WO2019206120A1 - 甲酰胺类化合物、其制备方法及其应用 - Google Patents

甲酰胺类化合物、其制备方法及其应用 Download PDF

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WO2019206120A1
WO2019206120A1 PCT/CN2019/083829 CN2019083829W WO2019206120A1 WO 2019206120 A1 WO2019206120 A1 WO 2019206120A1 CN 2019083829 W CN2019083829 W CN 2019083829W WO 2019206120 A1 WO2019206120 A1 WO 2019206120A1
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Prior art keywords
ring
alkyl
group
cycloalkyl
compound
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PCT/CN2019/083829
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English (en)
French (fr)
Inventor
杨千姣
鲁先平
李志斌
潘德思
山松
王晓亮
宋永连
张堃
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深圳微芯生物科技股份有限公司
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Priority to EP19791533.3A priority Critical patent/EP3789384A4/en
Priority to BR112020021664-0A priority patent/BR112020021664A2/pt
Priority to AU2019260217A priority patent/AU2019260217B2/en
Priority to UAA202007486A priority patent/UA125056C2/uk
Priority to US17/050,443 priority patent/US20210139454A1/en
Priority to MX2020011164A priority patent/MX2020011164A/es
Priority to CA3098202A priority patent/CA3098202A1/en
Priority to JP2020559445A priority patent/JP2021519808A/ja
Priority to KR1020207033670A priority patent/KR20210005135A/ko
Publication of WO2019206120A1 publication Critical patent/WO2019206120A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to the field of pharmaceutical technology, and relates to a carboxamide compound capable of inhibiting ASK1 kinase activity, and to a process for preparing the compound, a pharmaceutical composition comprising the compound as an active ingredient, and a pharmaceutical application thereof.
  • the compounds of the present invention are useful as inhibitors of ASK1 kinases for the treatment/prevention of diseases associated with the target, such as inflammatory diseases, metabolic diseases, autoimmune diseases, cardiovascular diseases, neurodegenerative diseases, Cancer and other diseases.
  • MAPKs Mitogen-activated protein kinases
  • MAP3K MEK kinase
  • MAPK2K MAPK kinase
  • MAPK MAP kinase
  • Apoptosis signal-regulating kinase 1 is a member of the MAP3K family.
  • ASK1 is capable of oxidative stress, reactive oxygen species (ROS), lipopolysaccharide (LPS), and tumor necrosis factor (TNF-).
  • ROS reactive oxygen species
  • LPS lipopolysaccharide
  • TNF- tumor necrosis factor
  • Various stimuli such as ⁇ ), endoplasmic reticulum (ER) stress, osmotic pressure, inflammation, etc. are first activated, thereby activating MAP2K, and MAP2K is phosphorylated to activate MAPK, such as c-Jun amino terminal protein kinase (c-JunN) -terminal protein kinase, JNK) and p38MAPK.
  • c-JunN c-Jun amino terminal protein kinase
  • JNK p38MAPK
  • ASK1 plays a key role in a variety of cell biology processes, including apoptosis, differentiation, and inflammation (Soga M., Matsuzawa A., Ichijo H., 2012, Int. J. Cell Biol., 2012). :1-5).
  • ASK1 activation of ASK1 plays an important role in many diseases, such as inflammatory diseases, metabolic diseases, autoimmune diseases, cardiovascular diseases, neurodegenerative diseases, cancer and other diseases (Soga M., Matsuzawa A. , Ichijo H., 2012, Int. J. Cell Biol., 2012: 1-5; Hayakawa R., Hayakawa T., Takeda K., et al, 2012, Proc. Jpn. Acad. Ser. BPhys. Biol. Sci., 88: 434-453). Therefore, it has been found that a pharmaceutically active molecule having an activity of inhibiting ASK1 will bring significant benefits to patients suffering from the above diseases.
  • ASK1 inhibitor patent applications include triazolopyridines WO2009027283, pyrazolo[1,5-A]pyrimidines WO2011041293, aromatic/aromatic heterocyclic amines WO2011008709, heterocyclic amines US20120004267 and thiazolamide Class US20170173031 and so on.
  • the activation of ASK1 is associated with a variety of diseases, and its inhibitors have important clinical value and good application prospects as medicines in the field of medicine, but there are currently no approved drugs listed in the world. Therefore, we expect to develop new ASK1 inhibitors to meet unmet clinical needs.
  • the present invention provides a novel cycloalkylcarboxamide ASK1 inhibitor for treating/preventing diseases associated with the target, such as inflammatory diseases, metabolic diseases, autoimmune diseases, cardiovascular diseases, Neurodegenerative diseases, cancer and other diseases.
  • diseases associated with the target such as inflammatory diseases, metabolic diseases, autoimmune diseases, cardiovascular diseases, Neurodegenerative diseases, cancer and other diseases.
  • these compounds or pharmaceutical compositions containing them as active ingredients can maximize the clinical efficacy of these diseases within a safe therapeutic window.
  • the invention relates to a cycloalkyl carboxamide compound which inhibits ASK1 kinase activity of Formula I, including pharmaceutically acceptable salts, hydrates, other solvates, stereoisomers thereof and the like Derivatives such as medicines.
  • Another aspect of the invention relates to a process for the preparation of the compounds described herein.
  • a further aspect of the invention relates to a pharmaceutical composition comprising the compound of the invention as an active ingredient, and to the clinical use of a compound or pharmaceutical composition of the invention for the treatment/prevention of a disease associated with ASK1 kinase, and a compound or combination of the invention Use in the preparation of a medicament for the treatment and/or prevention of a disease associated with ASK1 kinase.
  • the present invention also relates to a method of treating and/or preventing a disease associated with ASK1 kinase comprising administering a compound or pharmaceutical composition of the present invention to a subject in need thereof.
  • the present invention relates to compounds of formula I, including prodrugs, stereoisomers, pharmaceutically acceptable salts, hydrates or other solvates thereof,
  • R 1 is one or more substituents independently selected from the same or different H, halogen, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, NH 2 , COOH, C 1 -C 4 Alkylamino, C 1 -C 4 alkyloxy and Ar 1 ;
  • Ar 1 is selected from the group consisting of a benzene ring and a pyridine ring, and the benzene ring and the pyridine ring may be substituted by one or more substituents, which are independently selected from the same or different H, halogen, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, NH 2 , C 1 -C 4 alkylamino and C 1 -C 4 alkyloxy;
  • R 2 is one or more substituents independently selected from the same or different H, halogen, CN, C 1 -C 4 alkyl and C 1 -C 4 haloalkyl;
  • R 3 is C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 haloalkyl, halo C 3 -C 6 cycloalkyl, cyano substituted C 1 -C 4 alkyl, a C 3 -C 6 heterocycloalkyl group, a hydroxy-substituted C 1 -C 4 alkyl group or a C 1 -C 4 alkoxy-substituted C 1 -C 4 alkyl group;
  • X is selected from C and N;
  • A is selected from the group consisting of C 3 -C 7 cycloalkyl and C 3 -C 7 heterocycloalkyl;
  • a benzene ring is selected from the group consisting of a benzene ring, a pyridine ring, a thiazole ring, a furan ring, a thiophene ring, a pyrrole ring, a pyrazole ring, an oxazole ring, an isoxazole ring and a quinoline ring, and the aromatic ring may be one or more Substituted by a substituent which is independently selected from the same or different H, halogen, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, NH 2 , C 1 -C 4 alkylamino and C 1 -C 4 alkyl group;
  • n is an integer from 1 to 5;
  • n is an integer from 1 to 4.
  • the invention relates to a compound of formula I, including prodrugs, stereoisomers, pharmaceutically acceptable salts, hydrates or other solvates thereof, wherein
  • R 1 is one or more substituents independently selected from the same or different H, halogen, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, NH 2 , COOH, C 1 -C 4 Alkylamino, C 1 -C 4 alkyloxy and Ar 1 ;
  • Ar 1 is selected from the group consisting of a benzene ring and a pyridine ring, and the benzene ring and the pyridine ring may be substituted by one or more substituents independently selected from the same or different H, halogen, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, NH 2 , C 1 -C 4 alkylamino and C 1 -C 4 alkyloxy;
  • R 2 is one or more substituents independently selected from the same or different H, halogen, CN and C 1 -C 4 alkyl;
  • R 3 is C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 haloalkyl, halo C 3 -C 6 cycloalkyl, cyano substituted C 1 -C 4 alkyl, a C 3 -C 6 heterocycloalkyl group, a hydroxy-substituted C 1 -C 4 alkyl group and a C 1 -C 4 alkoxy-substituted C 1 -C 4 alkyl group;
  • X is selected from C and N;
  • A is selected from the group consisting of C 3 -C 7 cycloalkyl and C 3 -C 7 heterocycloalkyl;
  • B is an aromatic ring, preferably selected from the group consisting of a benzene ring, a pyridine ring, a thiazole ring, a furan ring, a thiophene ring, a pyrrole ring, a pyrazole ring, an oxazole ring, an isoxazole ring, and a quinoline ring, and the aromatic ring can be one Or substituted with a plurality of substituents independently selected from the same or different H, halogen, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, NH 2 , C 1 -C 4 alkane a base amino group and a C 1 -C 4 alkyloxy group;
  • n is an integer from 1 to 5;
  • n is an integer from 1 to 4.
  • the invention relates to a compound of formula I, including prodrugs, stereoisomers, pharmaceutically acceptable salts, hydrates or other solvates thereof, wherein
  • R 1 is one or more substituents independently selected from the same or different H, halogen, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, NH 2 , COOH, C 1 -C 4 An alkylamino group and a C 1 -C 4 alkyloxy group;
  • R 2 is one or more substituents independently selected from the same or different H, halogen, CN and C 1 -C 4 alkyl;
  • R 3 is C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 haloalkyl, halo C 3 -C 6 cycloalkyl, cyano substituted C 1 -C 4 alkyl, a C 3 -C 6 heterocycloalkyl group, a hydroxy-substituted C 1 -C 4 alkyl group and a C 1 -C 4 alkoxy-substituted C 1 -C 4 alkyl group;
  • X is selected from C and N;
  • A is selected from the group consisting of C 3 -C 7 cycloalkyl and C 3 -C 7 heterocycloalkyl;
  • B is an aromatic ring, preferably selected from the group consisting of a benzene ring, a pyridine ring, a thiazole ring, a furan ring, a thiophene ring, a pyrrole ring, a pyrazole ring, an oxazole ring, an isoxazole ring, and a quinoline ring, and the aromatic ring can be one Or substituted with a plurality of substituents independently selected from the same or different H, halogen, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, NH 2 , C 1 -C 4 alkane a base amino group and a C 1 -C 4 alkyloxy group;
  • n is an integer from 1 to 5;
  • n is an integer from 1 to 4.
  • the invention relates to a compound of formula I, including prodrugs, stereoisomers, pharmaceutically acceptable salts, hydrates or other solvates thereof, wherein
  • R 1 is one or more substituents independently selected from the same or different H, halogen, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, NH 2 , COOH, C 1 -C 4 An alkylamino group and a C 1 -C 4 alkyloxy group;
  • R 2 is one or more substituents independently selected from the same or different H, halogen, CN and C 1 -C 4 alkyl;
  • R 3 is C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 haloalkyl, halo C 3 -C 6 cycloalkyl and cyano substituted C 1 -C 4 alkyl ;
  • X is selected from C and N;
  • A is selected from the group consisting of C 3 -C 7 cycloalkyl and C 3 -C 7 heterocycloalkyl;
  • B is an aromatic ring, preferably selected from the group consisting of a benzene ring, a pyridine ring, a thiazole ring, a furan ring, a thiophene ring, a pyrrole ring, a pyrazole ring, an oxazole ring, an isoxazole ring, and a quinoline ring, and the aromatic ring can be one Or substituted with a plurality of substituents independently selected from the same or different H, halogen, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, NH 2 , C 1 -C 4 alkane a base amino group and a C 1 -C 4 alkyloxy group;
  • n is an integer from 1 to 5;
  • n is an integer from 1 to 4.
  • the invention relates to a compound of formula I, including prodrugs, stereoisomers, pharmaceutically acceptable salts, hydrates or other solvates thereof, wherein
  • R 1 is one or more substituents independently selected from the same or different H, halogen, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, NH 2 , COOH, C 1 -C 4 An alkylamino group and a C 1 -C 4 alkyloxy group;
  • R 2 is one or more substituents independently selected from the same or different H, halogen, CN and C 1 -C 4 alkyl;
  • R 3 is C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 haloalkyl, halo C 3 -C 6 cycloalkyl and cyano substituted C 1 -C 4 alkyl ;
  • X is selected from C and N;
  • A is selected from C 3 -C 5 cycloalkyl and C 3 -C 5 heterocycloalkyl;
  • B is an aromatic ring, preferably selected from the group consisting of a benzene ring, a pyridine ring and a thiazole ring, which may be substituted by one or more substituents independently selected from the same or different H, halogen, CN, C 1- C 4 alkyl, C 1 -C 4 haloalkyl, NH 2 , C 1 -C 4 alkylamino and C 1 -C 4 alkyloxy;
  • n is an integer from 1 to 5;
  • n is an integer from 1 to 4.
  • the invention relates to a compound of formula I, including prodrugs, stereoisomers, pharmaceutically acceptable salts, hydrates or other solvates thereof, wherein
  • R 1 is one or more substituents independently selected from the same or different H, halogen, CN and C 1 -C 4 alkyl;
  • R 2 is one or more substituents independently selected from the same or different H, halogen, CN, and methyl;
  • R 3 is C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 haloalkyl, halo C 3 -C 6 cycloalkyl or cyano substituted C 1 -C 4 alkyl ;
  • X is selected from C and N;
  • A is selected from the group consisting of C 3 -C 4 cycloalkyl and C 3 -C 4 heterocycloalkyl;
  • B is an aromatic ring, preferably selected from the group consisting of a benzene ring, a pyridine ring and a thiazole ring, which may be substituted by one or more substituents independently selected from the same or different H, halogen, CN, C 1- C 4 alkyl and C 1 -C 4 haloalkyl;
  • n is an integer from 1 to 5;
  • n is an integer from 1 to 4.
  • the invention relates to a compound of formula I, including prodrugs, stereoisomers, pharmaceutically acceptable salts, hydrates or other solvates thereof, wherein
  • R 1 is one or more substituents, independently selected from the same or different H, halogen and CN;
  • R 2 is one or more substituents independently selected from the same or different H, F, Cl, CN, and methyl;
  • R 3 is C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 haloalkyl, halo C 3 -C 6 cycloalkyl or cyano substituted C 1 -C 4 alkyl ;
  • X is selected from C and N;
  • A is selected from the group consisting of C 3 -C 4 cycloalkyl and C 3 -C 4 heterocycloalkyl;
  • B is an aromatic ring, preferably selected from the group consisting of a benzene ring, a pyridine ring and a thiazole ring, which may be substituted by one or more substituents independently selected from the same or different H, halogen, CN, A Base and CF 3 ;
  • n is an integer from 1 to 5;
  • n is an integer from 1 to 4.
  • the invention relates to a compound of formula I, including prodrugs, stereoisomers, pharmaceutically acceptable salts, hydrates or other solvates thereof, wherein
  • R 1 is H
  • R 2 is one or more substituents independently selected from the same or different H, F, Cl, CN, and methyl;
  • R 3 is C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 haloalkyl, halo C 3 -C 6 cycloalkyl or cyano substituted C 1 -C 4 alkyl ;
  • X is selected from C and N;
  • A is selected from C 3 -C 4 cycloalkyl
  • B is an aromatic ring, preferably selected from the group consisting of a benzene ring, a pyridine ring and a thiazole ring, which may be substituted by one or more substituents independently selected from the same or different H, halogen, CN, A Base and CF 3 ;
  • n 1;
  • n is an integer from 1 to 3.
  • the invention relates to a compound of formula I, including prodrugs, stereoisomers, pharmaceutically acceptable salts, hydrates or other solvates thereof, wherein
  • R 1 is H
  • R 2 is one or more substituents independently selected from the same or different H, F, Cl, CN, and methyl;
  • R 3 is C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 haloalkyl, halo C 3 -C 6 cycloalkyl or cyano substituted C 1 -C 4 alkyl ;
  • X is selected from C and N;
  • A is selected from C 3 -C 4 cycloalkyl
  • B is an aromatic ring, preferably selected from the group consisting of a benzene ring, a pyridine ring and a thiazole ring, which may be substituted by one or more substituents independently selected from the same or different H, halogen, CN, A Base and CF 3 ;
  • n 1;
  • n is an integer from 1 to 2.
  • halogen as used in the present invention is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
  • Alkyl as used in the present invention includes straight or branched alkyl groups.
  • the C 1 -C 4 alkyl group as used in the present invention means an alkyl group having 1 to 4 carbon atoms, preferably methyl, ethyl, propyl or isopropyl, n-butyl or isobutyl or Tert-butyl.
  • the alkyl group in the compound of the present invention may be optionally substituted or unsubstituted, and the substituent may include an alkyl group, a halogen, an alkoxy group, a halogenated alkyl group, a cyano group, a hydroxyl group or the like.
  • Examples of the alkyl group of the present invention include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl and the like.
  • the "cycloalkyl group” of the present invention includes a 3-7 membered cycloalkyl group, preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
  • the cycloalkyl group in the compound of the present invention may be optionally substituted or unsubstituted, and the substituent may include an alkyl group, a halogen, an alkoxy group, a hydrocarbon group, a hydroxyl group and the like.
  • heterocycloalkyl group of the present invention includes a 3-7 membered heterocycloalkyl group.
  • the heterocycloalkyl group in the compound of the present invention may be optionally substituted or unsubstituted, and the substituent may include an alkyl group, a halogen, an alkoxy group, a halogenated alkyl group, a cyano group, a hydroxyl group or the like.
  • alkoxy group refers to a group formed by linking the above alkyl group to an oxygen atom, wherein the oxygen atom has a free bonding ability such as a methoxy group, an ethoxy group, a propoxy group, or a butyl group.
  • alkylamino group as used in the present invention means a group formed by linking the above alkyl group to an amino group, such as methylamino group, ethylamino group, 4-dimethylamino group or the like.
  • substituted with one or more substituents means substituted by one or more than one substituent, for example, substituted with 1, 2, 3 or 4 substituents; Ground, substituted by 1, 2 or 3 substituents.
  • another solvate means a solvate formed with a solvent other than water.
  • “Pharmaceutically acceptable” or “pharmaceutically acceptable” as used herein is understood to be suitable for human and animal use within a reasonable medical range, tolerable and without unacceptable side effects including toxicity, allergic reactions. , stimuli and complications.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the above formula I, including a prodrug, a stereoisomer, a pharmaceutically acceptable salt, a hydrate or other solvate thereof as an active ingredient.
  • the compounds of the present invention may optionally be used in combination with one or more other active ingredients, the respective amounts and ratios of which may be adjusted by one skilled in the art depending on the particular condition and the particular circumstances of the patient, the clinical need, and the like.
  • Preparation method The definitions of the following variables are as described above, and the new variables are defined as described in this section.
  • the compounds of the formula I and the intermediates involved can be purified by conventional separation methods such as extraction, recrystallization and separation by silica gel column chromatography.
  • the 200-300 mesh silica gel and thin layer chromatography silica gel plates used were all produced by Qingdao Ocean Chemical Plant.
  • the chemical reagents used are either analytically pure or chemically pure commercial products of the general reagents, and are used without further purification.
  • the commercially available II-1 is methylated or ethylated by a usual method such as acid chloride/methanol (CH 3 OH) or ethanol (C 2 H 5 OH), sulfuric acid/CH 3 OH or C 2 H 5 OH.
  • II-2 Dissolving II-2 in CH 3 OH or C 2 H 5 OH under the action of common reducing agents including, but not limited to, iron powder/ammonium chloride (Fe/NH 4 Cl) or iron powder/hydrochloric acid, etc.
  • II-3 is obtained after reacting at 70-100 ° C for about 2-4 h.
  • Dissolve II-3 (home-made or commercially available) in common solvents (including but not limited to dichloromethane (CH 2 Cl 2 ), tetrahydrofuran (THF), N,N'-dimethylformamide (DMF) or pyridine ( In Py), etc.
  • the acid chloride II-4 is added dropwise to the above solution under the catalysis of a common base such as triethylamine (TEA) and N,N'-diisopropylethylamine (DIPEA).
  • a common base such as triethylamine (TEA) and N,N'-diisopropylethylamine (DIPEA).
  • TEA triethylamine
  • DIPEA N,N'-diisopropylethylamine
  • the carboxylic acid II-4 may be added dropwise to the above solution under the action of a common condensing agent to obtain II-5.
  • the II-5 is dissolved in a mixed solvent of CH 3 OH, C 2 H 5 OH or THF and water at room temperature, and is subjected to carboxylic acid by an inorganic base such as lithium hydroxide (LiOH) or sodium hydroxide (NaOH).
  • an inorganic base such as lithium hydroxide (LiOH) or sodium hydroxide (NaOH).
  • LiOH lithium hydroxide
  • NaOH sodium hydroxide
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • HBTt 1 -hydroxybenzotriazole
  • PyBOP 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate
  • T 3 P 1-propylphosphoric anhydride
  • R ' is OH or Cl; R 4 is alkyl; each of the other variables are as previously defined.
  • III-1 Under reflux conditions, commercially available III-1 is reacted with hydrazine hydrate in a suitable protic solvent for about 1-3 hours to obtain III-2; under reflux conditions, III-2 and N,N'-dimethylformate are obtained under reflux conditions.
  • the key intermediate III is obtained by reacting for at least 24 h.
  • the protic solvent described in the present route may be CH 3 OH, C 2 H 5 OH or the like, but is not limited thereto.
  • III'-1 is dissolved in THF or 1,4-dioxane under N 2 protection conditions, and passed through n-butyllithium (n-BuLi) and CO 2 at a low temperature of -70 ° C. The halogen therein is converted to a carboxyl group, and the reaction is carried out for about 1-3 hours to obtain III'-2.
  • III'-6 Under the condition of N 2 protection, III'-6 is dissolved in a mixed solvent of 1,4-dioxane and water, benzophenone imine is added, and catalyzed by palladium, common ligand and base The CN coupling reaction was completed, and the reaction was obtained under reflux conditions to give III'-7.
  • the key intermediate III is obtained after hydrolysis of III'-7 by dilute hydrochloric acid for about 24 h at room temperature.
  • the base is TEA, DIPEA, potassium carbonate (K 2 CO 3 ), cesium carbonate (Cs) 2 CO 3 ) and sodium t-butoxide (t-BuONa), etc., but are not limited thereto;
  • the palladium reagent is tribenzylideneacetone dipalladium (Pd 2 (dba) 3 ), Pd 2 (dba) 3 a dichloromethane complex and palladium acetate (Pd(OAc) 2 ), etc., but are not limited thereto; the ligand 4,5-bisdiphenylphosphino-9,9-dimethyloxaxime ( Xantphos), 2-bicyclohexylphosphine-2',6'-dimethoxybiphenyl (Sphos) and 1,1'-binaphthyl-2,2
  • the key intermediate II is prepared into an acid chloride by thionyl chloride (SOCl 2 ), oxalyl chloride ((COCl) 2 ), phosphorus trichloride (PCl 3 ) or phosphorus pentachloride (PCl 5 ), followed by intermediate activity
  • SOCl 2 thionyl chloride
  • (COCl) 2 oxalyl chloride
  • PCl 3 phosphorus trichloride
  • PCl 5 phosphorus pentachloride
  • the compound of the formula I can also be obtained by using a common condensing agent such as HATU, HOBt, PyBOP and T 3 P, etc., but is not limited to the basic catalysts such as TEA, DIPEA and K 2 CO 3 described in this route. But it is not limited to this.
  • a common condensing agent such as HATU, HOBt, PyBOP and T 3 P, etc.
  • the basic catalysts such as TEA, DIPEA and K 2 CO 3 described in this route. But it is not limited to this.
  • the structural formula I of the present invention can also be obtained by starting from the starting materials II and IV-1 by a similar synthetic method as in Scheme 2, as shown in the following Scheme 5; in addition, the formula I can also be obtained from the compound V and the compound of the formula II-4. It is obtained by carrying out a condensation reaction under base catalysis.
  • R ' is OH or Cl; R 4 is alkyl; each of the other variables are as previously defined.
  • Mass spectrometry conditions instrument Thermo MSQ Plus; ion source ESI (EA + EA-); cone voltage 30V; capillary voltage 3.00KV; source temperature 350 ° C;
  • Chromatographic conditions instrument Thermo U3000; detector DAD-3000 (RS) (diode array detector); column Shimadzu Inertsil ODS-HL HP 3 ⁇ m 3.0 ⁇ 100mm; flow rate 0.4mL / min; column temperature 30 ° C; mobile phase CH 3 OH/H 2 O/HCOOH (75/25/0.5).
  • Representative compounds I-1 to I-20 were prepared according to the methods described above.
  • the present invention is further illustrated by the following specific examples, but the scope of the present invention is not limited to these examples.
  • the percentages stated in the present invention are all percentages by weight unless otherwise specified.
  • the range of values described in the specification, such as units of measure, reaction conditions, physical state of the compound, or percentage, are intended to provide an unambiguous written reference. It is still possible for a person skilled in the art to use the temperature, concentration, amount, number of carbon atoms, etc. outside of this range or different from a single value in the practice of the present invention, and it is still possible to obtain the desired result.
  • IIc-3 (1.52g, 10.0mmol, 1.0eq) was dissolved in CH 2 Cl 2 (20mL), was added TEA (4.04g, 40.0mmol, 4.0eq) , an ice / salt bath to 0 °C
  • IIa-4 (1.56 g, 15.0 mmol, 1.5 eq) was added dropwise and the obtained mixture was stirred at ambient temperature for 16 h. The reaction was monitored by TLC. The reaction mixture was concentrated. EtOAc mjjjjjj LC-MS MS-ESI (m / z) 221.4 [M + H] +.
  • IId-3 (1.84g, 10.0mmol, 1.0eq) was dissolved in CH 2 Cl 2 (20mL), was added TEA (4.04g, 40.0mmol, 4.0eq) , an ice / salt bath to 0 °C, IIa-4 (1.56 g, 15.0 mmol, 1.5 eq) was added and the obtained mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated. EtOAc mjjjjjj LC-MS MS-ESI (m / z) 321.2 [M + H] +.
  • IIIa-1 (10.00 g, 66.0 mmol, 1.0 eq) was added, followed by methanol (200 mL), hydrazine hydrate (66.07 g, 132.0 mmol, 2.0 eq), and refluxed for 2 h. Most of the solvent of the reaction mixture was concentrated, washed, washed with EtOAc and dried. A white solid, IIIa-2, 10.20 g was obtained.
  • MS-ESI m / z
  • IIIa-3 (260.0 mg, 1.0 mmol, 1.0 eq) and IIIf-4 (445.5 mg, 5.0 mmol, 5.0 eq) were dissolved in CH 3 CN/AcOH (4/1, 25 mL), and the mixture was heated to reflux for 24 h. solution, extracted with water, 1N NaOH solution was adjusted to pH 10, EtOAc and extracted three times, dried over anhydrous MgSO 4, the organic phase was concentrated to give a yellow solid IIIf 180.0mg (38.0% yield).
  • LC-MS MS-ESI (m / z) 233.1 [M + H] +.
  • IIIa-3 (3.00 g, 11.5 mmol, 1.0 eq) and commercially available IIIg-4 (3.43 g, 45.8 mmol, 4.0 eq) were dissolved in CH 3 CN/AcOH (4/1, 37.5 mL). After stirring at 92 ° C for 24 h, the reaction was monitored by TLC, cooled to ambient temperature and concentrated. Diluted with water, adjusted to pH 8 with 1N NaOH solution, and concentrated. The resulting solid was washed with CH 2 Cl 2 / CH 3 OH (10 / 1,100mL) slurried, filtered and the filtrate was concentrated to give the crude product as a pale yellow sticky solid IIIg'7.40g.
  • Example 22 Compound: 5-(Cyclopropanoylamino)-2-fluoro-4-methyl-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl) Preparation of pyridin-2-yl)benzamide I-1
  • the IIa (237.0mg, 1.0mmol, 1.0eq) was suspended in SOCl 2 (5mL), heated to 60 °C, for 15min until all starting material was dissolved, and concentrated to give a yellow solid acid chloride was used directly in the next stage of the reaction.
  • the acid chloride was dissolved in ultra dry THF (10 mL).
  • TEA 0.5 mL
  • IIIb 100.0 mg, 0.5 mmol, 1.0 eq
  • Fetch III'-2 (8.35g, 40.1mmol, 1.2eq) was dissolved in CH 2 Cl 2 (100mL), at ambient temperature, to which was added HATU (12.7g, 33.4mmol, 1.0eq) , commercially available IIIc -4 (5.00 g, 33.4 mmol, 1.0 eq) and TEA (10.10 g, 100.0 mmol, 3.0 eq).
  • the reaction mixture was concentrated and dried (EtOAc mjjjjjjjjjj LC-MS MS-ESI (m / z) 302.0 [MH] -.
  • This assay is used to evaluate the in vitro protein level binding inhibitory activity of the compounds of the invention.
  • This assay is to comprehensively evaluate the effects of different compounds on ASK1 kinase inhibitory activity.
  • This test uses Homogeneous time-resolved fluorescence (HTRF) to evaluate the level of inhibition of the enzymatic activity of recombinant ASK1 in the in vitro reaction system.
  • HTRF Homogeneous time-resolved fluorescence
  • the basic principle of in vitro enzymatic activity detection is to use a specific substrate labeled with a terminal biotin to phosphorylate under the action of a kinase, a reaction product with an EU 3+ -Cryptate-labeled antibody that recognizes a phosphorylation site, and a XL665-labeled strand. Avidin is mixed. When two fluorescent molecules are simultaneously bound to the substrate, Eu stimulates 620 nM of fluorescence under the excitation of exogenous excitation light (320 nm), while XL665 is excited by energy transfer to produce 665 nm fluorescence.
  • Substrate phosphorylation was evaluated by comparing the changes in fluorescence at two wavelengths (620 nm and 665 nm). When different test compounds are added, their inhibition of kinase activity is manifested by a change in the degree of phosphorylation of the substrate, thereby exhibiting a different ratio of fluorescent signals (665/620), and thereby calculating the inhibitory activity of the compound on the kinase.
  • the basic detection principle is known in the art (Cisbio, Nature Method 2006, June 23; DOI: 10.1038/NMETH883).
  • Human recombinant ASK1 (MAP3K5) kinase, 2X kinase reaction buffer, ATP (10 mM) was purchased from Invitrogen (catalogue number: PR7349B), and HTRF detection kit HTRF KinEASE STK discovery kit was purchased from Cisbio (Cat. No. 62ST0PEB).
  • test reagent https://www.cisbio.com/sites/default/files/ressources/cisbio_dd_pi_62ST0PEB.pdf). The details are as follows:
  • the kinase reaction buffer (working solution) was prepared as required, and the test compound was diluted to a different concentration gradient (the highest concentration of the compound was 4 ⁇ M) using a kinase reaction buffer.
  • a 10 ⁇ L enzymatic reaction system (including 2.5 ⁇ L of the test compound, 5 ⁇ L of the kinase reaction buffer, and 2.5 ⁇ L of the ATP solution (provided by the kit)) was mixed and reacted at room temperature for 1 hour, and the enzymatic reaction was carried out in a 96-well microplate.
  • the reaction was simultaneously provided with a control reaction including a positive control to which no test compound was added and a negative control to which no ASK1 kinase was added. Multiple holes were used for all tests.
  • the fluorescence signal of each well was detected using a fluorescence detector (TecanSPARK 10M) at an excitation wavelength of 320 nm, and the detected emission wavelengths were 620 nm and 665 nm, respectively.
  • Table 2 HTRF method for detection of ASK1 enzymatic inhibition rate of representative compounds of the present invention (single concentration 100 nM)
  • Compound Inhibition rate% Compound Inhibition rate% Compound Inhibition rate% Compound Inhibition rate% I-1 54 I-3 51 I-4 32 I-6 13 I-8 twenty four I-9 33 I-10 44 I-11 27 I-13 18 I-14 42 I-16 twenty one I-17 15 I-18 34 I-19 52 I-20 16

Abstract

本发明涉及一种甲酰胺类化合物、其制备方法及其应用。所述化合物的结构如式(I)所示，式中各变量的定义如说明书所述。所述化合物能够抑制ASK1激酶的活性。本发明化合物可用于治疗/预防与ASK1激酶相关的疾病，例如炎性疾病、代谢性疾病、自身免疫性疾病、心血管疾病、神经退行性疾病、癌症及其它疾病。

Description

甲酰胺类化合物、其制备方法及其应用
本申请要求于2018年4月28日提交到中国专利局的发明名称为“甲酰胺类化合物、其制备方法及其应用”的中国专利申请201810404758.X的优先权，其内容通过引用以整体并入本文。
技术领域
本发明属于医药技术领域，涉及具有能够抑制ASK1激酶活性的甲酰胺类化合物，本发明还涉及所述化合物的制备方法、包含所述化合物作为活性成分的药物组合物以及其制药应用。本发明的化合物可作为靶向ASK1激酶的抑制剂，用于治疗/预防与该靶点相关的疾病，例如炎性疾病、代谢性疾病、自身免疫性疾病、心血管疾病、神经退行性疾病、癌症及其它疾病。
背景技术
丝裂原活化蛋白激酶(mitogen-activated protein kinases,MAPKs)是一种胞浆内广泛分布的Ser/Thr蛋白激酶，其是将信号从细胞表面转导至细胞核的重要传递者。MAPKs信号通路由三级激酶模式组成，包括MEK激酶(MAP3K)、MAPK激酶(MAP2K)、MAP激酶(MAPK)，该通路能够针对多种不同的细胞外刺激，如细胞因子、细胞应激、神经递质等启动自MAP3K到MAP2K再到MAPK的三级激酶级联反应，通过作用不同反应底物激活不同的MAPKs信号通路，从而调控基因表达、细胞生长、分化、凋亡、代谢、参与炎性反应等多种不同的病理和生理过程(Cargnello M.,Roux P.P.,2011,Microbiol.Mol.Biol.Rev.,75:50-83)。
凋亡信号调节激酶1(apoptosis signal-regulating kinase 1,ASK1)是MAP3K的家族成员之一，ASK1能够通过氧化应激、活性氧类(ROS)、脂多糖(LPS)、肿瘤坏死因子(TNF-α)、内质网(ER)应激、渗透压、炎症等多种不同刺激被首先激活，进而激活MAP2K，MAP2K被磷酸化后而激活MAPK，如c-Jun氨基末端蛋白激酶(c-JunN-terminal protein kinase,JNK)和p38MAPK。由此可见，ASK1在多种细胞生物学过程中发挥着关键作用，包括凋亡、分化及炎症等(Soga M.,Matsuzawa A.,Ichijo H.,2012,Int.J.Cell Biol.,2012:1-5)。
报道表明，激活ASK1在多种疾病中起着重要作用，如炎性疾病、代谢性疾病、自身免疫性疾病、心血管疾病、神经退行性疾病、癌症及其它疾病(Soga  M.,Matsuzawa A.,Ichijo H.,2012,Int.J.Cell Biol.,2012:1-5；Hayakawa R.,Hayakawa T.,Takeda K.,et al,2012,Proc.Jpn.Acad.Ser.BPhys.Biol.Sci.,88:434-453)。因此，发现具有抑制ASK1活性的药用活性分子将为上述疾病的患者带来重大益处。
至目前，公开的ASK1抑制剂专利申请包括三唑并吡啶类WO2009027283、吡唑并[1,5-A]嘧啶类WO2011041293、芳环/芳杂环胺类WO2011008709、杂环胺类US20120004267及噻唑胺类US20170173031等。如前所述，ASK1的激活与多种疾病相关，其抑制剂作为药物在医药领域具有重要的临床价值和良好的应用前景，但是全球目前尚无被批准上市药物。因此，我们期望开发新型的ASK1抑制剂以满足尚未满足的临床需求。
本发明提供了一种新颖的环烷基甲酰胺类的ASK1抑制剂，用于治疗/预防与该靶点相关的疾病，例如炎性疾病、代谢性疾病、自身免疫性疾病、心血管疾病、神经退行性疾病、癌症及其它疾病。同时，这些化合物或者包含其作为活性成分的药物组合物等可在安全治疗窗口内能将对这些疾病的临床疗效达到最大化。
发明内容
本发明的一个方面，涉及下式I所示的可抑制ASK1激酶活性的环烷基甲酰胺类化合物，包括其药学上可接受的盐、水合物、其它溶剂合物、立体异构体及前药等衍生物。
本发明另一方面涉及本文所述化合物的制备方法。
本发明的又一方面涉及包含其本发明化合物作为活性成分的药物组合物，以及本发明化合物或药物组合物用于治疗/预防与ASK1激酶相关的疾病的临床应用，以及本发明化合物或药物组合物在制备用于治疗和/或预防与ASK1激酶相关疾病的药物中的应用。相应地，本发明还涉及一种治疗和/或预防与ASK1激酶相关疾病的方法，包括向有此需要的对象给予本发明的化合物或药物组合物。
本发明涉及式I所示的化合物，包括其前药、立体异构体、药学上可接受的盐、水合物或其它溶剂合物，
Figure PCTCN2019083829-appb-000001
其中，
R 1为一个或多个取代基，独立地选自相同或不同的H、卤素、CN、C 1-C 4烷基、C 1-C 4卤代烷基、NH 2、COOH、C 1-C 4烷基氨基、C 1-C 4烷基氧基和Ar 1；
其中，Ar 1选自苯环和吡啶环，并且所述苯环和吡啶环可被一个或多个取代基取代，所示取代基独立地选自相同或不同的H、卤素、CN、C 1-C 4烷基、C 1-C 4卤代烷基、NH 2、C 1-C 4烷基氨基和C 1-C 4烷基氧基；
R 2为一个或多个取代基，独立地选自相同或不同的H、卤素、CN、C 1-C 4烷基和C 1-C 4卤代烷基；
R 3为C 1-C 4烷基、C 3-C 6环烷基、C 1-C 4卤代烷基、卤代C 3-C 6环烷基、氰基取代C 1-C 4烷基、C 3-C 6杂环烷基、羟基取代的C 1-C 4烷基或C 1-C 4烷氧基取代的C 1-C 4烷基；
X选自C和N；
A选自C 3-C 7环烷基和C 3-C 7杂环烷基；
B为芳香环，
优选选自苯环、吡啶环、噻唑环、呋喃环、噻吩环、吡咯环、吡唑环、噁唑环、异噁唑环和喹啉环，所述芳香环环上可被一个或多个取代基取代，所述取代基独立地选自相同或不同的H、卤素、CN、C 1-C 4烷基、C 1-C 4卤代烷基、NH 2、C 1-C 4烷基氨基和C 1-C 4烷基氧基；
m为1到5的整数；
n为1到4的整数。
在一个优选的方面，本发明涉及式I所示的化合物，包括其前药、立体异构体、药学上可接受的盐、水合物或其它溶剂合物，其中，
R 1为一个或多个取代基，独立地选自相同或不同的H、卤素、CN、C 1-C 4烷基、C 1-C 4卤代烷基、NH 2、COOH、C 1-C 4烷基氨基、C 1-C 4烷基氧基和Ar 1；
其中，Ar 1选自苯环和吡啶环，并且所述苯环和吡啶环可被一个或多个 取代基取代，所述取代基独立地选自相同或不同的H、卤素、CN、C 1-C 4烷基、C 1-C 4卤代烷基、NH 2、C 1-C 4烷基氨基和C 1-C 4烷基氧基；
R 2为一个或多个取代基，独立地选自相同或不同的H、卤素、CN和C 1-C 4烷基；
R 3为C 1-C 4烷基、C 3-C 6环烷基、C 1-C 4卤代烷基、卤代C 3-C 6环烷基、氰基取代C 1-C 4烷基、C 3-C 6杂环烷基、羟基取代的C 1-C 4烷基和C 1-C 4烷氧基取代的C 1-C 4烷基；
X选自C和N；
A选自C 3-C 7环烷基和C 3-C 7杂环烷基；
B为芳香环，优选选自苯环、吡啶环、噻唑环、呋喃环、噻吩环、吡咯环、吡唑环、噁唑环、异噁唑环和喹啉环，所述芳香环可被一个或多个取代基取代，所述取代基独立地选自相同或不同的H、卤素、CN、C 1-C 4烷基、C 1-C 4卤代烷基、NH 2、C 1-C 4烷基氨基和C 1-C 4烷基氧基；
m为1到5的整数；
n为1到4的整数。
在一个更优选的方面，本发明涉及式I所示的化合物，包括其前药、立体异构体、药学上可接受的盐、水合物或其它溶剂合物，其中，
R 1为一个或多个取代基，独立地选自相同或不同的H、卤素、CN、C 1-C 4烷基、C 1-C 4卤代烷基、NH 2、COOH、C 1-C 4烷基氨基和C 1-C 4烷基氧基；
R 2为一个或多个取代基，独立地选自相同或不同的H、卤素、CN和C 1-C 4烷基；
R 3为C 1-C 4烷基、C 3-C 6环烷基、C 1-C 4卤代烷基、卤代C 3-C 6环烷基、氰基取代C 1-C 4烷基、C 3-C 6杂环烷基、羟基取代的C 1-C 4烷基和C 1-C 4烷氧基取代的C 1-C 4烷基；
X选自C和N；
A选自C 3-C 7环烷基和C 3-C 7杂环烷基；
B为芳香环，优选选自苯环、吡啶环、噻唑环、呋喃环、噻吩环、吡咯环、吡唑环、噁唑环、异噁唑环和喹啉环，所述芳香环可被一个或多个取代基取代，所述取代基独立地选自相同或不同的H、卤素、CN、C 1-C 4烷基、C 1-C 4卤代烷基、NH 2、C 1-C 4烷基氨基和C 1-C 4烷基氧基；
m为1到5的整数；
n为1到4的整数。
在另一个更优选的方面，本发明涉及式I所示的化合物，包括其前药、立体异构体、药学上可接受的盐、水合物或其它溶剂合物，其中，
R 1为一个或多个取代基，独立地选自相同或不同的H、卤素、CN、C 1-C 4烷基、C 1-C 4卤代烷基、NH 2、COOH、C 1-C 4烷基氨基和C 1-C 4烷基氧基；
R 2为一个或多个取代基，独立地选自相同或不同的H、卤素、CN和C 1-C 4烷基；
R 3为C 1-C 4烷基、C 3-C 6环烷基、C 1-C 4卤代烷基、卤代C 3-C 6环烷基和氰基取代的C 1-C 4烷基；
X选自C和N；
A选自C 3-C 7环烷基和C 3-C 7杂环烷基；
B为芳香环，优选选自苯环、吡啶环、噻唑环、呋喃环、噻吩环、吡咯环、吡唑环、噁唑环、异噁唑环和喹啉环，所述芳香环可被一个或多个取代基取代，所述取代基独立地选自相同或不同的H、卤素、CN、C 1-C 4烷基、C 1-C 4卤代烷基、NH 2、C 1-C 4烷基氨基和C 1-C 4烷基氧基；
m为1到5的整数；
n为1到4的整数。
在另一个还更优选的方面，本发明涉及式I所示的化合物，包括其前药、立体异构体、药学上可接受的盐、水合物或其它溶剂合物，其中，
R 1为一个或多个取代基，独立地选自相同或不同的H、卤素、CN、C 1-C 4烷基、C 1-C 4卤代烷基、NH 2、COOH、C 1-C 4烷基氨基和C 1-C 4烷基氧基；
R 2为一个或多个取代基，独立地选自相同或不同的H、卤素、CN和C 1-C 4烷基；
R 3为C 1-C 4烷基、C 3-C 6环烷基、C 1-C 4卤代烷基、卤代C 3-C 6环烷基和氰基取代的C 1-C 4烷基；
X选自C和N；
A选自C 3-C 5环烷基和C 3-C 5杂环烷基；
B为芳香环，优选选自苯环、吡啶环和噻唑环，所述芳香环可被一个或多个 取代基取代，所述取代基独立地选自相同或不同的H、卤素、CN、C 1-C 4烷基、C 1-C 4卤代烷基、NH 2、C 1-C 4烷基氨基和C 1-C 4烷基氧基；
m为1到5的整数；
n为1到4的整数。
在另一个还更优选的方面，本发明涉及式I所示的化合物，包括其前药、立体异构体、药学上可接受的盐、水合物或其它溶剂合物，其中，
R 1为一个或多个取代基，独立地选自相同或不同的H、卤素、CN和C 1-C 4烷基；
R 2为一个或多个取代基，独立地选自相同或不同的H、卤素、CN和甲基；
R 3为C 1-C 4烷基、C 3-C 6环烷基、C 1-C 4卤代烷基、卤代C 3-C 6环烷基或氰基取代的C 1-C 4烷基；
X选自C和N；
A选自C 3-C 4环烷基和C 3-C 4杂环烷基；
B为芳香环，优选选自苯环、吡啶环和噻唑环，所述芳香环可被一个或多个取代基取代，所述取代基独立地选自相同或不同的H、卤素、CN、C 1-C 4烷基和C 1-C 4卤代烷基；
m为1到5的整数；
n为1到4的整数。
在另一个还更优选的方面，本发明涉及式I所示的化合物，包括其前药、立体异构体、药学上可接受的盐、水合物或其它溶剂合物，其中，
R 1为一个或多个取代基，独立地选自相同或不同的H、卤素和CN；
R 2为一个或多个取代基，独立地选自相同或不同的H、F、Cl、CN和甲基；
R 3为C 1-C 4烷基、C 3-C 6环烷基、C 1-C 4卤代烷基、卤代C 3-C 6环烷基或氰基取代的C 1-C 4烷基；
X选自C和N；
A选自C 3-C 4环烷基和C 3-C 4杂环烷基；
B为芳香环，优选选自苯环、吡啶环和噻唑环，所述芳香环可被一个或多个取代基取代，所述取代基独立地选自相同或不同的H、卤素、CN、甲基和CF 3；
m为1到5的整数；
n为1到4的整数。
在一个还更优选的方面，本发明涉及式I所示的化合物，包括其前药、立体异构体、药学上可接受的盐、水合物或其它溶剂合物，其中，
R 1为H；
R 2为一个或多个取代基，独立地选自相同或不同的H、F、Cl、CN和甲基；
R 3为C 1-C 4烷基、C 3-C 6环烷基、C 1-C 4卤代烷基、卤代C 3-C 6环烷基或氰基取代的C 1-C 4烷基；
X选自C和N；
A选自C 3-C 4环烷基；
B为芳香环，优选选自苯环、吡啶环和噻唑环，所述芳香环可被一个或多个取代基取代，所述取代基独立地选自相同或不同的H、卤素、CN、甲基和CF 3；
m为1；
n为1到3的整数。
在一个尤其更优选的方面，本发明涉及式I所示的化合物，包括其前药、立体异构体、药学上可接受的盐、水合物或其它溶剂合物，其中，
R 1为H；
R 2为一个或多个取代基，独立地选自相同或不同的H、F、Cl、CN和甲基；
R 3为C 1-C 4烷基、C 3-C 6环烷基、C 1-C 4卤代烷基、卤代C 3-C 6环烷基或氰基取代的C 1-C 4烷基；
X选自C和N；
A选自C 3-C 4环烷基；
B为芳香环，优选选自苯环、吡啶环和噻唑环，所述芳香环可被一个或多个取代基取代，所述取代基独立地选自相同或不同的H、卤素、CN、甲基和CF 3；
m为1；
n为1到2的整数。
具体实施方式
本发明所述的“卤素”为氟、氯、溴或碘，优先为氟或氯。
本发明所述的“烷基”，包括直链或支链的烷基。本发明中所述的C 1-C 4烷基， 是指碳原子数为1-4的烷基，优先为甲基、乙基、丙基或异丙基、正丁基、异丁基或叔丁基。本发明化合物中的烷基可以是任选取代或未取代的，取代基可以包括烷基、卤素、烷氧基、卤代烷基、氰基、羟基等。本发明烷基的实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基等。
本发明所述的“环烷基”，包括3-7元环烷基，优先为环丙基、环丁基、环戊基、环己基。本发明化合物中的环烷基可以是任选取代或未取代的，取代基可以包括烷基、卤素、烷氧基、烃基、羟基等。
本发明所述的“杂环烷基”，包括3-7元杂环烷基。本发明化合物中的杂环烷基可以是任选取代或未取代的，取代基可以包括烷基、卤素、烷氧基、卤代烷基、氰基、羟基等。
本发明所述的“烷氧基”，是指上述烷基与氧原子相连所形成的基团，其中，氧原子具有自由成键能力，如甲氧基、乙氧基、丙氧基、丁氧基、异丙氧基、叔丁氧基、环丙氧基等。
本发明所述的“烷基氨基”，是指上述烷基与氨基相连所形成的基团，如甲氨基、乙氨基、4-二甲氨基等。
在本文中，所提到的“被一个或多个取代基取代”意指被一个或多于一个的取代基取代，例如，被1个、2个、3个或4个取代基取代；优选地，被1个、2个或3个取代基取代。
本文中所述的“其它溶剂合物”意指与除水之外的其它溶剂形成的溶剂合物。
本发明所述的“可药用的”或“药学上可接受的”被理解为在合理的医学范围内适于人和动物使用，可耐受且并无不可接受的副作用包括毒性、过敏反应、刺激及并发症等。
本发明涉及药物组合物，所述药物组合物含有上述式I的化合物，包括其前药、立体异构体、药学上可接受的盐、水合物或其它溶剂合物作为活性成分。
本发明所述的化合物任选地可与其它一种或多种活性成分联合使用，其各自用量和比例可由本领域技术人员根据具体病症和患者具体情况以及临床需要等而进行调整。
本发明中所提供的实施例和制备例进一步阐明并举例说明了本发明所述化合物及其制备方法。应当理解，下述制备例和实施例不以任何方式限制本发明的范围。
下面的合成路线描述了本发明的式I化合物的制备方法，如下合成示意图中所用原料、试剂、催化剂、溶剂等均可通过有机化学领域普通技术人员熟知的方法制备或者可商购得到。本发明的全部最终衍生物都可都过示意图中所描述的方法或其类似方法制得，这些方法都是有机化学领域普通技术人员熟知的。这些示意图中应用的全部可变因素如下文定义或根据权利要求中的定义。
制备方法：下面各变量的定义如前所述，而新变量定义如本节内容所述。另外，式I所述的化合物及涉及的中间体均可通过常见的分离方法进行纯化，如萃取、重结晶及硅胶柱层析分离等。所用200-300目的硅胶和薄层层析硅胶板均由青岛海洋化工厂生产。所用化学试剂为一般试剂的分析纯或化学纯市售商品，使用时未经进一步纯化。
(a)关键中间体II可由如下示例性的合成方法制备：
通过酰氯/甲醇(CH 3OH)或乙醇(C 2H 5OH)、硫酸/CH 3OH或C 2H 5OH等常用方法将市售的II-1进行甲酯化或乙酯化而获得II-2。在常见还原剂(包括但并不限于铁粉/氯化铵(Fe/NH 4Cl)或铁粉/盐酸等)的作用下，将II-2溶解于CH 3OH或C 2H 5OH与水的混合溶剂中，在70-100℃的条件下反应约2-4h后得到II-3。将II-3(自制或市售)溶解于常见溶剂(包括但不限于二氯甲烷(CH 2Cl 2)、四氢呋喃(THF)、N,N’-二甲基甲酰胺(DMF)或吡啶(Py)等)中，在常用碱(如三乙胺(TEA)和N,N’-二异丙基乙基胺(DIPEA)等)的催化下，将酰氯II-4滴加到前述溶液中，或将羧酸II-4在常见缩合剂的作用下滴加到前述溶液中获得II-5。在室温条件下，将II-5溶解于CH 3OH、C 2H 5OH或THF等和水的混合溶剂中，通过如氢氧化锂(LiOH)、氢氧化钠(NaOH)等无机碱进行羧酸酯水解，通常反应经过夜完成后得到关键中间体II。本路线中所述的常见缩合剂如O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)、1-羟基苯并三唑(HOBt)、1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐(PyBOP)及1-丙基磷酸酐(T 3P)等，但并不限于此。
Figure PCTCN2019083829-appb-000002
其中，R’为OH或Cl；R 4为烷基；其它各变量如前述定义。
方案1关键中间体II的合成路线
(b)通过参考文献US20110009410并经研究发现，本发明无需在氨基上使用任何保护基即可获得中间体III。与文献US20110009410报道的方法相比，本发明方法缩短了反应步骤并节约了时间、节省了成本而且总收率从文献中报道的25％左右到本方法中的绝大多数化合物为30％-66％左右。关键中间体III可由如下示例性的合成方法制备：
在回流条件下，以市售的III-1与水合肼在合适的质子溶剂中反应约1-3h获得III-2；在回流条件下，将III-2与N,N’-二甲基甲酰胺二甲基缩醛(DMF-DMA)反应约3-10h获得III-3；在回流条件下，将III-3与市售的胺III-4在乙腈/冰醋酸(CH 3CN/AcOH)中反应至少24h得到关键中间体III。本路线中所述的质子性溶剂可为CH 3OH、C 2H 5OH等，但并不限于此。
Figure PCTCN2019083829-appb-000003
方案2关键中间体III的合成路线
(c)关键中间体III可由如下示例性的其它合成方法制备：
在N 2保护的条件下，将市售的III'-1溶解在THF或1,4-二氧六环中，在低温-70℃下，通过正丁基锂(n-BuLi)和CO 2将其中的卤素转为羧基，反应约1-3h得到III'-2。在室温条件下，将III'-2与市售的胺III-4溶解在如CH 2Cl 2、THF或DMF等溶剂中，并在常见缩合剂和常见碱的催化下，反应约3-5h后获得III'-3。在Lawesson's Reagent的作用下，反应温度从室温至120℃过夜，将氧代的III'-3转为硫代的III'-4。在回流条件下，将III'-4与水合肼反应约1-3h获得III'-5。在室温条件下，将III'-5溶解在C 2H 5OH中，加入原甲酸三乙酯(CH(OC 2H 5) 3)并通过硫酸的催化下实现闭环反应，经约过1-5h后获得III'-6。在N 2保护的条件下，将III'-6溶解在1,4-二氧六环和水的混合溶剂中，加入二苯甲酮亚胺，并在钯、常见的配体及碱的催化下完成C-N偶联反应，该反应在回流条件下过夜后得到III'-7。在室温条件下，将III'-7通过稀盐酸水解约24h后而得到关键中间体III。本路线中所述的常见缩合剂如如HATU、HOBt、PyBOP及T 3P等，但并不限于此；所述的碱为TEA、DIPEA、碳酸钾(K 2CO 3)、碳酸铯(Cs 2CO 3)及叔丁醇钠(t-BuONa)等，但并不限于此；所述的钯试剂为三亚 苄基丙酮二钯(Pd 2(dba) 3)、Pd 2(dba) 3的二氯甲烷络合物及醋酸钯(Pd(OAc) 2)等，但并不限于此；所述的配体4,5-双二苯基膦-9,9-二甲基氧杂蒽(Xantphos)、2-双环己基膦-2',6'-二甲氧基联苯(Sphos)及1,1'-联萘-2,2'-双二苯膦(BINAP)等，但并不限于此。
Figure PCTCN2019083829-appb-000004
方案3关键中间体III的其它合成路线
(d)本发明式I化合物可由如下示例性的合成方法制备：
将关键中间体II通过氯化亚砜(SOCl 2)、草酰氯((COCl) 2)、三氯化磷(PCl 3)或五氯化磷(PCl 5)制备成酰氯，随后将该活性中间体与关键中间体III溶解在超干溶剂中，如CH 2Cl 2、THF、DMF或Py等中，并加入常用的碱性催化剂而获得式I化合物。另外，还可通过使用常见缩合剂如HATU、HOBt、PyBOP及T 3P等来获得式I化合物，但并不限于此本路线所述的碱性催化剂如TEA、DIPEA和K 2CO 3等，但并不限于此。
Figure PCTCN2019083829-appb-000005
方案4式I化合物的合成路线
(e)本发明所述结构式I还可通过起始原料II和IV-1，采用方案2相似的合成方法获得，见如下方案5；另外，式I还可由V化合物与式II-4化合物在碱催化下进行缩合反应而得到。
Figure PCTCN2019083829-appb-000006
方案5式I化合物的其它合成路线
Figure PCTCN2019083829-appb-000007
其中，R’为OH或Cl；R 4为烷基；其它各变量如前述定义。
LC-MS分析方法：
质谱条件：仪器Thermo MSQ Plus；离子源ESI(EA+ EA-)；锥孔电压30V；毛细管电压3.00KV；源温度350℃；
色谱条件：仪器Thermo U3000；检测器DAD-3000(RS)(二极管阵列检测器)；色谱柱岛津Inertsil ODS-HL HP 3μm3.0×100mm；流速0.4mL/min；柱温30℃；流动相CH 3OH/H 2O/HCOOH(75/25/0.5)。
HPLC分析方法(一)：
仪器Thermo U3000；检测器VWD-3×00(RS)(紫外检测器)；色谱柱岛津Shim-pack VP-ODS 5μm 4.6×150mm；流速0.7mL/min；柱温30℃；流动相A CH 3OH/H 2O/AcOH/TEA(65/35/0.1/0.2)、流动相B CH 3OH/H 2O/AcOH/TEA(70/30/0.1/0.2)、流动相C CH 3OH/H 2O/AcOH/TEA(50/50/0.1/0.2)。
HPLC分析方法(二)：
仪器Thermo U3000；检测器VWD-3×00(RS)(紫外检测器)；色谱柱岛津 Shim-pack VP-ODS 5μm 4.6×150mm；流速0.6mL/min；柱温25℃；流动相D CH 3CN/H 2O/HCOOH(65/35/0.3)。
1H-NMR分析方法：
1H-NMR在室温下采用BRUKERAVANCE-400MHz或BRUKER FOURIER-300MHz型核磁共振波谱仪在DMSO-d 6和CDCl 3等中以TMS为内标物测定，信号峰表示为s(单峰)，d(双峰)，t(三重峰)，q(四重峰)，m(多重峰)，dd(双二重峰)。耦合常数(J)的单位为赫兹(Hz)。
按照上述说明方法，本发明制备了代表性化合物I-1—I-20(见表1)。
表1本发明所述的代表性化合物I-1—I-20
Figure PCTCN2019083829-appb-000008
Figure PCTCN2019083829-appb-000009
Figure PCTCN2019083829-appb-000010
下面结合具体实例进一步阐述本发明内容，但本发明的保护范围并不仅仅局限于这些实例。本发明所述的百分比除特别注明外，均为重量百分比。说明书中所描述的数值范围，如计量单位、反应条件、化合物物理状态或百分比，均是为了提供明白无误的书面参考。本领域技术人员在实施本发明时，使用在此范围之外或有别于单个数值的温度、浓度、数量、碳原子数等，仍然有可能得到预期结果。
实施例1中间体：2-氟-4-甲基-5-硝基苯甲酸甲酯IIa-2的制备
Figure PCTCN2019083829-appb-000011
取市售的IIa-1(1.00g,5.0mmol,1.0eq)和SOCl 2(15mL)于圆底烧瓶中，加热至85℃回流2h，浓缩后所得的黄色油状粗产物酰氯，直接用于下一阶段反应。将此粗品(17.60g,50.2mmol,1.0eq)的CH 2Cl 2(50mL)溶液缓慢滴加到CH 3OH(50mL)中，所得溶液在环境温度下搅拌30min，浓缩后所得的浅黄色固体粗产物IIa-2 24.60g直接用于下一步反应。
实施例2中间体：5-氨基-2-氟-4-甲基苯甲酸甲酯IIa-3的制备
Figure PCTCN2019083829-appb-000012
将IIa-2的粗品(24.60g,50.2mmol,1.0eq)溶于CH 3OH(200mL)中，加入水(40mL)，NH 4Cl(13.43g,251.0mmol,5.0eq)，Fe粉(11.24g,200.8mmol,4.0eq)。所得混合物在75℃下搅拌2h，LC-MS监测反应完毕。冷却至环境温度，过滤。浓缩滤液，粗品经硅胶柱(CH 2Cl 2/CH 3OH＝12/1)分离后，得浅黄色固体IIa-3 8.05g(收率87.7％)。LC-MS MS-ESI(m/z)184.1[M+H] +。
实施例3中间体：5-(环丙甲酰氨基)-2-氟-4-甲基苯甲酸甲酯IIa-5的制备
Figure PCTCN2019083829-appb-000013
将IIa-3(8.05g,44.0mmol,1.0eq)溶于CH 2Cl 2(80mL)中，加入TEA(17.78g,176.0mmol,4.0eq)，冰/盐浴冷却至0℃后滴加市售的IIa-4(5.5g,52.8mmol,1.2eq)。所得溶液在环境温度下搅拌3h，LC-MS监测反应完毕。加CH 2Cl 2(150mL)稀释反应液，用水洗1次。水相再用CH 2Cl 2萃取2次，合并有机相，浓缩得浅黄色固体粗品IIa-5 11.50g。LC-MS MS-ESI(m/z)252.1[M+H] +。
实施例4中间体：5-(环丙甲酰氨基)-2-氟-4-甲基苯甲酸IIa的制备
Figure PCTCN2019083829-appb-000014
将IIa-5的粗品(11.50g,44.0mmol,1.0eq)溶于THF(100mL)中，加入水(20mL)和LiOH·H 2O(18.65g,444.0mmol,10.0eq)。所得混合液在环境温度下搅拌16h。TLC监测反应完毕。浓缩溶剂，加水(100mL)稀释，用1N的稀盐酸调节pH为3-4。过滤收集固体，用CH 2Cl 2/CH 3OH(10/1,100mL)打浆洗1次，烘干得白色固体IIa 9.02g(收率86.7％)。LC-MS MS-ESI(m/z)238.1[M+H] +。
实施例5中间体：4-氯-2-氟-5-硝基苯甲酸甲酯IIb-2的制备
Figure PCTCN2019083829-appb-000015
取市售的IIb-1(2.20g,10.0mmol,1.0eq)和SOCl 2(25mL)于圆底烧瓶中，加热至85℃回流2h，浓缩后所得的黄色油状粗产物酰氯，直接用于下一阶段反应。将此粗品(2.40g,10.0mmol,1.0eq)的CH 2Cl 2(50mL)溶液缓慢滴加到CH 3OH(20mL)中，所得溶液在环境温度下搅拌30min，浓缩后所得的浅黄色固体粗产物IIb-2 2.34g直接用于下一步反应。
实施例6中间体：5-氨基-4-氯-2-氟苯甲酸甲酯IIb-3的制备
Figure PCTCN2019083829-appb-000016
将IIb-2的粗品(2.34g,10.0mmol,1.0eq)溶于CH 3OH(20mL)中，加入水(5mL)，NH 4Cl(2.67g,50.0mmol,5.0eq)，Fe粉(2.24g,40.0mmol,4.0eq)。所得混合物在75℃下搅拌2h，TLC监测反应完毕。冷却至环境温度，过滤，滤饼用CH 3OH洗5次，浓缩滤液。粗品经硅胶柱(EtOAc(乙酸乙酯/PE(石油醚)＝1/2)分离后得黄色固体IIb-3 1.33g(收率65.5％)。LC-MS MS-ESI(m/z)204.2[M+H] +。
实施例7中间体：4-氯-5-(环丙甲酰氨基)-2-氟苯甲酸甲酯IIb-5的制备
Figure PCTCN2019083829-appb-000017
将IIb-3(1.33g,6.5mmol,1.0eq)溶于CH 2Cl 2(20mL)中，加入TEA(2.64g,26.2mmol,4.0eq)，冰/盐浴冷却至0℃后滴加市售的IIa-4(1.02g,9.7mmol,1.5eq)。所得溶液在环境温度下搅拌16h，TLC监测反应完毕。浓缩反应液，粗品经硅胶柱(EtOAc/PE＝1/2)分离后得黄色固体IIb-5 562.0mg(收率31.9％)。LC-MS MS-ESI(m/z)272.2[M+H] +。
实施例8中间体：4-氯-5-(环丙甲酰氨基)-2-氟苯甲酸IIb的制备
Figure PCTCN2019083829-appb-000018
将IIb-5的粗品(562.0mg,2.1mmol,1.0eq)溶于THF(100mL)中，加入水(1mL)和LiOH·H 2O(868.0mg,21.0mmol,10.0eq)。所得混合液在环境温度下搅拌16h。TLC监测反应完毕。浓缩溶剂，加水(20mL)稀释，用1N的稀盐酸调节pH为3-4。过滤收集固体，用CH 2Cl 2/CH 3OH(10/1,100mL)打浆洗1次，烘干得白色固体IIb351.2mg(收率66.0％)。LC-MS MS-ESI(m/z)258.2[M+H] +。
实施例9中间体：4-(环丙甲酰氨基)-吡啶-2-甲酸甲酯IIc-5的制备
Figure PCTCN2019083829-appb-000019
将市售的IIc-3(1.52g,10.0mmol,1.0eq)溶于CH 2Cl 2(20mL)中，加入TEA(4.04g,40.0mmol,4.0eq)，冰/盐浴冷却至0℃，滴加市售的IIa-4(1.56g,15.0mmol,1.5eq)，所得溶液在环境温度下搅拌16h。TLC监测反应完毕。浓缩反应液，粗品经硅胶柱(EtOAc/PE＝1/2)分离后得黄色固体IIc-5 1.56g(收率70.9％)。LC-MS MS-ESI(m/z)221.4[M+H] +。
实施例10中间体：4-(环丙甲酰氨基)-吡啶-2-甲酸IIc的制备
Figure PCTCN2019083829-appb-000020
将IIc-5(1.56g,7.1mmol,1.0eq)溶于THF(20mL)中，加入水(2mL)和LiOH·H 2O(2.98g,70.9mmol,10.0eq)，所得混合液在环境温度下搅拌16h。浓缩反应液，加水(20mL)稀释，用1N的稀盐酸调节pH至3-4，浓缩至大量固体析出，过滤收集固体，烘干得白色固体IIc 1.35g(收率92.5％)。LC-MS MS-ESI(m/z)207.4[M+H] +。
实施例11中间体：4-(环丙甲酰氨基)-5-氟吡啶-2-甲酸甲酯IId-5的制备
Figure PCTCN2019083829-appb-000021
将市售的IId-3(1.84g,10.0mmol,1.0eq)溶于CH 2Cl 2(20mL)中，加入TEA(4.04g,40.0mmol,4.0eq)，冰/盐浴冷却至0℃，加入IIa-4(1.56g,15.0mmol,1.5eq)，所得溶液在环境温度下搅拌16h，TLC监测反应有产物生成。浓缩反应液，粗品经硅胶柱(EtOAc/PE＝1/1)分离后得浅黄色固体为双环丙甲酰氨基中间体941.0mg(收率29.4％)。LC-MS MS-ESI(m/z)321.2[M+H] +。将该中间体(941.0mg,2.9mmol,1.0eq)溶于7M的NH 3的甲醇溶液(10mL)中，所得溶液在环境温度下搅拌1h，LC-MS监测反应完毕。浓缩反应液得到浅黄色固体粗产物IId-5 1.27g。LC-MS MS-ESI(m/z)253.3[M+H] +。
实施例12中间体：4-(环丙甲酰氨基)-5-氟吡啶-2-甲酸IId的制备
Figure PCTCN2019083829-appb-000022
将IId-5粗品(1.27g,2.9mmol,1.0eq)溶于THF(15mL)中，加入水(3mL)和LiOH·H 2O(1.22g,2.9mmol,10.0eq)。所得混合物在环境温度下搅拌2h，TLC监测反应完毕。浓缩反应液，加水(15mL)稀释，用1N的稀盐酸调节pH至3-4，过滤收集固体，烘干得白色固体IId 494.0mg(收率76.1％)。LC-MS MS-ESI(m/z)225.2[M+H] +。
实施例13中间体：6-氨基-2-吡啶甲酰肼IIIa-2的制备
Figure PCTCN2019083829-appb-000023
分别取市售的IIIa-1(10.00g,66.0mmol,1.0eq)，依次加入甲醇(200mL)，水合肼(66.07g,132.0mmol,2.0eq)，加热回流2h，TLC监测反应完毕。浓缩反应液的大部分溶剂，抽虑，经EtOAc洗涤，烘干。得到白色固体IIIa-2 10.20g。LC-MS MS-ESI(m/z)152.1[M+H] +。
实施例14中间体：(E)-N’-(6-(2-((E)-(二甲胺基)亚甲基)肼-1-羰基)吡啶-2-基)-N,N’-二甲基甲酰亚胺IIIa-3的制备
Figure PCTCN2019083829-appb-000024
分别取IIIa-2(10.20g,66.0mmol,1.0eq)，加入市售的DMF-DMA(100mL)，加热回流8h，TLC监测反应完毕，冷却至室温，浓缩反应液，抽虑，经EtOAc洗涤，烘干。得到黄色固体IIIa-3 14.00g(收率82.0％)。LC-MS MS-ESI(m/z)262.2[M+H] +。
实施例15中间体：6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-胺IIIa的制备
Figure PCTCN2019083829-appb-000025
分别取IIIa-3(1.00g,3.8mmol,1.0eq)和IIIa-4(1.3mL,15.3mmol,4.0eq)溶于CH 3CN/AcOH(2/1,30mL)，加热至95℃，反应24h，LC-MS监测反应完 毕，浓缩溶剂，粗品经硅胶柱(CH 2Cl 2/CH 3OH＝10/1)分离后得粘稠固体IIIa490.0mg(收率63.3％)。LC-MS MS-ESI(m/z)204.1[M+H] +。
实施例16中间体：6-(4-环丙基-4H-1,2,4-三唑-3-基)吡啶-2-胺IIIb的制备
Figure PCTCN2019083829-appb-000026
分别取IIIa-3(1.00g,3.8mmol,1.0eq)和IIIb-4(1.1mL,15.3mmol,4.0eq)溶于CH 3CN/AcOH(2/1,30mL)，加热至95℃，反应24h，LC-MS监测反应完毕，浓缩溶剂，粗品经硅胶柱(CH 2Cl 2/CH 3OH＝10/1)分离后得粘稠固体IIIb 620.0mg(收率80.8％)。LC-MS MS-ESI(m/z)202.1[M+H] +。
实施例17中间体：(S)-6-(4-(1,1,1-三氟丙基-2-基)-4H-1,2,4-三唑-3-基)吡啶-2-胺IIIc的制备
Figure PCTCN2019083829-appb-000027
分别取IIIa-3(1.00g,3.8mmol,1.0eq)和IIIc-4(2.27g,15.3mmol,4.0eq)溶于CH 3CN/AcOH(2/1,30mL)，加热至95℃，反应24h，LC-MS监测反应完毕，浓缩溶剂，粗品经硅胶柱(CH 2Cl 2/CH 3OH＝10/1)分离后得粘稠固体IIIc 700.0mg(收率71.5％)。LC-MS MS-ESI(m/z)258.2[M+H] +。
实施例18中间体：6-(4-(2,2,2-三氟乙基)-4H-1,2,4-三唑-3-基)吡啶-2-胺IIId的制备
Figure PCTCN2019083829-appb-000028
分别取IIIa-3(1.00g,3.8mmol,1.0eq)和IIId-4(2.06g,15.3mmol,4.0eq)溶于CH 3CN/AcOH(2/1,30mL)，加热至95℃，反应24h，LC-MS监测反应完毕，浓缩溶剂，粗品经硅胶柱(CH 2Cl 2/CH 3OH＝10/1)分离后得粘稠固体IIId 500.0mg(收率54.0％)。LC-MS MS-ESI(m/z)244.1[M+H] +。
实施例19中间体：(R)-6-(4-(1,1,1-三氟丙基-2-基)-4H-1,2,4-三唑-3-基)吡啶-2-胺IIIe的制备
Figure PCTCN2019083829-appb-000029
分别取IIIa-3(1.00g,3.8mmol,1.0eq)和IIIe-4(2.27g,15.3mmol,4.0eq)溶于CH 3CN/AcOH(2/1,30mL)，加热至95℃，反应24h，LC-MS监测反应完毕，浓缩溶剂，粗品经硅胶柱(CH 2Cl 2/CH 3OH＝10/1)分离后得粘稠固体IIIe 700.0mg(收率71.5％)。LC-MS MS-ESI(m/z)258.2[M+H] +。
实施例20中间体：(R)-6-(4-(1-甲氧丙基-2-基)-4H-1,2,4-三唑-3-基)吡啶-2-胺IIIf的制备
Figure PCTCN2019083829-appb-000030
分别取IIIa-3(260.0mg,1.0mmol,1.0eq)和IIIf-4(445.5mg,5.0mmol,5.0eq)溶于CH 3CN/AcOH(4/1,25mL)，加热回流24h，浓缩反应液，加水萃取，使用1N的NaOH溶液调节pH至10，EtOAc萃取3次，无水MgSO 4干燥，浓缩有机相，得黄色固体IIIf 180.0mg(收率38.0％)。LC-MS MS-ESI(m/z)233.1[M+H] +。
实施例21中间体：6-(4-((2R)-1-((四氢-2H-吡喃-2-基)氧杂)丙基-2-基)-4H-1,2,4-三唑-3-基)吡啶-2-胺IIIg的制备
Figure PCTCN2019083829-appb-000031
分别取IIIa-3(3.00g,11.5mmol,1.0eq)和市售的IIIg-4(3.43g,45.8mmol,4.0eq)溶于CH 3CN/AcOH(4/1,37.5mL)，所得溶液在92℃下搅拌回流24h，TLC监测反应完毕，冷却至环境温度，浓缩。加水稀释，用1N的NaOH溶液调节pH为8，浓缩。所得固体用CH 2Cl 2/CH 3OH(10/1,100mL)打浆，过滤，浓缩滤液得浅黄色粘稠固体粗品IIIg'7.40g。LC-MS MS-ESI(m/z)220.4[M+H] +。将IIIg'(1.10g,5.0mmol,1.0eq)溶于CH 2Cl 2(30mL)中，加入市售的二氢吡喃(840.0mg,10.0mmol,2.0eq)和对甲苯磺酸(TsOH)(172.0mg, 1.0mmol,0.2eq)。所得混合溶液在环境温度下搅拌16h，LC-MS监测反应完毕。加CH 2Cl 2(150mL)稀释，用饱和NaHCO 3溶液(150mL)洗1次。水相再用CH 2Cl 2/CH 3OH(10/1,100mL)萃取7次。合并有机相，浓缩，粗品经硅胶柱(CH 2Cl 2/CH 3OH＝12/1,6/1,4/1)分离后得白色固体IIIg 281.2mg(收率18.5％)。LC-MS MS-ESI(m/z)303.9[M+H] +。
实施例22化合物：5-(环丙甲酰氨基)-2-氟-4-甲基-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)苯甲酰胺I-1的制备
Figure PCTCN2019083829-appb-000032
将IIa(237.0mg,1.0mmol,1.0eq)悬浮于SOCl 2(5mL)，加热至60℃，反应15min至原料全部溶解，浓缩得黄色固体酰氯，直接用于下一阶段反应。将酰氯溶于超干THF(10mL)中，加入TEA(0.5mL)和IIIa(102.0mg,0.5mmol,1.0eq)，所得溶液在65℃下搅拌3h，LC-MS监测反应完毕。冷却至环境温度，浓缩，粗品经制备TLC(CH 2Cl 2/CH 3OH＝15/1)分离后，得到浅黄色固体I-1 15.0mg(收率7.1％)。LC-MS MS-ESI(m/z)423.0[M+H]。 1H-NMR(400MHz,DMSO-d6)δppm 10.7(s,1H),9.67(s,1H),8.85(s,1H),8.18(d,J＝8.2Hz,1H),8.02(t,J＝7.9Hz,1H),7.88(d,J＝7.4Hz,1H),7.76(d,J＝6.9Hz,1H),7.27(d,J＝11.0Hz,1H),5.63-5.66(m,1H),2.29(s,3H),1.88-1.91(m,1H),1.43(d,J＝6.7Hz,6H),0.80-0.86(m,4H)。
实施例23化合物：5-(环丙甲酰氨基)-2-氟-4-甲基-N-(6-(4-环丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)苯甲酰胺I-2的制备
Figure PCTCN2019083829-appb-000033
将IIa(237.0mg,1.0mmol,1.0eq)悬浮于SOCl 2(5mL)，加热至60℃，反应15min至原料全部溶解，浓缩得黄色固体酰氯，直接用于下一阶段反应。将酰氯溶于超干THF(10mL)中，加入TEA(0.5mL)和IIIb(100.0mg,0.5mmol,1.0eq)，所得溶液在65℃下搅拌3h，LC-MS监测反应完毕。冷却至环境温度，浓缩，粗品经制备TLC(CH 2Cl 2/CH 3OH＝15/1)分离后，得到类白色固体I-2 5.5mg(收率2.6％)。LC-MS MS-ESI(m/z)421.2[M+H] +。 1H-NMR(400MHz,DMSO-d6)δppm 10.7(s,1H),9.90(s,1H),8.63(s,1H),8.22(d,J＝7.9Hz,1H),8.02(t,J＝7.8Hz,1H),7.84(d,J＝7.1Hz,1H),7.67(s,1H),7.24(d,J＝10.8Hz, 1H),4.17-4.18(m,1H),2.29(s,3H),1.98(m,1H),1.34-1.38(m,4H),1.08-1.13(m,4H)。
实施例24化合物：(S)-5-(环丙甲酰氨基)-2-氟-4-甲基-N-(6-(4-(1,1,1-三氟丙基-2-基)-4H-1,2,4-三唑-3-基)吡啶-2-基)苯甲酰胺I-3的制备
Figure PCTCN2019083829-appb-000034
将IIa(237.0mg,1.0mmol,1.0eq)悬浮于SOCl 2(5mL)，加热至60℃，反应15min至原料全部溶解，浓缩得黄色固体酰氯，直接用于下一阶段反应。将酰氯溶于超干THF(10mL)中，加入TEA(0.5mL)和IIIc(130.0mg,0.5mmol,1.0eq)，所得溶液在65℃下搅拌3h，LC-MS监测反应完毕。冷却至环境温度，浓缩，粗品经制备TLC(CH 2Cl 2/CH 3OH＝20/1)分离后，得到类白色固体I-3 39.4mg(收率16.5％)。LC-MS MS-ESI(m/z)477.2[M+H] +。 1H-NMR(400MHz,DMSO-d6)δppm 10.9(s,1H),9.68(s,1H),9.11(s,1H),8.13(d,J＝7.9Hz,1H),8.04(t,J＝7.9Hz,1H),7.98(d,J＝7.4Hz,1H),7.75(d,J＝6.9Hz,1H),7.29(d,J＝10.8Hz,1H),7.11-7.14(m,1H),2.29(s,3H),1.85-1.89(m,1H),1.80(d,J＝6.9Hz,3H),0.79-0.81(m,4H)。
实施例25化合物：5-(环丙甲酰氨基)-2-氟-4-甲基-N-(6-(4-(2,2,2-三氟乙基)-4H-1,2,4-三唑-3-基)吡啶-2-基)苯甲酰胺I-4的制备
Figure PCTCN2019083829-appb-000035
将IIa(237.0mg,1.0mmol,1.0eq)悬浮于SOCl 2(5mL)，加热至60℃，反应15min至原料全部溶解，浓缩得黄色固体酰氯，直接用于下一阶段反应。将酰氯溶于超干THF(10mL)中，加入TEA(0.5mL)和IIId(121.0mg,0.5mmol,1.0eq)，所得溶液在65℃下搅拌3h，LC-MS监测反应完毕。冷却至环境温度，浓缩，粗品经制备TLC(CH 2Cl 2/CH 3OH＝15/1)分离后，得到浅黄色固体I-4 5.0mg(收率2.1％)。LC-MS MS-ESI(m/z)463.2[M+H] +。 1H-NMR(400MHz,DMSO-d6)δppm 11.0(s,1H),9.70(s,1H),8.77(s,1H),8.17(d,J＝8.2Hz,1H),8.06(t,J＝8.0Hz,1H),7.95(d,J＝7.4Hz,1H),7.75(d,J＝6.8Hz,1H),7.28-7.30(m,1H),5.94-5.97(m,2H),2.30(s,3H),1.88-1.91(m,1H),0.80-0.82(m,4H)。
实施例26化合物：(R)-5-(环丙甲酰氨基)-2-氟-4-甲基-N-(6-(4-(1,1,1-三氟丙基-2- 基)-4H-1,2,4-三唑-3-基)吡啶-2-基)苯甲酰胺I-5的制备
Figure PCTCN2019083829-appb-000036
将IIa(237.0mg,1.0mmol,1.0eq)和SOCl 2(10mL)，加热至60℃，反应15min至原料全部溶解，浓缩得黄色固体酰氯，直接用于下一阶段反应。将酰氯溶于超干THF(10mL)中，加入TEA(1mL)和IIIe(257.1mg,1.0mmol,1.0eq)，所得溶液在65℃下搅拌2h，LC-MS监测反应完毕。冷却至环境温度，浓缩，粗品经制备TLC(CH 2Cl 2/CH 3OH＝12/1,CH 2Cl 2/CH 3OH/HCOOH＝12/1/1)分离2次后，得到白色固体I-5 48.9mg(收率10.3％)。LC-MS MS-ESI(m/z)477.2[M+H] +。 1H-NMR(400MHz,DMSO-d6)δppm 10.9(s,1H),9.74(s,1H),9.14(s,1H),8.15(d,J＝8.1Hz,1H),8.05(t,J＝8.0Hz,1H),7.98(d,J＝7.6Hz,1H),7.75(d,J＝6.8Hz,1H),7.30(d,J＝10.9Hz,1H),7.12-7.16(m,1H),2.30(s,3H),1.90-1.93(m,1H),1.81(d,J＝7.1Hz,3H),0.80-0.82(m,4H)。
实施例27化合物：(R)-5-(环丙甲酰氨基)-2-氟-N-6-(4-(1-甲氧丙基-2-基)-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基苯甲酰胺I-6的制备
Figure PCTCN2019083829-appb-000037
将IIa(200.0mg,0.84mmol,1.0eq)和SOCl 2(3mL)，加热至60℃，反应至固体全部溶解，浓缩得黄色固体酰氯，直接用于下一阶段反应。将酰氯溶于超干THF(10mL)中，加入TEA(1mL)和IIIf(196.0mg,0.84mmol,1.0eq)，所得溶液在65℃下搅拌2h，LC-MS监测反应完毕。冷却至环境温度，浓缩，粗品经制备TLC(CH 2Cl 2/CH 3OH＝12/1)分离后，得到白色固体I-6 20.0mg(收率5.0％)。LC-MS MS-ESI(m/z)453.2[M+H] +。 1H-NMR(400MHz,DMSO-d6)δppm 10.7(s,1H),9.68(s,1H),8.82(s,1H),8.17(d,J＝8.3Hz,1H),8.02(t,J＝8.1Hz,1H),7.89(d,J＝7.7Hz,1H),7.76(d,J＝7.0Hz,1H),7.27(d,J＝11.0Hz,1H),5.82-5.86(m,1H),3.63-3.68(m,1H),3.51-3.55(m,1H),3.16(s,3H),2.29(s,3H),1.90(m,1H),1.43(d,J＝6.8Hz,3H),0.80-0.85(m,4H)。
实施例28化合物：(R)-5-(环丙甲酰氨基)-2-氟-N-6-(4-(1-羟丙基-2-基)-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基苯甲酰胺I-7的制备
Figure PCTCN2019083829-appb-000038
将IIa(203.0mg,0.86mmol,1.0eq)和SOCl 2(10mL)的混合物加热至固体完全溶解，浓缩得黄色固体酰氯，直接用于下一阶段反应。将酰氯溶于超干THF(10mL)中，加入TEA(1mL)和IIIg(280.0mg,0.93mmol,1.1eq)，所得溶液在65℃下搅拌2.5h，LC-MS监测反应完毕。冷却至环境温度，浓缩，粗品经制备TLC(CH 2Cl 2/CH 3OH＝12/1)分离后，得到橙色化合物I-7' 320.0mg(收率71.7％)。LC-MS MS-ESI(m/z)523.3[M+H] +。
将I-7'(156.6mg,0.30mmol,1.0eq)溶于CH 3OH(5mL)中，加入TsOH(103.2mg,0.60mmol,2.0eq)。所得溶液在环境温度下搅拌16h，LC-MS监测反应完毕。浓缩反应液，粗品经制备TLC(CH 2Cl 2/CH 3OH＝12/1)分离后，得浅黄色固体I-7 34.0mg(收率25.9％)。LC-MS MS-ESI(m/z)439.3[M+H] +。 1H-NMR(400MHz,DMSO-d6)δppm 9.63(s,1H),8.76(s,1H),7.76(d,J＝7.0Hz,1H),7.26(d,J＝6.7Hz,1H),7.20(s,1H),7.14-7.17(m,1H),6.48(d,J＝8.3Hz,1H),6.11(s,2H),5.89-5.93(m,1H),4.58(d,J＝5.3Hz,2H),2.25(s,3H),1.87(t,J＝6.2Hz,1H),1.57(d,J＝7.0Hz,3H),0.81-0.85(m,4H)。
实施例29中间体：(S)-2-(4-(1,1,1-三氟丙基-2-基)-4H-1,2,4-三唑-3-基)噻唑-4-胺IIIh的制备
Figure PCTCN2019083829-appb-000039
在-70℃和N 2保护条件下，将n-BuLi的THF(2.5M,27.5mmol,11mL,1.1eq)溶液滴加到市售的III'-1中(6.00g,24.7mmol,1.0eq)，反应液维持在-70℃下搅拌1h后通入CO 2，并在此低温环境下继续搅拌1h，随后向反应液中加入水并用乙醚(Et 2O)提取，水层用2N的稀盐酸调节pH为2，再用EtOAc萃取，合并有机层，经干燥、浓缩后得白色固体III'-2 4.50g(收率87.5％)。LC-MS MS-ESI(m/z)207.0[M-H] -。 1H-NMR(300MHz,DMSO-d 6)δppm 8.22(s,1H)。
取III'-2(8.35g,40.1mmol,1.2eq)溶于CH 2Cl 2(100mL)中，在环境温度下，向其中加入HATU(12.7g,33.4mmol,1.0eq)、市售的IIIc-4(5.00g,33.4mmol,1.0eq)和TEA(10.10g,100.0mmol,3.0eq)，继续搅拌3h后，TLC监测反应结束。浓缩反应液并将粗品经硅胶柱(PE/EtOAc＝15/1)分离后，得白色固体III'-3 9.60g(收率94.8％)。LC-MS MS-ESI(m/z)302.0[M-H] -。 1H-NMR(300MHz,CDCl 3)δppm7.55(s,1H),4.88-4.80(m,1H),1.48(d,J＝7.2Hz,3H)。
取III'-3(9.60g,31.7mmol,1.0eq)溶于甲苯中，在室温下加入Lawesson’s Reagent(19.20g,47.5mmol,1.5eq)。将该混合物加热至120℃反应过夜，TLC监测反应结束。浓缩反应液并将粗品经硅胶柱(PE/EtOAc＝15/1-10/1)分离后，得黄色油状物III'-4 9.96g(收率98.0％)。LC-MS MS-ESI(m/z)318.0[M-H] -。 1H-NMR(300MHz,CDCl 3)δppm8.88-8.85(m,1H),7.53(s,1H),5.50-5.42(m,1H),1.55(d,J＝6.6Hz,3H)。
取III'-4(9.96g,31.2mmol,1.0eq)溶于水合肼(51.5g,1.03mol,33.0eq)中，将该混合物加热至125℃反应1.5h，TLC监测反应结束。浓缩反应液并将粗品经硅胶柱(PE/EtOAc＝10/1-3/1)分离后，得黄色油状物III'-5 4.95g(收率50.0％)。LC-MS MS-ESI(m/z)316.1[M-H] -。
取III'-5(4.95g,15.6mmol,1.0eq)溶于C 2H 5OH(50mL)中，在室温下加入CH(OC 2H 5) 3(11.6g,78.0mmol,5.0eq)和催化量浓H 2SO 4(0.05mL)。将该混合物维持在室温下反应2h，TLC监测反应结束。浓缩反应液并将粗品经硅胶柱(PE/EtOAc＝15/1-3/1)分离后，得黄色油状物III'-6 5.00g(收率98.0％)。LC-MS MS-ESI(m/z)328.1[M+H] +。 1H-NMR(300MHz,CDCl 3)δppm8.45(s,1H),7.41(s,1H),6.54-6.45(m,1H),1.82(d,J＝7.2Hz,3H)。
取III'-6(5.00g,15.3mmol,1.0eq)溶于1,4-二氧六环和水中(4/1,75mL)，在N 2保护条件下，向其中加入二苯甲酮亚胺(5.54g,30.6mmol,2.0eq)、K 2CO 3(4.22g,30.6mmol,2.0eq)、Pd 2(dba) 3(1.40g,1.54mmol,0.1eq)和Xantphos(3.24g,7.64mmol,0.5eq)。将该混合物加热至100℃反应过夜，TLC监测反应结束。用水(30mL)稀释反应液并用EtOAc提取3次，合并有机相并将粗品经硅胶柱(PE/EtOAc＝10/1-1/3)分离后，得黄色油状物III'-7 3.00g(收率46.0％)。LC-MS MS-ESI(m/z)428.1[M+H] +。 1H-NMR(300MHz,CDCl 3)δppm8.34(s,1H),7.80-7.78(m,2H),7.53(d,J＝0.6Hz,1H),7.47-7.44(m,2H),7.38-7.28(m,3H),7.21-7.18(m,2H),6.68(s,1H),6.05-5.97(m,1H),1.60(d,J＝7.2Hz,3H)。
取III'-7(3.00g,3.8mmol,1.0eq)溶于2N的稀盐酸和EtOAc中(50mL)，在室温下搅拌该混合物过夜，TLC监测反应结束。浓缩反应液并将粗品经制备HPLC分离后，得黄色固体IIIh0.45g(收率35.0％)。LC-MS MS-ESI(m/z)264.1[M+H] +。 1H-NMR(300MHz,CDCl 3)δppm9.27(s,1H),7.20(s,1H),6.48-6.41(m,1H),1.83(d,J＝7.2Hz,3H)。
实施例30化合物：(S)-5-(环丙甲酰氨基)-2-氟-4-甲基-N-2-(4-(1,1,1-三氟丙基-2-基)-4H-1,2,4-三唑-3-基)噻唑-4-基)苯甲酰胺I-8的制备
Figure PCTCN2019083829-appb-000040
将IIa(100.0mg,0.42mmol,1.0eq)和SOCl 2(6mL)的混合物加热至固体完全溶解，浓缩得黄色固体酰氯，直接用于下一阶段反应。将酰氯溶于超干THF(10mL)中，加入TEA(1mL)和自制的IIIh盐酸盐(50.0mg,0.17mmol,0.4eq)，所得溶液在65℃下搅拌2h，LC-MS监测反应完毕。冷却至环境温度，浓缩，粗品经制备TLC(CH 2Cl 2/CH 3OH＝12/1,CH 2Cl 2/CH 3OH/HCOOH＝12/1/1,EtOAc/PE＝2/1)分离3次后，得白色固体I-8 18.5mg(收率9.2％)。LC-MS MS-ESI(m/z)482.2[M+H] +。 1H-NMR(400MHz,DMSO-d6)δppm 11.4(s,1H),9.67(s,1H),9.22(s,1H),7.95(s,1H),7.73(d,J＝7.0Hz,1H),7.26(d,J＝11.0Hz,1H), 6.62(t,J＝7.8Hz,1H),2.27(s,3H),1.88-1.91(m,1H),1.83(d,J＝7.2Hz,3H),0.80(d,J＝6.1Hz,4H)。
实施例31化合物：(S)-4-氯-5-(环丙甲酰氨基)-2-氟-N-(6-(4-(1,1,1-三氟丙基-2-基)-4H-1,2,4-三唑-3-基)吡啶-2-基)苯甲酰胺I-9的制备
Figure PCTCN2019083829-appb-000041
将IIb(130.0mg,0.5mmol,2.0eq)和SOCl 2(6mL)的混合物加热至固体完全溶解，浓缩得黄色固体酰氯，直接用于下一阶段反应。将酰氯溶于超干THF(10mL)中，加入TEA(1mL)和IIIc(65.0mg,0.3mmol,1.0eq)，所得溶液在65℃下搅拌3h，LC-MS监测反应完毕。浓缩并将粗品经制备TLC(CH 2Cl 2/CH 3OH＝20/1)分离后，得浅黄色固体I-9 6.0mg(收率4.8％)。LC-MS MS-ESI(m/z)497.1[M+H] +。
实施例32化合物：(S)-4-(环丙甲酰氨基)-N-(6-(4-(1,1,1-三氟丙基-2-基)-4H-1,2,4-三唑-3-基)吡啶-2-基)吡啶-2-甲酰胺I-10的制备
Figure PCTCN2019083829-appb-000042
将IIc(154.5mg,0.8mmol,1.5eq)溶于超干DMF中(5mL)，加入HATU(406.2mg,1.3mmol,2.5eq)，DIPEA(258.0mg,2.0mmol,4.0eq)和IIIc(128.5mg,0.5mmol,1.0eq)，所得溶液在环境温度下搅拌16h。加水(50mL)淬灭反应，用EtOAc(50mL)萃取3次。合并有机相，用饱和食盐水(100mL)洗3次，无水Na 2SO 4干燥，浓缩。粗品经制备TLC(CH 2Cl 2/CH 3OH＝12/1,CH 2Cl 2/CH 3OH/HCOOH＝24/1/1)分离2次后得白色固体I-10 10.9mg(收率4.9％)。LC-MS MS-ESI(m/z)446.2[M+H] +。 1H-NMR(400MHz,DMSO-d6)δppm 11.0(s,1H),10.93(s,1H),9.14(s,1H),8.61(d,J＝5.5Hz,1H),8.39(s,1H),8.23(d,J＝8.2Hz,1H),8.08(t,J＝7.9Hz,1H),7.97(d,J＝7.6Hz,1H),7.92(d,J＝5.4Hz,1H),7.01-7.08(m,1H),1.83(d,J＝7.0Hz,3H),1.24(s,1H),0.81-0.93(m,4H)。
实施例33化合物：(S)-4-(环丙甲酰氨基)-5-氟-N-(6-(4-(1,1,1-三氟丙基-2-基)-4H-1,2,4-三唑-3-基)吡啶-2-基)吡啶-2-甲酰胺I-11的制备
Figure PCTCN2019083829-appb-000043
分别取IId(33.6mg,0.3mmol,1.5eq)和IIIc(52.0mg,0.2mmol,1.0eq)溶于EtOAc/Py(2/1,12mL)，反应液用冰水浴降温至5℃以下，滴加T 3P的50％EtOAc溶液(250.0mg,0.4mmol,2.0eq)，滴毕，在室温下继续搅拌3h，TLC监测反应完毕。将反应液加水稀释(50mL)，加入EtOAc萃取2次，合并有机相，饱和碳酸氢钠洗涤1次，再用饱和食盐水洗1次，有机相干燥浓缩，粗品经制备TLC(CH 2Cl 2/CH 3OH＝15/1)分离后得白色固体I-11 7.0mg(收率7.5％)。LC-MS MS-ESI(m/z)464.2[M+H] +。 1H-NMR(400MHz,DMSO-d6)δppm 10.9(s,1H),10.73(s,1H),9.14(s,1H),9.09(d,J＝6.5Hz,1H),8.73(d,J＝2.4Hz,1H),8.22(d,J＝8.3Hz,1H),8.08(t,J＝8.0Hz,1H),7.97(d,J＝7.6Hz,1H),7.00-7.07(m,1H),2.18-2.23(m,1H),1.83(d,J＝7.1Hz,3H),0.91-0.93(m,4H)。
实施例34中间体：3-(5-(环丙甲酰胺基)-2-氟-4-甲基苯甲酰胺)苯甲酸甲酯IVa-2的制备
Figure PCTCN2019083829-appb-000044
分别取IIa(948.0mg,4.0mmol,1.0eq)和市售的IVa-1(604.0mg,4.0mmol,1.0eq)溶于DMF(20mL)中，加入DIPEA(2.6M,16.0mmol,4.0eq)，随后一次性加入HATU(2.28g,6.0mmol,1.5eq)，将该反应液在室温下搅拌过夜，LC-MS监测反应完毕。向反应液中加入EtOAc(60mL)，水洗3次，饱和食盐水洗1次，有机相干燥浓缩，粗品经柱层析(EtOAc/PE＝1/1)分离后得白色固体IVa-2 450.0mg(收率30.4％)。LC-MS MS-ESI(m/z)371.3[M+H] +,741.3[2M+H] +。
实施例35中间体：3-(5-(环丙甲酰胺基)-2-氟-4-甲基苯甲酰胺)苯甲酰肼IVa-3的制备
Figure PCTCN2019083829-appb-000045
取IVa-2(450.0mg,1.2mmol,1.0eq)溶于C 2H 5OH(15mL)，加入水合肼(4.12g,82.2mmol,68.0eq)，加热至85℃，反应3h，析出白色固体，将反应液冷却至室温、抽滤、滤饼用EtOAc洗涤、烘干，得到白色固体IVa-3 320.0mg (收率71.1％)。LC-MS MS-ESI(m/z)371.2[M+H] +。
实施例36中间体：(E)-5-(环丙甲酰胺基)-N-(3-(2-((二甲胺基)亚甲基)肼-1-羰基)苯基)-2-氟-4-甲基苯甲酰胺IVa-4的制备
Figure PCTCN2019083829-appb-000046
取IVa-3(320.0mg,0.86mmol,1.0eq)悬浮于DMF-DMA(10mL)，加热至100℃，反应3h，TLC监测反应完毕，析出白色固体，抽滤，滤饼用EtOAc洗涤、烘干，得到白色固体IVa-4 350.0mg(收率95.5％)。LC-MS MS-ESI(m/z)426.2[M+H] +。
实施例37化合物：(S)-5-(环丙甲酰胺基)-2-氟-4-甲基-N-(3-(4-(1,1,1-三氟丙基-2-基)-4H-1,2,4-三唑-3-基)苯基)苯甲酰胺I-12的制备
Figure PCTCN2019083829-appb-000047
分别取IVa-4(106.0mg,0.3mmol,1.0eq)和IIIc-4(150.0mg,1.0mmol,3.3eq)悬浮于甲苯(15mL)，滴加三氟乙酸(TFA)2滴，加热至110℃，反应12h，LC-MS监测反应完毕。浓缩反应液，用EtOAc(60mL)溶解、0.1N的稀盐酸洗涤2次、饱和食盐水洗涤1次，有机相干燥浓缩，粗品经制备TLC(CH 2Cl 2/CH 3OH＝15/1)分离后得白色固体I-12 9.0mg(收率7.5％)。LC-MS MS-ESI(m/z)476.2[M+H] +。 1H-NMR(400MHz,DMSO-d6)δppm 10.5(s,1H),9.69(s,1H),9.07(s,1H),7.97(s,1H),7.90(d,J＝7.7Hz,1H),7.72(d,J＝6.0Hz,1H),7.56(t,J＝7.7Hz,1H),7.34(d,J＝7.1Hz,1H),7.26(d,J＝10.5Hz,1H),5.18-5.21(m,1H),2.28(s,3H),1.89(s,1H),1.78(d,J＝6.3Hz,3H),0.79-0.80(m,4H)。
实施例38中间体：2-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基-5-硝基苯甲酰胺Va-1的制备
Figure PCTCN2019083829-appb-000048
取市售的IIa-1(1.00g,5.0mmol,1.0eq)和SOCl 2(15mL)于圆底烧瓶中，加热至85℃回流2h，浓缩后所得的黄色油状粗产物酰氯，直接用于下一阶段反应。(收率按100％计算)。将此粗品(1.72g,5.0mmol,1.0eq)溶于超干THF(20mL)中，加入TEA(2.03g,20.1mmol,4.0eq)和IIIa(1.02g,5.0mmol,1.0eq)，所得混合物在65℃下搅拌3h，LC-MS监测反应完毕。冷却至环境温度，过滤收集固体，用EtOAc(15mL)打浆洗1次后烘干，得类白色固体Va-1 1.18g(收率62.0％)。LC-MS MS-ESI(m/z)385.2[M+H] +。
实施例39中间体：5-氨基-2-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基苯甲酰胺Va的制备
Figure PCTCN2019083829-appb-000049
将Va-1(1.18g,3.1mmol,1.0eq)溶于CH 3OH(20mL)和水(4mL)中，加入NH 4Cl(819.0mg,15.3mmol,5.0eq)和Fe粉(685.0mg,12.2mmol,4.0eq)，所得混合物在75℃下搅拌3h，LC-MS监测反应完毕。冷却至环境温度，过滤，浓缩滤液。所得固体用CH 2Cl 2(15mL)打浆洗1次并烘干，得灰色固体Va1.03g(收率95.3％)。LC-MS MS-ESI(m/z)355.3[M+H] +。
实施例40中间体：(S)-2-氟-4-甲基-5-硝基-N-(6-(4-(1,1,1-三氟丙基-2-基)-4H-1,2,4-三唑-3-基)吡啶-2-基)苯甲酰胺Vb-1的制备
Figure PCTCN2019083829-appb-000050
将市售的IIa-1(1.99g,10.0mmol,1.0eq)加入到SOCl 2(20mL)中，所得溶液在85℃下回流2h，浓缩。加入超干THF(20mL)再次浓缩，即为酰氯中间体。将酰氯溶于超干THF(20mL)中，加入TEA(2.5mL)和IIIc(1.12g,4.4mmol,0.4eq)，所得溶液在65℃下搅拌2h，LC-MS监测反应完毕。冷却至环境温度，浓缩。粗品经硅胶柱(CH 2Cl 2/CH 3OH＝12/1)分离后得黄色粘稠固体Vb-1 662.0mg(收率34.4％)。LC-MS MS-ESI(m/z)439.2[M+H] +。
实施例41中间体：(S)-5-氨基-2-氟-4-甲基-N-(6-(4-(1,1,1-三氟丙基-2-基)-4H-1,2,4-三唑-3-基)吡啶-2-基)苯甲酰胺Vb的制备
Figure PCTCN2019083829-appb-000051
将Vb-1(662.0mg,1.5mmol,1.0eq)溶于CH 3OH(15mL)中，加入水(3mL)，NH 4Cl(404.0mg,7.6mmol,5.0eq)和Fe粉(338.2mg,6.0mmol,4.0eq)，所得混合液在75℃下搅拌2h，LC-MS监测反应完毕。过滤，滤饼用CH 3OH洗5次，浓缩滤液。粗品经硅胶柱(CH 2Cl 2/CH 3OH＝12/1)分离后得黄色固体Vb 342.0mg(收率55.5％)。LC-MS MS-ESI(m/z)409.3[M+H] +。
实施例42化合物：2-氟-5-(2-(4-氟苯基)环丙基-1-甲酰氨基)-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基苯甲酰胺I-13的制备
Figure PCTCN2019083829-appb-000052
将市售的IIb-4(72.0mg,0.4mmol,2.0eq)和Va(72.0mg,0.2mmol,1.0eq)溶于EtOAc(8mL)和Py(4mL)中，用冰/盐浴冷却至0℃，滴加T 3P的50％EtOAc溶液(0.3mL)，所得溶液在环境温度下搅拌5h，LC-MS监测反应完毕。用EtOAc(40mL)稀释反应液，并通过1N的稀盐酸洗1次，水相再用EtOAc萃取2次，合并有机相，无水Na 2SO 4干燥，浓缩有机相。粗品经制备TLC(CH 2Cl 2/CH 3OH＝6/1)分离后，得白色固体I-13 16.0mg(收率15.5％)。LC-MS MS-ESI(m/z)517.3[M+H] +。 1H-NMR(400MHz,DMSO-d6)δppm 10.7(s,1H),9.71(s,1H),8.85(s,1H),8.18(d,J＝8.2Hz,1H),8.04(t,J＝8.0Hz,1H),7.85-7.90(m,2H),7.23-7.28(m,3H),7.13(t,J＝8.7Hz,2H),5.61-5.66(m,1H),2.39-2.43(m,1H),2.29(s,3H),2.19-2.21(m,1H),1.46-1.50(m,1H),1.44(d,J＝6.6Hz,6H),1.33-1.37(m,1H)。
实施例43化合物：5-(环丁甲酰氨基)-2-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基苯甲酰胺I-14的制备
Figure PCTCN2019083829-appb-000053
将市售的IIc-4(30.0mg,0.3mmol,1.5eq)和Va(72.0mg,0.2mmol,1.0eq)溶于EtOAc(12mL)和Py(6mL)中，用冰/盐浴冷却至0℃，滴加T 3P的50％EtOAc溶液(0.3mL)，所得溶液在环境温度下搅拌5h，LC-MS监测反应完毕。用CH 2Cl 2(50mL)稀释反应液，并通过1N的稀盐酸洗1次，水相再用CH 2Cl 2/CH 3OH(10/1)萃取7次，合并有机相，无水Na 2SO 4干燥，浓缩有机相。 粗品经制备TLC(CH 2Cl 2/CH 3OH＝12/1)分离后，得类白色固体I-14 36.0mg(收率34.9％)。LC-MS MS-ESI(m/z)437.2[M+H] +。 1H-NMR(400MHz,DMSO-d6)δppm 10.7(s,1H),9.25(s,1H),8.85(s,1H),8.18(d,J＝8.2Hz,1H),8.02(t,J＝7.8Hz,1H),7.88(d,J＝7.6Hz,1H),7.70(d,J＝6.9Hz,1H),7.26(d,J＝11.0Hz,1H),5.63-5.66(m,1H),2.24(s,3H),2.19-2.21(m,2H),2.13-2.15(m,2H),1.94-1.96(m,2H),1.81-1.84(m,1H),1.44(d,J＝6.7Hz,6H)。
实施例44化合物：2-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基-5-(1-(三氟甲基)环丙基-1-甲酰氨基)苯甲酰胺I-15的制备
Figure PCTCN2019083829-appb-000054
将市售的IId-4(47.0mg,0.3mmol,1.5eq)和Va(72.0mg,0.2mmol,1.0eq)溶于EtOAc(12mL)和Py(6mL)中，用冰/盐浴冷却至0℃，滴加T 3P的50％EtOAc溶液(0.3mL)，所得溶液在环境温度下搅拌5h，LC-MS监测反应完毕。用CH 2Cl 2(50mL)稀释反应液，并通过1N的稀盐酸洗1次，水相再用CH 2Cl 2/CH 3OH(10/1)萃取7次，合并有机相，无水Na 2SO 4干燥，浓缩有机相。粗品经制备TLC(CH 2Cl 2/CH 3OH＝12/1)分离后，得类白色固体I-15 14.0mg(收率13.6％)。LC-MS MS-ESI(m/z)491.2[M+H] +。 1H-NMR(400MHz,DMSO-d6)δppm 10.7(s,1H),9.42(s,1H),8.85(s,1H),8.18(d,J＝8.0Hz,1H),8.02(t,J＝7.4Hz,1H),7.89(d,J＝7.4Hz,1H),7.52(d,J＝6.4Hz,1H),7.31(d,J＝10.9Hz,1H),5.66-5.63(m,1H),2.22(s,3H),1.52-1.50(m,2H),1.44(d,J＝6.4Hz,6H),1.35-1.33(m,2H)。
实施例45化合物：2-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基-5-(1-(氟)环丙基-1-甲酰氨基)苯甲酰胺I-16的制备
Figure PCTCN2019083829-appb-000055
分别取市售的IIe-4(44mg,0.4mmol,1.5eq)和Va(88.1mg,0.2mmol,1.0eq)溶于无水DMF/Py(2/1,6mL)中，在冰水浴条件下，滴加T 3P的50％EtOAc溶液(0.3mL)，TLC监测反应完毕。用CH 2Cl 2/CH 3OH(10/1,20mL)稀释反应液，加水萃取，合并有机相，水洗，饱和碳酸氢钠、饱和食盐水洗涤，无水硫酸钠干燥，浓缩溶剂。粗品经柱层析(CH 2Cl 2/CH 3OH＝20/1)分离后，得到黄色粘稠状固体I-16 15.0mg。LC-MS MS-ESI(m/z)441.2[M+H] +。 1H-NMR(400 MHz,DMSO-d6)δppm 10.8(s,1H),10.01(s,1H),8.86(s,1H),8.19(d,J＝8.1Hz,1H),8.02(t,J＝8.1Hz,1H),7.88(d,J＝7.3Hz,1H),7.60(d,J＝6.8Hz,1H),7.32(d,J＝11.1Hz,1H),5.64-5.67(m,1H),2.27(s,3H),1.44(d,J＝6.7Hz,6H),1.39-1.41(m,2H),1.27-1.33(m,2H)。
实施例46化合物：2-氟-5-((1R,2R)-2-氟环丙基-1-甲酰氨基)-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基苯甲酰胺I-17的制备
Figure PCTCN2019083829-appb-000056
将市售的IIf-4(31.2mg,0.3mmol,1.5eq)和Va(71.0mg,0.2mmol,1.0eq)溶于EtOAc(8mL)和Py(4mL)中，用冰水浴冷却至5℃以下，滴加T 3P的50％EtOAc溶液(0.3mL)，所得溶液在环境温度下搅拌3h，LC-MS监测反应完毕。用水(50mL)稀释反应液，水相再用EtOAc萃取2次，合并有机相，饱和碳酸氢钠、饱和食盐水洗涤，无水Na 2SO 4干燥，浓缩有机相。粗品经制备TLC(CH 2Cl 2/CH 3OH＝15/1)分离后，得类白色固体I-17 19.0mg(收率21.5％)。LC-MS MS-ESI(m/z)441.2[M+H] +。 1H-NMR(400MHz,DMSO-d6)δppm 10.7(s,1H),9.93(s,1H),8.86(s,1H),8.18(d,J＝8.2Hz,1H),8.02(t,J＝8.0Hz,1H),7.88(d,J＝7.5Hz,1H),7.77(d,J＝6.9Hz,1H),7.28(d,J＝11.0Hz,1H),5.63-5.66(m,1H),4.79-4.96(m,1H),2.30(s,3H),1.48-1.54(m,1H),1.45(d,J＝6.8Hz,6H),1.20-1.25(m,2H)。
实施例47化合物：2-氟-5-((1R,2S)-2-氟环丙基-1-甲酰氨基)-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基苯甲酰胺I-18的制备
Figure PCTCN2019083829-appb-000057
将市售的IIg-4(31.2mg,0.3mmol,1.5eq)和Va(71.0mg,0.2mmol,1.0eq)溶于EtOAc(8mL)和Py(4mL)中，用冰水浴冷却至5℃以下，滴加T 3P的50％EtOAc溶液(0.3mL)，所得溶液在环境温度下搅拌3h，LC-MS监测反应完毕。用水(50mL)稀释反应液，水相再用EtOAc萃取2次，合并有机相，饱和碳酸氢钠、饱和食盐水洗涤，无水Na 2SO 4干燥，浓缩有机相。粗品经制备TLC(CH 2Cl 2/CH 3OH＝15/1)分离后，得类白色固体I-18 18.0mg(收率20.4％)。LC-MS MS-ESI(m/z)441.2[M+H] +。 1H-NMR(400MHz,DMSO-d6)δppm 10.7(s,1H),9.94(s,1H),8.85(s,1H),8.18(d,J＝8.2Hz,1H),8.02(t,J＝7.9Hz,1H),7.88 (d,J＝7.6Hz,1H),7.72(d,J＝6.8Hz,1H),7.27(d,J＝11.0Hz,1H),5.61-5.68(m,1H),4.85-5.02(m,1H),2.28(s,3H),1.57-1.65(m,1H),1.43(d,J＝6.6Hz,6H),1.07-1.23(m,2H)。
实施例48化合物：(S)-5-(环戊甲酰氨基)-2-氟-4-甲基-N-(6-(4-(1,1,1-三氟丙基-2-基)-4H-1,2,4-三唑-3-基)吡啶-2-基)苯甲酰胺I-19的制备
Figure PCTCN2019083829-appb-000058
将Vb(170.0mg,0.4mmol,1.0eq)溶于CH 2Cl 2(10mL)中，加入TEA(1mL)，用冰/盐浴冷却至0℃，加入市售的IIh-4(83.2mg,0.6mmol,1.5eq)，所得溶液在环境温度下搅拌4h，LC-MS监测反应完毕。浓缩反应液，粗品经制备TLC(CH 2Cl 2/CH 3OH＝12/1,EtOAc/CH 3OH＝6/1)分离2次后，得白色固体I-19 50.2mg(收率23.7％)。LC-MS MS-ESI(m/z)505.2[M+H] +。 1H-NMR(400MHz,DMSO-d6)δppm 10.9(s,1H),9.40(s,1H),9.12(s,1H),8.14(d,J＝8.2Hz,1H),8.05(t,J＝7.9Hz,1H),7.99(d,J＝7.5Hz,1H),7.68(d,J＝6.9Hz,1H),7.30(d,J＝10.9Hz,1H),7.12-7.15(m,1H),2.84-2.88(m,1H),2.26(s,3H),1.87-1.89(m,2H),1.81(d,J＝7.1Hz,3H),1.67-1.75(m,4H),1.55-1.66(m,2H)。
实施例49化合物：(S)-5-(环庚甲酰氨基)-2-氟-4-甲基-N-(6-(4-(1,1,1-三氟丙基-2-基)-4H-1,2,4-三唑-3-基)吡啶-2-基)苯甲酰胺I-20的制备
Figure PCTCN2019083829-appb-000059
将市售的IIi-4(160.1mg,1.0mmol,1.0eq)加入到SOCl 2(5mL)中，所得混合液在85℃下搅拌回流1h，浓缩。加入超干THF(10mL)再次浓缩，所得黄色油状物即为酰氯中间体。将Vb(80.0mg,0.2mmol,0.2eq)溶于CH 2Cl 2(10mL)中，加入TEA(0.5mL)，用冰/盐浴冷却至0℃，加入酰氯中间体。所得溶液在环境温度下搅拌4h。浓缩反应液，粗品经制备TLC(CH 2Cl 2/CH 3OH＝10/1,CH 2Cl 2/CH 3OH/HCOOH＝24/1/1)分离2次后，得浅黄色固体I-20 3.8mg(收率3.6％)。LC-MS MS-ESI(m/z)533.2[M+H] +。 1H-NMR(400MHz,DMSO-d6)δppm 10.9(s,1H),9.34(s,1H),9.12(s,1H),8.14(d,J＝8.0Hz,1H),8.05(t,J＝7.9Hz,1H),7.98(d,J＝7.5Hz,1H),7.64(d,J＝6.9Hz,1H),7.29(d,J＝10.9Hz, 1H),7.12-7.15(m,1H),2.54-2.60(m,1H),2.25(s,3H),1.86-1.91(m,2H),1.81(d,J＝7.1Hz,3H),1.46-1.75(m,12H)。
体外生物学评价
本检测方法用于评价本发明所述化合物的体外蛋白水平结合抑制活性。
本检测的目的在于综合评价不同化合物对ASK1激酶抑制活性的影响。
实施例A体外ASK1的酶学抑制筛选方法
本检测采用均相时间分辨荧光分析法(Homogeneous timeresolvedfluorescence,HTRF)评价化合物在体外反应体系中对重组人ASK1的酶学活性抑制水平。
实验主要原理
体外酶学活性检测的基本原理是利用末端生物素标记的特异性底物，在激酶作用下进行磷酸化，反应产物与识别磷酸化位点的EU 3+-Cryptate标记的抗体以及XL665标记的链亲和素混合，当两种荧光分子同时结合在底物上时，在外源激发光(320nm)刺激下，Eu会产生620nM荧光，同时通过能量转移激发XL665产生665nm荧光。通过比较两种波长荧光的变化(620nm与665nm)，评价底物磷酸化情况。当加入不同测试化合物时，其对激酶活性的抑制体现为底物磷酸化的程度改变，从而表现出不同的荧光信号比例(665/620)，并以此计算化合物对激酶的抑制活性。基本的检测原理是现有技术中已知的(Cisbio,Nature Method 2006,June 23；DOI:10.1038/NMETH883)。
实验主要过程
人重组ASK1(MAP3K5)激酶、2X激酶反应缓冲液、ATP(10mM)购自Invitrogen(货号：PR7349B)，HTRF检测试剂盒HTRF KinEASE STK discovery kit购自Cisbio(货号：62ST0PEB)。
实验过程按照检测试剂使用说明书要求的流程进行(https://www.cisbio.com/sites/default/files/ressources/cisbio_dd_pi_62ST0PEB.pdf)。具体内容如下：
(1)实验准备：按照要求配制激酶反应缓冲液(工作液)，用激酶反应缓冲液将测试化合物稀释成不同浓度梯度(化合物最高浓度为4μM)。
(2)将10μL酶学反应体系(包括2.5μL测试化合物、5μL激酶反应缓冲液和2.5μL ATP溶液(试剂盒提供))混匀后室温反应1h，酶学反应在96 孔微孔板进行。
(3)EU3+-Cryptate标记的抗体以及XL665标记的链亲和素以反应终止缓冲液按适当的比例稀释，每个反应孔分别加入5μL两种稀释检测液，室温反应2h。
(4)反应同时设置有对照反应，包括未添加测试化合物的阳性对照和未添加ASK1激酶的阴性对照。所有检测采用复孔。
(5)反应结束后，使用荧光检测仪(TecanSPARK 10M)检测每孔的荧光信号，激发波长为320nm，检测的发射波长分别为620nm和665nm。
(6)分别计算每孔的665/620比值，阳性对照孔减去阴性对照孔作为底物磷酸化基础水平，测试化合物的酶学抑制率计算公式：抑制率(％)＝1-(检测孔比值-阴性孔比值)/底物磷酸化基础水平值。针对不同浓度梯度的测试化合物分别计算出磷酸化抑制率后利用IC 50计算器计算酶学半抑制浓度(IC 50)。本发明所述代表性化合物的总结数据如下(见表2)。
表2 HTRF方法检测本发明代表性化合物的ASK1酶学抑制率(单浓度100nM)
化合物 抑制率％ 化合物 抑制率％ 化合物 抑制率％
I-1 54 I-3 51 I-4 32
I-6 13 I-8 24 I-9 33
I-10 44 I-11 27 I-13 18
I-14 42 I-16 21 I-17 15
I-18 34 I-19 52 I-20 16
由上述结果可见，本发明所述的代表性化合物具有良好的体外抑制ASK1的酶学活性。

Claims (22)

  1. 式I化合物，
    Figure PCTCN2019083829-appb-100001
    包括其前药、立体异构体、药学上可接受的盐、水合物或其它溶剂合物，
    其中，
    R 1为一个或多个取代基，独立地选自相同或不同的H、卤素、CN、C 1-C 4烷基、C 1-C 4卤代烷基、NH 2、COOH、C 1-C 4烷基氨基、C 1-C 4烷基氧基和Ar 1；
    其中，Ar 1选自苯环和吡啶环，并且所述苯环和吡啶环可被一个或多个取代基取代，所述取代基独立地选自相同或不同的H、卤素、CN、C 1-C 4烷基、C 1-C 4卤代烷基、NH 2、C 1-C 4烷基氨基和C 1-C 4烷基氧基；
    R 2为一个或多个取代基，独立地选自相同或不同的H、卤素、CN、C 1-C 4烷基和C 1-C 4卤代烷基；
    R 3为C 1-C 4烷基、C 3-C 6环烷基、C 1-C 4卤代烷基、卤代C 3-C 6环烷基、氰基取代的C 1-C 4烷基、C 3-C 6杂环烷基、羟基取代的C 1-C 4烷基或C 1-C 4烷氧基取代的C 1-C 4烷基；
    X选自C和N；
    A选自C 3-C 7环烷基和C 3-C 7杂环烷基；
    B为芳香环，
    优选选自苯环、吡啶环、噻唑环、呋喃环、噻吩环、吡咯环、吡唑环、噁唑环、异噁唑环以及喹啉环，所述芳香环可被一个或多个取代基取代，所述取代基独立地选自相同或不同的H、卤素、CN、C 1-C 4烷基、C 1-C 4卤代烷基、NH 2、C 1-C 4烷基氨基和C 1-C 4烷基氧基；
    m为1到5的整数；
    n为1到4的整数。
  2. 根据权利要求1所述的式I化合物，
    其中，
    R 1为一个或多个取代基，独立地选自相同或不同的H、卤素、CN、C 1-C 4 烷基、C 1-C 4卤代烷基、NH 2、COOH、C 1-C 4烷基氨基、C 1-C 4烷基氧基和Ar 1；
    其中，Ar 1选自苯环和吡啶环，并且所述苯环和吡啶环可被一个或多个取代基取代，所述取代基独立地选自相同或不同的H、卤素、CN、C 1-C 4烷基、C 1-C 4卤代烷基、NH 2、C 1-C 4烷基氨基和C 1-C 4烷基氧基；
    R 2为一个或多个取代基，独立地选自相同或不同的H、卤素、CN和C 1-C 4烷基；
    R 3为C 1-C 4烷基、C 3-C 6环烷基、C 1-C 4卤代烷基、卤代C 3-C 6环烷基、氰基取代的C 1-C 4烷基、C 3-C 6杂环烷基、羟基取代的C 1-C 4烷基或C 1-C 4烷氧基取代的C 1-C 4烷基；
    X选自C和N；
    A选自C 3-C 7环烷基和C 3-C 7杂环烷基；
    B为芳香环，
    优选选自苯环、吡啶环、噻唑环、呋喃环、噻吩环、吡咯环、吡唑环、噁唑环、异噁唑环和喹啉，所述芳香环可被一个或多个取代基取代，所述取代基独立地选自相同或不同的H、卤素、CN、C 1-C 4烷基、C 1-C 4卤代烷基、NH 2、C 1-C 4烷基氨基和C 1-C 4烷基氧基；
    m为1到5的整数；
    n为1到4的整数。
  3. 根据权利要求1所述的式I化合物，
    其中，
    R 1为一个或多个取代基，独立地选自相同或不同的H、卤素、CN、C 1-C 4烷基、C 1-C 4卤代烷基、NH 2、COOH、C 1-C 4烷基氨基和C 1-C 4烷基氧基；
    R 2为一个或多个取代基，独立地选自相同或不同的H、卤素、CN和C 1-C 4烷基；
    R 3为C 1-C 4烷基、C 3-C 6环烷基、C 1-C 4卤代烷基、卤代C 3-C 6环烷基、氰基取代C 1-C 4烷基、C 3-C 6杂环烷基、羟基取代的C 1-C 4烷基或C 1-C 4烷氧基取代的C 1-C 4烷基；
    X选自C和N；
    A选自C 3-C 7环烷基和C 3-C 7杂环烷基；
    B为芳香环，
    优选选自苯环、吡啶环、噻唑环、呋喃环、噻吩环、吡咯环、吡唑环、噁唑环、异噁唑环和喹啉环，所述芳香环可被一个或多个取代基取代，所述取代基独立地选自相同或不同的H、卤素、CN、C 1-C 4烷基、C 1-C 4卤代烷基、NH 2、C 1-C 4烷基氨基和C 1-C 4烷基氧基；
    m为1到5的整数；
    n为1到4的整数。
  4. 根据权利要求1所述的式I化合物，
    其中，
    R 1为一个或多个取代基，独立地选自相同或不同的H、卤素、CN、C 1-C 4烷基、C 1-C 4卤代烷基、NH 2、COOH、C 1-C 4烷基氨基和C 1-C 4烷基氧基；
    R 2为一个或多个取代基，独立地选自相同或不同的H、卤素、CN和C 1-C 4烷基；
    R 3为C 1-C 4烷基、C 3-C 6环烷基、C 1-C 4卤代烷基、卤代C 3-C 6环烷基或氰基取代的C 1-C 4烷基；
    X选自C和N；
    A选自C 3-C 7环烷基和C 3-C 7杂环烷基；
    B为芳香环，
    优选选自苯环、吡啶环、噻唑环、呋喃环、噻吩环、吡咯环、吡唑环、噁唑环、异噁唑环和喹啉环，所述芳香环可被一个或多个取代基取代，所述取代基独立地选自相同或不同的H、卤素、CN、C 1-C 4烷基、C 1-C 4卤代烷基、NH 2、C 1-C 4烷基氨基和C 1-C 4烷基氧基；
    m为1到5的整数；
    n为1到4的整数。
  5. 根据权利要求1所述的式I化合物，
    其中，
    R 1为一个或多个取代基，独立地选自相同或不同的H、卤素、CN、C 1-C 4烷基、C 1-C 4卤代烷基、NH 2、COOH、C 1-C 4烷基氨基和C 1-C 4烷基氧基；
    R 2为一个或多个取代基，独立地选自相同或不同的H、卤素、CN和C 1-C 4烷基；
    R 3为C 1-C 4烷基、C 3-C 6环烷基、C 1-C 4卤代烷基、卤代C 3-C 6环烷基或氰基取代的C 1-C 4烷基；
    X选自C和N；
    A选自C 3-C 5环烷基和C 3-C 5杂环烷基；
    B为芳香环，优选选自苯环、吡啶环和噻唑环,所述芳香环可被一个或多个取代基取代，所述取代基独立地选自相同或不同的H、卤素、CN、C 1-C 4烷基、C 1-C 4卤代烷基、NH 2、C 1-C 4烷基氨基和C 1-C 4烷基氧基；
    m为1到5的整数；
    n为1到4的整数。
  6. 根据权利要求1所述的式I化合物，
    其中，
    R 1为一个或多个取代基，独立地选自相同或不同的H、卤素、CN和C 1-C 4烷基；
    R 2为一个或多个取代基，独立地选自相同或不同的H、卤素、CN和甲基；
    R 3为C 1-C 4烷基、C 3-C 6环烷基、C 1-C 4卤代烷基、卤代C 3-C 6环烷基或氰基取代的C 1-C 4烷基；
    X选自C和N；
    A选自C 3-C 4环烷基和C 3-C 4杂环烷基；
    B为芳香环，
    优选选自苯环、吡啶环和噻唑环，所述芳香环可被一个或多个取代基取代，所述取代基独立地选自相同或不同的H、卤素、CN、C 1-C 4烷基和C 1-C 4卤代烷基；
    m为1到5的整数；
    n为1到4的整数。
  7. 根据权利要求1所述的式I化合物，
    其中，
    R 1为一个或多个取代基，独立地选自相同或不同的H、卤素和CN；
    R 2为一个或多个取代基，独立地选自相同或不同的H、F、Cl、CN和甲基；
    R 3为C 1-C 4烷基、C 3-C 6环烷基、C 1-C 4卤代烷基、卤代C 3-C 6环烷基或氰基取代的C 1-C 4烷基；
    X选自C和N；
    A选自C 3-C 4环烷基和C 3-C 4杂环烷基；
    B为芳香环，
    优选选自苯环、吡啶环和噻唑环，所述芳香环可被一个或多个取代基取代，所述取代基独立地选自相同或不同的H、卤素、CN、甲基和CF 3；
    m为1到5的整数；
    n为1到4的整数。
  8. 根据权利要求1所述的式I化合物，
    其中，
    R 1为H；
    R 2为一个或多个取代基，独立地选自相同或不同的H、F、Cl、CN和甲基；
    R 3为C 1-C 4烷基、C 3-C 6环烷基、C 1-C 4卤代烷基、卤代C 3-C 6环烷基和氰基取代的C 1-C 4烷基；
    X选自C和N；
    A选自C 3-C 4环烷基；
    B为芳香环，优选选自苯环、吡啶环和噻唑环，所述芳香环可被一个或多个取代基取代，所述取代基独立地选自相同或不同的H、卤素、CN、甲基和CF 3；
    m为1；
    n为1到3的整数。
  9. 根据权利要求1所述的式I化合物，
    其中，
    R 1为H；
    R 2为一个或多个取代基，独立地选自相同或不同的H、F、Cl、CN和甲基；
    R 3为C 1-C 4烷基、C 3-C 6环烷基、C 1-C 4卤代烷基、卤代C 3-C 6环烷基或氰基取代的C 1-C 4烷基；
    X选自C和N；
    A选自C 3-C 4环烷基；
    B为芳香环，优选选自苯环、吡啶环和噻唑环，所述芳香环可被一个或多个取代基取代，所述取代基独立地选自相同或不同的H、卤素、CN、甲基和CF 3；
    m为1；
    n为1到2的整数。
  10. 根据权利要求1所述的式I，其中所述化合物选自：
    5-(环丙甲酰氨基)-2-氟-4-甲基-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)苯甲酰胺；
    5-(环丙甲酰氨基)-2-氟-4-甲基-N-(6-(4-环丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)苯甲酰胺；
    (S)-5-(环丙甲酰氨基)-2-氟-4-甲基-N-(6-(4-(1,1,1-三氟丙基-2-基)-4H-1,2,4-三唑-3-基)吡啶-2-基)苯甲酰胺；
    5-(环丙甲酰氨基)-2-氟-4-甲基-N-(6-(4-(2,2,2-三氟乙基)-4H-1,2,4-三唑-3-基)吡啶-2-基)苯甲酰胺；
    (R)-5-(环丙甲酰氨基)-2-氟-4-甲基-N-(6-(4-(1,1,1-三氟丙基-2-基)-4H-1,2,4-三唑-3-基)吡啶-2-基)苯甲酰胺；
    (R)-5-(环丙甲酰氨基)-2-氟-N-6-(4-(1-甲氧丙基-2-基)-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基苯甲酰胺；
    (R)-5-(环丙甲酰氨基)-2-氟-N-6-(4-(1-羟丙基-2-基)-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基苯甲酰胺；
    (S)-5-(环丙甲酰氨基)-2-氟-4-甲基-N-2-(4-(1,1,1-三氟丙基-2-基)-4H-1,2,4-三唑-3-基)噻唑-4-基)苯甲酰胺；
    (S)-4-氯-5-(环丙甲酰氨基)-2-氟-N-(6-(4-(1,1,1-三氟丙基-2-基)-4H-1,2,4-三唑-3-基)吡啶-2-基)苯甲酰胺；
    (S)-4-(环丙甲酰氨基)-N-(6-(4-(1,1,1-三氟丙基-2-基)-4H-1,2,4-三唑-3-基)吡啶-2-基)吡啶-2-甲酰胺；
    (S)-4-(环丙甲酰氨基)-5-氟-N-(6-(4-(1,1,1-三氟丙基-2-基)-4H-1,2,4-三唑-3-基)吡啶-2-基)吡啶-2-甲酰胺；
    (S)-5-(环丙甲酰胺基)-2-氟-4-甲基-N-(3-(4-(1,1,1-三氟丙基-2-基)-4H-1,2,4-三唑-3-基)苯基)苯甲酰胺；
    2-氟-5-(2-(4-氟苯基)环丙基-1-甲酰氨基)-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基苯甲酰胺；
    5-(环丁甲酰氨基)-2-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基苯甲酰胺；
    2-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基-5-(1-(三氟甲基)环丙 基-1-甲酰氨基)苯甲酰胺；
    2-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基-5-(1-(氟)环丙基-1-甲酰氨基)苯甲酰胺；
    2-氟-5-((1R,2R)-2-氟环丙基-1-甲酰氨基)-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基苯甲酰胺；
    2-氟-5-((1R,2S)-2-氟环丙基-1-甲酰氨基)-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-甲基苯甲酰胺；
    (S)-5-(环戊甲酰氨基)-2-氟-4-甲基-N-(6-(4-(1,1,1-三氟丙基-2-基)-4H-1,2,4-三唑-3-基)吡啶-2-基)苯甲酰胺；和
    (S)-5-(环庚甲酰氨基)-2-氟-4-甲基-N-(6-(4-(1,1,1-三氟丙基-2-基)-4H-1,2,4-三唑-3-基)吡啶-2-基)苯甲酰胺。
  11. 制备根据权利要求1所述的式I化合物的方法，包括使式II化合物或其酰氯化物与式III化合物在碱催化下进行缩合反应，
    Figure PCTCN2019083829-appb-100002
    其中，各变量如权利要求1所定义。
  12. 制备根据权利要求1所述的式I化合物的方法，包括以式II化合物和IV-1化合物为起始原料，通过下式所示反应步骤制得，
    Figure PCTCN2019083829-appb-100003
    其中，各变量如权利要求1所定义。
  13. 制备根据权利要求1所述的式I化合物的方法，包括使式V化合物与式II-4 化合物在碱催化下进行缩合反应，
    Figure PCTCN2019083829-appb-100004
    其中，R’为OH或Cl；其它各变量如权利要求1所定义。
  14. 根据权利要求11或13所述的制备方法，其中所述碱催化剂选自TEA、DIPEA和Py。
  15. 根据权利要求13所述的制备方法，其中所述缩合反应在缩合剂存在下进行，所述缩合剂选自HATU、HOBt、PyBOP和T 3P。
  16. 根据权利要求11所述的制备方法，其中所述式II化合物由如下合成路线制备，
    Figure PCTCN2019083829-appb-100005
    其中，R’为OH或Cl；R 4为烷基；其它各变量如权利要求1所定义。
  17. 根据权利要求11或12所述的制备方法，其中所述式III化合物由如下合成路线制备，
    Figure PCTCN2019083829-appb-100006
    其中，各变量如权利要求1所定义。
  18. 一种药物组合物，其包含权利要求1至10中任一项所述的式I化合物以及任选的可药用载体、辅料或稀释剂。
  19. 权利要求1至10中任一项所述的化合物在制备用于治疗或预防与ASK1激 酶相关的疾病的药物中的应用。
  20. 根据权利要求19的应用，其中所述与ASK1激酶相关的疾病选自炎性疾病、代谢性疾病、自身免疫性疾病、心血管疾病、神经退行性疾病和癌症。
  21. 权利要求18所述的药物组合物在制备用于治疗或预防与ASK1靶点相关的疾病的药物中的应用。
  22. 根据权利要求21所述的应用，其中所述与ASK1靶点相关的疾病选自炎性疾病、代谢性疾病、自身免疫性疾病、心血管疾病、神经退行性疾病、癌症及其它疾病。
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