WO2019149205A1 - Dérivé de benzohétéroaryle et son procédé de préparation et son application médicale - Google Patents

Dérivé de benzohétéroaryle et son procédé de préparation et son application médicale Download PDF

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WO2019149205A1
WO2019149205A1 PCT/CN2019/073815 CN2019073815W WO2019149205A1 WO 2019149205 A1 WO2019149205 A1 WO 2019149205A1 CN 2019073815 W CN2019073815 W CN 2019073815W WO 2019149205 A1 WO2019149205 A1 WO 2019149205A1
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group
compound
atom
formula
alkyl
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PCT/CN2019/073815
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Chinese (zh)
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杨方龙
张羚
韩吉慧
贺峰
陶维康
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CN201980004474.4A priority Critical patent/CN111094300B/zh
Publication of WO2019149205A1 publication Critical patent/WO2019149205A1/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
    • A61K31/41—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
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention belongs to the field of medicine, and relates to a novel benzoheteroaryl derivative represented by the formula (I), a process for preparing the same, and a pharmaceutical composition containing the same, and as a therapeutic agent, particularly as a PAR Use of the -4 antagonist.
  • Protease-activated receptors a G-protein-coupled receptor on the cell surface, are members of the G-protein coupled receptor superfamily. Like other types of G protein-coupled receptors, protease-activated receptors also have the property of single-stranded seven-pass transmembrane. As one of the major receptors on the surface of platelets, a total of four protease-activated receptors have been discovered in the family to date, named PAR-1, PAR-2, PAR-3 and PAR-4. Human platelets express PAR-1 and PAR-4, while murine platelets express PAR-3 and PAR-4, but not PAR-1.
  • PAR-4 in 1998 and further cloned the PAR-4 gene and obtained its sequence from lymphoma cells, with a total length of 4.9 kb (eg, Wenfeng, W. et al., Proc. Natl. Acad). .Sci. 95:6642-6646 (1998)). Structurally, the N-terminal and C-terminal amino acid sequences of PAR-4 differ from other PARs. PAR-4 consists of 385 amino acids and contains a signal peptide and an extracellular N-terminal Arg/Gly serine protease binding site.
  • the genes for PAR-1, PAR-2 and PAR-3 are located on human chromosome 5q13, and fluorescence in situ hybridization experiments show that the human PAR-4 gene is located on chromosome 19p12. Unlike the PAR-1 and PAR-3 binding sites, PAR-4 has no thromboplastin-binding hirudin binding site and has a lower affinity for thrombin than PAR-1 and PAR-3. Therefore, in order to activate PAR-4, a higher concentration of thrombin is required.
  • the activation principle of PAR-4 is: first, thrombin binds to the extracellular N-terminus of PAR-4, and cleaves the N-terminal 47 arginine/48-glycine to produce a new N-terminal, tyrosin ligand GYPGQV, which is The second extracellular domain binds to and activates the receptor causing a series of signal transductions.
  • the polypeptide fragment GYPGQV (hPAR-4) or AYPGKF (mPAR-4) at the end of the synthetic tethered ligand can also directly activate PAR-4 (eg, Tatjana, F. et al., J. Biol. Chem. 275: 19728). -19734 (2000)).
  • PAR-1 small molecule antagonist Vorapaxar was approved by the FDA for the prevention of thrombosis and is currently the only drug that treats thrombus by antagonizing thrombin receptor activity (eg, French, S. Etc., Blood Reviews. 29: 179-189 (2015)).
  • antithrombotic drugs targeting the PAR-1 receptor often cause bleeding, so Vorapaxar cannot be used in patients with cerebral hemorrhage.
  • PAR-4 small molecule antagonists are considered to be potentially more safe and effective antithrombotic drugs compared to antagonizing PAR-1, which has a relatively low risk of antagonizing PAR-4.
  • PAR-4 is mainly expressed in the lung, pancreas, thyroid, testis and small intestine, and is moderately expressed in the digestive tract. In addition to thrombosis, PAR-4 is involved in other important aspects such as regulating vasoactivity, mediating cytokines, releasing inflammatory mediators, and regulating the immune system.
  • the main coupling pathway for signal transduction between PAR-4 and G protein subunits is the activation of phospholipase C (PLC) by the G protein Gq, resulting in the production of inositol triphosphate (IP3) and diglycerylglycerol (DAG).
  • IP3 inositol triphosphate
  • DAG diglycerylglycerol
  • PKC protein kinase C
  • PAR-4 is activated by a variety of serine proteases, which regulate edema (via the kallikrein-kinin system) and recruit granulocytes in the inflammatory response.
  • the disclosed antagonists of PAR-4 receptors include WO2013163241, WO2013163244, WO2013163279, WO2016134450, WO2016138199, WO2017019828, WO2017066661, WO2017066683 and WO2017184520, and the like.
  • the present invention will provide a novel structure of a highly potent PAR-4 receptor antagonist for prophylactic and therapeutic use in suffering from thrombosis (thromboses) ), a population of patients associated with embolism, hypercoagulability, or fibrotic alteration.
  • X is an O atom or an S atom
  • W is an O atom or an S atom
  • Ring A is selected from the group consisting of cycloalkyl, aryl and heteroaryl;
  • Ring B is a heteroaryl group
  • R 1 is the same or different and is each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, and a hetero group.
  • a cycloalkyl, aryl and heteroaryl group wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halo, alkyl, alkoxy, haloalkyl Substituting one or more substituents of a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R 2 is selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl base;
  • R 3 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, and a hetero group. a cyclic group, an aryl group and a heteroaryl group;
  • R 4 and R 5 are the same or different and are each independently a hydrogen atom or an alkyl group
  • R 6 is selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl a group wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyanide Base, amino, nitro, -CONR 9 R 10 , -CH 2 NR 9 R 10 , -NR 9 R 10 , -S(O) 2 R 11 , -COR 11 , -COOR 12 , -OR 12 , naphthenic Substituted by one or more substituents in the group, heterocyclic group, aryl group and heteroaryl group;
  • R 6 is Wherein J is a covalent bond or an alkylene group, wherein the alkylene group is optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cyclo Substituted by one or more substituents of an alkyl group, a heterocyclic group, an aryl group and a heteroaryl group, the ring C is selected from the group consisting of an aryl group, a heteroaryl group, a cycloalkyl group and a heterocyclic group, and R 8 is the same or different, and Each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, -CONR 9 R 10 , -CH 2 NR 9 R 10 , -NR 9 R 10 ,
  • R 7 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, and a hetero group.
  • a cycloalkyl, aryl and heteroaryl group wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halo, alkyl, alkoxy, haloalkyl Substituting one or more substituents of a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R 9 and R 10 are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • R 9 and R 10 together with the attached nitrogen atom form a heterocyclic group, wherein the heterocyclic group optionally contains 1 to 2 identical or different selected from N atom, O in addition to 1 nitrogen atom.
  • a hetero atom of an atom and an S atom and the heterocyclic group is optionally selected from the group consisting of alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, -COR 11 Substituting one or more substituents of a cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl and heteroaryl group;
  • R 11 is selected from the group consisting of alkyl, haloalkyl, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 12 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • n 0, 1, 2 or 3;
  • s 0, 1, 2, 3 or 4;
  • p 0, 1, 2 or 3;
  • t 0, 1, 2 or 3.
  • the compound of formula (I) is a compound of formula (II):
  • G is N atom, CR 3 or CH;
  • Ring C is selected from the group consisting of an aryl group, a heteroaryl group, a cycloalkyl group, and a heterocyclic group;
  • R 8 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, -CONR 9 R 10 , -CH 2 NR 9 R 10 , -S(O) 2 R 11 , -COR 11 and -COOR 12 ;
  • W, ring A, R 1 to R 5 , R 7 , R 9 to R 12 , X, n, s, p and t are as defined in the formula (I).
  • the compound of the formula (I) is a compound of the formula (IIcc):
  • G is N atom, CR 3 or CH;
  • Z is selected from the group consisting of O atoms, NR 16 and CH 2 ;
  • Ring C is selected from the group consisting of heterocyclic groups, aryl groups and heteroaryl groups;
  • R b is the same or different and is each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, and an amino group;
  • R 16 is selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, -S(O) 2 R 11 , -COR 11 , cycloalkyl And cycloalkylalkyl;
  • q is 0 or 1
  • r 0, 1, 2 or 3;
  • W, ring A, R 1 to R 5 , R 7 , R 11 , X, n, s, p and t are as defined in the formula (I).
  • the compound of the formula (I) is a compound of the formula (IIaa):
  • G is N atom, CR 3 or CH;
  • Ring C is selected from the group consisting of an aryl group, a heteroaryl group, a cycloalkyl group, and a heterocyclic group;
  • R 8 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, -CONR 9 R 10 , -CH 2 NR 9 R 10 , -S(O) 2 R 11 , -COR 11 and -COOR 12 ;
  • W, ring C, R 1 to R 5 , R 7 , R 9 to R 12 , X, n, s, p and t are as defined in the formula (I).
  • the compound of the formula (I) is a compound of the formula (III), formula (IV) or formula (V):
  • Ring C is selected from the group consisting of an aryl group, a heteroaryl group, a cycloalkyl group, and a heterocyclic group;
  • R 8 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, -CONR 9 R 10 , -CH 2 NR 9 R 10 , -S(O) 2 R 11 , -COR 11 and -COOR 12 ;
  • Ring A, R 1 to R 5 , R 7 , R 9 to R 12 , X, n, s, p and t are as defined in the formula (I).
  • the compound of the formula (I) is a compound of the formula (III'), the formula (IV') or the formula (V') :
  • Ring C is selected from the group consisting of an aryl group, a heteroaryl group, a cycloalkyl group, and a heterocyclic group;
  • R 8 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, -CONR 9 R 10 , -CH 2 NR 9 R 10 , -S(O) 2 R 11 , -COR 11 and -COOR 12 ;
  • R 1 to R 5 , R 7 , R 9 to R 12 , X, n, s, p and t are as defined in the formula (I).
  • the compound of formula (I) is a compound of formula (IIbb):
  • G is N atom, CR 3 or CH;
  • Ring C is selected from the group consisting of heterocyclic groups, aryl groups and heteroaryl groups;
  • R 9 and R 10 are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • R 9 and R 10 together with the attached nitrogen atom form a heterocyclic group, wherein the heterocyclic group optionally contains 1 to 2 identical or different selected from N atom, O in addition to 1 nitrogen atom.
  • a hetero atom of an atom and an S atom and the heterocyclic group is optionally selected from the group consisting of alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, -COR 11 Substituting one or more substituents of a cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl and heteroaryl group;
  • W, ring A, R 1 to R 5 , R 7 , R 11 , X, n, s and p are as defined in the formula (I).
  • the compound of the formula (I) wherein the ring C is selected from the group consisting of phenyl, 5- to 6-membered heteroaryl, C 3-8 cycloalkyl And a 3 to 8 membered heterocyclic group, each of the heteroaryl and heterocyclic groups optionally containing 1 to 3 hetero atoms which are the same or different from the N atom, the O atom and the S atom;
  • the ring C is preferably selected from the group consisting of benzene Base, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, piperidinyl, piperazinyl, 1,2,3,6-tetrahydropyridyl, 1,2,3,4-tetrahydro Pyridyl and morpholine.
  • the compound of formula (I) wherein X is O is O.
  • Typical compounds of the invention include, but are not limited to:
  • a tautomer a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention relates to a compound of the formula (IA):
  • M is selected from halogen, -OH or -OS(O) 2 R 13 ;
  • X is an O atom or an S atom
  • Ring B is a heteroaryl group
  • R 1 is the same or different and is each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, and a hetero group.
  • a cycloalkyl, aryl and heteroaryl group wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halo, alkyl, alkoxy, haloalkyl Substituting one or more substituents of a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R 2 is selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl base;
  • R 3 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, and a hetero group. a cyclic group, an aryl group and a heteroaryl group;
  • R 4 and R 5 are the same or different and are each independently a hydrogen atom or an alkyl group
  • R 13 is alkyl, amino, -NR 14 R 15 or cycloalkyl
  • R 14 and R 15 are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • R 14 and R 15 together with the attached nitrogen atom form a heterocyclic group, wherein the heterocyclic group optionally contains 1 to 2 identical or different selected from N atom, O in addition to 1 nitrogen atom.
  • a hetero atom of an atom and an S atom and said heterocyclic group is optionally selected from the group consisting of alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl Substituting one or more substituents in a heterocyclic group, an aryl group, and a heteroaryl group;
  • n 0, 1, 2 or 3;
  • s 0, 1, 2, 3 or 4.
  • Another preferred embodiment of the invention relates to a compound of the formula (IA) which is of the formula (IIA):
  • G is N atom, CR 3 or CH;
  • M, X, R 1 to R 5 , n and s are as defined in the formula (IA).
  • Another preferred embodiment of the invention relates to a compound of the formula (IA), or a tautomer, a mesogen, a racemate, an enantiomer, a non-pair a conjugate, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is of the formula (IIIA), formula (IVA) or formula (VA):
  • M, X, R 1 to R 5 , n and s are as defined in the formula (IA).
  • Typical intermediates of the invention include, but are not limited to:
  • a tautomer a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention relates to a process for the preparation of a compound of formula (I), which process comprises:
  • a compound of the formula (IA) is reacted with a compound of the formula (IB) to give a compound of the formula (I),
  • M is selected from the group consisting of halogen, -OH and -OS(O) 2 R 13 ;
  • R 13 is selected from the group consisting of alkyl, amino, NR 14 R 15 and cycloalkyl;
  • R 14 and R 15 are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • R 14 and R 15 together with the attached nitrogen atom form a heterocyclic group, wherein the heterocyclic group optionally contains 1 to 2 identical or different selected from N atom, O in addition to 1 nitrogen atom.
  • a hetero atom of an atom and an S atom and said heterocyclic group is optionally selected from the group consisting of alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl Substituting one or more substituents in a heterocyclic group, an aryl group, and a heteroaryl group;
  • Ring A, Ring B, W, X, R 1 to R 7 , n, s and p are as defined in the general formula (I).
  • Another aspect of the invention relates to a process for the preparation of a compound of formula (II), the process comprising:
  • M is selected from the group consisting of halogen, -OH and -OS(O) 2 R 13 ;
  • R 13 is alkyl, amino, NR 14 R 15 and cycloalkyl
  • R 14 and R 15 are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • R 14 and R 15 together with the attached nitrogen atom form a heterocyclic group, wherein the heterocyclic group optionally contains 1 to 2 identical or different selected from N atom, O in addition to 1 nitrogen atom.
  • a hetero atom of an atom and an S atom and said heterocyclic group is optionally selected from the group consisting of alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl Substituting one or more substituents in a heterocyclic group, an aryl group, and a heteroaryl group;
  • Ring A, Ring C, W, X, G, Y, R 1 to R 5 , R 7 , R 8 , n, s, p and t are as defined in the formula (II).
  • Another aspect of the invention relates to a process for the preparation of a compound of the formula (IIbb) which comprises:
  • a compound of the formula (IIA) is reacted with a compound of the formula (IIb) to give a compound of the formula (IIbb),
  • M is selected from the group consisting of halogen, -OH and -OS(O) 2 R 13 ;
  • R 13 is selected from the group consisting of alkyl, amino, -NR 14 R 15 and cycloalkyl;
  • R 14 and R 15 are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • R 14 and R 15 together with the attached nitrogen atom form a heterocyclic group, wherein the heterocyclic group optionally contains 1 to 2 identical or different selected from N atom, O in addition to 1 nitrogen atom.
  • a hetero atom of an atom and an S atom and said heterocyclic group is optionally selected from the group consisting of alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl Substituting one or more substituents in a heterocyclic group, an aryl group, and a heteroaryl group;
  • Ring A, Ring C, W, X, G, Y, R 1 to R 5 , R 7 , R 9 , R 10 , n, s and p are as defined in the formula (II).
  • Another aspect of the invention relates to a process for the preparation of a compound of formula (III), formula (IV) or formula (V), the process comprising:
  • a compound of the formula (VA) is reacted with a compound of the formula (IIB) to give a compound of the formula (V),
  • M is selected from the group consisting of halogen, -OH and -OS(O) 2 R 13 ;
  • R 13 is alkyl, amino, -NR 14 R 15 or cycloalkyl
  • R 14 and R 15 are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • R 14 and R 15 together with the attached nitrogen atom form a heterocyclic group, wherein the heterocyclic group optionally contains 1 to 2 identical or different selected from N atom, O in addition to 1 nitrogen atom.
  • a hetero atom of an atom and an S atom and said heterocyclic group is optionally selected from the group consisting of alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl Substituting one or more substituents in a heterocyclic group, an aryl group, and a heteroaryl group;
  • Ring A, Ring C, W, X, R 1 to R 5 , R 7 , R 8 , n, s, p and t are as defined in Formula (III), Formula (IV) or Formula (V) .
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, a mesogen, a racemate, an enantiomer a form, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent and excipient.
  • Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a medicament.
  • Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof A form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the manufacture of a medicament for antagonizing PAR-4.
  • Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a PAR-4 antagonist.
  • Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof
  • a form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment or prevention of a disease of platelet aggregation.
  • Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof
  • a form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating or preventing a thromboembolic disease
  • the thromboembolic disease is selected from the group consisting of arterial cardiovascular thromboembolism Disease, venous cardiovascular thromboembolic disease, cerebrovascular thromboembolic disease, and thromboembolic disease in the heart or peripheral circulation.
  • Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof A form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment or prevention of a disease of platelet aggregation.
  • Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment or prevention of a thromboembolic disease, preferably, the thromboembolic disease is selected from the group consisting of an arterial cardiovascular thromboembolic disease, venous cardiovascular Thromboembolic disease, cerebrovascular thromboembolic disease, and thromboembolic disease in the heart or peripheral circulation.
  • Another aspect of the invention relates to a method of antagonizing PAR-4 comprising administering to a patient a therapeutically effective amount of a compound of formula (I) or a tautomer thereof, a mesogen, racemic Or a pharmaceutically acceptable salt or a pharmaceutical composition comprising the same, or an enantiomer, a diastereomer or a mixture thereof.
  • Another aspect of the invention relates to a method of treating or preventing a disease of platelet aggregation comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, a mesogen thereof, A racemic form, enantiomer, diastereomer or mixture thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.
  • Another aspect of the invention relates to a method of treating or preventing a thromboembolic disease comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, a mesogen thereof, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, preferably, the thromboembolic disease is selected from the group consisting of Arterial cardiovascular thromboembolic disease, venous cardiovascular thromboembolic disease, cerebrovascular thromboembolic disease, and thromboembolic disease in the heart chamber or peripheral circulation.
  • a suitable unit dose may be from 0.1 to 1000 mg.
  • the pharmaceutical composition of the present invention may contain, in addition to the active compound, one or more excipients selected from the group consisting of fillers (diluents), binders, wetting agents, disintegrating agents or Shape agent, etc.
  • the composition may contain from 0.1 to 99% by weight of active compound, depending on the method of administration.
  • the active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture.
  • Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives, To provide a pleasing and tasty pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of a tablet for admixture.
  • excipients can be inert excipients, granulating agents, disintegrating agents, binders, and lubricants. These tablets may be uncoated or may be coated by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract, thus providing a sustained release effect over a longer period of time.
  • Oral formulations can also be provided in soft gelatine capsules in which the active ingredient is mixed with an inert solid diluent or the active ingredient in admixture with a water-soluble vehicle or an oil vehicle.
  • the aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing. Such excipients are suspending, dispersing or wetting agents.
  • the aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
  • the oil suspension can be formulated by suspending the active ingredient in vegetable oil, or mineral oil.
  • the oil suspension may contain a thickening agent.
  • the above sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of an antioxidant.
  • compositions of the invention may also be in the form of an oil-in-water emulsion.
  • the oil phase can be a vegetable oil, or a mineral oil or a mixture thereof.
  • Suitable emulsifiers can be naturally occurring phospholipids, and emulsions can also contain sweeteners, flavoring agents, preservatives, and antioxidants.
  • Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • the pharmaceutical compositions of the invention 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 oily phase.
  • the injection or microemulsion is injected into the bloodstream of the patient by topical injection.
  • the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the invention.
  • a continuous intravenous delivery device 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 aqueous or oily suspension for intramuscular and subcutaneous administration.
  • the suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent.
  • sterile fixed oils may conveniently be employed as a solvent or suspension medium.
  • the compounds of the invention may be administered in the form of a suppository for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug.
  • suitable non-irritating excipient include a mixture of cocoa butter, glycerin gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.
  • the dosage of the drug to be administered depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient. , the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment modality such as the mode of treatment, the daily dosage of the compound of formula (I) or the pharmaceutically acceptable salt
  • the type can be verified according to traditional treatment options.
  • alkyl refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbons.
  • the alkyl group of the atom is a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbons.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -methylhexyl, 3-methylhexyl, 4-methylhexyl,
  • lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, which is independently optionally selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy.
  • haloalkoxy alkylthio, alkylamino, alkenyl, alkynyl, decyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl Substituted by one or more substituents of a cycloalkoxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, and an oxo group.
  • alkylene refers to a saturated straight or branched aliphatic hydrocarbon radical having two residues derived from the removal of two hydrogen atoms from the same carbon atom of the parent alkane or two different carbon atoms.
  • Non-limiting examples of alkylene include, but are not limited to, methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 ) CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), and the like.
  • the alkylene group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, which is independently optionally selected from the group consisting of halogen, alkyl, haloalkyl, alkane.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, which is independently optionally selected from halogen, alkyl, haloalkyl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. One carbon atom, most preferably from 5 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • a polycycloalkyl group includes a spiro ring, a fused ring, and a cycloalkyl group.
  • spirocycloalkyl refers to a polycyclic group that shares a carbon atom (referred to as a spiro atom) between 5 to 20 members of a single ring, which may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the rings.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to 5 to 20 members, and each ring in the system shares an all-carbon polycyclic group of an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have complete Conjugate ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, more preferably a bicyclic ring or a tricyclic ring.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring includes the above cycloalkyl (eg, monocyclic, fused, spiro, and bridged cycloalkyl) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the parent structure is attached
  • the ring together is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like; preferably phenylcyclopentyl, tetrahydronaphthyl.
  • the cycloalkyl group can be optionally substituted or unsubstituted, and when substituted, the substituent can be substituted at any available point of attachment, which is independently optionally selected from the group consisting of halogen, alkyl, haloalkyl.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from nitrogen, oxygen or S(O).
  • a hetero atom of m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • It preferably comprises from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms; most preferably from 3 to 8 (eg 3, 4, 5, 6, 7 or 8) ring atoms, of which 1 to 3 (eg 1, 2 or 3) are heteroatoms; most preferably 5 to 6 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, Hydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like are preferably tetrahydropyranyl, piperidinyl or pyrrolidinyl.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • spiroheterocyclyl refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5 to 20 members of a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O). ) m (where m is an integer 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of shared spiro atoms between the ring and the ring, and is preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group.
  • Non-limiting examples of spiroheterocyclyl groups include:
  • fused heterocyclyl refers to 5 to 20 members, and each ring in the system shares an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more Double bond, but none of the rings have a fully conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining rings
  • the atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • fused heterocyclic groups include:
  • bridge heterocyclyl refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have a total A ⁇ -electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • bridge heterocyclic groups include:
  • the heterocyclyl ring includes the above heterocyclic group (for example, a monocyclic ring, a fused ring, a spiro ring, and a bridged heterocyclic group) fused to an aryl group, a heteroaryl group or a cycloalkyl ring, wherein the structure is bonded to the parent structure.
  • the ring together is a heterocyclic group, non-limiting examples of which include:
  • the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, which is independently optionally selected from the group consisting of halogen, alkyl, haloalkyl , alkoxy, haloalkoxy, alkylthio, alkylamino, alkenyl, alkynyl, decyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, Substituted by one or more substituents of a heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo group.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene. Base and naphthyl.
  • the aryl ring includes the above aryl group fused to a heteroaryl group, a heterocyclic group or a cycloalkyl ring, wherein the ring bonded to the parent structure is an aryl ring, non-limiting examples of which include:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, which is independently optionally selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy , haloalkoxy, alkylthio, alkylamino, alkenyl, alkynyl, decyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl Substituted by one or more substituents of a cycloalkoxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, and an oxo group.
  • heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 5 to 10 members, and has 1 to 3 hetero atoms; more preferably 5 or 6 members, and 1 to 2 hetero atoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyridyl Azyl, oxazolyl, pyrrolyl, 1H-1,2,3-triazolyl, 4H-1,2,4-triazolyl, 4H-1,2,3-triazolyl, 1H-tetrazole a group, 2H-tetrazolyl, 5H-tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl or the like, preferably imidazolyl,
  • the heteroaryl ring includes a heteroaryl group as defined above fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples of which include:
  • the heteroaryl group can be optionally substituted or unsubstituted, and when substituted, the substituent can be substituted at any available point of attachment, which is independently optionally selected from the group consisting of halogen, alkyl, haloalkyl.
  • haloalkyl refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy means that the alkoxy group is substituted by one or more halogens, wherein alkoxy is as defined above.
  • cycloalkylalkyl refers to an alkyl group substituted by one or more cycloalkyl groups, wherein alkyl and cycloalkyl are as defined above.
  • hydroxy refers to an -OH group.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
  • halogen means fluoro, chloro, bromo or iodo.
  • amino means -NH 2.
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.
  • the present invention provides a novel PAR-4 antagonist having the structure of the general formula (I), which has a marked improvement in solvent solubility and a drug-absorbable property as compared with the prior art compound.
  • a method for preparing a medicinal salt comprising the steps of:
  • M is selected from halogen, -OH or -OS(O) 2 R 13 ;
  • R 13 is selected from the group consisting of alkyl, amino, -NR 14 R 15 and cycloalkyl;
  • R 14 and R 15 are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • R 14 and R 15 together with the attached nitrogen atom form a heterocyclic group, wherein the heterocyclic group optionally contains 1 to 2 identical or different selected from N atom, O in addition to 1 nitrogen atom.
  • a hetero atom of an atom and an S atom and said heterocyclic group is optionally selected from the group consisting of alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl Substituting one or more substituents in a heterocyclic group, an aryl group, and a heteroaryl group;
  • Ring A, Ring B, W, X, R 1 to R 7 , n, s and p are as defined in the general formula (I).
  • M is halogen or -OS(O) 2 R 13
  • the compound of the formula (IA) and the compound of the formula (IB) undergo nucleophilic substitution reaction under basic conditions to give a compound of the formula (I) ;
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases. , bis-trimethylsilylamino lithium, potassium acetate, potassium acetate, sodium t-butoxide, potassium t-butoxide and sodium n-butoxide, said inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, Potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide, preferably cesium carbonate;
  • Reagents that provide Mitsunobu etherification reaction conditions include, but are not limited to, tri-n-butylphosphoric acid and azodiyldipiperidine, tri-n-butylphosphine, and N,N,N',N'-tetramethylazo Amide or triphenylphosphine and diethyl azodicarboxylate;
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
  • a method for preparing a medicinal salt comprising the steps of:
  • M is selected from halogen, -OH or -OS(O) 2 R 13 ;
  • R 13 is selected from the group consisting of alkyl, amino, -NR 14 R 15 and cycloalkyl;
  • R 14 and R 15 are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • R 14 and R 15 together with the attached nitrogen atom form a heterocyclic group, wherein the heterocyclic group optionally contains 1 to 2 identical or different selected from N atom, O in addition to 1 nitrogen atom.
  • a hetero atom of an atom and an S atom and said heterocyclic group is optionally selected from the group consisting of alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl Substituting one or more substituents in a heterocyclic group, an aryl group, and a heteroaryl group;
  • Ring A, Ring C, W, X, G, Y, R 1 to R 5 , R 7 , R 8 , n, s, p and t are as defined in the formula (II).
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases. , bis-trimethylsilylamino lithium, potassium acetate, potassium acetate, sodium t-butoxide, potassium t-butoxide and sodium n-butoxide, said inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, Potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide, preferably cesium carbonate;
  • Reagents that provide Mitsunobu etherification reaction conditions include, but are not limited to, tri-n-butylphosphoric acid and azodiyldipiperidine, tri-n-butylphosphine, and N,N,N',N'-tetramethylazo Amide or triphenylphosphine and diethyl azodicarboxylate;
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
  • a method for preparing a medicinal salt comprising the steps of:
  • M is selected from halogen, -OH or -OS(O) 2 R 13 ;
  • R 13 is selected from the group consisting of alkyl, amino, -NR 14 R 15 and cycloalkyl;
  • R 14 and R 15 are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • R 14 and R 15 together with the attached nitrogen atom form a heterocyclic group, wherein the heterocyclic group optionally contains 1 to 2 identical or different selected from N atom, O in addition to 1 nitrogen atom.
  • a hetero atom of an atom and an S atom and said heterocyclic group is optionally selected from the group consisting of alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl Substituting one or more substituents in a heterocyclic group, an aryl group, and a heteroaryl group;
  • Ring A, Ring C, W, X, R 1 to R 5 , R 7 , R 8 , n, s, p and t are as defined in the formula (III).
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases. , bis-trimethylsilylamino lithium, potassium acetate, potassium acetate, sodium t-butoxide, potassium t-butoxide and sodium n-butoxide, said inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, Potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide, preferably cesium carbonate;
  • Reagents that provide Mitsunobu etherification reaction conditions include, but are not limited to, tri-n-butylphosphoric acid and azodiyldipiperidine, tri-n-butylphosphine, and N,N,N',N'-tetramethylazo Amide or triphenylphosphine and diethyl azodicarboxylate;
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
  • a method for preparing a medicinal salt comprising the steps of:
  • M is selected from halogen, -OH or -OS(O) 2 R 13 ;
  • R 13 is selected from the group consisting of alkyl, amino, -NR 14 R 15 and cycloalkyl;
  • R 14 and R 15 are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • R 14 and R 15 together with the attached nitrogen atom form a heterocyclic group, wherein the heterocyclic group optionally contains 1 to 2 identical or different selected from N atom, O in addition to 1 nitrogen atom.
  • a hetero atom of an atom and an S atom and said heterocyclic group is optionally selected from the group consisting of alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl Substituting one or more substituents in a heterocyclic group, an aryl group, and a heteroaryl group;
  • Ring A, Ring C, W, X, R 1 to R 5 , R 7 , R 8 , n, s, p and t are as defined in the general formula (IV).
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases. , bis-trimethylsilylamino lithium, potassium acetate, potassium acetate, sodium t-butoxide, potassium t-butoxide and sodium n-butoxide, said inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, Potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide, preferably cesium carbonate;
  • Reagents that provide Mitsunobu etherification reaction conditions include, but are not limited to, tri-n-butylphosphoric acid and azodiyldipiperidine, tri-n-butylphosphine, and N,N,N',N'-tetramethylazo Amide or triphenylphosphine and diethyl azodicarboxylate;
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
  • a method for preparing a medicinal salt comprising the steps of:
  • M is selected from halogen, -OH or -OS(O) 2 R 13 ;
  • R 13 is selected from the group consisting of alkyl, amino, -NR 14 R 15 and cycloalkyl;
  • R 14 and R 15 are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • R 14 and R 15 together with the attached nitrogen atom form a heterocyclic group, wherein the heterocyclic group optionally contains 1 to 2 identical or different selected from N atom, O in addition to 1 nitrogen atom.
  • a hetero atom of an atom and an S atom and said heterocyclic group is optionally selected from the group consisting of alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl Substituting one or more substituents in a heterocyclic group, an aryl group, and a heteroaryl group;
  • Ring A, Ring C, W, X, R 1 to R 5 , R 7 , R 8 , n, s, p and t are as defined in the formula (V).
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases. , bis-trimethylsilylamino lithium, potassium acetate, potassium acetate, sodium t-butoxide, potassium t-butoxide and sodium n-butoxide, said inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, Potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide, preferably cesium carbonate;
  • Reagents that provide Mitsunobu etherification reaction conditions include, but are not limited to, tri-n-butylphosphoric acid and azodiyldipiperidine, tri-n-butylphosphine, and N,N,N',N'-tetramethylazo Amide or triphenylphosphine and diethyl azodicarboxylate;
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • the NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four.
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS Methyl silane
  • the measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • ESI FINNIGAN LCQAd
  • HPLC High performance liquid chromatography
  • Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.
  • the CombiFlash Rapid Preparer uses the Combiflash Rf200 (TELEDYNE ISCO).
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Dari Companies such as chemicals.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • the microwave reaction used a CEM Discover-S Model 908860 microwave reactor.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature and is 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC), the developing agent used for the reaction, the column chromatography eluent system used for the purification of the compound, and the thin layer chromatography developing solvent system including: A: Methylene chloride/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, D: dichloromethane/ethyl acetate solvent volume ratio is adjusted according to the polarity of the compound, It can also be adjusted by adding a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid.
  • TLC thin layer chromatography
  • 3-hydroxyphenylboronic acid 1b (276 mg, 2.0 mmol, Shanghai Haoyuan Reagent Co., Ltd.), tetrakis(triphenylphosphine)palladium (231 mg, 0.2 mmol), sodium carbonate (424 mg, 4.0 mmol), heated to an argon atmosphere Stir at 90 ° C for 18 hours. The reaction was cooled, EtOAc EtOAc (EtOAc (EtOAc)EtOAc. Chromatography on eluent B afforded the title compound 1c (300 mg).
  • 1-(4-Benzyloxy-6-methoxybenzofuran-2-yl)ethanone 1d (10 g, 33.7 mmol, prepared by the method disclosed in the patent application "WO2013163244”) dissolved in 200 mL of two In methyl chloride, it was cooled to -78 ° C, and pentamethylbenzene (35 g, 236.1 mmol) and a boron trichloride dichloromethane solution (1M, 50.6 mL) were added and reacted for 40 minutes. Saturated ammonium chloride (30 mL), EtOAc (EtOAc) The organic layer was concentrated under reduced pressure.
  • the reaction was stirred for 0.5 hours, 50 mL of saturated sodium bicarbonate solution was added, and ethyl acetate was added (80 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, evaporated, evaporated.
  • the crude compound 1i (1300 mg, 3.2 mmol) was dissolved in 15 mL of methanol and 12 mL of dichloromethane, and a solution of fresh sodium methoxide in methanol (2.1 M, 3 mL) was added and reacted for 3 hours. The organic layer was concentrated under reduced pressure.
  • the compound 11 (30 mg, 86 ⁇ mol) and the compound 2b (26 mg, 132 ⁇ mol) were dissolved in 5 mL of N,N'-dimethylformamide, and cesium carbonate (140 mg, 430 ⁇ mol) was added thereto, and the mixture was heated to 50 ° C, and the reaction was stirred for 1 hour. The reaction mixture was concentrated under reduced vacuo.
  • 2-Bromo-5-methoxypyrimidine 7a (189 mg, 1.00 mmol, Shanghai Bied Pharmaceutical Technology Co., Ltd.) and Compound 1b (138 mg, 1.00 mmol) were dissolved in 5 mL of 1,4-dioxane under an argon atmosphere.
  • tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) and sodium carbonate (212 mg, 2.00 mmol) were added, and the mixture was reacted at 100 ° C for 18 hours.
  • 10 mL of water (3 mL, EtOAc, EtOAc) Yield: 89%.
  • Piperazine (9.68 g, 112.38 mmol) was dissolved in 50 mL of ethanol, and 1-bromopropane (3.07 g, 24.96 mmol, Shanghai Titan Technology Co., Ltd.) and triethylamine (2.53 g, 25.00 mmol) were added to the above reaction.
  • the system was heated to 80 ° C in an oil bath and the reaction was stirred at this temperature for 18 hours.
  • the reaction was cooled, EtOAc (3 mL, dry dry.
  • the compound 19b (60 mg, 0.26 mmol) was dissolved in 5 mL of methanol, and then sodium hydroxide (102 mg, 2.55 mmol) was dissolved in 2.5 mL of water, and then added to the above reaction system, and the reaction was stirred at room temperature for 2 hours. After removing most of the methanol under reduced pressure, 10 mL of water was added to the residue, and then 1 M hydrochloric acid was added until the pH of the reaction mixture was 2 to 3, and extracted with ethyl acetate (10 mL ⁇ 2). The residue was evaporated to dryness crystall
  • 5-bromothiazole-2-carboxylic acid 20a 250 mg, 1.20 mmol, Nanjing Pharmaceutical Co., Ltd.
  • compound 14d was added at room temperature.
  • 1-Bromo-3-methoxybenzene 28a (3.74 g, 20 mmol, Shunyuan Technology (Shanghai) Co., Ltd.) was dissolved in 100 mL of toluene under argon atmosphere, and compound compound 26a (2.74 g, 14.7 mmol) was added.
  • Tri-tert-butylphosphine (30 mg, 0.14 mmol), tris(dibenzylideneacetone)dipalladium (150 mg, 0.16 mmol) and potassium t-butoxide (2.5 g, 22.2 mmol), heated at 100 ° C, stirred for 12 hours, cold To room temperature. 40 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL ⁇ 2). Filtration, and the filtrate was concentrated under reduced pressure.

Abstract

La présente invention concerne un dérivé de benzohétéroaryle et son procédé de préparation et son application médicale. En particulier, la présente invention concerne un nouveau dérivé de benzohétéroaryle représenté par la formule générale (I), un procédé de préparation de celui-ci, une composition pharmaceutique comprenant le dérivé, et une utilisation de celui-ci en tant qu'agent thérapeutique, en particulier en tant qu'antagoniste de PAR-4. La définition de chaque substituant dans la formule générale (I) est la même que la définition dans la spécification.
PCT/CN2019/073815 2018-01-31 2019-01-30 Dérivé de benzohétéroaryle et son procédé de préparation et son application médicale WO2019149205A1 (fr)

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CN102241621A (zh) * 2010-05-11 2011-11-16 江苏恒瑞医药股份有限公司 5,5-双取代-2-亚氨基吡咯烷类衍生物、其制备方法及其在医药上的应用
CN104540835A (zh) * 2012-04-26 2015-04-22 百时美施贵宝公司 用于治疗血小板聚集的作为蛋白酶激活受体4(par4)抑制剂的咪唑并噻二唑衍生物
CN104583218A (zh) * 2012-04-26 2015-04-29 百时美施贵宝公司 作为蛋白酶活化受体4(par4)抑制剂用于治疗血小板聚集的咪唑并噻二唑和咪唑并吡嗪的衍生物
CN104640869A (zh) * 2012-04-26 2015-05-20 百时美施贵宝公司 作为用于治疗血小板聚集的蛋白酶激活受体4(par4)抑制剂的咪唑并噻二唑和咪唑并哒嗪衍生物
WO2017066863A1 (fr) * 2015-10-19 2017-04-27 Universite De Montreal Utilisation de composés hétérocycliques comme inhibiteurs de l'agrégation plaquettaire
CN107602589A (zh) * 2017-11-06 2018-01-19 中国药科大学 一种化合物的制备方法

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US8927688B2 (en) * 2012-04-26 2015-01-06 Bristol-Myers Squibb Company PAR4 agonist peptides

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Publication number Priority date Publication date Assignee Title
CN102241621A (zh) * 2010-05-11 2011-11-16 江苏恒瑞医药股份有限公司 5,5-双取代-2-亚氨基吡咯烷类衍生物、其制备方法及其在医药上的应用
CN104540835A (zh) * 2012-04-26 2015-04-22 百时美施贵宝公司 用于治疗血小板聚集的作为蛋白酶激活受体4(par4)抑制剂的咪唑并噻二唑衍生物
CN104583218A (zh) * 2012-04-26 2015-04-29 百时美施贵宝公司 作为蛋白酶活化受体4(par4)抑制剂用于治疗血小板聚集的咪唑并噻二唑和咪唑并吡嗪的衍生物
CN104640869A (zh) * 2012-04-26 2015-05-20 百时美施贵宝公司 作为用于治疗血小板聚集的蛋白酶激活受体4(par4)抑制剂的咪唑并噻二唑和咪唑并哒嗪衍生物
WO2017066863A1 (fr) * 2015-10-19 2017-04-27 Universite De Montreal Utilisation de composés hétérocycliques comme inhibiteurs de l'agrégation plaquettaire
CN107602589A (zh) * 2017-11-06 2018-01-19 中国药科大学 一种化合物的制备方法

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