WO2019015559A1 - Composé hétérocyclique agissant en tant qu'inhibiteur d'ask et utilisation de celui-ci - Google Patents

Composé hétérocyclique agissant en tant qu'inhibiteur d'ask et utilisation de celui-ci Download PDF

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WO2019015559A1
WO2019015559A1 PCT/CN2018/095897 CN2018095897W WO2019015559A1 WO 2019015559 A1 WO2019015559 A1 WO 2019015559A1 CN 2018095897 W CN2018095897 W CN 2018095897W WO 2019015559 A1 WO2019015559 A1 WO 2019015559A1
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group
alkyl
acyl
amino
hydroxy
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PCT/CN2018/095897
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English (en)
Chinese (zh)
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王勇
赵立文
葛崇勋
黄奕强
曹陈
李晴晴
江宏
韩伟
张着伟
张亚楠
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南京圣和药业股份有限公司
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Publication of WO2019015559A1 publication Critical patent/WO2019015559A1/fr

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    • 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
    • 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
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    • 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
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine 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
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D417/14—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 three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems
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    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems

Definitions

  • the present invention belongs to the field of medical chemistry, and specifically relates to a heterocyclic compound or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof as an ASK inhibitor, a preparation method thereof, and a medicament containing the same Use of the compositions and these compounds or compositions for the treatment and/or prevention of apoptotic signaling modulating kinase 1 associated diseases.
  • Apoptosis signal-regulating kinase 1 is one of the major members of the mitogen-activated protein kinase kinase (MAP3Ks) family.
  • ASK1 balances and integrates many endogenous and exogenous stimuli, allowing cells to respond appropriately to different stimuli.
  • ASK1 puts ASK1 in an inactive state by binding to thioredoxin (Trx).
  • Trx thioredoxin
  • stress damage such as oxidative stress, ROS, endoplasmic reticulum stress, calcium influx, etc.
  • pro-inflammatory factors H 2 O 2 , TNF- ⁇ , etc.
  • the downstream JNK and p38-MAPK kinase signaling pathways are sequentially activated to respond to stress by regulating cell growth, differentiation, inflammation, and apoptosis.
  • ASK2 is a member of the MAP3K family with a 45% homologous sequence to ASK1.
  • ASK2 and ASK1 are highly similar in the kinase region, ASK1 is widely distributed in various tissues, and ASK2 is only specifically distributed in tissues exposed to body surface. Such as skin, lung and gastrointestinal tract, it is generally believed that ASK1 and ASK2 interact to form an endogenous ASK1-ASK2 complex to play a physiological role.
  • Oxidative stress refers to the process in which the body's reactive oxygen species (ROS) are excessively produced and/or the antioxidant defense function is weakened, causing cell damage and death, resulting in tissue damage repair.
  • ROS reactive oxygen species
  • the production of reactive oxygen species ROS is at a lower level and can be rapidly degraded.
  • ROS promotes Trx and ASK1.
  • ASK1 is activated and permanently aberrantly activated, which in turn regulates apoptosis and damage responses. Due to the important role of ASK1 in the process of apoptosis signaling, ASK1 is closely related to the occurrence and development of various diseases such as inflammation, metabolic syndrome, neurodegenerative diseases, cardiovascular diseases and tumors.
  • Organ fibrosis refers to the continuous excessive deposition of extracellular matrix (ECM) in tissues and organs caused by various pathogenic factors, which ultimately leads to structural changes and dysfunction of tissues and organs.
  • ECM extracellular matrix
  • Oxidative stress is one of the important pathogenesis of organ fibrosis. Long-term stimulation of various harmful factors leads to persistent damage to the liver, kidneys and alveoli, activation of oxidative stress pathways, repeated destruction, repair and reconstruction of organs. Oxidative stress plays an important role in the occurrence of liver fibrosis.
  • Hepatic fibrosis is a necessary process and common pathway for various liver diseases to progress to cirrhosis, suffering from viral hepatitis, alcoholic liver disease and In chronic diseases such as steatohepatitis, the liver may be damaged. Liver damage and inflammation may induce the production of ROS, cause cytokines such as TNF- ⁇ and TGF- ⁇ 1, and ROS and TNF- ⁇ may activate ASK1 and activate downstream. JNK and p38MAPK signaling pathways induce hepatocyte apoptosis and necrosis on the one hand, and activate ECM in hepatic stellate cells on the other hand. The persistent excessive deposition of ECM in liver tissue causes and accelerates the occurrence and development of liver fibrosis.
  • ASK1 inhibitors in chronic kidney disease (diabetic nephropathy, end-stage renal disease, renal fibrosis, etc.), cardiovascular disease (heart failure, etc.), neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease and tumors have certain research and application, especially ASK1-targeted drugs have important clinical significance in the study of chronic liver diseases such as nonalcoholic steatohepatitis (NASH) and liver fibrosis, and A certain clinical effect has been achieved.
  • NASH nonalcoholic steatohepatitis
  • liver fibrosis liver fibrosis
  • Ring A is selected from the group consisting of cycloalkyl, aryl and heteroaryl, wherein said cycloalkyl, aryl and heteroaryl are optionally substituted by one or more halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, Alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkyl acylamino, alkyl acyl, amino acyl, alkylamino acyl, dialkylamino, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or oxo group;
  • Ring B is selected from the group consisting of a monocyclic aryl group, a bicyclic aryl group, a bicyclic heteroaryl group, and a bicyclic heterocyclic group, wherein the monocyclic aryl group, the bicyclic aryl group, the bicyclic heteroaryl group, and the bicyclic heterocyclic ring are described.
  • the group is optionally selected from one or more of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, Alkynoylamino, alkylacyl, aminoacyl, alkylaminoacyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or oxo group;
  • Ring C is a monocyclic heteroaryl group wherein the heteroaryl group is optionally substituted by one or more halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, Nitro, carboxyl, cyano, amino, monoalkylamino, alkyl acylamino, alkyl acyl, amino acyl, alkylamino acyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclic Or a heteroaryl group;
  • Ring D is selected from And tetrazole, wherein the group is optionally substituted by one or more halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano a base, an amino group, a monoalkylamino group, an alkylacylamino group, an alkyl acyl group, an aminoacyl group, an alkylamino acyl group, a bisalkylamino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group or a heteroaryl group;
  • Z 1 is an acyl group, an alkylene group or is absent
  • Z 2 is -CONH-, -NHCO- or does not exist
  • R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkyl
  • ring A is heteroaryl and is optionally substituted by one or more halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitrate Base, carboxyl, cyano, amino, monoalkylamino, alkyl acylamino, alkyl acyl, amino acyl, alkylamino acyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl or oxo group Replace
  • ring D is tetrazolium.
  • Another object of the invention is to provide a process for the preparation of a compound of formula A of the invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof.
  • a further object of the present invention is to provide a composition
  • a composition comprising a compound of the formula A of the present invention, or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, and a pharmaceutically acceptable carrier, and the present invention
  • a compound of formula A or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal or prodrug and a combination of another drug or drugs is to provide a composition comprising a compound of the formula A of the present invention, or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal or prodrug and a combination of another drug or drugs.
  • a further object of the present invention is to provide a compound of the formula A of the present invention or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof for the treatment and/or prevention of apoptosis signal-regulated kinase 1 A method of disease, and a compound of the formula A of the present invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof thereof, for the preparation of a kinase 1 for the treatment and/or prevention of apoptosis The application of the disease in medicine.
  • the present invention provides a compound of the formula A or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug,
  • Ring A is selected from the group consisting of cycloalkyl, aryl and heteroaryl, wherein said cycloalkyl, aryl and heteroaryl are optionally substituted by one or more halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, Alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkyl acylamino, alkyl acyl, amino acyl, alkylamino acyl, dialkylamino, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or oxo group;
  • Ring B is selected from the group consisting of a monocyclic aryl group, a bicyclic aryl group, a bicyclic heteroaryl group, and a bicyclic heterocyclic group, wherein the monocyclic aryl group, the bicyclic aryl group, the bicyclic heteroaryl group, and the bicyclic heterocyclic ring are described.
  • the group is optionally selected from one or more of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, Alkynoylamino, alkylacyl, aminoacyl, alkylaminoacyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or oxo group;
  • Ring C is a monocyclic heteroaryl group wherein the heteroaryl group is optionally substituted by one or more halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, Nitro, carboxyl, cyano, amino, monoalkylamino, alkyl acylamino, alkyl acyl, amino acyl, alkylamino acyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclic Or a heteroaryl group;
  • Ring D is selected from And tetrazole, wherein the group is optionally substituted by one or more halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano a base, an amino group, a monoalkylamino group, an alkylacylamino group, an alkyl acyl group, an aminoacyl group, an alkylamino acyl group, a bisalkylamino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group or a heteroaryl group;
  • Z 1 is an acyl group, an alkylene group or is absent
  • Z 2 is -CONH-, -NHCO- or does not exist
  • R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkyl
  • ring A is heteroaryl and is optionally substituted by one or more halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitrate Base, carboxyl, cyano, amino, monoalkylamino, alkyl acylamino, alkyl acyl, amino acyl, alkylamino acyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl or oxo group Replace
  • ring D is tetrazolium.
  • the present invention provides a compound of Formula A, or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein Formula A has the structure of Formula I below.
  • Ring A is selected from the group consisting of cycloalkyl, aryl and heteroaryl, wherein said cycloalkyl, aryl and heteroaryl are optionally substituted by one or more halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, Alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkyl acylamino, alkyl acyl, amino acyl, alkylamino acyl, dialkylamino, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or oxo group;
  • Ring B is selected from the group consisting of a bicyclic aryl group, a bicyclic heteroaryl group, and a bicyclic heterocyclic group, wherein the bicyclic aryl group, the bicyclic heteroaryl group, and the bicyclic heterocyclic group are optionally substituted by one or more halogens, Hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkyl acylamino, alkyl acyl, amino Acyl, alkylaminoacyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or oxo group;
  • Ring C is a monocyclic heteroaryl group wherein the heteroaryl group is optionally substituted by one or more halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, Nitro, carboxyl, cyano, amino, monoalkylamino, alkyl acylamino, alkyl acyl, amino acyl, alkylamino acyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclic Or a heteroaryl group;
  • Z 1 is an acyl group, an alkylene group or is absent
  • Z 2 is -CONH-, -NHCO- or does not exist
  • R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkyl
  • ring A is heteroaryl and is optionally substituted by one or more halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitrate Base, carboxyl, cyano, amino, monoalkylamino, alkyl acylamino, alkyl acyl, amino acyl, alkylamino acyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl or oxo group Replace.
  • the compound of the invention is a compound of Formula A or Formula I, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
  • Ring A is selected from the group consisting of C 3-12 cycloalkyl, C 6-18 aryl and 5-20 membered heteroaryl, wherein said cycloalkyl, aryl and heteroaryl are optionally substituted by one or more halogens, Hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkane Oxy, nitro, carboxy, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylamino acyl , Bi C 1-6 alkylamino, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic, 6-12 membered aryl, 5-12 Substituted aryl or
  • ring A is selected from the group consisting of C 3-8 cycloalkyl, C 6-12 aryl and 5-12 membered heteroaryl, wherein said cycloalkyl, aryl and heteroaryl are optionally one or a plurality of halogen, hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkoxy group, nitro group, carboxyl group, cyano group, amino group, mono C 1-6 alkylamino group, C 1-6 alkyl acylamino group, C 1-6 alkyl acyl group, amino acyl group, C 1-6 Alkylaminoacyl, bisC 1-6 alkylamino, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl
  • ring A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, iso Thiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl, wherein said group is optionally One or more halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, Hydroxy C 1-6 alkoxy, nitro, carboxy, cyano, amino, mono C 1-6 alkylamino, C 1-6 al
  • the compound of the invention is a compound of Formula A or Formula I, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
  • Ring B is selected from the group consisting of a 10-18 membered bicyclic aryl group, a 9- or 10-membered bicyclic heteroaryl group, a 9- or 10-membered bicyclic heterocyclic group, wherein the bicyclic aryl group and the bicyclic heteroaryl group are described.
  • bicyclic heterocyclic group are optionally substituted by one or more halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, nitro, carboxy, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1- 6 alkyl acyl, amino acyl, C 1-6 alkylamino acyl, bis C 1-6 alkylamino, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3- a 12-membered heterocyclic group, a 6-12 membered aryl group, a 5-12 membered heteroaryl group or an oxo group;
  • ring B is selected from the group consisting of naphthyl, 9- or 10-membered benzathione, 9- or 10-membered benzoxacyclic, 9- or 10-membered benzothiazepine, a 9- or 10-membered benzodiazepine group, a 9- or 10-membered benzodioxanylene group, a 9- or 10-membered benzodithioheterocyclyl group, a 9- or 10-membered benzophenone An oxazacycline, 9- or 10-membered benzothiazepine substrate, wherein said group is optionally substituted by one or more halogen, hydroxy, C 1-6 alkyl, halo C 1-6 Alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, hydroxy C 1-6 alkoxy, nitro, carboxy, cyano, amino, mono C 1-6 alkylamino, C 1-6 alky
  • ring B is selected from the group consisting of naphthyl, anthracenyl, isodecyl, porphyrinyl, isoindolyl, benzofuranyl, dihydrobenzofuranyl, benzopyranyl, Dihydrobenzopyranyl, benzothienyl, dihydrobenzothiophenyl, benzoxazolinone, benzopyrazolyl, dihydrobenzopyrazole, benzimidazolyl, dihydrobenzene Imidazolyl, benzopyrazolyl, dihydrobenzopyrazolyl, benzoxazolyl, dihydrobenzoxazolyl, benzothiazolyl, dihydrobenzothiazolyl, benzisoxazole , dihydrobenzoisoxazolyl, benzisothiazolyl, dihydrobenzisothiazolyl, quinolyl, tetrahydroquinolyl, isoquinolyl
  • the compound of the invention is a compound of Formula A or Formula I, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
  • Ring C is a 5-12 membered monocyclic heteroaryl group wherein the heteroaryl group is optionally substituted by one or more halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1 -6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, hydroxy C 1-6 alkoxy, nitro, carboxy, cyano, amino, mono C 1-6 alkylamino , C 1-6 alkyl acylamino, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylamino acyl, bis C 1-6 alkylamino, C 2-10 alkenyl, C 2-10 Alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl;
  • ring C is a 5-6 membered monocyclic heteroaryl group, wherein said heteroaryl group is optionally substituted by one or more halogen, hydroxy, C 1-3 alkyl, halo C 1-3 alkyl , hydroxy C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxy, cyano, amino, mono C 1- a 3- alkylamino group, a C 1-3 alkyl acylamino group, a C 1-3 alkyl acyl group, an amino acyl group, a C 1-3 alkylamino acyl group, a bis C 1-3 alkylamino group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 3-6 cycloalkyl group, a 3-6 membered heterocyclic group or a 5-10 membered heteroaryl group;
  • ring C is selected from the group consisting of furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl , oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and 1,3,5-triazinyl, wherein said group is optionally substituted by one or more halogens, hydroxyl groups, C 1- 3- alkyl, halo C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, hydroxy C 1-3 alkoxy, nitro , carboxy, cyano, amino, mono C 1-3 alkylamino, C 1-3 alkyl acylamino, C 1-3 alkyl acyl, amino acyl
  • the compound of the invention is a compound of Formula A or Formula I, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
  • Z 1 is an acyl group, a C 1-6 alkyl acyl group or is absent;
  • Z 1 is an acyl group, a C 1-6 alkyl acyl group or is absent;
  • Z 1 is Or does not exist.
  • the compound of the invention is a compound of Formula A or Formula I, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
  • R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy a group, a hydroxy C 1-6 alkoxy group, a nitro group, a carboxyl group, a cyano group, an amino group, a mono C 1-6 alkylamino group, a C 1-6 alkyl acylamino group, a C 1-6 alkyl acyl group, an amino acyl group, C 1-6 alkylamino acyl, bis C 1-6 alkylamino, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl and 3-12 membered heterocyclic, 6- 12-membered aryl or 5-12-membered heteroaryl;
  • R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, C 1-3 alkyl, halogenated C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1 -3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxy, cyano, amino, mono C 1-3 alkylamino, C 1-3 alkyl acylamino, C 1-3 alkyl acyl , aminoacyl, C 1-3 alkylamino acyl, bis C 1-3 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic ring a group, a 6-10 membered aryl group or a 5-10 membered heteroaryl group;
  • R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, methyl, ethyl, propyl, isopropyl, halo C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkane Oxy, halo C 1-3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxy, cyano, amino, mono C 1-3 alkylamino, C 1-3 alkyl acylamino, C 1-3 alkyl acyl, amino acyl, C 1-3 alkylamino acyl, bis C 1-3 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl A 3-8 membered heterocyclic group, a 6-10 membered aryl group or a 5-10 membered heteroaryl group.
  • the compound of the invention is a compound of formula A or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
  • Ring D is selected from the group consisting of tetrazolium, which is optionally substituted with one or more R 2 ;
  • ring D is selected from the group Said group is optionally substituted by one or more R 2 ;
  • ring D is selected from the group
  • R 2 is selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, hydroxyhaloalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano , amino, monoalkylamino, alkyl acylamino, alkyl acyl, amino acyl, alkyl amino acyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl And one or more of the oxo groups.
  • the invention provides a compound of Formula Ia, or an isomer, pharmaceutically acceptable salt, solvate, crystal, or prodrug thereof,
  • Y is selected from the group consisting of alkylene, alkenylene and cycloalkylene, wherein the alkylene, alkenylene and cycloalkylene are optionally substituted by one or more alkyl, haloalkyl, hydroxy, hydroxyalkyl a halogen, an oxo group, an alkoxy group, a carboxyl group, a cyano group, an amino group, a monoalkylamino group or a dialkylamino group, or when Y is an alkylene group and is substituted by two alkyl groups, the two Alkyl groups may form a cycloalkyl group together with the C atom to which they are attached;
  • W is selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkyl acyl Amino, alkyl acyl, amino acyl, alkylamino acyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • M is selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkyl acyl An amino group, an alkyl acyl group, an amino acyl group, an alkylamino acyl group, a bisalkylamino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group;
  • R 1 The definition of R 1 is as described above.
  • the compound of the invention is a compound of formula Ia or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
  • Y is selected from the group consisting of a C 1-6 alkyl group, a C 2-10 alkenylene group, and a C 3-10 cycloalkyl group, wherein the C 1-6 alkyl group, the C 2-10 alkenylene group, and the C 3 group -10 cycloalkylene may be one or more C 1-6 alkyl, halo C 1-6 alkyl, hydroxy, hydroxy C 1-6 alkyl, halogen, oxo, C 1-6 alkane Oxygen, carboxyl, cyano, amino, mono C 1-6 alkylamino or di C 1-6 alkylamino, or when Y is C 1-6 alkyl and substituted by two alkyl
  • the two alkyl groups described may form a C 3-8 cycloalkyl group together with the C atom to which they are attached;
  • Y is selected from the group consisting of a C 1-3 alkyl group, a C 2-6 alkenylene group, and a C 3-6 cycloalkylene group, wherein the C 1-3 alkyl group, the C 2-6 alkylene group And C 3-6 cycloalkylene may be one or more C 1-3 alkyl, halo C 1-3 alkyl, hydroxy, hydroxy C 1-3 alkyl, halogen, oxo, C 1-3 alkoxy, carboxy, cyano, amino, mono C 1-3 alkylamino or di C 1-3 alkylamino, or when Y is C 1-3 alkyl and is dialkyl When substituted, the two alkyl groups may form a C 3-6 cycloalkyl group together with the C atom to which they are attached;
  • Y is selected from the group consisting of a methylene group, an ethylene group, a propylene group, a vinylidene group, a propylene group, and a cyclopropylene group, wherein the methylene group, the ethylene group, the propylene group, and the sub
  • the vinyl, propylene group and cyclopropylene are optionally substituted by one or more halogen, methyl, ethyl, propyl, isopropyl, oxo groups, or when Y is methylene and is When substituted with an alkyl group, the two alkyl groups may form a C 3 -C 6 cycloalkyl group together with the C atom to which they are attached.
  • the compound of the invention is a compound of formula Ia or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
  • M is selected from the group consisting of hydrogen, halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy , hydroxy C 1-6 alkoxy, nitro, carboxy, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylamino acyl group, bis C 1-6 alkylamino group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-12 cycloalkyl group, 3-12 membered heterocyclic group, 6-12 a aryl group or a 5-12 membered heteroaryl group;
  • M is selected from the group consisting of hydrogen, halogen, hydroxy, C 1-3 alkyl, halo C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halogen C 1- 3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxy, cyano, amino, mono C 1-3 alkylamino, C 1-3 alkyl acylamino, C 1-3 alkyl acyl, Aminoacyl group, C 1-3 alkylamino acyl group, bis C 1-3 alkylamino group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 3-8 cycloalkyl group, 3-8 membered heterocyclic group , 6-10 membered aryl or 5-10 membered heteroaryl.
  • a compound of Formula Ia or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, according to the invention, wherein Selected from
  • a compound of Formula Ia or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, according to the invention, wherein M is hydrogen,
  • the compound of the invention is a compound of formula Ia or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
  • W is selected from the group consisting of hydrogen, halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy , hydroxy C 1-6 alkoxy, nitro, carboxy, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylamino acyl group, bis C 1-6 alkylamino group, C 2-10 alkenyl group, C 2-10 alkynyl group, C 3-12 cycloalkyl group, 3-12 membered heterocyclic group, 6-12 a aryl group or a 5-12 membered heteroaryl group;
  • W is selected from the group consisting of hydrogen, halogen, hydroxy, C 1-3 alkyl, halo C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halogen C 1- 3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxy, cyano, amino, mono C 1-3 alkylamino, C 1-3 alkyl acylamino, C 1-3 alkyl acyl, Aminoacyl group, C 1-3 alkylamino acyl group, bis C 1-3 alkylamino group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-10 cycloalkyl group, 3-10 membered heterocyclic group , 6-10 membered aryl or 5-10 membered heteroaryl;
  • W is selected from the group consisting of hydrogen, halogen, hydroxy, methyl, ethyl, propyl, isopropyl, halo C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy , halogenated C 1-3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxy, cyano, amino, mono C 1-3 alkylamino, C 1-3 alkyl acylamino, C 1-3 alkyl acyl group, amino acyl group, C 1-3 alkylamino acyl group, bis C 1-3 alkylamino group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 cycloalkyl group, 3-8 membered heterocyclic group, 6-8 membered aryl group or 5-8 membered heteroaryl group.
  • a compound of Formula Ia or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, according to the invention, wherein:
  • W is selected from the group consisting of hydrogen, halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy , hydroxy C 1-6 alkoxy, nitro, carboxy, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylamino acyl group, bis C 1-6 alkylamino group, C 2-10 alkenyl group, C 2-10 alkynyl group, C 3-12 cycloalkyl group, 3-12 membered heterocyclic group, 6-12 a aryl group or a 5-12 membered heteroaryl group;
  • R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy a group, a hydroxy C 1-6 alkoxy group, a nitro group, a carboxyl group, a cyano group, an amino group, a mono C 1-6 alkylamino group, a C 1-6 alkyl acylamino group, a C 1-6 alkyl acyl group, an amino acyl group, C 1-6 alkylamino acyl, bis C 1-6 alkylamino, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl and 3-12 membered heterocyclic, 6- 12-membered aryl or 5-12-membered heteroaryl.
  • the invention provides a compound of Formula Ib, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof,
  • W, R 1 , Z 1 , Z 2 , ring B and ring C are as defined above.
  • the invention provides a compound of Formula Ic, or an isomer, pharmaceutically acceptable salt, solvate, crystal, or prodrug thereof,
  • W, R 1 , Y and ring C are as defined above, and X 1 and X 2 are each independently selected from C(R 2 ) and N, wherein R 2 is selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, Haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkyl acylamino, alkyl acyl, amino acyl, alkylamino Acyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • the compound of the invention is a compound of formula Ic or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
  • R 2 is selected from the group consisting of hydrogen, halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy a group, a hydroxy C 1-6 alkoxy group, a nitro group, a carboxyl group, a cyano group, an amino group, a mono C 1-6 alkylamino group, a C 1-6 alkyl acylamino group, a C 1-6 alkyl acyl group, an amino acyl group, C 1-6 alkylamino acyl group, bis C 1-6 alkylamino group, C 2-10 alkenyl group, C 2-10 alkynyl group, C 3-12 cycloalkyl group, 3-12 membered heterocyclic group, 6- 12-membered aryl or 5-12-membered heteroaryl;
  • R 2 is selected from the group consisting of hydrogen, halogen, hydroxy, C 1-3 alkyl, halogenated C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1 -3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxy, cyano, amino, mono C 1-3 alkylamino, C 1-3 alkyl acylamino, C 1-3 alkyl acyl , aminoacyl, C 1-3 alkylamino acyl, bis C 1-3 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic ring a group, a 6-10 membered aryl group or a 5-10 membered heteroaryl group;
  • R 2 is selected from the group consisting of hydrogen, halogen, hydroxy, methyl, ethyl, propyl, isopropyl, halo C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkane Oxy, halo C 1-3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxy, cyano, amino, mono C 1-3 alkylamino, C 1-3 alkyl acylamino, C 1-3 alkyl acyl, amino acyl, C 1-3 alkylamino acyl, bis C 1-3 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl 3-8 membered heterocyclic group, 6-8 membered aryl group and 5-8 membered heteroaryl group.
  • the invention provides a compound of the formula Id or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof,
  • Ring B is selected from the group consisting of monocyclic aryl groups and It is optionally selected from one or more selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkyl Amino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and oxo groups Replace
  • R 2 is selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, hydroxyhaloalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino , monoalkylamino, alkyl acylamino, alkyl acyl, amino acyl, alkylamino acyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and oxygen One or more of the generation groups; and
  • W, Z 2 are as defined in the above formula A, I, Ia, Ib or Ic.
  • a compound of Formula Id, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, according to the invention wherein Ring B is selected from phenyl and It is optionally selected from one or more selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1 -6 alkoxy, hydroxy C 1-6 alkoxy, nitro, carboxy, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl , aminoacyl group, C 1-6 alkylamino acyl group, bis C 1-6 alkylamino group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-6 cycloalkyl group, C 3-6 heterocyclic ring Substituents of aryl, aryl,
  • the compound of Formula Ib, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, according to the invention wherein Ring B is selected from the group consisting of phenyl and It is optionally selected from one or more selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1 -6 alkoxy, hydroxy C 1-6 alkoxy, nitro, carboxy, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl , aminoacyl group, C 1-6 alkylamino acyl group, bis C 1-6 alkylamino group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-6 cycloalkyl group, C 3-6 heterocyclic ring Substituents of aryl
  • the present invention provides the following specific compounds or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof:
  • the invention provides a process for the preparation of a compound of the formula of the invention, for example:
  • X is a halogen, preferably chlorine or bromine
  • R 1 , W, Y, M are as defined in the above formula Ia.
  • X is a halogen, preferably chlorine, bromine, R 2 , W, Z 2 and ring B are as defined in the above formula Id.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, further comprising a group selected from the group consisting of One or more agents: one or more angiotensin converting enzyme (ACE) inhibitors, such as enalapril, captopril, ramipril, lisinopril, and quinapril; or blood vessels Angiotensin II receptor blockers (ARB), such as losartan, olmesartan, and irbesartan; or antihypertensive agents such as amlodipine, nifedipine, and felodipine; antibiotics, analgesics , antidepressants and / or anti-anxiety agents.
  • ACE angiotensin converting enzyme
  • ARB Angiotensin II receptor blockers
  • antihypertensive agents such as amlodipine, nif
  • the invention provides a compound of the invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, and a compound comprising the same, or an isomer thereof, pharmaceutically acceptable
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier.
  • the compound of the present invention or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof may be mixed with a pharmaceutically acceptable carrier, diluent or excipient to prepare a pharmaceutical preparation suitable for oral or oral administration.
  • a pharmaceutically acceptable carrier diluent or excipient
  • Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes.
  • the formulation may be administered by any route, for example by infusion or bolus injection, by a route of absorption through the epithelium or skin mucosa (e.g., oral mucosa or rectum, etc.). Administration can be systemic or topical.
  • orally administered preparations include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like.
  • the formulations may be prepared by methods known in the art and comprise carriers, diluents or excipients conventionally employed in the field of pharmaceutical formulations.
  • the present invention provides a compound represented by the formula A, I, Ia, Ib, Ic or Id of the present invention or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, or comprises the same
  • a pharmaceutical composition for the preparation of a medicament for the treatment and/or prevention of an apoptosis signal that modulates kinase 1-related diseases wherein the apoptosis-regulating kinase 1-related diseases or conditions include, but are not limited to, neurodegeneration Diseases, cardiovascular diseases, inflammation, autoimmune diseases, tumors and metabolic disorders, etc., in particular, ASK1 inhibitors for the treatment of diseases include: kidney diseases (such as diabetic nephropathy, diabetic nephropathy, end-stage renal disease, chronic kidney disease, etc.) ), fibrotic diseases (such as lung, kidney fibrosis, etc.), cardiovascular diseases (such as heart failure, etc.), respiratory diseases (such as chronic obstructive
  • Haldrogen in the compounds of the invention include all isotopes thereof. Isotopes are understood to include those atoms having the same number of atoms but having different mass numbers. For example, isotopes of hydrogen include ruthenium, osmium, and iridium, carbon isotopes include 12 C, 13 C, and 14 C, and isotopes of oxygen include 16 O and 18 O.
  • halogen of the present invention means fluorine, chlorine, bromine or iodine.
  • Halo as used in the present invention means substituted by fluorine, chlorine, bromine or iodine.
  • alkyl group of the present invention means a linear or branched saturated aliphatic hydrocarbon group, preferably a linear or branched group having 1 to 6 carbon atoms, further preferably a linear or branched having 1 to 3 carbon atoms.
  • Chain groups non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethyl Propyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, and the like.
  • the alkyl group can be substituted or unsubstituted, and when substituted, the substituent can be at any point of attachment that can be used.
  • alkylene group of the present invention means a group in which an alkyl group is formally removed from a hydrogen atom, such as a methylene group (-CH 2 -), an ethylene group (-CH 2 -CH 2 -), A propylene group (-CH 2 -CH 2 -CH 2 -), etc.
  • a "C 1-6 alkyl group” as used herein means that a C 1-6 alkyl group is formally removed from a hydrogen atom.
  • the lower group, the "subC 1-3 alkyl group” means a group in which a C 1-3 alkyl group is formally removed from a hydrogen atom.
  • the alkylene group can be substituted or unsubstituted, and when substituted, the substituent can be at any point of attachment that can be used.
  • C 2-10 alkenyl as used herein means a group in which a C 2-10 alkenyl group is formally removed from a hydrogen atom.
  • substituteC 2-6 alkenyl group means a group in which a C 2-6 alkenyl group is formally removed from a hydrogen atom.
  • cycloalkylene of the present invention means a group in which a cycloalkyl group is formally removed from a hydrogen atom, such as a cyclopropylene group.
  • Cyclobutylene and, as used herein, “C 3-10 cycloalkyl” refers to a group in which a C 3-10 cycloalkyl group is formally removed from a hydrogen atom, said “C 3 - 3 6- Cycloalkyl” means a group in which a C 3-6 cycloalkyl group is formally removed from a hydrogen atom.
  • alkylidinoyl group of the present invention means a group in which an alkyl group is formally removed from a hydrogen atom, such as a methylene group (-CH 2 CO-), an ethylene group (-CH 2 CH). 2 CO-), propylene amino group (-CH 2 CH 2 CH 2 CO-), and the like.
  • alkoxy group of the present invention means an -O-alkyl group.
  • alkoxy groups include: methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, isobutoxy, sec-butoxy, and the like.
  • the alkoxy group can be optionally substituted or unsubstituted, and when substituted, the substituent can be at any point of attachment that can be used.
  • cycloalkyl group of the present invention means a cyclic saturated hydrocarbon group. Suitable cycloalkyl groups may be substituted or unsubstituted monocyclic, bicyclic or tricyclic saturated hydrocarbon groups having 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • heterocyclyl of the present invention means a 3- to 12-membered non-aromatic having 1 to 4 ring heteroatoms in which each heteroatom is independently selected from the group consisting of nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. a group of the ring system ("3-12 membered heterocyclic group").
  • the point of attachment may be a carbon or nitrogen atom as long as the valency permits.
  • the heterocyclyl group may alternatively be a monocyclic ("monocyclic heterocyclic") or a fused, bridged or spiro ring system (eg, a bicyclic system ("bicyclic heterocyclyl”)) And it can be saturated or can be partially unsaturated.
  • the heterocyclic bicyclic ring system may include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein a heterocycle, as defined above, is fused to one or more carbocyclyl groups (wherein the point of attachment is on a carbocyclic group or on a heterocyclic ring), or a ring system
  • the heterocyclic ring as defined above, is fused to one or more aryl or heteroaryl groups (wherein the point of attachment is on the heterocyclic ring), and in such cases, the number of ring members continues to be referred to as hetero The number of ring members in the ring system.
  • each instance of a heterocyclic group is independently optionally substituted, that is, unsubstituted ("unsubstituted heterocyclic") or substituted with one or more substituents ("substituted hetero A cyclic group "), such as a substituted or unsubstituted piperidinyl group, a substituted or unsubstituted bridged morphinolyl group, and the like.
  • the heterocyclyl group is a substituted 3-10 membered heterocyclyl.
  • Exemplary 5-membered heterocyclyl groups include, but are not limited to, indolinyl, iso indolinyl, two Hydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like.
  • Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocycles) fused to an aryl ring include, but are not limited to, tetrahydroquinolyl, tetrahydroisoquinolinyl, and the like. .
  • the "aryl” of the present invention means an aromatic system which may comprise a monocyclic or fused polycyclic ring, preferably a monocyclic or fused bicyclic aromatic system containing from 6 to 18 carbon atoms, preferably from about 6 to about 12 carbon atoms.
  • Suitable aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, tetrahydronaphthyl, anthracenyl, indanyl.
  • the aryl group can be optionally substituted or unsubstituted, and when substituted, the substituent can be at any available point of attachment.
  • heteroaryl group of the present invention means an aryl group having at least one carbon atom replaced by a hetero atom, composed of 5-20 atoms (5-20 membered heteroaryl group), and further preferably composed of 5-12 atoms ( 5-12 membered heteroaryl), said hetero atom is O, S, N, including but not limited to imidazolyl, benzimidazolyl, imidazopyridyl, quinazolinone, pyrrolyl, imidazolidinyl , furyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl, Pyrimidopyrazolyl, pyrimidoimidazolyl and the like.
  • the heteroaryl group can be optionally substituted or unsubsti
  • the "isomer” of the present invention is a compound having the same molecular formula but differing in nature or on the bond sequence of its atom or in the spatial arrangement of its atoms.
  • Stereoisomers are isomers whose atoms are spatially distinct.
  • Stereoisomers that are not mirror images of each other are diastereomers and that the stereoisomers that are non-overlapping mirror images of each other are enantiomers.
  • a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • Enantiomers are characterized by the absolute configuration of their asymmetric centers and are described by Rahn and S-sequence rules of Cahn and Prelog, or by methods of rotating the plane of polarized light by molecules and designated as right-handed or left-handed ( That is, as (+) or (-)-isomers, respectively.
  • the chiral compound can exist as a single enantiomer or a mixture thereof.
  • An equal proportion of mixtures comprising enantiomers is referred to as a "racemic mixture".
  • compositions of the present invention refer to salts of the compounds of the present invention which are safe and effective for use in mammals and which have the desired biological activity.
  • solvate refers in a conventional sense to a complex formed by a combination of a solute (such as an active compound, a salt of an active compound) and a solvent (such as water).
  • Solvent refers to a solvent known or readily determinable by those skilled in the art.
  • the solvate is generally referred to as a hydrate such as a hemihydrate, a monohydrate, a dihydrate, a trihydrate or a substituted amount thereof.
  • the in vivo action of a compound of formula (A) can be exerted, in part, by one or more metabolites formed in the human or animal body following administration of a compound of formula (A). As described above, the in vivo action of the compound of formula (A) can also be exerted via metabolism of the precursor compound ("prodrug").
  • the "prodrug” of the present invention refers to a compound which is converted into a compound of the formula (A) by a reaction with an enzyme, gastric acid or the like under physiological conditions in a living body, that is, a compound converted by oxidation, reduction, hydrolysis or the like of an enzyme.
  • a compound of the compound of (A) and/or a compound which is converted into a compound of the formula (A) by a hydrolysis reaction such as gastric acid or the like.
  • the "crystallization" of the present invention means that the internal structure is a solid formed by regularly repeating constituent atoms (or a group thereof) in three dimensions, and is different from an amorphous solid having an internal structure not having such a regularity.
  • a "pharmaceutical composition” is meant to include any one of the compounds described herein, including the corresponding isomers, prodrugs, solvates, pharmaceutically acceptable salts or chemically protected forms thereof, and one or A plurality of pharmaceutically acceptable carriers and/or mixtures of one or more drugs.
  • the purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
  • the compositions are typically used in the manufacture of a medicament for the treatment and/or prevention of a disease mediated by one or more kinases.
  • the "pharmaceutically acceptable carrier” of the present invention means a carrier which does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, and includes all solvents, diluents or other excipients, dispersing agents, and surface active agents. Isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, and the like. Unless any conventional carrier medium is incompatible with the compounds of the invention.
  • pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, And cellulose and cellulose acetate; malt, gelatin and the like.
  • Excipient refers to an inert substance that is added to a pharmaceutical composition to further facilitate administration of the compound.
  • Excipients can include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols.
  • Step 4 Preparation of methyl 1-(2-oxo-2-phenylethyl)-1H-benzo[d]imidazole-6-carboxylate
  • Step 6 N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-(2-oxo-2-phenylethyl) Preparation of -1H-benzo[d]imidazole-6-carboxamide
  • Step 4 2-Benzyl-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)isoindole-5-carboxamide preparation
  • Step 5 Preparation of N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)isoindole-5-carboxamide
  • N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)isoindole-5-carboxamide (200 mg, obtained in Step 5) 0.570 mmol) was dissolved in methylene chloride, and N,N-diisopropylethylamine (190 mg, 1.44 mmol) was added, and the mixture was stirred for 3 min, and then added with cyclopropylcarbonyl chloride (71.0 mg, 0.680 mmol). After the reaction was completed, the reaction mixture was diluted with water (50 mL), dichloromethane: EtOAc: EtOAc: EtOAc (EtOAc) The title compound was prepared.
  • Step 1 Preparation of methyl 6-(4-cyclopropyl-1H-imidazol-1-yl)-2-naphthoate
  • Methyl 6-bromo-2-naphthoate (491 mg, 1.85 mmol) and 4-cyclopropyl-1H-imidazole (200 mg, 1.85 mmol) were placed in a 100 mL single-necked flask, followed by the addition of 8-hydroxyquinoline (27.0 mg, 0.185 mmol), potassium carbonate (511 mg, 3.70 mmol) and cuprous iodide (35.2 mg, 0.185 mmol), and finally dissolved in dimethyl sulfoxide (5 mL). After nitrogen substitution, the mixture was heated to 120 ° C for 6 h. The reaction of the starting material was confirmed by LC-MS.
  • Step 3 6-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine- Preparation of 2-yl)-2-naphthalenecarboxamide
  • 6-(4-Cyclopropyl-1H-imidazol-1-yl)-2-naphthoic acid 600 mg, 2.16 mmol
  • 6-(4-isopropyl-4H-1,2,4-triazole- 3-yl)pyridin-2-amine 438 mg, 2.16 mmol
  • o-xylene 30 mL
  • N,N-dimethylformamide 10 mL
  • phosphorus pentachloride 225 mg, 1.08 mmol
  • Step 1 Preparation of methyl 4-bromo-1,3-thiazole-2-carboxylate
  • Step 5 Preparation of 6-bromo-2-(2-(4-isopropyl-4H-1,2,4-triazol-3-yl)thiazol-4-yl)isoindolin-1-one
  • Step 6 6-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(2-(4-isopropyl-4H-1,2,4-triazol-3-yl)thiazole- Preparation of 4-yl)-isoindoline-1-one
  • Example 5 7-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)-3,4-dihydroisoquinoline-1(2H)-one
  • Step 4 7-Bromo-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3,4-dihydroisoquinoline Preparation of -1(2H)-one
  • Step 5 7-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine-Preparation of 2-yl)-3,4-dihydroisoquinoline-1(2H)-one
  • Example 6 6-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)isoindoline-1-one
  • Step 1 Preparation of 6-bromo-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)isoindolin-1-one
  • 6-Bromoisoindoline-1-one (1.00 g, 4.72 mmol), 2-bromo-6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine (1.26 g, 4.72 mmol) and potassium phosphate (2.51 g, 11.8 mmol) were dissolved in dioxane (30 mL) and 4,5-bisdiphenylphosphino-9,9-dimethyloxaxene (Xant) -phos, 272 mg, 0.472 mmol) and tris(dibenzylideneacetone)dipalladium Pd 2 (dba) 3 (431 mg, 0.472 mmol), which was subjected to a nitrogen atmosphere and then reacted at 130 ° C for 70 min.
  • Step 2 6-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine- Preparation of 2-yl)isoindoline-1-one
  • the preparation method was similar to the preparation method of Example 6, except that the starting material 4-cyclopropyl-1(3)H-imidazole was replaced with 4-methyl-1(3)H-imidazole to give the title compound.
  • 1 H NMR 300MHz, DMSO- d 6) ⁇ 8.95 (s, 1H), 8.66 (d, 1H), 8.33 (s, 1H), 8.06-8.13 (m, 2H), 7.87-7.99 (m, 3H ), 7.64 (s, 1H), 5.48-5.57 (m, 1H), 5.20 (s, 2H), 2.19 (s, 3H), 1.59 (d, 6H).
  • LC-MS m/z: [M+H ] + 400.
  • Example 8 6-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)-3,3-dimethylisoindole-1-one
  • Step 1 6-Bromo-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3,3-dimethylisoindole Preparation of indole-1-one
  • 6-Bromo-3,3-dimethylisoindolin-1-one (1.13 g, 4.72 mmol)
  • 2-bromo-6-(4-isopropyl-4H-1,2,4-tri Zin-3-yl)pyridine (1.26 g, 4.72 mmol)
  • potassium phosphate (2.51 g, 11.8 mmol) were dissolved in dioxane (10 mL), and Xant-phos (272 mg, 0.472 mmol) and Pd 2 (dba) were added.
  • 3 (431 mg, 0.472 mmol), after nitrogen substitution, microwave reaction at 130 ° C for 70 min.
  • Step 2 6-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine-Preparation of 2-yl)-3,3-dimethylisoindole-1-one
  • Step 4 2-Benzyl-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)isoindole-5-carboxamide preparation
  • Step 5 Preparation of N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)isoindole-5-carboxamide
  • Benzoic acid (50.0 mg, 0.389 mmol) was placed in a 25 mL single-mouth bottle, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluron hexafluorophosphate was added. (246 mg, 0.646 mmol), N,N-diisopropylethylamine (90.0 mg, 0.646 mmol) was added under cooling, stirred for 10 min, then N-(6-(4-isopropyl)- 4H-1,2,4-Triazol-3-yl)pyridin-2-yl)isoindole-5-carboxamide (90.0 mg, 0.258 mmol).
  • Step 3 5-(4-Cyclopropyl-1H-imidazol-1-yl)-1-ethyl-2-(6-(4-isopropyl-4H-1,2,4-triazole-3) Of -pyridyl-2-yl)-oxazol-3-one
  • Step 2 Preparation of methyl 6-(4-cyclopropyl-1H-imidazol-1-yl)-1-methyl-1H-indole-4-carboxylate
  • Step 4 6-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine- Preparation of 2-yl)-1-methyl-1H-indole-4-carboxamide
  • 6-(4-cyclopropyl-1H-imidazol-1-yl)-1-methyl-1H-indole-4-carboxylic acid 260 mg, 0.93 mmol
  • pyridine 10.0 mL
  • Example 12 2-(6-(4-Isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-7-(4-(trifluoromethyl)- 1H-imidazol-1-yl)-3,4-dihydroisoquinoline-1(2H)-one
  • Step 1 7-Bromo-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)isoquinolin-1(2H)-one
  • Step 2 2-(6-(4-Isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-7-(4-(trifluoromethyl)-1H
  • Step 2 2-(6-(4-Isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-7-(4-(trifluoromethyl)-1H
  • Step 4 3-Bromo-6-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6,7-dihydro-5H- Preparation of pyrrolo[3,4-b]pyridin-5-one
  • Step 5 3-(4-Cyclopropyl-1H-imidazol-1-yl)-6-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine- Preparation of 2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one
  • Hydrogen peroxide (1.4 mL) was added to a mixed solvent of acetic acid (18 mL) and water (3.5 mL), and the mixture was heated to 45 ° C, then 5-(4-cyclopropyl-2-indolyl-1H-imidazole-1- 2-fluoro-4-methylbenzonitrile (1.1 g, 4 mmol), maintained at an internal temperature not higher than 55 ° C, stirred at 45 ° C for 0.5 h, then cooled to room temperature.
  • Step 8 5-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(5-isopropyl-1H-tetrazol-1-yl)pyridin-2-yl)-2 -Preparation of fluoro-4-methylbenzamide
  • 6-Bromo-2-pyridinecarboxylic acid (3.0 g, 15 mmol) was added to thionyl chloride (11 mL), heated to 85 ° C under argon and stirred for 2 h. After cooling to room temperature, the reaction solution was concentrated under reduced pressure to remove thionyl chloride.
  • Step 3 5-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(1-isopropyl-1H-tetrazol-5-yl)pyridin-2-yl)-2 -Preparation of fluoro-4-methylbenzamide
  • Example 30 7-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)benzo[d][1,3]dioxole-5-carboxamide
  • Step 2 7-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine- Preparation of 2-yl)benzo[d][1,3]dioxol-5-carboxamide
  • Step 7 5-Methyl-8-nitro-5,6-dihydrobenzo[f][1,2,4]triazolo[4,3-d][1,4]oxazepine preparation
  • Step 8 Preparation of 5-methyl-5,6-dihydrobenzo[f][1,2,4]triazolo[4,3-d][1,4]oxazepine-8-amine
  • Step 9 5-(4-Cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(5-methyl-5,6-dihydrobenzo[f][ Preparation of 1,2,4]triazolo[4,3-d][1,4]oxazepine-8-yl)benzamide
  • Example 32 5-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)isoindoline-1-one
  • Step 1 Preparation of 5-bromo-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)isoindolin-1-one
  • Step 2 5-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine- Preparation of 2-yl)isoindoline-1-one
  • Example 33 6-(4-Cyclopropyl-1H-imidazol-1-yl)-3,3-dimethyl-2-(2-(4-(1,1,1-trifluoroprop-2) -yl)-4H-1,2,4-triazol-3-yl)thiazol-4-yl)isoindolin-1-one
  • Step 3 Preparation of 4-bromo-N-(1,1,1-trifluoropropan-2-yl)thiazole-2-aminocarboxamidine
  • Step 4 Preparation of 4-bromo-2-(4-(1,1,1-trifluoropropan-2-yl)-4H-1,2,4-triazol-3-yl)thiazole
  • Step 5 Preparation of 6-(4-cyclopropyl-1H-imidazol-1-yl)-2-(4-methoxybenzyl)-3,3-dimethylisoindoline-1-one
  • Step 7 6-(4-Cyclopropyl-1H-imidazol-1-yl)-3,3-dimethyl-2-(2-(4-(1,1,1-trifluoroprop-2-) Of 4-)-4H-1,2,4-triazol-3-yl)thiazol-4-yl)isoindolin-1-one
  • 6-(4-Cyclopropyl-1H-imidazol-1-yl)-3,3-dimethylisoindolin-1-one (100 mg, 0.375 mmol) prepared in step 6 was placed in a microwave tube , 4-bromo-2-(4-(1,1,1-trifluoropropan-2-yl)-4H-1,2,4-triazol-3-yl)thiazole prepared in Step 4 (146 mg) , 0.450 mmol), cuprous iodide (14.0 mg, 0.0750 mmol), N,N-dimethylethylenediamine (6.60 mg, 0.0750 mmol), potassium carbonate (103 mg, 0.750 mmol), dioxane (8 mL) ), nitrogen was pumped 3 times, and reacted at 110 ° C for 80 min.
  • Example 34 6-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)-5-morpholinopidoindolin-1-one
  • Step 6 Preparation of 5-morpholino-6-nitro-1-oxoisoindoline-2-carboxylic acid tert-butyl ester
  • Step 7 Preparation of 6-amino-5-morpholino-1-oxoisoindoline-2-carboxylic acid tert-butyl ester
  • Step 8 Preparation of 6-((2-cyclopropyl-2-oxoethyl)amino)-5-morpholino-1-oxoisoindoline-2-carboxylic acid tert-butyl ester
  • 6-Amino-5-morpholino-1-oxoisoindoline-2-carboxylic acid tert-butyl ester obtained in Step 7 (1.21 g, 3.62 mmol), potassium carbonate (750 mg, 5.43 mmol), potassium iodide (720 mg, 4.34 mmol) was dissolved in 15 mL of N,N-dimethylformamide and stirred at room temperature for 10 min under nitrogen. 2-Bromocyclopropyl-1-one (703 mg, 4.34 mmol) was added and reacted at 60 ° C for 4 hours.
  • Step 9 6-(N-(2-Cyclopropyl-2-oxoethyl)formylamino)-5-morpholino-1-oxoisoindoline-2-carboxylic acid tert-butyl ester preparation
  • Step 10 Preparation of 6-(4-cyclopropyl-1H-imidazol-1-yl)-5-morpholino-1-oxoisoindoline-2-carboxylic acid tert-butyl ester
  • Step 12 6-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine-Preparation of 2-yl)-5-morpholinopidoindolin-1-one
  • Example 27 5-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-6-(4-cyclopropyl-1H-imidazole-1 -yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)isoindolin-1-one
  • Step 1 6-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(1-isopropyl-1H-tetrazol-5-yl)pyridin-2-yl)-3 Preparation of 3-dimethylisoindoline-1-one
  • ASK1 purchased from Carna Bioscience
  • ADP-Glo Kinase Assay purchased from Promega;
  • Test compound The compound of the invention prepared in the above examples.
  • test compound Dilute the test compound to 1.11 mM or 1 mM using DMSO;
  • reaction system was placed at 25 ° C for 90 minutes, it was incubated with 20 ⁇ L of ADP-Glo Reagent for 40 min.
  • High control (HC) DMSO
  • Low control (LC) staurosporine 1 ⁇ M
  • mice Male BALB/c mice, SPF grade, purchased from Changzhou Cavans Laboratory Animal Co., Ltd.; 17-21 g, license number: SCXK (Su) 2016-0010; 2 to 3 days acclimation period before the experiment.
  • Methanol and acetonitrile were purchased from Merck; anhydrous ethanol, PEG200 and physiological saline were purchased from Nanjing Kaiji Biotechnology Development Co., Ltd.; o-toluene was purchased from Shanghai Ziqi Biotechnology Co., Ltd.
  • API 4000 triple quadrupole LC/MS, Analyst QS A01.01 chromatography workstation were purchased from AB SCIEX, USA; Milli-Q ultrapure water was purchased from Millipore; CF16R XII desktop high speed refrigerated centrifuge was purchased from Hitachi The company; Qilinbeier Vortex-5 oscillator was purchased from Germany IKA company; electric thermostatic water bath was purchased from Changzhou Guohua Electric Co., Ltd.; electric pipette was purchased from Thermo Company, USA; microanalytical balance was purchased from Shanghai METTLER Co., Ltd.
  • test compound (as free base), add to 7.5 mL of ethanol-PEG200-normal saline (5:20:75), vortex for 2 min, sonicate for 3 min, and prepare a concentration of 0.2 mg/mL.
  • the solution is used for oral administration; 100 ⁇ L of the test solution is made up to 10 ng/mL with methanol, and the same concentration of the reference substance is prepared at the same time. The concentration of the test sample and the reference solution is detected by HPLC, and the test sample is calculated. Accuracy.
  • mice were given a single oral administration of 2 mg/kg of test compound at a dose of 10 mL/kg. After administration, the mice were bled at 1, 4, and 6 h and sacrificed. Blood and whole liver were collected and placed on ice. on.
  • the whole blood was anticoagulated with heparin sodium and centrifuged (centrifugation conditions: 8000 rpm/min, 5 min, 4 ° C), 40 ⁇ L of the upper layer plasma was transferred, and 400 ⁇ L of methanol-acetonitrile (50:50) precipitant (containing 5 ng/mL o-toluene) was added. After shaking for 3 min, centrifugation (4500 rpm, 5 min, 4 ° C), the supernatant was added to the mobile phase for dilution, and the supernatant was taken. The content of the compound in the supernatant sample was analyzed by LC-MS/MS. The results are shown in Table 5.
  • the compounds of the present invention have a high distribution in the liver, and the liver selectivity and targeting are good. Therefore, the compound of the present invention is expected to be a more effective and safer drug for treating metabolic liver diseases such as fatty liver and nonalcoholic fatty liver hepatitis (NASH).
  • metabolic liver diseases such as fatty liver and nonalcoholic fatty liver hepatitis (NASH).
  • Liver steatosis was induced by high-fat diet (HFD).
  • HFD high-fat diet
  • CCL4 carbon tetrachloride
  • This model is similar to the pathogenesis and pathological phenomenon of human NASH disease.
  • the purpose of this experiment was to evaluate the efficacy of the compounds of the invention in HFD-CCL4-induced NASH models of C57BL/6 mice using GS-4997 as a control compound.
  • HFD-CCL4 was induced for 10 weeks, and drug intervention was performed for 4 weeks to observe the therapeutic effect of the drug on NASH and liver fibrosis.
  • This compound was prepared by the method described in WO2013/112741 and identified by hydrogen spectroscopy and mass spectrometry.
  • mice Male, 18-20 g were purchased from Beijing Weitong Lihua Co., Ltd.
  • test compound and GS-4997 of the examples of the present invention were diluted to 0.3 mg/mL, 1 mg/mL, and 3 mg/mL with a solution of 0.045 M hydrochloric acid-propylene glycol (50:50), and were administered alternately.
  • HFD-CCL4 induces C57BL/6 mouse NASH model: After 3-7 days of adaptive feeding in the SPF barrier of KCI experimental animal center, the animals were replaced with HFD feed, and the feeding cycle was 10 weeks. At the end of the 6th week of HFD feeding, the HFD group was randomized according to the body weight of the animals, and 10 rats in each group were orally administered with CCl4 (three times a week, 9-10 am) for 4 weeks.
  • CCl4 three times a week, 9-10 am
  • the HCD-CCl4-induced male C57BL/6 mouse NASH model was established according to the established method of KCI.
  • the modeling agent was Olive Oil+CCl4 solution (formulated by KCI). Six animals randomly assigned to the normal maintenance diet were fed as a normal control group.
  • the animals were divided into a normal control group, a HFD-CCL4 model control group (model group, 0.045 M hydrochloric acid-propylene glycol (50:50)), and a compound group (test compound group of the present invention, GS-4997 group).
  • the test compound of the present invention and GS-4997 were administered intragastrically once a day for 4 weeks, and the administration was terminated at the 10th week.
  • the dose of the test compound group of the present invention is 3 mg/kg/d
  • the dose of the GS-4997 group is 30 mg/kg/d, that is, the dose of the test compound group of the present invention is administered by the GS-4997 group.
  • Hematoxylin-eosin staining reflects the extent of tissue inflammation, fat deposition, vacuolar degeneration and tissue fibrosis.
  • the semi-quantitative analysis criteria for lesion severity are shown in Table 6.
  • the liver tissue was made into 5 ⁇ m sections, dried for 2 h, and re-watered and stained with Sirius Red (Beijing Hyde Venture, Cat. No. 26357) for 30 min at room temperature, and then dehydrated and sealed for image analysis.
  • Aperio ScanScope CS2 (Leica) was used to scan the pathological sections at 200 ⁇ magnification, and then the scanned images were opened in the Aperio ImageScope program to remove the blood vessels, and the target image was analyzed by Color Deconvolution v9.
  • the fibrotic portion stained red was identified as a positive signal using software and the percentage of fibrosis was calculated.
  • liver fibrosis area was significantly increased in the model group compared with the normal control group; the compound group of Example 5 and Example 29 (3 mg/kg/d) significantly reduced liver fibrosis compared with the model group.
  • the area, the improvement of fibrosis is significantly better than the GS-4997 group (30mg/kg/d).
  • the experimental results are shown in Table 8.
  • the compound of the present invention has a certain therapeutic effect on the HFD-CCL4-induced mouse NASH model; in histopathology, it can effectively reduce hepatic steatosis, hepatocyte injury and reduce liver fibrosis compared with the model group. .

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Abstract

La présente invention se rapporte au domaine de la chimie médicale et concerne un composé hétérocyclique utilisé en tant qu'inhibiteurs d'ASK et son utilisation. Plus particulièrement, l'invention concerne des composés tels que représentés par la formule A ou des isomères, des sels pharmaceutiquement acceptables, des solvates, des cristaux ou des promédicaments de ceux-ci, des procédés de préparation de ceux-ci, des compositions pharmaceutiques contenant ces composés et l'utilisation de ces composés ou compositions dans le traitement et/ou la prévention de maladies associées à la kinase 1 régulatrice du signal d'apoptose. Les composés de la présente invention ont une excellente activité inhibitrice de la kinase 1 régulatrice du signal d'apoptose, et sont prometteurs pour devenir des agents thérapeutiques pour des maladies associées à la kinase 1 régulatrice du signal d'apoptose.
PCT/CN2018/095897 2017-07-18 2018-07-17 Composé hétérocyclique agissant en tant qu'inhibiteur d'ask et utilisation de celui-ci WO2019015559A1 (fr)

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EP3572401A4 (fr) * 2017-01-22 2020-08-26 Fujian Cosunter Pharmaceutical Co., Ltd. Inhibiteur de ask1, sa méthode de préparation et son utilisation
US10919911B2 (en) 2018-04-12 2021-02-16 Terns, Inc. Tricyclic ASK1 inhibitors
US11142525B2 (en) 2018-11-15 2021-10-12 Pfizer Inc. Azalactam compounds as HPK1 inhibitors
WO2021220185A1 (fr) * 2020-05-01 2021-11-04 Pfizer Inc. Composés d'azalactame utilisé en tant qu'inhibiteurs de hpk1
WO2021224818A1 (fr) * 2020-05-08 2021-11-11 Pfizer Inc. Composés d'isoindolone en tant qu'inhibiteurs de hpk1
WO2022003610A1 (fr) 2020-07-02 2022-01-06 Pi Industries Ltd. Dérivés de 2-(4,5-dihydroisoxazol-3-yl) isoindoline-5-carboxamide et composés similaires utilisés comme pesticides pour la protection des cultures
WO2023030478A1 (fr) * 2021-09-03 2023-03-09 浙江海正药业股份有限公司 Dérivé de pyridolactame, son procédé de préparation et son utilisation
WO2023037253A1 (fr) 2021-09-08 2023-03-16 Pi Industries Ltd Composés d'isoxazoline et leur utilisation en tant qu'agents de lutte contre les nuisibles
WO2023057883A1 (fr) * 2021-10-05 2023-04-13 Pfizer Inc. Forme cristalline d'un composé d'azalactam
RU2819642C1 (ru) * 2020-05-01 2024-05-22 Пфайзер Инк. Соединения азалактама в качестве ингибиторов hpk1

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WO2019213244A1 (fr) * 2018-05-02 2019-11-07 Enanta Pharmaceuticals, Inc. Inhibiteurs de la kinase 1 régulant le signal d'apoptose contenant des tétrazoles et leurs méthodes d'utilisation
CN111423422A (zh) * 2019-01-09 2020-07-17 苏州泽璟生物制药股份有限公司 芳基酰胺类抑制剂及其制备方法和应用

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CN104080771A (zh) * 2012-01-27 2014-10-01 吉利德科学公司 细胞凋亡信号调节激酶抑制剂
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EP3572401A4 (fr) * 2017-01-22 2020-08-26 Fujian Cosunter Pharmaceutical Co., Ltd. Inhibiteur de ask1, sa méthode de préparation et son utilisation
US10919911B2 (en) 2018-04-12 2021-02-16 Terns, Inc. Tricyclic ASK1 inhibitors
US11142525B2 (en) 2018-11-15 2021-10-12 Pfizer Inc. Azalactam compounds as HPK1 inhibitors
CN115698004A (zh) * 2020-05-01 2023-02-03 辉瑞公司 作为hpk1抑制剂的氮杂内酰胺化合物
WO2021220185A1 (fr) * 2020-05-01 2021-11-04 Pfizer Inc. Composés d'azalactame utilisé en tant qu'inhibiteurs de hpk1
TWI806043B (zh) * 2020-05-01 2023-06-21 美商輝瑞大藥廠 作為hpk1抑制劑之氮雜內醯胺化合物
US11684616B2 (en) 2020-05-01 2023-06-27 Pfizer Inc. Azalactam compounds as HPK1 inhibitors
RU2819642C1 (ru) * 2020-05-01 2024-05-22 Пфайзер Инк. Соединения азалактама в качестве ингибиторов hpk1
WO2021224818A1 (fr) * 2020-05-08 2021-11-11 Pfizer Inc. Composés d'isoindolone en tant qu'inhibiteurs de hpk1
WO2022003610A1 (fr) 2020-07-02 2022-01-06 Pi Industries Ltd. Dérivés de 2-(4,5-dihydroisoxazol-3-yl) isoindoline-5-carboxamide et composés similaires utilisés comme pesticides pour la protection des cultures
WO2023030478A1 (fr) * 2021-09-03 2023-03-09 浙江海正药业股份有限公司 Dérivé de pyridolactame, son procédé de préparation et son utilisation
WO2023037253A1 (fr) 2021-09-08 2023-03-16 Pi Industries Ltd Composés d'isoxazoline et leur utilisation en tant qu'agents de lutte contre les nuisibles
WO2023057883A1 (fr) * 2021-10-05 2023-04-13 Pfizer Inc. Forme cristalline d'un composé d'azalactam

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