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WO2015087996A1 - Dérivé d'imidazopyridine - Google Patents

Dérivé d'imidazopyridine Download PDF

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Publication number
WO2015087996A1
WO2015087996A1 PCT/JP2014/082945 JP2014082945W WO2015087996A1 WO 2015087996 A1 WO2015087996 A1 WO 2015087996A1 JP 2014082945 W JP2014082945 W JP 2014082945W WO 2015087996 A1 WO2015087996 A1 WO 2015087996A1
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Prior art keywords
group
trifluoromethyl
acceptable salt
pharmacologically acceptable
compound
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Japanese (ja)
Inventor
敏雄 斧田
俊雄 金子
雅巳 荒井
小林　英樹
直生 寺坂
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Daiichi Sankyo Co Ltd
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Daiichi Sankyo Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to an imidazopyridine derivative having an excellent lecithin cholesterol acetyltransferase (hereinafter referred to as LCAT) activating action (preferably a reversible LCAT activating action) or a pharmacologically acceptable salt thereof.
  • LCAT lecithin cholesterol acetyltransferase
  • cardiovascular diseases for example, heart disease, cerebrovascular disease, kidney disease, etc.
  • hypertension for example, hypertension, dyslipidemia, diabetes, etc.
  • Antihypertensive drugs, antilipidemia drugs, and antidiabetic drugs are used for the treatment of hypertension, dyslipidemia, and hyperglycemia, respectively.
  • ⁇ and ⁇ blockers, diuretics, calcium antagonists, ACE inhibitors, and A-II antagonists are used as antihypertensive agents, and HMG-CoA reductase inhibitors, Insulin, sulfonylureas, metformin, glitazones, DPP4 inhibitors, and the like are used as antidiabetics such as ion exchange resins, nicotinic acid derivatives, probucol, and fibrates.
  • These drugs contribute to the regulation of blood pressure and blood lipid or blood glucose levels.
  • mortality due to heart disease, cerebrovascular disease and kidney disease has not been greatly improved even by the use of these drugs, and development of better therapeutic agents for these diseases is desired.
  • a direct risk factor for cardiovascular disease is arteriosclerosis accompanied by thickening of the arterial wall, and the cause of the thickening is due to accumulation of oxidized low density lipoprotein (hereinafter referred to as LDL) cholesterol in macrophages in the arterial wall. It is the formation of plaque (Non-Patent Documents 1 and 2). This plaque inhibits blood flow and promotes thrombus formation.
  • LDL oxidized low density lipoprotein
  • Non-Patent Document 3 An increase in the concentration of LDL cholesterol in the blood and a decrease in the concentration of high-density lipoprotein (hereinafter referred to as HDL) cholesterol are both risk factors for coronary artery disease.
  • HDL high-density lipoprotein
  • Peripheral tissue cholesterol is extracted by HDL and esterified by LCAT on HDL to become cholesteryl ester.
  • Increased LCAT activity promotes the withdrawal of cholesterol from macrophages (for example, Non-Patent Documents 4 and 5). Therefore, it is considered that a drug that enhances LCAT activity is useful as a medicament for treating or preventing diseases such as dyslipidemia and arteriosclerosis.
  • Non-patent Document 6 examples of known drugs that enhance LCAT activity include peptide compounds (for example, Non-patent Document 6) and, as small molecules, for example, compounds described in Patent Document 1.
  • Patent Document 2 As the compound having a pyrazolopyridine skeleton, the compound described in Patent Document 2 is known. Patent Document 2 describes an anti-LPA receptor action, but does not describe an LCAT activation action.
  • the present inventors have conducted various synthetic studies aiming at obtaining new anti-arteriosclerotic drugs by having an excellent LCAT activation action and promoting cholesterol withdrawal directly from macrophages. As a result, the present inventors have found that an imidazopyridine derivative having a specific structure or a pharmacologically acceptable salt thereof has an excellent LCAT activation action, thereby completing the present invention.
  • the present invention provides an imidazopyridine derivative having an excellent LCAT activating action (preferably a reversible LCAT activating action) or a pharmacologically acceptable salt thereof and a medicament containing these.
  • R 1 represents an aryl group which may be substituted (the substituent is a halogen atom, a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, a cyano group; , C 1-6 alkoxy, C 3-7 cycloalkoxy group, a phenyl group, C 2-7 alkoxycarbonyl group, benzyloxycarbonyl group, di (C 1-6 alkyl) aminocarbonyl Moto ⁇ busy (C 1-6 Alkyl) an identical or different 1 to 3 group selected from the group consisting of amino groups), or An optionally substituted heteroaryl group (the heteroaryl is a 5- or 6-membered ring.
  • the heteroatom on the ring of the heteroaryl group is 1 or 2 nitrogen atoms, and further 1 nitrogen atom,
  • An oxygen atom or a sulfur atom may be contained, and the substituent is a halogen atom, a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, a cyano group, C 1-6 alkoxy, C 3-7 cycloalkoxy group, a phenyl group, C 2-7 alkoxycarbonyl group, benzyloxycarbonyl group, di (C 1-6 alkyl) aminocarbonyl Moto ⁇ busy (C 1-6 alkyl And the same or different groups selected from the group consisting of amino groups.
  • a group represented by R 2 is a hydrogen atom or a hydroxyl group.
  • R 1 is an aryl group which may be substituted (the substituent is a halogen atom, a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group) , Cyano group, C 1-6 alkoxy group, C 3-7 cycloalkoxy group, phenyl group, C 2-7 alkoxycarbonyl group, benzyloxycarbonyl group, di (C 1-6 alkyl) aminocarbonyl group and di (C 1-6 alkyl) the same or different 1 to 3 groups selected from the group consisting of amino groups), or the pharmacologically of the compound according to any one of (1) to (3) Acceptable salts, (5) R 1 is a substituted aryl group (the substituent is a chlorine atom, a fluorine atom, a C 1-3 alkyl group, a trifluoromethyl group, a difluorome
  • R 1 is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of a chlorine atom, a difluoromethoxy group, a trifluoromethoxy group and a cyano group) Or the pharmacologically acceptable salt thereof according to any one of (1) to (3), (7) R 1 is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of a difluoromethoxy group, a trifluoromethoxy group, and a cyano group).
  • R 1 is an optionally substituted heteroaryl group (the heteroaryl is a 5-membered or 6-membered ring.
  • the heteroatoms on the ring of the heteroaryl group are 1 or 2 nitrogen atoms, Furthermore, it may contain one nitrogen atom, oxygen atom or sulfur atom, and the substituent is a halogen atom, C 1-6 alkyl group, C 3-7 cycloalkyl group, trifluoromethyl group, difluoromethoxy group, Fluoromethoxy group, cyano group, C 1-6 alkoxy group, C 3-7 cycloalkoxy group, phenyl group, C 2-7 alkoxycarbonyl group, benzyloxycarbonyl group, di (C 1-6 alkyl) aminocarbonyl group and di is a (C 1-6 alkyl) the same or different 1 or 2 groups selected from the group consisting of amino groups.) is, in any one of (1)
  • the heteroatom on the ring of the heteroaryl group is one nitrogen atom, and one more Or a substituent such as a halogen atom, a C 1-3 alkyl group, a C 3-6 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group.
  • a substituent such as a halogen atom, a C 1-3 alkyl group, a C 3-6 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group.
  • R 1 is a substituted pyridyl group, pyrimidyl group, pyrazinyl group, pyridazinyl group, thiadiazolyl group or thiazolyl group (the substituent is a chlorine atom, a fluorine atom, a C 1-3 alkyl group, a cyclopropyl group) 1 or 2 selected from the group consisting of trifluoromethyl group, difluoromethoxy group, trifluoromethoxy group, cyano group, C 1-3 alkoxy group, C 2-4 alkoxycarbonyl group and benzyloxycarbonyl group Or a pharmacologically acceptable salt thereof according to any one of (1) to (3),
  • R 1 is a substituted pyridyl group, pyrimidyl group, pyrazinyl group, pyridazinyl group, thiadiazolyl group or thiazolyl group (the substituent is a chlorine atom, a fluorine atom, a C 1-3 alkyl group, a cyclopropyl group) 1 or 2 selected from the group consisting of trifluoromethyl group, difluoromethoxy group, trifluoromethoxy group, cyano group, C 1-3 alkoxy group, C 2-4 alkoxycarbonyl group and benzyloxycarbonyl group Or a pharmacologically acceptable salt thereof according to (1), wherein R 2 is a hydrogen atom and n is 2.
  • R 1 is a substituted pyridyl group, pyrimidyl group, pyrazinyl group or pyridazinyl group (the substituent is selected from the group consisting of isopropyl group, trifluoromethyl group, difluoromethoxy group, cyano group and isopropoxy group)
  • R 2 is a hydrogen atom
  • n is 2, or a pharmacologically acceptable salt thereof according to (1)
  • (23) The compound according to ( 1 ), wherein R 1 is a pyridyl group, pyrimidyl group or pyrazinyl group substituted with a trifluoromethyl group, R 2 is a hydrogen atom, and n is 2.
  • R 1 is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of a chlorine atom, a difluoromethoxy group, a trifluoromethoxy group and a cyano group) ), R 2 is a hydroxyl group, and n is 2, the compound according to (1) or a pharmacologically acceptable salt thereof, (25) R 1 is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of a difluoromethoxy group, a trifluoromethoxy group, and a cyano group).
  • R 1 is a substituted pyridyl group, pyrimidyl group, pyrazinyl group, pyridazinyl group, thiadiazolyl group or thiazolyl group (the substituent is a chlorine atom, a fluorine atom, a C 1-3 alkyl group, a cyclopropyl group) 1 or 2 selected from the group consisting of trifluoromethyl group, difluoromethoxy group, trifluoromethoxy group, cyano group, C 1-3 alkoxy group, C 2-4 alkoxycarbonyl group and benzyloxycarbonyl group Or a pharmacologically acceptable salt thereof according to (1), wherein R 2 is a hydroxyl group and n is 2.
  • R 1 is a substituted pyridyl group, pyrimidyl group, pyrazinyl group or pyridazinyl group (the substituent is selected from the group consisting of isopropyl group, trifluoromethyl group, difluoromethoxy group, cyano group and isopropoxy group)
  • R 2 is a hydroxyl group
  • n is 2, or a pharmacologically acceptable salt thereof
  • a pharmacologically acceptable salt (29) The compound according to any one of (1) to (28), wherein the 4-position trifluoromethyl group and the 5-position hydroxyl group of the imidazopyridine ring are cis, or a pharmaceutically acceptable salt thereof, (30) The compound according to any one of (1) to (14), (16), (17) and (19) to (28), wherein the optical rotation is (+), or a pharmacologically acceptable salt thereof Salt, (31) A pharmaceutical composition comprising the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof as an active ingredient, (32) Arteriosclerosis, arteriosclerotic heart disease, coronary heart disease, comprising as an active ingredient the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof, A pharmaceutical composition for the prevention or treatment of cerebrovascular disease, peripheral vascular disease, dyslipidemia, low HDL cholesterolemia, high LDL cholesterolemia, or renal disease, (33) A prophylactic or therapeutic agent for arteriosclerosis comprising the compound according to any
  • Or therapeutic agent A prophylactic agent for a disease caused by a decrease in the concentration of HDL cholesterol in blood, comprising as an active ingredient the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof.
  • Or therapeutic agent (37) an LCAT activator comprising the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof as an active ingredient, (38) A reversible LCAT activator comprising the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof as an active ingredient, (39) An anti-arteriosclerosis agent comprising the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof as an active ingredient, (40) A method for activating LCAT comprising administering to a human an effective amount of the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof, (41) A method for the prevention or treatment of a disease, comprising administering an effective amount of the compound according to any one of (1) to (30)
  • Method, (43) For prevention or treatment of dyslipidemia, comprising administering to a human an effective amount of the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof.
  • Method, (44) By increasing the concentration of LDL cholesterol in blood, comprising administering to a human an effective amount of the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof.
  • a method for the prevention or treatment of the disease caused (46) The compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof for use in a method for treating or preventing arteriosclerosis, (47) The compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof for use in a method for treating or preventing dyslipidemia, (48) The compound according to any one of (1) to (30) or a pharmacologically thereof for use in a method for treating or preventing a disease caused by an increase in the concentration of LDL cholesterol in blood Acceptable salts, and (49) The compound according to any one of (1) to (30) or a pharmacologically thereof for use in a method for treating or preventing a disease caused by a decrease in the concentration of HDL cholesterol in blood It is an acceptable salt.
  • any isomer of a tautomer is contained in the present compound (I).
  • the compound (I) containing any isomer is referred to as a compound (I).
  • the “aryl group” is, for example, a phenyl group or a naphthyl group, and is preferably a phenyl group.
  • the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom, and more preferably a chlorine atom.
  • the “C 1-6 alkyl group” is a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, It may be an isopropyl group, a butyl group, a sec-butyl group, a tert-butyl group, an isobutyl group, a pentyl group or a hexyl group, and is preferably a linear or branched saturated hydrocarbon group having 1 to 3 carbon atoms ( C 1-3 alkyl group), more preferably a methyl group.
  • the “C 3-7 cycloalkyl group” is a cyclic saturated hydrocarbon group having 3 to 7 carbon atoms such as cyclopropyl group, cyclobutyl group, cyclopentyl group or cyclohexyl group, A cyclic saturated hydrocarbon group having 3 to 6 carbon atoms (C 3-6 cycloalkyl group) is preferable, and a cyclopropyl group is more preferable.
  • the “C 1-6 alkoxy group” is an oxygen atom to which the “C 1-6 alkyl group” is bonded.
  • a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group Alternatively, it may be a butoxy group, preferably an oxygen atom (C 1-3 alkoxy group) to which the “C 1-3 alkyl group” is bonded, and more preferably a methoxy group.
  • the “C 3-7 cycloalkoxy group” is an oxygen atom to which the “C 3-7 cycloalkyl group” is bonded, and includes a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group.
  • Group, a cyclohexyloxy group, or a cycloheptyloxy group preferably an oxygen atom (C 1-3 alkoxy group) to which the “C 1-3 alkyl group” is bonded, more preferably a methoxy group It is.
  • the “C 2-7 alkoxycarbonyl group” is a carbonyl group to which the “C 1-6 alkoxy group” is bonded, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, and a propoxycarbonyl group. Or a butoxycarbonyl group, preferably a carbonyl group to which the “C 1-3 alkoxy group” is bonded (C 2-4 alkoxycarbonyl group), more preferably a methoxycarbonyl group or an ethoxycarbonyl group. It is.
  • the “di (C 1-6 alkyl group) amino group” is an amino group to which two identical or different “C 1-6 alkyl groups” are bonded. Is a dimethylamino group.
  • the “di (C 1-6 alkyl group) aminocarbonyl group” is a carbonyl group to which the “di (C 1-6 alkyl group) amino group” is bonded. , A dimethylaminocarbonyl group.
  • a heteroaryl group (the heteroaryl is a 5- or 6-membered ring.
  • the hetero atom on the ring of the heteroaryl group is 1 or 2 nitrogen atoms; 1 nitrogen atom, oxygen atom or sulfur atom may be included.)
  • Nyl group, thiadiazolyl group or thiazolyl group still more preferably a pyridyl group, pyrimidyl group, pyrazinyl group or pyridazinyl group, still more preferably a pyridyl group, pyrimidyl group, pyrazinyl group or thiadiazolyl group
  • Particularly preferred is a pyridyl group, a pyrimidyl group or a pyrazinyl group.
  • “pharmacologically acceptable salts” include, for example, hydrohalides such as hydrofluoric acid salts, hydrochlorides, hydrobromides, hydroiodides; nitrates, perchlorates.
  • Inorganic salts such as sulfates and phosphates; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate; aryl sulfones such as benzene sulfonate and p-toluene sulfonate Acid salts; organic acid salts such as acetic acid, malic acid, fumarate, succinate, citrate, tartrate, succinate, maleate; and amino acid salts such as ornithate, glutamate, aspartate Can be mentioned.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof may absorb water and become a hydrate when left in the atmosphere, and such a hydrate is also included in the present invention. Is done.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof may be taken out from the solvent and become a solvate by leaving it in a solvent, and such a solvate is also encompassed in the present invention. Is done.
  • Compound (I) of the present invention has an optical isomer based on an asymmetric center in the molecule. Unless otherwise specified, in the compounds of the present invention, these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Accordingly, the present invention includes all of these isomers and mixtures of these isomers.
  • the compound (I) of the present invention has a geometric isomer at the 4-5 position of the imidazopyridine ring, and both cis and trans isomers are included in the present invention unless otherwise specified. For example, by producing both geometric isomers and comparing their instrument data, the respective structure can be determined.
  • the 4-position trifluoromethyl group and the 5-position hydroxyl group are preferably cis.
  • Compound (I) of the present invention may also contain an unnatural proportion of atomic isotopes at one or more of the atoms constituting the compound.
  • atomic isotopes include deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), carbon-14 ( 14 C), and the like.
  • the compound may be radiolabeled with a radioisotope such as tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C).
  • Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent LCAT activating action, and is arteriosclerosis, arteriosclerotic heart disease, coronary heart disease (heart failure). , Including myocardial infarction, angina pectoris, cardiac ischemia, cardiovascular disorder and angiogenic restenosis), cerebrovascular disease (including stroke and cerebral infarction), peripheral vascular disease (including diabetic vascular complications), lipid abnormalities It is useful as an active ingredient of a therapeutic or prophylactic agent for renal disease, low HDL cholesterolemia, high LDL cholesterolemia, or renal disease, particularly an anti-arteriosclerotic agent.
  • Production method 1 is a method for producing compound (I) of the present invention from compound (II).
  • R and R 2 are as defined above
  • R 3 is a hydrogen atom or a formula —O—R 5
  • R 5 is a hydrogen atom, a methyl group, a triethylsilyl group, a tert-butyldimethylsilyl group or a tert-butyl group).
  • -Re represents a butyldiphenylsilyl group
  • R 4 represents a methyl group or an ethyl group.
  • This step is a step for producing compound (I) by heating and condensing compound (II) and compound (III) in a solvent inert to the reaction or in the absence of a solvent.
  • Solvents used in this step include organic acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid or trifluoromethanesulfonic acid; diethyl ether, diisopropyl ether, Ethers such as tetrahydrofuran, dioxane, dimethoxyethane or tert-butyl methyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxy Alcohols such as ethanol, diethylene glycol or glycerine; aromatic hydrocarbons such as benzene, toluene or xylene; or these It is
  • the reaction temperature in this step is usually 40 ° C. to 150 ° C., preferably 50 ° C. to 130 ° C., more preferably 60 ° C. to the reflux temperature of the solvent.
  • microwaves can be irradiated.
  • the reaction time in this step is usually 5 minutes to 72 hours, preferably 15 minutes to 24 hours, and more preferably 30 minutes to 3 hours.
  • R 5 of the compound (III) is a methyl group, a triethylsilyl group, a tert-butyldimethylsilyl group or a tert-butyldiphenylsilyl group
  • the compound prepared by the above reaction is exemplified by P.I. G. Wuts, T.W. W. Greene, Greene's Protective Groups in Organic Synthesis. Third Edition, 2006, John Wiley & Sons, Inc. Etc. can be used to remove the hydroxyl-protecting group to produce compound (I).
  • Manufacturing method 2 The intermediate (II) of the compound of the present invention can be produced, for example, by the following method.
  • R represents the same meaning as described above, and X represents a chlorine atom, a bromine atom, an iodine atom, a p-toluenesulfonyl group, a methanesulfonyl group or a trifluoromethanesulfonyl group.
  • This step is a step for producing compound (VI) by reacting compound (IV) with compound (V) in an inert solvent using a base.
  • Solvents used in this step are halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or tert- Ethers such as butyl methyl ether; aromatic hydrocarbons such as benzene, toluene or xylene; nitriles such as acetonitrile or propionitrile; formamide, N, N-dimethylformamide, dimethylacetamide, N-methyl- Amides such as 2-pyrrolidone or hexamethylphosphorotriamide; or sulfoxides such as dimethyl sulfoxide; preferably amides or sulfoxides An earth, more preferably, N, is N- dimethylformamide or dimethyl sulfoxide.
  • the base used in this step is preferably an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate, and more preferably potassium carbonate or cesium carbonate. .
  • the reaction temperature in this step is preferably ⁇ 10 ° C. to 150 ° C., and more preferably 20 ° C. to 120 ° C.
  • the reaction time in this step is preferably 30 minutes to 10 hours, and more preferably 1 minute to 4 hours.
  • Step 2-2 This step is a step for producing compound (II) by catalytic hydrogenation of compound (VI) in the presence of a metal catalyst in an inert solvent.
  • Solvents used in this step are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol or glycerin.
  • alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol or glycerin.
  • An ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or tert-butyl methyl ether; an aromatic hydrocarbon such as benzene, toluene or xylene; or a mixed solvent thereof, preferably Is a mixed solvent of alcohols or ethers and alcohols, more preferably a mixture of ethanol or methanol and tetrahydrofuran. It is a medium.
  • the metal catalyst used in this step may be platinum, palladium-activated carbon, palladium-activated carbon diphenyl sulfide complex or nickel, and is preferably palladium-activated carbon or palladium-activated carbon diphenyl sulfide complex.
  • the hydrogenating agent used in this step can be hydrogen gas or ammonium formate, preferably hydrogen gas.
  • the reaction temperature in this step is preferably 0 ° C. to 100 ° C., and more preferably 5 ° C. to 40 ° C.
  • the reaction time in this step is preferably 5 minutes to 10 hours, and more preferably 20 minutes to 2 hours.
  • Production method 3 is a method for producing compounds (Ib) and (Ic) of the present invention from compound (VIII).
  • R 1 and R 2 are as defined above, Boc represents a tert-butoxycarbonyl group, and n represents 1 or 2.
  • Compound (VIII) can be produced, for example, according to the methods described in Reference Examples 1 and 2, or Reference Examples 9, 10, 11, and 12.
  • Step 4-1 This step is a step for producing compound (Ib) by removing the Boc group in compound (VIII).
  • reagents used for removing Boc in compound (VIII) include P.I. G. Wuts, T.W. W. Greene, Green's Protective Groups in Organic Synthesis. Third Edition, 2006, John Wiley & Sons, Inc. And the like which can remove Boc described in the above.
  • the solvent used in this step is preferably an alcohol such as methanol or ethanol; an ether such as tetrahydrofuran or 1,4-dioxane; an alkyl halide such as dichloromethane or chloroform; Esters; aromatic hydrocarbons such as toluene; or a mixed solvent thereof, more preferably ethers or alkyl halides, and even more preferably dichloromethane.
  • an alcohol such as methanol or ethanol
  • an ether such as tetrahydrofuran or 1,4-dioxane
  • an alkyl halide such as dichloromethane or chloroform
  • Esters aromatic hydrocarbons such as toluene
  • a mixed solvent thereof more preferably ethers or alkyl halides, and even more preferably dichloromethane.
  • the reagent used in this step is preferably hydrochloric acid or trifluoroacetic acid, and more preferably trifluoroacetic acid.
  • the reaction temperature in this step is preferably 0 ° C. to 100 ° C., and more preferably 0 ° C. to 50 ° C.
  • the reaction time in this step is preferably 5 minutes to 24 hours, and more preferably 10 minutes to 6 hours.
  • Step 3-2 This step is a step for producing compound (Ic) by reacting compound (Ib) with an arylating agent or heteroarylating agent.
  • Solvents used in this step are halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or tert- Ethers such as butyl methyl ether; aromatic hydrocarbons such as benzene, toluene or xylene; nitriles such as acetonitrile or propionitrile; formamide, N, N-dimethylformamide, dimethylacetamide, N-methyl- Amides such as 2-pyrrolidone or hexamethylphosphorotriamide; or sulfoxides such as dimethyl sulfoxide; preferably sulfoxides More preferably a dimethyl sulfoxide.
  • halogenated hydrocarbons such as dichloromethane,
  • the base used in this step is an organic base such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene, N-methylmorpholine, pyridine, dimethylaminopyridine or 2,6-lutidine.
  • organic base such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene, pyridine or dimethylaminopyridine.
  • the arylating agent or heteroarylating agent used in this step is a compound having the formula R 1 -F, the formula R 1 -Cl or the formula R 1 -Br, preferably the formula R 1 -F or the formula R 1- Cl-containing compound (R 1 is as defined above).
  • the reaction temperature in this step is preferably 20 ° C to 200 ° C.
  • microwaves can be irradiated.
  • the reaction time in this step is preferably 5 minutes to 120 hours, more preferably 10 minutes to 96 hours.
  • n and R 1 are as defined above.
  • Step 4-1) This step is a step of producing compound (IVb) by reacting compound (IVa) with an arylating agent or heteroarylating agent in the presence of a ligand and a base in addition to a palladium catalyst.
  • the palladium catalyst, ligand, base and reaction conditions used in this step are not particularly limited as long as they are reagents and conditions usually used for the Buchwald-Hartwig reaction. R. Muci, S .; L. Buchwald, Top. Curr. Chem. 2002, 219, p. 131.
  • the solvent used in this step is an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or tert-butyl-methyl ether; or an aromatic hydrocarbon such as benzene, toluene or xylene. , Preferably toluene or dioxane, and more preferably toluene.
  • the palladium catalyst used in this step is preferably palladium (II) acetate or palladium (0) dibenzylideneacetone.
  • the ligand used in this step is preferably 2- (di-tert-butylphosphino) biphenyl, tri-tert-butylphosphine, tricyclohexylphosphine, 1,3-bis (diphenylphosphino) propane, 2, 2′-bis (diphenylphosphanyl) 1,1′-binaphthyl, 2- (dicyclohexylphosphino) biphenyl or 2-dicyclohexylphosphino-2 ′-(N, N-dimethylamino) biphenyl, more preferably 2- (di-tert-butylphosphino) biphenyl, tri-tert-butylphosphine or 2,2′-bis (diphenylphosphanyl) 1,1′-binaphthyl.
  • the base used in this step is preferably sodium carbonate, potassium carbonate, cesium carbonate, tert-butoxy sodium or tert-butoxy potassium, and more preferably tert-butoxy sodium.
  • the arylating or heteroarylating agent used in this step is a compound having the formula R 1 -Cl, the formula R 1 -Br or the formula R 1 -I, preferably the formula R 1 -Cl or the formula R 1- Br (R 1 is as defined above).
  • the reaction temperature in this step is preferably 20 ° C. to 150 ° C., and more preferably 50 ° C. to the reflux temperature of the solvent.
  • the reaction time in this step is preferably 30 minutes to 12 hours, and more preferably 1 hour to 4 hours.
  • this step is a step of producing compound (IVb) by reacting compound (IVa) with an arylating agent or heteroarylating agent in the presence of a base in an inert solvent.
  • This step can be performed under the same conditions as in step 3-2.
  • Step 4-2 the hydroxyl group in compound (IVb) is methanesulfonylated to produce compound (Ic).
  • the solvent used in this step is preferably a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxy Ethers such as ethane or tert-butyl methyl ether; aromatic hydrocarbons such as benzene, toluene or xylene, or a mixed solvent thereof, more preferably alkyl halides, and still more preferably Is dichloromethane.
  • a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene
  • diethyl ether diisopropyl ether, tetrahydrofuran, dioxane
  • the reagent used in this step is preferably methanesulfonyl chloride or methanesulfonic anhydride, and more preferably methanesulfonyl chloride.
  • the reaction temperature in this step is preferably 0 ° C. to 100 ° C., and more preferably 0 ° C. to 30 ° C.
  • the reaction time in this step is preferably 5 minutes to 24 hours, and more preferably 10 minutes to 6 hours.
  • the product of each of the above steps is a free compound or a salt thereof, after completion of the reaction, if necessary, a conventional method, for example, (1) a method of concentrating the reaction solution as it is, or (2) filtering insoluble matter such as a catalyst. (3) A method in which water and a solvent immiscible with water (for example, dichloroethane, diethyl ether, ethyl acetate, toluene, etc.) are added to the reaction solution, and the product is extracted (4) )
  • the crystallized or precipitated product can be isolated from the reaction mixture, such as by filtration.
  • the isolated product can be purified by a conventional method such as recrystallization, reprecipitation, various chromatographies and the like, if necessary.
  • the product of each step can be used in the next step without isolation or purification.
  • Compound (I) of the present invention is isolated and purified as a free compound, a pharmacologically acceptable salt, hydrate, or solvate thereof.
  • the pharmacologically acceptable salt of the compound (I) of the present invention can be produced by subjecting it to a conventional salt formation reaction. Isolation and purification are carried out by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, or various chromatography.
  • Various isomers can be separated by utilizing differences in physicochemical properties between isomers.
  • a racemic mixture can be converted to an optically pure isomer, such as by fractional crystallization leading to a diastereomeric salt with an optically active base or acid, or chromatography using a chiral column.
  • the diastereo mixture can be separated by fractional crystallization or various chromatographies.
  • An optically active compound can also be produced by using an appropriate optically active raw material.
  • Examples of the administration form of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof include oral administration by tablet, granule, powder, capsule or syrup, or injection or suppository. Parenteral administration, and the like, and can be administered systemically or locally.
  • Examples of the oral pharmaceutical form of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof include tablets, pills, granules, powders, capsules, solutions, suspensions, emulsions, Examples include syrups and elixirs.
  • Examples of pharmaceutical forms for parenteral use include injections, ointments, gels, creams, patches, sprays, inhalants, sprays, eye drops, and suppositories. These forms of pharmaceuticals are pharmaceutically acceptable, such as excipients, binders, diluents, stabilizers, preservatives, colorants, solubilizers, suspending agents, buffering agents, or wetting agents.
  • the additive can be prepared according to a conventional method using additives appropriately selected as necessary.
  • the dosage of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is as follows: symptoms, body weight, age, administration method of the administered person (warm-blooded animal, eg, human) Varies depending on etc.
  • the lower limit is 0.01 mg / kg body weight (preferably 0.03 mg / kg body weight) and the upper limit is 300 mg / kg body weight (preferably 100 mg / kg body weight). It is desirable to administer one to several times a day depending on the symptoms.
  • the lower limit is 0.01 mg / kg body weight (preferably 0.03 mg / kg body weight) and the upper limit is 300 mg / kg body weight (preferably 100 mg / kg body weight). Is preferably administered one to several times per day depending on the symptoms.
  • hexane represents n-hexane
  • THF represents tetrahydrofuran
  • IPA 2-propanol
  • DMF represents N, N′-dimethylformamide
  • DMSO dimethyl sulfoxide
  • the product was purified to obtain the target compound (188 mg, yield: 47%, optically active substance).
  • the reaction solution was cooled to room temperature and then filtered, and the solvent of the filtrate was distilled off under reduced pressure.
  • the reaction solution was cooled to room temperature, and then the solvent of the reaction solution was distilled off under reduced pressure.
  • the obtained organic phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the compound A-1 eluting first (2 g, yield: 42%) and the compound A-2 eluting later (1.77 g, 37%) were obtained respectively.
  • the solvent of the reaction solution was distilled off under reduced pressure, and N, N-diisopropylethylamine (126 ⁇ L, 0.741 mmol) and 2-fluoro-5- (trifluoromethyl) pyridine were added to a solution of the obtained residue in DMSO (1 mL). (44.6 ⁇ L, 0.370 mmol) was added and stirred overnight.
  • Trifluoroacetic acid (3.4 mL, 44.0 mmol) was added to a dichloromethane (20 mL) solution of the compound produced in Reference Example 2 (2.15 g, 5.32 mmol), and the mixture was stirred at room temperature for 3 hours.
  • the reaction solution was added dropwise to a mixed solvent of diethyl ether (90 mL) and hexane (20 mL) at 0 ° C. and stirred at room temperature for 3 hours.
  • the resulting solid was collected by filtration to obtain a trifluoroacetate compound (2.36 g).
  • the solvent was distilled off under reduced pressure, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added, and the mixture was extracted 3 times with ethyl acetate.
  • the obtained organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and dried under reduced pressure.
  • the solvent was distilled off.
  • Example 21 1- ⁇ 1- [2-Cyclopropyl-6- (trifluoromethyl) pyrimidin-4-yl] piperidin-4-yl ⁇ -7-hydroxy-7- (trifluoromethyl) -1, 4,6,7-Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one
  • Test Example 1 Measurement of LCAT activity (in vitro) A density gradient centrifugation was performed to obtain a fraction composed of HDL3 (1.125 ⁇ specific gravity ⁇ 1.210 g / mL) from plasma of a healthy person. The obtained fraction was dialyzed with phosphate buffered saline (pH 7.4) and used as an enzyme source and acceptor of LCAT. The test drug was prepared by dissolving in dimethyl sulfoxide.
  • the radioactivity of the portion corresponding to cholesterol oleate was measured with an imaging analyzer BAS-2500 (manufactured by Fuji Film). Samples to which no test drug was added were similarly processed and measured. Using the following equation, compared with no addition of test drug was calculated EC 50 values of LCAT activation. The results are shown in Table 1.
  • X represents the logarithm of the concentration of the test drug
  • Y represents the response of the test drug (LCAT activity)
  • Top indicates the maximum value (maximum plateau)
  • Bottom indicates a minimum value (minimum flat area);
  • EC 50 indicates a 50% effective concentration.
  • the compound of the present invention has an excellent LCAT activation action and is useful as a medicament for the treatment or prevention of diseases such as dyslipidemia and arteriosclerosis.
  • Test Example 2 Measurement of LCAT activity (plasma) Human, cynomolgus monkey or human LCAT transgenic mouse plasma is used as an enzyme source and acceptor for LCAT.
  • the test drug is prepared by dissolving in dimethyl sulfoxide. [14C] cholesterol containing DTNB (Ielman's reagent, final concentration 0.5 mM), mercaptoethanol (final concentration 12.5 mM), and 0.6% bovine serum albumin was added to 5 ⁇ L of each plasma and 45 ⁇ L of PBS. Add the test drug at a concentration to make the total volume 80 ⁇ L. After incubating this mixture at 37 ° C.
  • X represents the logarithm of the concentration of the test drug
  • Y represents the response of the test drug (LCAT activity)
  • Top indicates the maximum value (maximum plateau)
  • Bottom indicates a minimum value (minimum flat area);
  • EC 50 indicates a 50% effective concentration.
  • DTNB Ielman's reagent, final concentration 0.26 mM
  • mercaptoethanol final concentration 2 mM
  • bovine serum albumin 0.6% bovine serum albumin
  • the radioactivity of the portion corresponding to cholesterol oleate is measured with an imaging analyzer BAS-2500 (manufactured by Fuji Film). Compared with the LCAT activity before administration, the rate of change in LCAT activation at each time point is calculated.
  • Test Example 4 Cynomolgus monkey efficacy test
  • the test drug was propylene glycol (Sigma-Aldrich) -Tween 80 (Sigma-Aldrich) mixed solution [4/1 (v / v)] or 0.5% (w / v) It was dissolved in an aqueous methylcellulose solution and orally administered to cynomolgus monkeys for 1 or 7 days. Blood was collected before and after administration on the first or seventh day of administration to obtain plasma. Plasma cholesterol content was measured using a commercially available measurement kit (cholesterol-E Wako, Wako Pure Chemical Industries). The lipoprotein profile was analyzed by HPLC (column: Lipopropak XL, manufactured by Tosoh Corporation). The contents of HDL cholesterol and non-HDL cholesterol were calculated according to the following calculation formula.
  • HDL cholesterol content plasma cholesterol content ⁇ (HDL cholesterol peak area / sum of each peak)
  • non-HDL cholesterol content plasma cholesterol content ⁇ (peak area of non-HDL cholesterol / sum of each peak)
  • the increase rate (%) of HDL after a single administration of 10 mg / kg as compared to before administration was determined from AUC before administration and 24 hours after administration, and the results are shown in Table 2.
  • Test Example 5 Human LCAT transgenic mouse drug efficacy test The test drug was dissolved in polypropylene glycol-Tween 80 mixed solution [4/1 (v / v)] or 0.5% (w / v) methylcellulose aqueous solution, Human LCAT transgenic mice are orally administered for 1, 4 or 7 days. Blood is collected before and after administration on the first, fourth or seventh day of administration to obtain plasma. The cholesterol content in plasma is measured using a commercially available measurement kit (cholesterol-E Wako, Wako Pure Chemical Industries). The lipoprotein profile is analyzed by HPLC (column: Lipopropak XL, Tosoh). The content of HDL cholesterol and non-HDL cholesterol is calculated according to the following calculation formula.
  • HDL cholesterol content plasma cholesterol content ⁇ (HDL cholesterol peak area / sum of each peak)
  • non-HDL cholesterol content plasma cholesterol content ⁇ (peak area of non-HDL cholesterol / sum of each peak)
  • Formulation Example 1 Hard Capsule Each standard bipartite hard gelatin capsule contains 100 mg of the powdered compound of Example 1, 150 mg lactose, 50 mg cellulose and 6 mg magnesium stearate. The unit capsule is manufactured by filling, and after washing, dried.
  • Formulation Example 3 Tablet According to conventional methods, 100 mg of the compound of Example 3, 0.2 mg colloidal silicon dioxide, 5 mg magnesium stearate, 275 mg microcrystalline cellulose, 11 mg starch and 98.8 mg Manufactured using lactose.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent LCAT activation action, and in particular, arteriosclerosis, arteriosclerotic heart disease, coronary heart disease.
  • arteriosclerosis arteriosclerotic heart disease
  • coronary heart disease including acute coronary syndrome, heart failure, myocardial infarction, angina, cardiac ischemia, cardiovascular disorders and angiogenic restenosis), cerebrovascular disease (including stroke and cerebral infarction), peripheral vascular disease (peripheral arterial disease, Treatment of diabetic vascular complications), dyslipidemia, LCAT deficiency, low HDL cholesterolemia, high LDL cholesterolemia, diabetes, hypertension, metabolic syndrome, Alzheimer's disease, corneal opacity, or renal disease or It is useful as an active ingredient of prophylactic agents, particularly anti-arteriosclerotic agents.

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Abstract

L'invention concerne un composé possédant d'excellents effets d'activation de LCAT, et utilisé en tant qu'ingrédient actif d'un agent préventif ou thérapeutique de l'artériosclérose, des maladies cardiovasculaires artériosclérotiques, de la coronaropathie (notamment, l'insuffisance cardiaque, l'infarctus du myocarde, l'angine, l'ischémie cardiaque, les troubles cardiovasculaires et la resténose post-angioplastique), les maladies cérébrovasculaires (notamment, les accidents cérébrovasculaires et l'infarctus cérébral), les maladies vasculaires périphériques (notamment, les complications vasculaires dues au diabète), la dyslipidémie, l'hypo-HDL-cholestérolémie, l'hyper-HDL-cholestérolémie ou les maladies des reins ; et en particulier, d'un agent anti-artériosclérose. Le composé est représenté par la formule dans laquelle n est 1 ou 2, et R1 représente un groupe aryle qui peut être substitué ou un groupe hétéroaryle qui peut être substitué. L'invention concerne également un sel du composé pharmacologiquement acceptable.
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WO2016199877A1 (fr) * 2015-06-11 2016-12-15 第一三共株式会社 Cristal de dérivé de 5-hydroxy-4-(trifluorométhyl)pyrazolopyridine
US10137122B2 (en) 2012-10-12 2018-11-27 The Broad Institute, Inc. Kinase inhibitors and methods of use thereof
US11203601B2 (en) 2017-04-05 2021-12-21 The Broad Institute, Inc. Tricyclic compounds as glycogen synthase kinase 3 (GSK3) inhibitors and uses thereof
US12486289B2 (en) 2021-10-22 2025-12-02 The Broad Institute, Inc. Tricyclic compounds as glycogen synthase kinase 3 (GSK3) inhibitors and uses thereof

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JP2013536807A (ja) * 2010-09-02 2013-09-26 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｌｐａ受容体アンタゴニストとしてのピラゾロピリジノン誘導体
WO2013187462A1 (fr) * 2012-06-14 2013-12-19 第一三共株式会社 Dérivé de pipéridinylpyrazolopyridine

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WO2008002591A2 (fr) * 2006-06-26 2008-01-03 Amgen Inc Procédés de traitement de l'athérosclérose
JP2013536807A (ja) * 2010-09-02 2013-09-26 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｌｐａ受容体アンタゴニストとしてのピラゾロピリジノン誘導体
WO2013187462A1 (fr) * 2012-06-14 2013-12-19 第一三共株式会社 Dérivé de pipéridinylpyrazolopyridine

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10137122B2 (en) 2012-10-12 2018-11-27 The Broad Institute, Inc. Kinase inhibitors and methods of use thereof
US11052080B2 (en) 2012-10-12 2021-07-06 The Broad Institute, Inc. Kinase inhibitors and methods of use thereof
US12419885B2 (en) 2012-10-12 2025-09-23 The Broad Institute, Inc. Kinase inhibitors and methods of use thereof
WO2016199877A1 (fr) * 2015-06-11 2016-12-15 第一三共株式会社 Cristal de dérivé de 5-hydroxy-4-(trifluorométhyl)pyrazolopyridine
US10138240B2 (en) 2015-06-11 2018-11-27 Daiichi Sankyo Company, Limited Crystal of 5-hydroxy-4-(trifluoromethyl)pyrazolopyridine derivative
US11203601B2 (en) 2017-04-05 2021-12-21 The Broad Institute, Inc. Tricyclic compounds as glycogen synthase kinase 3 (GSK3) inhibitors and uses thereof
US12486289B2 (en) 2021-10-22 2025-12-02 The Broad Institute, Inc. Tricyclic compounds as glycogen synthase kinase 3 (GSK3) inhibitors and uses thereof

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