WO2020030107A1 - Composition pharmaceutique contenant des dérivés amides, son procédé de préparation et application associée - Google Patents

Composition pharmaceutique contenant des dérivés amides, son procédé de préparation et application associée Download PDF

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Publication number
WO2020030107A1
WO2020030107A1 PCT/CN2019/099971 CN2019099971W WO2020030107A1 WO 2020030107 A1 WO2020030107 A1 WO 2020030107A1 CN 2019099971 W CN2019099971 W CN 2019099971W WO 2020030107 A1 WO2020030107 A1 WO 2020030107A1
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group
alkyl
heteroaryl
cycloalkyl
alkoxy
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PCT/CN2019/099971
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English (en)
Chinese (zh)
Inventor
高鹏
孙广俊
王少宝
张福军
包如迪
Original Assignee
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 CN201980004523.4A priority Critical patent/CN111107848B/zh
Publication of WO2020030107A1 publication Critical patent/WO2020030107A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the field of pharmaceutical synthesis, and particularly relates to a pharmaceutical composition containing an amide derivative, and a preparation method and application thereof.
  • the mitogen-activated protein kinase (MAPK) signaling pathway mediates many different cell functions, including cell growth, differentiation, inflammation, survival, and apoptosis, and is a key signaling pathway for cell mitosis and apoptosis.
  • MAPK mitogen-activated protein kinase kinase kinase
  • MAP3K mitogen-activated protein kinase kinase kinase
  • MAP2K mitogen-activated protein kinase kinase
  • MAPK mitogen-activated protein kinase kinase
  • MAP3K is activated by environmental signals, which activates MAP2K and MAP2K.
  • MAPK which mediates the corresponding cellular effects by phosphorylating its downstream substrates such as transcription factors.
  • Apoptosis signal-regulated kinase 1 (ASK1) is also called mitogen-activated protein kinase kinase kinase 5 (MAP3K5). It belongs to the MAPK family and mediates the activation of MAPK signaling pathways.
  • ASK1 can be used in stress responses including oxidative stress, endoplasmic It is activated by autophosphorylation under conditions such as network stress and calcium influx, thereby activating its downstream MAP2K (such as MKK3 / 6 and MKK4 / 7), further activating c-Jun N-terminal kinase (JNK) and p38 mitosis-activated protein kinase, leading to Related cellular effects such as apoptosis, ASK1 activation and its signaling pathways play important roles in neuroretirement diseases, cardiovascular diseases, inflammation, autoimmune and metabolic diseases.
  • MAP2K such as MKK3 / 6 and MKK4 / 7
  • JNK c-Jun N-terminal kinase
  • p38 mitosis-activated protein kinase leading to Related cellular effects such as apoptosis, ASK1 activation and its signaling pathways play important roles in neuroretirement diseases, cardiovascular diseases, inflammation, autoimmune and metabolic diseases.
  • NASH non-alcoholic steatohepatitis
  • ASK1 inhibitors have great potential for clinical treatment of NASH, and also have potential application value in the treatment of other disease areas including neuroretirement diseases, cardiovascular diseases, inflammation, autoimmune and metabolic diseases.
  • ASK1 inhibitors have good application prospects as medicines in the pharmaceutical industry.
  • the present invention will provide a novel structure of selective ASK1 inhibitor compositions, and it is found that compounds having such structures exhibit pharmacological and pharmacological activity Excellent effect and function.
  • An object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and its structure is as follows:
  • 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 deuterium, alkyl, deuterated alkyl, halogen, amino, nitro, hydroxyl, cyano, 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 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R
  • R 1 is the same or different, and each is independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen group, an amino group, a nitro group, a hydroxy group, a cyano group, a cyclic group Alkyl, 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) NHR 10 ,-(CH 2
  • R 2 is the same or different, and each is independently selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen group, an amino group, a nitro group, a hydroxyl group, a cyano group, and a ring Alkyl, 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) NHR 10 ,
  • R 3 is selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; Alkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkane Group, 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 3 and M 3 , M 3 and M 4 are respectively linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is described
  • cycloalkyl, heterocyclyl, aryl or heteroaryl is described
  • haloalkyl, halogen amino, nitro, hydroxy, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, Heterocyclyl, aryl and heteroaryl,-(CR 9 R 10 ) n -,-(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
  • R 1 and X or Y, M 1 and X or Y are respectively linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or Heteroaryl is optionally further selected from deuterium, alkyl, deuterated alkyl, haloalkyl, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cyclic Alkyl, heterocyclyl, aryl and heteroaryl,-(CR 9 R 10 ) n -,-(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)
  • R 6 , R 7 and R 8 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, Hydroxyl, 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) NHR 10 ,-(CH 2 ) n
  • R 9 is selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyl group, an amino group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; Said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium, alkyl, halogen, amino, nitro, cyano, hydroxy, hydroxyalkyl, Alkoxy, cycloalkyl, heterocyclyl, 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 ,-
  • R 10 and R 11 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group
  • said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of a deuterium 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 , -(
  • R 12 and R 13 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyl group, an amino group, an ester group, a cycloalkyl group, a heterocyclic group, an aryl group, and Heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium, alkyl, halogen, hydroxyl, amino, nitro, cyano, ester Substituted with one or more substituents of aryl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • 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 pharmaceutical composition is characterized in that the weight percentage of the active ingredient is 1% to 95%, preferably 5% to 85%, more preferably 10% to 60%, even more preferably 10% to 50%.
  • the pharmaceutical composition is characterized in that the dosage range is 0.5-120 mg, preferably 1-100 mg, further preferably 1-50 mg, and even more preferably 1-30 mg.
  • the pharmaceutical composition is characterized in that the compound of the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the following compounds of the general formula (II):
  • R 4 is selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxy 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 ; the alkyl, haloalkyl, cycloalkyl, heterocyclic ring Aryl, aryl and heteroaryl are optionally further selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, halo
  • R 3 and R 4 are linked to form a heterocyclic ring or heteroaromatic ring, wherein the heterocyclic ring or heteroaromatic ring is optionally further selected from the group consisting of a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a halogen group, an amino group, and a nitrate group.
  • R 3 and R 4 are linked to form a heterocyclic ring or heteroaryl ring, and any two substituents on the heterocyclic ring or heteroaryl ring may form a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein
  • the cycloalkyl, aromatic ring, heterocyclyl or heteroaryl ring group is optionally further selected from the group consisting of a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, Alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 ,-( CH 2 ) n SR 9
  • Rings A, M 1 , M 2 , X, Y, R 1 -R 3 , x, y, m and n are as described in the general formula (I).
  • the pharmaceutical composition is characterized in that the compound of the general formula (I) is represented by the general formula (III):
  • Ring B is selected from heterocyclyl or heteroaryl; wherein, heterocyclyl preferably contains 3 to 20 ring atoms, of which one or more ring atoms are selected from nitrogen, oxygen, phosphorus or S (O) t, and the remaining rings
  • the atom is carbon
  • the heterocyclic group further preferably contains 3 to 12 ring atoms, of which 1 to 4 ring atoms are selected from nitrogen, oxygen, and phosphorus, and the remaining ring atoms are carbon
  • the heterocyclic group more preferably contains 3 to 8 ring atoms. Wherein 1 to 3 ring atoms are selected from nitrogen and oxygen, and the remaining ring atoms are carbon.
  • heterocyclic group most preferably contains 5 to 7 ring atoms, of which 1 to 2 ring atoms are selected from nitrogen and oxygen, and the remaining ring atoms
  • heterocyclyl is further preferably selected from pyrrole, piperidine, azacycloheptane, morpholine, piperazine;
  • heteroaryl preferably contains 5 to 14 ring atoms, of which 1 to 4 ring atoms are selected from nitrogen, oxygen , Phosphorus or S (O) t, the remaining ring atoms are carbon, and the heteroaryl group further preferably contains 5 to 10 ring atoms, of which 1 to 4 ring atoms are selected from nitrogen, oxygen, phosphorus or S (O) t, and the rest
  • the ring atom is carbon
  • the heteroaryl group more preferably contains 5 to 10 ring atoms, of which 1 to 3 ring atoms are selected from nitrogen, oxygen, and phosphorus, the remaining ring atoms are carbon
  • R a is selected from the group consisting of a hydrogen atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group, and a heterocyclic ring.
  • R a is optionally further selected from the group consisting of a deuterium atom, an alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxy group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cyclic group Alkyl, heterocyclyl, 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
  • any two R a substituents on ring B form a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the hetero atom is 1 to 4 selected from nitrogen, oxygen, sulfur, and phosphorus, preferably any
  • the two R a substituents form a C 3-8 cycloalkyl group, a C 3-8 heterocyclyl group, a C 6-14 aryl group, and a C 5-14 heteroaryl group, wherein the hetero atom is selected from nitrogen, oxygen, sulfur, 1 to 3, more preferably any two R a substituents in phosphorus form C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-10 aryl, and C 5-10 heteroaryl, wherein Heteroatoms are 1 to 2 selected from nitrogen and oxygen, most preferably any two R a substituents form cyclopropyl, cyclobutyl, cyclopentyl, C 3-5 heterocyclyl, C 6-7
  • the ring formed by any two R a substituents is optionally further selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, and an alkenyl group.
  • z is an integer of 0, 1, 2, 3, 4 or 5;
  • t 0, 1, or 2.
  • the pharmaceutical composition is characterized in that the compound of the general formula (I) is represented by the general formula (IV):
  • M 5 is O, -CR 6 or -NR 7 ;
  • R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyanide Group, 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) NHR 10 ,-(CH 2 )
  • R 6 and R 7 are optionally further selected from a deuterium atom, an alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, and a cyclic Alkyl, heterocyclyl, 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)
  • q 0, 1, or 2.
  • the pharmaceutical composition is characterized in that the compound of the general formula (I) is represented by the general formula (V):
  • o is an integer of 0, 1, 2, 3, 4 or 5.
  • the pharmaceutical composition is characterized by:
  • M 1 and M 2 are each independently selected from N or -CR 6 , and optional M 1 and M 2 are different;
  • X and Y are each independently selected from a bond, -NR 7- , -CR 7 R 8- , -S (O) m- , The optional X and Y are different;
  • Ring A is selected from aryl or heteroaryl; the aryl is 6 to 14 membered full carbon monocyclic or fused polycyclic, preferably 6 to 10 members, more preferably phenyl or naphthyl; the heteroaryl The group preferably contains 5 to 14 ring atoms, of which 1 to 4 ring atoms are selected from nitrogen, oxygen, phosphorus or S (O) t, the remaining ring atoms are carbon, and the heteroaryl group further preferably contains 5 to 10 ring atoms, Wherein 1 to 4 ring atoms are selected from nitrogen, oxygen, phosphorus or S (O) t, the remaining ring atoms are carbon, and the heteroaryl group more preferably contains 5 to 10 ring atoms, of which 1 to 3 ring atoms are selected from nitrogen , Oxygen, phosphorus, the remaining ring atoms are carbon, most preferably imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl,
  • Heteroaryl is further most preferably comprising 5 or 6 ring atoms, of which 1 to 2 atoms are selected from nitrogen and oxygen;
  • the ring A is optionally further selected from a deuterium atom, an alkyl group, a deuterated alkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group , 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 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CHCH 2
  • R 2 is the same or different, and each is independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen group, an amino group, a nitro group, a hydroxy group, a cyano group, a cyclic Alkyl, 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) NHR 10 ,-(CH 2 )
  • the pharmaceutical composition is characterized in that the compound of the general formula (I) is represented by the general formula (III-A):
  • the pharmaceutical composition is characterized in that the compound of the general formula (I) is represented by the general formula (III-A1) or the general formula (III-A2):
  • Ring C is a 4-7 membered heterocyclyl or heteroaryl group, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S (O) t, and the remaining ring atoms are carbon, preferably containing 1-2 5-membered heterocyclic group of nitrogen or oxygen atom; the heteroaryl group preferably contains 1 to 4 heteroatoms, wherein the heteroatom is selected from the group consisting of oxygen, sulfur and nitrogen, preferably a heteroatom containing 1 to 2 nitrogen or oxygen 5- or 6-membered heteroaryl; preferably, ring C has the following structure:
  • R b is selected from a hydrogen atom, a C 1-8 alkyl group, a C 1-8 deuterated alkyl group, or a C 1-8 haloalkyl group
  • t 0, 1, or 2.
  • the pharmaceutical composition is characterized in that: R 1 is the same or different and each is independently selected from a hydrogen atom, a deuterium atom, and a C 1-8 alkyl group , Deuterated C 1-8 alkyl, halo C 1-8 alkyl, C 1-8 alkoxy, halo C 1-8 alkoxy, halogen, amino, nitro, hydroxyl, cyano, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 6-14 aryl, C 5-14 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 (
  • R 1 is optionally further selected from the group consisting of a deuterium 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 hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group.
  • the pharmaceutical composition is characterized in that R 1 is the same or different, and each is independently selected from the group consisting of a hydrogen atom, a deuterium atom, a C 1-3 alkyl group, and deuterium.
  • the pharmaceutical composition is characterized in that: R 1 is selected from a hydrogen atom, a deuterium atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, Deuterated methyl, deuterated ethyl, deuterated propyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, Chloropropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropyl Oxygen, fluorine, chlorine, bromine, iodine, amino, nitro, hydroxyl, cyano, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrol
  • the pharmaceutical composition is characterized in that the compound of the general formula (I) is represented by the general formula (VI-A) or the general formula (VI-B):
  • R 5 is selected from the group consisting of a hydrogen atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cyano group, a cycloalkyl group, a heterocyclic group, 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 )
  • R 5 is optionally further selected from the group consisting of a deuterium atom, an alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxy group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group.
  • x-1 is an integer of 1, 2, 3, or 4.
  • the pharmaceutical composition is characterized in that the compound of the general formula (I) is represented by the general formula (VI-A1) or the general formula (VI-B1):
  • M 5 is O, -CR 6 or -NR 7 ;
  • R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyanide Group, 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) NHR 10 ,-(CH 2 )
  • R 6 and R 7 are optionally further selected from a deuterium atom, an alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, and a cyclic Alkyl, heterocyclyl, 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)
  • q 0, 1, or 2.
  • the pharmaceutical composition is characterized in that the compound of the general formula (I) is represented by the general formula (VI-A2) or the general formula (VI-B2):
  • o is an integer of 0, 1, 2, 3, 4 or 5.
  • the pharmaceutical composition is characterized in that the compound of general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the following compounds of general formula (VII):
  • Ring B is selected from heterocyclyl or heteroaryl
  • R 5 is selected from the group consisting of a hydrogen atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cyano group, a cycloalkyl group, a heterocyclic group, 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 )
  • R a is selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, and a cycloalkyl group , Heterocyclyl, aryl, heteroaryl,-(CR 9 R 10 ) n -,-(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
  • any two R a substituents on the B ring may form a new cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said forming a new cycloalkyl, aromatic ring, heterocyclyl or
  • the heteroaryl ring group is optionally further selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkoxy group, a hydroxyalkyl group, and a cycloalkyl group.
  • x-1 is an integer of 1, 2, 3, or 4;
  • z is an integer of 0, 1, 2, 3, 4 or 5;
  • Rings 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 pharmaceutical composition is characterized in that when ring B is selected from a heterocyclic group, it preferably contains 3 to 20 ring atoms, wherein one or more ring atoms are selected from A heteroatom of nitrogen, oxygen or S (O) t, t is 0, 1 or 2, and the remaining ring atoms are carbon; more preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms selected from nitrogen and oxygen Atom; most preferably contains 5 to 7 ring atoms, of which 1 to 2 are heteroatoms selected from nitrogen and oxygen; when ring B is selected from heteroaryl, it preferably contains 1 to 4 heteroatoms and 5 to 14 rings Atom heteroaryl, wherein the heteroatom is selected from the group consisting of oxygen, sulfur, and nitrogen, more preferably a 5- to 10-membered heteroaryl containing 1 to 2 heteroatoms, wherein the heteroatom is selected from the group consisting of oxygen and nitrogen, and most preferably 1 A 5- or 6-membered heteroaryl group to
  • the pharmaceutical composition is characterized in that the compound of the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the compounds of the general formula (VIII):
  • the pharmaceutical composition is characterized in that the compound of the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the compounds of the general formula (IX):
  • Ring B, R 1, R 5, R a, x-1 , and z are as in formula (I) said.
  • the pharmaceutical composition is characterized in that the compound of the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the compounds of the following general formula (X-A):
  • M 5 is O, -CR 6 or -NR 7 ;
  • R 1 is selected from a hydrogen atom, a C 1-8 alkyl group or a halogen
  • R 5 is selected from C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, or 3-6 membered heterocyclic group;
  • R a is the same or different and each is independently selected from the group consisting of a hydrogen atom, a cyano group, a C 1-8 alkyl group, a C 2-8 alkenyl group, a C 2-8 alkynyl group, a C 1-8 haloalkyl group, and a C 1-8 hydroxy group Alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl,-(CH 2 ) n OR 9 ,-(CR 9 R 10 ) n -or-(CH 2 ) n C (O) R 9 , wherein the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halo C 1-8 alkyl, C 1-8 hydroxyalkyl, C 1-8 alkane
  • An oxy group and a C 3-8 cycloalkyl group are optionally further selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group,
  • R 9 and R 10 are the same or different and are each independently selected from a hydrogen atom, a C 1-8 alkyl group, a C 1-8 haloalkyl group, a C 1-8 hydroxyalkyl group, or a C 1-8 alkoxy group;
  • x-1 is an integer of 1, 2, 3 or 4;
  • q 0, 1, or 2;
  • z is an integer of 0, 1, 2, 3, 4 or 5.
  • the pharmaceutical composition is characterized in that the compound of the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the compounds of the general formula (XI):
  • o is an integer of 0, 1, 2, 3, 4 or 5;
  • R 1, R 5, R a , x and z are as formula (VI) said.
  • the pharmaceutical composition is characterized in that the compound of general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the following compounds of general formula (XII):
  • R a is the same or different and each is independently selected from the group consisting of hydrogen atom, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkane Oxy, C 3-6 cycloalkyl,-(CH 2 ) n OR 9 or-(CR 9 R 10 ) n- , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2 -6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 3-6 cycloalkyl are optionally further selected from hydrogen atom, halogen, cyano, hydroxy, C 1-6 alkyl or Substituted with one or more substituents in C 1-6 alkoxy; or any two R a substituents may form a 3-6 membered cycloalkyl, and
  • z is an integer of 0, 1, 2 or 3.
  • the pharmaceutical composition is characterized in that the compound of general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the following general formula (XIII-A) Compound:
  • M 5 is selected from S or CH;
  • R 3 is selected from 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 ring Group, wherein said C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl and 3-10 member
  • the heterocyclyl is optionally further selected from a hydrogen atom, a deuterium atom, a C 1-8 alkyl group, a C 1-8 deuterated alkyl group, a C 1-8 haloalkyl group, a halogen group, an amino group, a hydroxyl group, a cyano group, and C 1 One or more of -8alkoxy , C 1-8 hydroxyalkyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5
  • R 4 is selected from a hydrogen atom, C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl, or 3-10 Heterocyclic
  • a 3-10 membered heterocyclic ring or a 5-10 membered heteroaromatic ring formed by linking R 3 and R 4 wherein the 3-10 membered heterocyclic ring or 5-10 membered heteroaromatic ring is optionally further selected from a deuterium atom , Alkyl, deuterated alkyl, haloalkyl, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and hetero Aryl,-(CR 9 R 10 ) n -,-(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
  • R b is selected from a hydrogen atom, a C 1-8 alkyl group, a C 1-8 deuterated alkyl group, or a C 1-8 haloalkyl group; wherein R b may be substituted on the oxo ring or the M 5 ring;
  • p is an integer of 0, 1, 2, 3, or 4;
  • q is an integer of 0 or 1.
  • the pharmaceutical composition is characterized in that ring C is a 4- to 7-membered heterocyclic group or a heteroaryl group, preferably a 5-membered heterocyclic group.
  • ring C is a 4- to 7-membered heterocyclic group or a heteroaryl group, preferably a 5-membered heterocyclic group.
  • the most preferred structure of the ring, C is as follows:
  • the pharmaceutical composition is characterized in that the compound of general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the following general formula (XIII-B ) Compound:
  • Ring C is a 4- to 7-membered heterocyclic group or a heteroaryl group, preferably a 5-membered heterocyclic group;
  • R a each independently selected from hydrogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, - (CH 2 ) n OR 9 ,-(CR 9 R 10 ) n -or-(CH 2 ) n C (O) R 9 , or any two R a substituents may form a 3-6 membered cycloalkyl group;
  • R b is selected from a hydrogen atom, a C 1-8 alkyl group, a C 1-8 deuterated alkyl group, or a C 1-8 haloalkyl group;
  • R 9 and R 10 are independently selected from a hydrogen atom or a C 1-8 alkyl group
  • z is an integer of 0, 1, 2, 3, or 4;
  • p 0, 1, or 2.
  • each of the general formulas, stereoisomers, or pharmaceutically acceptable salts thereof is shown, wherein R 1 is selected from C 1-8 alkyl, C 3-8 Cycloalkyl, 5- to 10-membered heteroaryl, and halogen, preferably 5- to 6-membered heteroaryl, halogen, and C 1-6 alkyl, more preferably pyrazole, fluorine atom, and methyl.
  • each of the general formulas, stereoisomers, or pharmaceutically acceptable salts thereof is shown, wherein Ra is selected from a hydrogen atom, a cyano group, and a C 1-8 alkane.
  • each of the general formulas, stereoisomers, or pharmaceutically acceptable salts thereof shown is characterized in that any two of R a optionally form a 3-6 membered ring Alkyl is preferably cyclopropyl.
  • each of the formulas, stereoisomers, or pharmaceutically acceptable salts thereof is shown, wherein R 5 is selected from a hydrogen atom, a C 1-8 alkyl group, and C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, halogen, C 3-8 cycloalkyl, 3-10 membered heterocyclic group, preferably From hydrogen atom, C 1-6 alkyl, hydroxy C 1-6 alkyl C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group; R 5 is most preferably cyclopropyl, Isopropyl, hydroxyisopropyl, t-butyl, trifluoromethyl or
  • the present invention also relates to a method of treating and / or treating a disease preventing ASK1-mediated pathological features, which comprises administering to a patient a therapeutically effective dose of a pharmaceutical composition.
  • the invention further relates to the pharmaceutical composition, which is characterized in that the compound represented by the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is used in the preparation of an ASK1 inhibitor medicine.
  • the pharmaceutical composition which is characterized in that the compound represented by the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is used in the preparation of an ASK1 inhibitor medicine.
  • the invention further relates to the application of the pharmaceutical composition in the preparation of a medicament for treating neurodegenerative disorder, cardiovascular disorder, inflammatory disorder, metabolic disorder and ASK1.
  • the inflammatory disorder is preferably non-alcoholic steatohepatitis (NASH ).
  • the present invention further relates to the pharmaceutical composition for preparing a method for treating non-alcoholic steatohepatitis (NASH).
  • NASH non-alcoholic steatohepatitis
  • the present invention also relates to a method for treating prevention and / or treatment of a pre-prepared treatment of neurodegenerative, cardiovascular, inflammatory, and metabolic disorders, which comprises administering a therapeutically effective dose of a pharmaceutical composition to a patient.
  • the active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, dragees, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture.
  • Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, colorants, and preservatives, To provide pleasing and delicious medicinal preparations. Tablets contain the active ingredients and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing.
  • excipients can be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn Starch or alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc.
  • These tablets can be uncoated or they can be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release over a longer period.
  • water-soluble taste-masking substances such as hydroxypropyl methyl cellulose or hydroxypropyl cellulose, or prolonged substances, such as ethyl cellulose, cellulose acetate butyrate, can be used.
  • an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin
  • a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin, or olive oil
  • Soft gelatin capsules are provided as an oral preparation.
  • Aqueous suspensions contain the active substance and excipients suitable for the preparation of the aqueous suspension for mixing.
  • excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, and gum arabic; dispersants or wetting agents may be naturally occurring Phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecyloxycetyl alcohol (heptadecaethyleneoxycetanol), or the condensation product of ethylene oxide with a partial ester derived from a fatty acid and hexitol, such as polyethylene oxide sorbitol monooleate, or ethylene oxide with a derivative of fatty acid and hexitol anhydride Condensation products of partial esters, such as polyethylene oxide sorbitan
  • the aqueous suspension may also contain one or more preservatives such as ethyl paraben or n-propyl paraben, one or more colorants, one or more flavoring agents, and one or more sweeteners.
  • preservatives such as ethyl paraben or n-propyl paraben
  • colorants such as ethyl paraben or n-propyl paraben
  • flavoring agents such as sucrose, saccharin or aspartame.
  • Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin.
  • the oil suspension may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • the sweeteners and flavoring agents described above can be added to provide a palatable formulation. These compositions can be preserved by the addition of an antioxidant such as fenoxyfen or alpha-tocopherol.
  • dispersible powders and granules suitable for preparing aqueous suspensions can be provided with active ingredients and dispersing or wetting agents, suspending agents or one or more preservatives for mixing. Suitable dispersing or wetting agents and suspending agents can illustrate the above examples. Other excipients such as sweeteners, flavors and colorants can also be added. These compositions are preserved by the addition of an antioxidant such as ascorbic acid.
  • the pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion.
  • the oily phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, such as soybean lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and the condensation products of said partial esters and ethylene oxide, For example, polyethylene oxide sorbitol monooleate.
  • Emulsions may also contain sweeteners, flavoring agents, preservatives and antioxidants.
  • Syrups and elixirs can be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous solution.
  • acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is then added to a mixture of water and glycerol to form a microemulsion. Injections or microemulsions can be injected into a patient's bloodstream by local, large injections.
  • solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of a compound of the invention.
  • continuous intravenous drug delivery devices can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.
  • the pharmaceutical composition may be in the form of a sterile injectable water or oily suspension for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent, for example, a solution prepared in 1,3-butanediol.
  • a sterile fixed oil can be conveniently used as a solvent or suspension medium.
  • any blended fixing oil including synthetic mono- or diesters can be used.
  • fatty acids such as oleic acid can also be prepared for injection.
  • the compounds of the invention may be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and therefore will dissolve in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, glycerin gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.
  • the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient Quilt, patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc .;
  • the best treatment methods such as the mode of treatment, the daily dosage of the general compound (I) or a pharmaceutically acceptable salt The type can be verified according to traditional treatment protocols.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms Alkyl, most preferably 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 2,2-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-methylhex
  • the alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkane Alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups, methyl, ethyl, isopropyl, t-butyl, haloalkyl are preferred in the present invention , Deuterated alkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.
  • alkylene means that a hydrogen atom of an alkyl group is further substituted, for example: "methylene” means -CH 2- , “ethylene” means-(CH 2 ) 2- , “propylene” Refers to-(CH 2 ) 3- , “butylene” refers to-(CH 2 ) 4- , etc., the above substituents may be connected to different carbon atoms to form a carbon chain, or may be connected to one carbon atom to form a cycloalkyl group.
  • alkenyl refers to an alkyl group, as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3 -Butenyl and the like. Alkenyl may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 Carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • Polycyclic cycloalkyl includes spiro, fused and bridged cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent that contains 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S (O) A heteroatom of m (where m is an integer from 0 to 2), excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 8 ring atoms; and most preferably 3 to 8 ring atoms.
  • Non-limiting examples of monocyclic heterocyclyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidine Group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., and tetrahydrofuranyl, pyrazolyl, morpholinyl, piperazinyl, and pyranyl are preferred.
  • Polycyclic heterocyclyls include spiro, fused, and bridged heterocyclic groups; the involved spiro, fused, and bridged heterocyclic groups are optionally connected to other groups through a single bond, or through a ring Any two or more of the above atoms are further connected with other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups in a ring; the heterocyclyl may be optionally substituted or unsubstituted, when substituted
  • the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano , Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carb
  • aryl refers to a 6 to 14 membered, all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 members, such as benzene And naphthyl. More preferred is phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:
  • an aryl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen.
  • Heteroaryl is preferably 5- to 10-membered, more preferably 5- or 6-membered, 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 preferably triazolyl, pyrrolyl, thienyl , Thiazolyl and pyrimidinyl.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or
  • Heteroaryl may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.
  • alkoxy refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is as defined above.
  • An alkoxy group containing 1 to 8 carbon atoms is preferred, an alkoxy group having 1 to 6 carbon atoms is more preferred, and an alkoxy group having 1 to 3 carbon atoms is most preferred.
  • Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.
  • Haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • Haloalkoxy refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
  • Hydroalkyl refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
  • Alkenyl means an alkenyl group, also known as an alkenyl group, preferably an alkenyl group containing 2 to 8 carbon atoms, more preferably an alkenyl group containing 2 to 6 carbon atoms, and most preferably an alkenyl group containing 2 to 3 carbon atoms ; Where the alkenyl group may be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano , Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
  • Alkynyl means (CH ⁇ C-), preferably an alkynyl group containing 2 to 8 carbon atoms, more preferably an alkynyl group having 2 to 6 carbon atoms, and most preferably an alkynyl group having 2 to 3 carbon atoms.
  • the alkynyl group may be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
  • other related groups such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • Amino means -NH 2.
  • Cyano refers to -CN.
  • Niro refers to -NO 2.
  • Carboxy refers to -C (O) OH.
  • THF tetrahydrofuran
  • EtOAc means ethyl acetate
  • MeOH means methanol
  • DMF N, N-dimethylformamide
  • DIPEA diisopropylethylamine
  • TFA trifluoroacetic acid
  • DMA refers to N, N-dimethylacetamide.
  • Et 2 O refers to diethyl ether
  • DCE refers to 1,2-dichloroethane.
  • DIPEA N, N-diisopropylethylamine
  • NBS N-bromosuccinimide
  • NIS N-iodosuccinimide
  • Cbz-Cl refers to benzyl chloroformate
  • Pd 2 (dba) 3 refers to tris (dibenzylideneacetone) dipalladium.
  • Dppf refers to 1,1'-bisdiphenylphosphine ferrocene.
  • HATU refers to 2- (7-benzotriazole) -N, N, N ', N'-tetramethylurea hexafluorophosphate.
  • KHMDS refers to potassium hexamethyldisilazide
  • LiHMDS refers to lithium bistrimethylsilylamine.
  • MeLi means methyl lithium
  • N-BuLi refers to 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, or C
  • other terms all express the same Meaning, meaning that X can be any one or several of A, B, and C.
  • Stepoisomerism includes three types of geometric isomerism (cis-trans isomerism), optical isomerism, and conformational isomerism.
  • the hydrogen atom according to the present invention may be replaced by its isotope deuterium, and any hydrogen atom in the compound of the embodiment according to the present invention may also be replaced by a deuterium atom.
  • an heterocyclic group optionally substituted with an alkyl group means that the alkyl group may but need not exist, and this description includes a case where the heterocyclic group is substituted with an alkyl group and a case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted refers to one or more hydrogen atoms in a group, preferably up to 5 and more preferably 1 to 3 hydrogen atoms independently of one another 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 can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (eg, olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiological / pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as physiological / pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and then exerts the biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the present invention. Such salts are safe and effective when used in mammals, and have due biological activity.
  • the compound structure of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid-mass chromatography (LC-MS). NMR chemical shifts ( ⁇ ) are given in parts per million (ppm).
  • the NMR measurement was performed with Bruker AVANCE-400 nuclear magnetic analyzer. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ). The internal standard was four. Methylsilane (TMS).
  • Liquid chromatography-mass spectrometry LC-MS was measured using an Agilent 1200 Infinity Series mass spectrometer.
  • Agilent 1200 DAD high-pressure liquid chromatography (Sunfire C18 150 ⁇ 4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatography (Gimini C18 150 ⁇ 4.6 mm column) were used.
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specifications adopted by TLC are 0.15mm ⁇ 0.20mm, and the specifications adopted by thin layer chromatography purification products are 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the starting materials in the examples of the present invention are known and commercially available, or they can be synthesized or synthesized according to methods known in the art.
  • Step 2 Preparation of 5-((2-cyclopropyl-2-carbonylethyl) amino) -2-fluoro-4-methylbenzonitrile
  • Step 6 Synthesis of 6- (6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-amine
  • 6-aminomethylpyridylhydrazide 300mg, 1.97mmol was dissolved in 2-pentanol (5mL) and acetic acid (1mL), and 5-methoxy-3,4-dihydro-2H- Pyrrole (195 mg, 1.97 mmol).
  • the reaction was heated to 125 ° C, stirred at this temperature for 12 hours, cooled to room temperature, and then concentrated under reduced pressure. Then, a saturated NaHCO 3 aqueous solution (5 mL) was added, and dichloromethane (50 mL ⁇ 2) was extracted.
  • Step 7 Synthesis of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride
  • 6-aminomethylpyridylhydrazide (2.35g, 15.4mmol) was dissolved in 2-pentanol (15mL) and acetic acid (2mL), 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 under reduced pressure. Then, a saturated NaHCO 3 aqueous solution (5 mL) was added, and dichloromethane (50 mL ⁇ 2) was extracted.
  • 6-aminomethylpyridylhydrazide (435mg, 2.86mmol) was dissolved in 2-pentanol (15mL) and acetic acid (2mL), and 5-methoxy-2,2-dimethyl-3 was added.
  • 4-dihydro-2H-pyrrole (404 mg, 3.2 mmol).
  • the reaction was heated to 125 ° C, stirred at this temperature for 12 hours, cooled to room temperature, and concentrated under reduced pressure. Then, a saturated NaHCO 3 aqueous solution (5 mL) was added, and dichloromethane (50 mL ⁇ 2) was extracted.
  • the third step 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5,5-dimethyl-6,7-dihydro-5H-pyrrolo [2,1 -c] [1,2,4] Triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
  • Step 1 Synthesis of (S) -5-methoxy-2-vinyl-3,4-dihydro-2H-pyrrole
  • 6-aminomethylpyridinyl hydrazide (321 mg, 2.11 mmol) was dissolved in a mixed solvent of 2-pentanol (10 mL) and acetic acid (1 mL), and (S) -5-methoxy-2- Vinyl-3,4-dihydro-2H-pyrrole (293 mg, 2.34 mmol).
  • the reaction was heated to 125 ° C and stirred at this temperature for 12 hours.
  • the organic solvent was concentrated under reduced pressure, and then a saturated NaHCO 3 aqueous solution (5 mL) was added, and extracted with dichloromethane (50 mL ⁇ 2).
  • the organic phase was saturated with common salt.
  • Step 1 Synthesis of (S) -5-methoxy-2- (trifluoromethyl) -3,4-dihydro-2H-pyrrole
  • 6-aminomethylpyridylhydrazide (620 mg, 3.71 mmol) was dissolved in 2-pentanol (15 mL) and acetic acid (1 mL), and (S) -5-methoxy-2- (trifluoro (Methyl) -3,4-dihydro-2H-pyrrole (650 mg, 3.89 mmol).
  • the reaction was heated to 125 ° C, stirred at this temperature for 12 hours, cooled to room temperature, and concentrated under reduced pressure. Then, a saturated NaHCO 3 aqueous solution (5 mL) was added, and dichloromethane (50 mL ⁇ 2) was extracted.
  • Step 1 Synthesis of S-ethyl (S) -5-carbonylpyrrolidine-2-methylsulfate
  • Step 2 Synthesis of tert-butyl (S) -2-((ethylthio) carbonyl) -5-carbonylpyrrolidine-1-carboxylic acid ester
  • Step 3 Synthesis of tert-butyl (S) -2-formyl-5-carbonylpyrrolidine-1-carboxylic acid ester
  • Step 4 Synthesis of (S) -5-carbonylpyrrolidine-2-carboxaldehyde
  • t-butyl (S) -2-formyl-5-carbonylpyrrolidine-1-carboxylic acid ester (0.72 g, 3.38 mmol) was dissolved in CH 2 Cl 2 (10 mL), and then sequentially added TFA (2.5 mL). The reaction was slowly raised to room temperature, and after stirring at this temperature for 2 hours, the crude product (400 mg) was obtained after concentration under reduced pressure and used directly in the next step.
  • Step 5 Synthesis of (S) -5-ethynylpyrrolidin-2-one
  • 6-aminomethylpyridyl hydrazide (320 mg, 2.1 mmol) was dissolved in 2-pentanol (15 mL) and acetic acid (1 mL), and (S) -2-ethynyl-5-methoxy- 3,4-dihydro-2H-pyrrole (315 mg, crude product from previous step).
  • the reaction was heated to 125 ° C, stirred at this temperature for 12 hours, cooled to room temperature, and concentrated under reduced pressure. Then, a saturated NaHCO 3 aqueous solution (5 mL) was added, and dichloromethane (50 mL ⁇ 2) was extracted.
  • Step 1 Synthesis of (S) -2- (fluoromethyl) -5-methoxy-3,4-dihydro-2H-pyrrole
  • 6-aminomethylpyridylhydrazide (900mg, 6.0mmol) was dissolved in 2-pentanol (15mL) and acetic acid (1mL), and (S) -2- (fluoromethyl) -5-formaldehyde was added.
  • Oxy-3,4-dihydro-2H-pyrrole (783 mg, 6.0 mmol). The reaction was heated to 125 ° C, stirred at this temperature for 12 hours, cooled to room temperature, and then concentrated under reduced pressure. Then, a saturated NaHCO 3 aqueous solution (5 mL) was added, and dichloromethane (50 mL ⁇ 2) was extracted.
  • cuprous iodide (1.06g, 5.6mmol) was dissolved in tetrahydrofuran (6mL), replaced with nitrogen three times, and methyl lithium (7.4mL, 11.1mmol) was added dropwise.
  • the reaction was stirred at 0 ° C for 45min, and cooled At -20 ° C, a solution of (S)-(5-carbonylpyrrolidin-2-yl) methyl 4-methylbenzenesulfonate (500 mg, 1.9 mmol) in tetrahydrofuran (6 mL) was added dropwise to the reaction system. After stirring at -20 ° C for 45 min, the temperature was gradually raised to room temperature to react overnight.
  • 6-aminomethylpyridyl hydrazide 243 mg, 1.59 mmol was dissolved in 2-pentanol (5 mL) and acetic acid (2 mL), and (R) -2-ethyl-5-methoxy- 3,4-dihydro-2H-pyrrole (202 mg, 1.59 mmol).
  • the reaction was heated to 125 ° C, stirred at this temperature for 12 hours, cooled to room temperature, and then concentrated under reduced pressure. Then, a saturated NaHCO 3 aqueous solution (5 mL) was added, and dichloromethane (50 mL ⁇ 2) was extracted.
  • Step 6 Synthesis of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride
  • 6-aminomethylpyridylhydrazide 500mg, 4.5mmol was dissolved in 2-pentanol (15mL) and acetic acid (1mL), and 5-methoxy-4-azaspiro [2.4] heptane was added 4-ene (930 mg, 6.3 mmol).
  • the reaction was heated to 125 ° C, stirred at this temperature for 12 hours, cooled to room temperature, and then concentrated under reduced pressure. Then, a saturated NaHCO 3 aqueous solution (5 mL) was added, and dichloromethane (50 mL ⁇ 2) was extracted.
  • Methyl 5-amino-2-bromo-4-methylbenzoate (900 mg, 3.69 mmol), CuCN (657 mg, 7.38 mmol) were mixed in NMP (10 mL), stirred at 180 ° C for 2 hours, and added to water after cooling , Filtered, and the filter cake was dried to obtain the crude methyl 5-amino-2-cyano-4-methylbenzoate (1.5 g) as the title compound, which was directly used in the next step.
  • 6-amino-5-methylisoindolin-1-one (370mg, 2.28mmol), 2-bromo-1-cyclopropylethane-1-one (409mg, 2.51mmol), KI (38.0mg , 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 hours. Cool, add water to the mixture, and extract twice with dichloromethane. After the organic phases were combined, the organic phase was washed three times with saturated brine, and after drying, the organic solvent was removed under reduced pressure, and the crude product was directly used in the next step.
  • Step 4 Preparation of 6- (4-cyclopropyl-2-mercapto-1H-imidazol-1-yl) -5-methylisodihydroindol-1-one
  • the crude product from 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 product was used directly in the next step.
  • Step 5 Preparation of 6- (4-cyclopropyl-1H-imidazol-1-yl) -5-methylisodihydroindol-1-one
  • the crude product in the fourth step was dissolved in a mixed solvent of AcOH (10 mL) and water (2 mL), stirred, and hydrogen peroxide (30 wt%, 10.0 g, 87.8 mmol) was slowly added dropwise to the solution at 50 ° C. After completion of the dropwise addition, 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, followed by stirring at room temperature for 30 minutes. The organic solvent was removed under reduced pressure, and the aqueous phase was extracted twice with dichloromethane.
  • Step 6 Preparation of 3- (6-chloropyridin-2-yl) -6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazole
  • 6- (4-cyclopropyl-1H-imidazol-1-yl) -5-methylisodihydroindol-1-one (50 mg, 0.197 mmol), 2-chloro-6- (4-isopropyl -4H-1,2,4-triazol-3-yl) pyridine (48 mg, 0.22 mmol) and cesium carbonate (86 mg, 0.30 mml) were mixed in 1,4-dioxane (4 mL), and nitrogen was used to remove oxygen 5 minutes, add Pd 2 (dba) 3 (18mg, 0.02mmol), deoxidize with nitrogen for 5 minutes, add Xantphos (23mg, 0.04mmol), continue deoxidizing with nitrogen for 5 minutes, and then stir at 120 ° C for two days .
  • TR-FRET fluorescence resonance energy transfer
  • Adding 1 to 5 uL of the substrate mixed solution contains a final concentration of the substrate polypeptide of 100 to 5000 nM and a final concentration of ATP of 100 to 1000 uM.
  • the microplate reader measures the fluorescence signal values of about 615nm and 665nm of each plate well.
  • Example 15 1.4 Example 16 4.1 Example 30 11.4 Example 31 10.9 Example 32 4.9 Example 33 7.2 Example 34 5.2 Example 36 9.1 Example 37 3.5 Example 38 4.1 Example 40 1.9 Example 41 7.7 Example 43 1.9 Example 44 3.6 Example 48 6.1 Example 50 9.6 Example 51 4.9 Example 53 8.2 Example 55 1.9 Example 56 5.0 Example 59 2.9 Example 60 6.6 Example 61 1.9 Example 62 3.0 Example 63 8.4 Example 64 5.5 Example 65 9.4
  • the compounds of the above examples can significantly inhibit the enzymatic activity of ASK1 kinase, some compounds show a strong inhibitory effect on ASK1 kinase, and the IC 50 of kinase enzyme activity inhibition is less than 10 nM. These compounds are effective inhibitors of ASK1 for the treatment of NASH Has huge application potential.
  • the mouse pharmacokinetic test of the preferred embodiment of the present invention is performed using a Balb / c male mouse (Shanghai Jiesijie Experimental Animal Co., Ltd.).
  • Orbital blood was collected from 0.1 mL, placed in a K 2 EDTA test tube, and the plasma was separated by centrifugation at 1000 to 3000 ⁇ g at room temperature for 5 to 20 minutes, and stored at -80 ° C.
  • a liquid is 0.1% formic acid aqueous solution
  • B liquid is acetonitrile
  • the rat pharmacokinetic test of the preferred embodiment of the present invention is performed by using SD male rats (Shanghai Jiesijie Experimental Animal Co., Ltd.).
  • Mass spectrometry AB Sciex API 4000 mass spectrometer
  • a liquid is 0.1% formic acid aqueous solution
  • B liquid is acetonitrile
  • the purpose of this test case is to test whether the compound 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
  • mice were adaptively reared in the SPF (No Specific Pathogens) barrier for 3-7 days, they were replaced with HFD feeds. The rearing period was 8 weeks, and the HFD was raised for the fifth week.
  • Mice were randomly divided into groups and induced by oral administration of CCl 4 twice a week for 4 weeks. Oral administration was started on the day of CCl 4 modelling. The frequency of administration was once a day for 28 consecutive days. The administration volume was 10 mL / kg; 48 hours after the last administration of CCl 4 , the mice were euthanized with CO 2 , and non-anticoagulated venous blood was collected from the heart. The whole blood was left at room temperature for at least 30 minutes. Centrifuge under the conditions of centrifugation at 4 ° C, 5000 rpm for 5 minutes, separate the serum, aliquot it into two aliquots, place them in 1.5mL EP tubes, store at -80 ° C, and reserve.
  • ALT / GPT alanine aminotransferase
  • AST / GOT aspartate aminotransferase
  • Absolute OD value OD value of the measurement well-OD value of the control well; bring the absolute OD value into the standard curve to obtain the ALT (or AST) content in the sample.
  • the serum should be diluted to a suitable concentration and restarted. Detection.
  • Example 34 67% 60%
  • Example 37 57% 62%
  • Example 40 50% 65%
  • Example 43 65% 58%
  • Example 55 56%
  • Example 61 50% 54%
  • Example 64 51% 47%
  • Example 65 46% 52%
  • the compound of the present invention shows a good effect in down-regulating the levels of ALT and AST in the serum of non-alcoholic steatohepatitis mice.
  • Examples 9 and 43 of the present invention at 10, 30, and 100 mg / kg doses, male SD rats were repeatedly administered orally once a day for 7 consecutive days to evaluate possible toxic reactions and metabolism in the body.
  • the compound prepared with the vehicle 0.5% CMC-Na (control group) was placed on a magnetic stirrer and stirred for at least 15 minutes, and continuously stirred during the administration.
  • the required volume of the compound / control is accurately orally administered according to the measured weight.
  • the observations include but are not limited to mental state, behavioral activity, skin, coat, eyes, ears, nose, Abdomen, external genitalia, anus, limbs, feet, breathing; animals in each group were weighed twice a week.
  • the toxicokinetic blood samples were collected before the first and last administration, 0.5h, 1h, 2h, 4h, 8h, 12h, and 24h after the administration.
  • centrifuge tubes containing EDTA-K 2 were placed in a refrigerator at 2-8 ° C. Store temporarily in an ice bath; collect the blood into the labeled centrifuge tube, invert it manually at least 5 times, temporarily store in the ice bath; centrifugation conditions: 4 °C, 1500g, centrifugation for 10min, complete the centrifugation within 2 hours, The centrifuged plasma was transferred to a new labeled centrifuge tube and stored below -70 ° C.
  • Example 43 showed a fluffy coat on individual animals at the dose of 100mg / kg on the 7th to 8th days after administration, and there were no abnormal changes in the clinical observations of the animals in each time period.
  • 4Clinical pathology Compared with the vehicle control group on the eighth day, at the doses of 10, 30, and 100 mg / kg in Examples 9 and 43, the blood cell count, coagulation function, and blood biochemical indexes of male rats showed no toxicological significance.
  • Toxicology In the dose range of 10-100 mg / kg, no accumulation of Examples 9 and 43 was observed in the plasma of male rats.
  • Examples 9 and 43 were administered to male SD rats repeatedly at a dose of 10, 30, and 100 mg / kg, respectively, once a day for 7 consecutive days.
  • the animals were well tolerated, and the maximum tolerated dose (MTD) was 100 mg. / kg, and good safety.
  • MTD maximum tolerated dose

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Abstract

L'invention concerne une composition pharmaceutique contenant des dérivés amides, son procédé de préparation, et une application associée. L'invention concerne en particulier une composition pharmaceutique, comprenant un composé de formule (I) et un stéréoisomère ou un sel pharmacologiquement acceptable de celui-ci, un excipient pharmaceutiquement acceptable, et son utilisation en tant qu'inhibiteur de l'ASK1 dans le traitement de maladies neurodégénératives, de maladies cardiovasculaires, d'inflammations et de maladies auto-immunes et métaboliques..
PCT/CN2019/099971 2018-08-10 2019-08-09 Composition pharmaceutique contenant des dérivés amides, son procédé de préparation et application associée WO2020030107A1 (fr)

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CN110577540B (zh) * 2019-07-16 2021-07-23 广州安岩仁医药科技有限公司 苯甲酰氨基吡啶衍生物的盐及其在药物中的应用
CN110577539B (zh) * 2019-07-16 2021-07-23 广州安岩仁医药科技有限公司 苯甲酰氨基吡啶衍生物的盐及其在药物中的应用
CN110577541B (zh) * 2019-07-16 2021-07-23 广州安岩仁医药科技有限公司 苯甲酰氨基吡啶衍生物的盐及其在药物中的应用
CN110577537B (zh) * 2019-07-16 2021-07-23 广州安岩仁医药科技有限公司 苯甲酰氨基吡啶衍生物的盐及其在药物中的应用
CN110577535B (zh) * 2019-07-16 2021-07-23 广州安岩仁医药科技有限公司 苯甲酰氨基吡啶衍生物的盐及其在药物中的应用
CN110577533B (zh) * 2019-07-16 2021-07-23 广州安岩仁医药科技有限公司 苯甲酰氨基吡啶衍生物的盐及其在药物中的应用
CN110577538B (zh) * 2019-07-16 2021-07-23 广州安岩仁医药科技有限公司 苯甲酰氨基吡啶衍生物的盐及其在药物中的应用
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