHz,CDCl 3)δ9.18(d,J＝15.6Hz,1H),8.51(d,J＝8.4Hz,1H),8.09(m,2H),8.01(m,1H),7.47(s,1H),7.22(d,J＝12.4Hz,1H),6.81(s,1H),5.72(m,1H),2.30(s,3H),1.92(m,1H),1.72(d,J＝6.8Hz,6H),0.91(m,2H),0.85(m,2H)；
MS m/z(ESI):447.2[M+H] +.
实施例52
2-(4-环丙基-1H-咪唑-1-基)-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)噻唑-4-甲酰胺
Figure PCTCN2018077873-appb-000138
2-(4-环丙基-1H-咪唑-1-基)-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)噻唑-4-甲酰胺的制备方法参照实施例21。
1H NMR(400MHz,CD 3OD)δ8.74(s,1H),8.21-8.15(m,2H),8.10(s,1H),7.86(t,J＝8.0Hz,1H),7.72(d,J＝7.2Hz,1H),7.37(s,1H),5.48-5.39(m,1H),1.82-1.76(m,1H),1.48(d,J＝6.7Hz,7H),0.83-0.78(m,2H),0.70-0.64(m,2H)；
MS m/z(ESI):421.1[M+H] +.
实施例53
2-(4-环丙基-1H-咪唑-1-基)-5-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)噻吩并[3,2-c]吡啶-4(5H)-酮
Figure PCTCN2018077873-appb-000139
2-(4-环丙基-1H-咪唑-1-基)-5-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)噻吩并[3,2-c]吡啶-4(5H)-酮的制备方法参照实施例48。
1H NMR(400MHz,CD 3OD)δ8.89(s,1H),8.27-8.20(m,2H),8.05(d,J＝1.4Hz,1H),7.98(dd,J＝7.2,1.8Hz,1H),7.89(d,J＝7.5Hz,1H),7.68(s,1H),7.35(d,J＝1.4Hz,1H),7.08(d,J＝7.4Hz,1H),5.52-5.44(m,1H),1.96-1.88(m,1H),1.59(d,J＝6.7Hz,6H),0.95-0.89(m,2H),0.81-0.76(m,2H)；
MS m/z(ESI):444.1[M+H] +.
生物学测试评价
以下结合测试例进一步描述解释本发明，但这些实施例并非意味着限制本发明的范围。
1.测试ASK1酶学实验
本实验采用荧光共振能量转移(TR-FRET)的方法测试化合物对ASK1激酶活性的抑制作用，并得出化合物对ASK1激酶活性的半数抑制浓度IC 50。
1)在384孔板中加入1～5uL ASK1酶溶液，酶终浓度为0.2～20nM。
2)加入1～5uL梯度稀释好的化合物溶液。
3)加入1～5uL底物混合液包含底物多肽终浓度100～5000nM和ATP终浓度100～1000uM。
4)室温孵育0.5～5小时。
5)加入10uL EDTA和含标记抗体的检测液，室温孵育2～24小时。
6)酶标仪测定各板孔的约615nm和665nm荧光信号值。
7)通过荧光信号值计算抑制率。
8)根据不同浓度的抑制率通过曲线拟合得出化合物的IC 50。
本发明中实施例化合物酶学活性见表1。
表1 本发明中实施例化合物酶学活性
化合物编号 ASK1 IC 50(nM)
实施例1 6.7
实施例3 33.8
实施例9 12.2
实施例13 2.2
实施例21 9.9
实施例22 2.5
实施例23 28.0
实施例29 5.6
实施例31 49.9
实施例42 9.1
实施例43 3.9
实施例44 3.9
实施例45 4.9
实施例46 13.9
实施例50 14.1
实施例51 2.5
实施例53 32.7
以上实施例化合物都能显著抑制ASK1激酶的酶学活性，部分化合物对ASK1激酶表现出强效的抑制作用，激酶酶活性抑制的IC 50小于10nM，这些化合物作为ASK1的有效抑制剂对NASH的治疗具有巨大的应用潜力。
2.大鼠PK分析
本发明优选实施例的大鼠药物代谢动力学试验采用SD雄性大鼠(上海杰思捷实验动物有限公司)进行。
■给药方式：单次灌胃给药。
■给药剂量：5毫克/10毫升/千克。
■制剂处方：5％EtOH-75％PG-10％Kolliphor-10％Water，超声溶解。
■取样点：给药后0.5、1、2、4、6、8和24小时。
■样品处理：
1)静脉采血0.2mL，置于K 2EDTA试管中，室温1000～3000×g离心5～20min分离血浆，于-80℃保存。
2)血浆样品40uL加入160uL乙腈沉淀,混合后500～2000×g离心5～20分钟。
3)取处理后上清溶液100uL进行LC/MS/MS分析待测化合物的浓度。
■液相分析：
●液相条件：Shimadzu LC-20AD泵
●质谱条件:AB Sciex API 4000质谱仪
●色谱柱：phenomenex Gemiu 5um C18 50×4.6mm
●移动相：A液为0.1％甲酸水溶液，B液为乙腈
●流速：0.8mL/min
●洗脱时间：0-3.5分钟梯度洗脱
■药代动力学：
主要参数用WinNonlin 6.1计算得到，大鼠药代实验结果见下表2：
表2
Figure PCTCN2018077873-appb-000140
从表中大鼠药代实验结果可以看出：本发明实施例化合物表现出良好的代谢性质，暴露量AUC和最大血药浓度C max都表现良好。
3.小鼠PK分析
本发明优选实施例的小鼠药物代谢动力学试验采用Balb/c雄性小鼠(上海杰思捷实验动物有限公司)进行。
■给药方式：单次灌胃给药。
■给药剂量：5毫克/10毫升/千克。
■制剂处方：0.5％CMC-Na，超声溶解。
■取样点：给药后0.5、1、2、4、6、8和24小时。
■样品处理：
1)眼眶采血0.1mL，置于K 2EDTA试管中，室温1000～3000×g离心5～20min分离血浆，于-80℃保存。
2)血浆样品40uL加入160uL乙腈沉淀，混合后500～2000×g离心5～20分钟。
3)取处理后上清溶液100uL进行LC/MS/MS分析待测化合物的浓度。
■LC-MS/MS分析：
●液相条件：Shimadzu LC-20AD泵
●质谱条件:AB Sciex API 4000质谱仪
●色谱柱：phenomenex Gemiu 5um C18 50×4.6mm
●移动相：A液为0.1％甲酸水溶液，B液为乙腈
●流速：0.8mL/min
●洗脱时间：0-3.5分钟梯度洗脱
■药代动力学：
主要参数用WinNonlin 6.1计算得到，小鼠药代实验结果见下表3：
表3
Figure PCTCN2018077873-appb-000141
从表中小鼠药代实验结果可以看出：本发明实施例化合物表现出良好的代谢性质，暴露量AUC和最大血药浓度C max都表现良好。
4.本发明化合物对HFD(高脂饲料)+CCl 4诱导的非酒精性脂肪肝炎小鼠ALT和AST水平的影响
1、实验目的：
该测试例的目的是检测本发明化合物是否能下调非酒精性脂肪肝炎小鼠血清中ALT和AST的水平。
2、实验原料和仪器：
利用谷丙转氨酶(ALT/GPT)测试盒：南京建成科技有限公司
谷草转氨酶(AST/GOT)测试盒：南京建成科技有限公司
96孔板：Corning公司；
BioTek Synergy H1酶标仪：美国BioTek公司
3、实验步骤：
C57BL/6小鼠在SPF(无特定病原体)屏障内进行3-7天的适应性饲养后，更换HFD饲料饲养，饲养周期为8周。HFD饲养第五周，根据动物体重将HFD诱导后的小鼠随机分组，口服给予一周两次CCl 4诱导，并持续4周。给予CCl 4建模当日开始口服给药，给药频率每天一次，连续给药28天。溶媒对照组给予供试品对应的溶媒，给药体积为10mL/kg。CCl 4最后一次给予48小时后，用CO 2将小鼠安乐死，从心脏处采集动物非抗凝静脉血，全血在常温下放置至少30分钟，在4度5000转5分钟离心条件下离心，分离血清，分装成两份，装入1.5mL的EP管中，-80℃保存，备用。
利用谷丙转氨酶(ALT/GPT)测试盒和谷草转氨酶(AST/GOT)测试盒检测小鼠血清ALT和AST水平。将ALT(或AST)检测基质液放入37℃恒温箱中预热；吸取20uL基质液加入96孔板中，再吸取5uL血清加入96孔板中作为测定孔，混匀后使用封口膜封板放入37℃恒温箱中孵育30min。配制ALT(或AST)标准曲线，吸取25uL加入96孔板中；再吸取20uL血浆加入96孔板中作为对照孔；各孔分别加入2,4-二硝基苯肼液20uL，混匀后使用封口膜封板放入37℃恒温箱中孵育20min。各孔加入0.4M的NaOH溶液200uL，放入摇板仪上摇动15min，在BioTek Synergy H1仪器上使用检测OD程序进行读板，波长为510nm，根据各孔OD值计算绝对OD值。绝对OD值＝测定孔OD值-对照孔OD值。将绝对OD值带入标准曲线中求得样品中ALT(或AST)的含量，超出标曲范围的样品需将血清稀释至合适浓度后重新检测。
数据处理：(％ALT降低率)＝(溶媒对照组-测试化合物)/溶媒对照组╳100％；
(％AST降低率)＝(溶媒对照组-测试化合物)/溶媒对照组╳100％。
4、实验结果：
Figure PCTCN2018077873-appb-000142
5、实验结论：
本发明化合物在下调非酒精性脂肪肝炎小鼠血清中ALT和AST的水平中相较于现有技术的ASK1表现出良好的效果。

Claims (18)

  1. 一种通式(I)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2018077873-appb-100001
    其中：
    M 1、M 2、M 3和M 4各自独立地选自N或-CR 6；
    X和Y各自独立地选自键、
    Figure PCTCN2018077873-appb-100002
    -NR 7-、-CR 7R 8-、-S(O) m-、
    Figure PCTCN2018077873-appb-100003
    Figure PCTCN2018077873-appb-100004
    环A选自芳基或杂芳基，其中所述的芳基和杂芳基任选进一步被选自氘原子、烷基、氘代烷基、卤素、氨基、硝基、羟基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代；
    R 1相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9；其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代；
    R 2相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、 -(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9；
    R 3选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟基、氨基、环烷基、杂环基、芳基和杂芳基，所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9；
    或者，R 3和M 3、M 3和M 4链接分别形成一个环烷基、芳环基、杂环基或杂芳环基，其中所述的环烷基、芳环基、杂环基或杂芳环基任选进一步被选自氘原子、烷基、氘代烷基、卤代烷基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代；
    又或者，R 1和X或Y、M 1和X或Y链接分别形成一个环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基或杂芳基任选进一步被选自氘原子、烷基、氘代烷基、卤代烷基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代；
    R 6、R 7和R 8相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9；其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代；
    R 9选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟基、氨基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤素、氨基、 硝基、氰基、羟基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代；
    R 10和R 11相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟基、氨基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤素、羟基、氨基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代；
    R 12和R 13相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟基、氨基、酯基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤素、羟基、氨基、硝基、氰基、酯基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    x为0、1、2、3或4的整数；
    y为0、1或2的整数；
    m为0、1或2的整数；且
    n为0、1、2、3、4或5的整数。
  2. 根据权利要求1所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(II)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2018077873-appb-100005
    其中：
    R 4选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9；其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 12、 -(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代；
    R 3和R 4链接形成一个杂环或杂芳环，其中所述的杂环或杂芳环任选进一步被选自烷基、氘代烷基、卤代烷基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代；
    或者，R 3和R 4链接形成的杂环或杂芳环，所述杂环或杂芳环上的任意两个取代基可以形成新的环烷基、杂环基、芳基和杂芳基，其中所述的形成新的环烷基、芳环基、杂环基或杂芳环基任选进一步被选自氘原子、烷基、氘代烷基、卤代烷基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代；
    环A、M 1、M 2、X、Y、R 1-R 3、R 6-R 13、x、y、m和n如权利要求1所述。
  3. 根据权利要求2所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(III)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2018077873-appb-100006
    其中：
    R 5选自氢原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、羟烷基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9；其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、 -(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代；优选环丙基；
    环A、M 1、M 2、X、Y、R 1-R 3、R 6-R 13、y、m和n如权利要求1所述；
    R4如权利要求2所述；
    x为1、2、3或4的整数。
  4. 根据权利要求1-3所述的通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，其特征在于，-Y-X-选自如下基团：
    Figure PCTCN2018077873-appb-100007
  5. 根据权利要求1所述的通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，其为通式(IV)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2018077873-appb-100008
    其中：
    M 1为CR 6或N；优选CH；
    M 2为CR 6或N；优选N；
    R 1选自氢原子、C 1-8烷基、卤素、C 3-8环烷基、卤代C 1-8烷基、C 1-8氘代烷基或-(CH 2) nS(O) mR 9；优选C 1-6烷基或卤素；
    R 2选自氢原子或C 1-8烷基；优选氢原子；
    R 3选自C 1-8烷基、C 3-8环烷基、卤代C 1-8烷基、C 1-8氘代烷基或3-6元杂环基，其中所述的C 1-8烷基、C 3-8环烷基、卤代C 1-8烷基、C 1-8氘代烷基和3-6元杂环基任选进一步被选自氘原子、C 1-8烷基、C 1-8卤代烷基、卤素、羟基、C 1-8烷氧基、C 1-8羟烷基、C 3-8环烷基或3-6元杂环基中的一个或多个取代基所取代；优选异丙基；
    R 4选自氢原子、C 1-8烷基、卤素、C 3-8环烷基、卤代C 1-8烷基或C 1-8氘代烷基；优选氢原子；
    或者R 3和R 4一起形成一个5-6元杂环，其中所述的5-6元杂环任选进一步被选自氢原子、C 1-8烷基或被C 1-8烷氧基取代的C 1-8烷基中的一个或多个取代基所取代；优选C 1-6烷基；
    R 5选自氢原子、C 1-8烷基、C 3-8环烷基；优选环丙基；
    x为1、2、3、或4的整数；且
    y为0、1或2的整数。
  6. 根据权利要求5所述的通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，其为通式(V)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2018077873-appb-100009
    其中：
    M 1、M 2、R 1-R 5、x和y如权利要求5所述。
  7. 根据权利要求6所述的通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，其为通式(VI)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2018077873-appb-100010
    其中：
    -Y-X-选自
    Figure PCTCN2018077873-appb-100011
    R 1选自氢原子、C 1-6烷基或卤素；
    R 3选自C 1-6烷基或C 3-6环烷基；
    R 4选自氢原子、C 1-6烷基、C 1-6卤代烷基或C 3-6环烷基；且
    x为1、2、3、或4的整数。
  8. 根据权利要求7所述的通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，其为通式(VII)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2018077873-appb-100012
    其中：
    R 1选自C 1-8烷基、卤素、C 3-8环烷基、卤代C 1-8烷基或C 1-8氘代烷基；
    R 3选自氢原子、C 1-8烷基、C 1-8氘代烷基、卤代C 1-8烷基或C 3-8环烷基；且x选自1、2、3或4。
  9. 根据权利要求1所述的通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，其为通式(VIII)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2018077873-appb-100013
    其中：
    M 5选自S或CH；优选CH；
    环B为杂环或杂芳环；
    R 1选自氢原子、卤素、C 1-8烷基、C 1-8氘代烷基、C 1-8烷氧基、C 1-8卤代烷氧基、C 3-8环烷基和3-10元杂环基
    R 3选自C 1-8烷基、C 1-8氘代烷基、C 1-8烷氧基、C 1-8卤代烷氧基、C 3-8环烷基和3-10元杂环基；
    R 4选自氢原子、C 1-8烷基；
    R b选自氢原子、C 1-8烷基、C 1-8氘代烷基或C 1-8卤代烷基；
    x选自2、3或4；
    p为0、1、2、3或4的整数；且
    q为0或1的整数。
  10. 根据权利要求1-5任一项所示各通式、其立体异构体或其药学上可接受的盐，其特征在于，环A选自如下基团：
    Figure PCTCN2018077873-appb-100014
  11. 根据权利要求1-10任一项所示各通式、其立体异构体或其药学上可接受的盐，其特征在于，R 1选自C 1-8烷基、C 3-8环烷基、环丙基取代的5-10元杂芳基、C 1-8氘代烷基、-(CH 2) nS(O) mR 9和卤素，优选环丙基取代的5-6元杂芳基、卤素、C 1-6烷基和C 1-6氘代烷基，更优选环丙基取代的吡唑、氟原子、甲基和氘代甲基，其中所述的R 9为C 1-6烷基和C 1-6氘代烷基；R 2选自氢原子；R 3选自氢原子、C 1-8烷基、C 1-8氘代烷基、C 1-8烷氧基、C 1-8卤代烷氧基、C 3-8环烷基和3-10元杂环基，其中所述的C 1-8烷基任选进一步被选自氢原子、C 1-8烷氧基、C 1-8卤代烷氧基、C 3-8环烷基和3-10元杂环基中的一个或多个取代基所取代；优选C 1-6烷基；更优选异丙基。
  12. 根据权利要求1-6、10-11任一项所示各通式、其立体异构体或其药学上可接受的盐，其特征在于，M 1为-CR 6，其中所述的R 6选氢原子、C 1-8烷基或C 3-8环烷基，优选氢原子；M 2为N。
  13. 根据权利要求2-7、9-12任一项所示各通式、其立体异构体或其药学上可接受的盐，其特征在于，R 4选自氢原子、C 1-8烷基、C 1-8氘代烷基、卤代C 1-8烷基和C 3-8环烷基；优选氢原子；R 5选自氢原子、C 1-8烷基、C 3-8环烷基，优选环丙基。
  14. 根据权利要求1-13任一所示的通式(I)化合物、其立体异构体或其药学上可接受的盐，其特征在于，选自如下化合物：
    Figure PCTCN2018077873-appb-100015
    Figure PCTCN2018077873-appb-100016
    Figure PCTCN2018077873-appb-100017
  15. 一种药用组合物，其包括治疗有效剂量的权利要求1-14任一所示的通式(I)化合物、其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  16. 权利要求3所示的通式(III)化合物、其立体异构体或其药学上可接受的盐的制备方法，包括如下步骤：
    Figure PCTCN2018077873-appb-100018
    通式(VI-A)化合物和通式(VI-B)化合物缩合后得到通式(III)化合物，该通式(III)化合物任选进一步硫代，进一步被缩合得到不同的通式(III)化合物，其中硫代反应中硫代试剂优选Lawesson试剂；
    其中：
    W 1和W 2相同或不同，且各自独立地选自为
    Figure PCTCN2018077873-appb-100019
    -NH 2、-S(O) mW、
    Figure PCTCN2018077873-appb-100020
    或W；其中所述的W为羟基或卤素，卤素优选溴和氯；
    环A、M 1、M 2、X、Y、R 1-R 3x、y、m和n如权利要求1所述；R 4如权利要求2所述；R 5如权力要求3所述。
  17. 根据权利要求1-14任一所示的通式(I)化合物、其立体异构体或其药学上可接受的盐，或权利要求15所述的药物组合物在制备ASK1抑制剂药物中的应用。
  18. 根据权利要求1-14任一所示的通式(I)化合物、其立体异构体或其药学上可接受的盐，或权利要求15所述的药物组合物在制备治疗神经变性障碍、心血管障碍、炎性障碍、代谢障碍和ASK1的药物中的应用；所述的炎症障碍优选非酒精性脂肪性肝炎(NASH)。
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